Intersticial lung Disease I

1. Review
Interstitial lung diseases in dogs and cats part I: The idiopathic
interstitial pneumonias
Carol Reinero
Department of Veterinary Medicine, University of Missouri, Columbia, MO 65211, USA
A R T I C L E I N F O
Article history:
Accepted 15 November 2018
Keywords:
Diffuse parenchymal lung disease
Hypoxemia
Pulmonary fibrosis
Restrictive lung disease
Spontaneous respiratory disease
A B S T R A C T
Interstitial lung diseases (ILDs), also called diffuse parenchymal lung diseases, are a large heterogenous
group of non-infectious, non-neoplastic disorders characterized by varied patterns of inflammation and
fibrosis (Travis et al., 2002). In humans, accurate classification of interstitial lung diseases (ILDs) requires
multidisciplinary collaboration between clinicians, radiologists and pathologists. The same is likely to be
true for canine and feline ILDs; however, this collaborative approach is rarely taken, leading to a paucity
of knowledge of ILDs in small animal species. A proposed classification scheme of canine and feline ILDs,
modified from a human classification scheme, consists of three major groups: idiopathic interstitial
pneumonias (IIPs), ILDs secondary to known causes, and miscellaneous ILDs (Travis et al., 2002). The
focus of this review is on the IIPs in dogs and cats. A framework of what is known about the major IIPs in
humans will be used to draw parallels when relevant to the canine and feline species. Differences will
also be highlighted. When available from the veterinary literature, clinical presentation, diagnostic
results, treatment and/or prognosis will be reported. The review underscores that to advance in our
knowledge of veterinary IIPs and other ILDs, clinicopathologic features, advanced imaging and
histopathology must be carefully integrated and larger groups of animals studied.
© 2018 Elsevier Ltd. All rights reserved.
Introduction
Collectively, it has been estimated that interstitial lung diseases
(ILDs) account for roughly 20% of all lung diseases encountered in
human pulmonary medicine (Meyer, 2017). In veterinary medicine,
ILDs are poorly characterized and comparatively infrequently
diagnosed. The term “interstitial” in ILDs is misleading, because
these diverse pulmonary disorders involve changes to the distal
lung parenchyma including airways, pulmonary parenchyma,
blood vessels and/or the pleura; the term diffuse parenchymal
lung diseases is sometimes used interchangeably in humans. While
many ILDs affect the true interstitium defined as the anatomic
space lined by alveolar epithelial cells and capillary endothelial
cells as well as loose-binding connective tissue, some ILDs are
bronchiolocentric (Smith, 2016) and others more closely resemble
alveolar filling disorders (Castellana et al., 2015; Hadda and
Khilnani, 2010). ILDs are grouped based on similar clinical signs,
imaging features, and physiologic and pathologic manifestations
and encompass many distinct syndromes that are not primarily
infectious or neoplastic. They share in common varying combi-
nations of inflammation and fibrosis (Mikolasch et al., 2017). This
article focuses on idiopathic triggers of injury; however, it is
important to note that initial injury to the distal lung parenchyma
can be via hematogenous routes (e.g. drugs, immune disease,
collagen vascular disorders in humans) or be airborne (mineral
fibers, dusts, antigens in sensitized individuals). In response to
inciting injury, resident cells recruit and activate inflammatory
cells; with persistent injury, or if resident or visiting cells are cued
to elaborate proinflammatory and profibrotic cytokines, pathologic
inflammation and fibrosis ensue (Tighe and Noble, 2011).
Over 200 distinct ILDs are recognized in humans (Mikolasch
et al., 2017). Classification is important in understanding more
about etiology, clinical features, pathogenesis and response to
therapy. However, even in human medicine there is not a
uniformly used classification system (Maher, 2012; Mikolasch
et al., 2017; Travis et al., 2002). The diffuse parenchymal lung
diseases consistently have a group of ILDs of unknown cause
termed interstitial idiopathic pneumonias (IIPs) (Maher, 2012;
Travis et al., 2002), which are the most common type of ILD (Maher,
2012; Shlobin et al., 2017). Alternatively, ILDs with similar
histopathologic patterns may be secondary to drugs, radiation
therapy, systemic disease, occupational exposures, or allergens,
among others (Mikolasch et al., 2017). Realizing that future
refinement will be needed, as a starting point for canine and feline
ILDs, recognized syndromes will be described with parallels drawn
E-mail address: reineroc@missouri.edu (C. Reinero).
https://doi.org/10.1016/j.tvjl.2018.11.010
1090-0233/© 2018 Elsevier Ltd. All rights reserved.
The Veterinary Journal 243 (2019) 48–54
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journal homepage: www.elsevier.com/locate/tvjl

2. to similar human ILDs proposed in an international multidisci-
plinary consensus (Travis et al., 2002). The broad classification
scheme proposed in dogs and cats, and modified from that used in
humans, includes IIPs, known causes of ILD (inhalational, drugs,
radiation, and immune-mediated diseases), and miscellaneous ILD
(Fig. 1) (Maher, 2012; Travis et al., 2002). This review will focus on
the IIPs.
Multidisciplinary collaboration: understanding the role of
histopathology in ILD diagnosis
On a microscopic level, lung tissue responds to injury in a
limited number of ways (i.e. “patterns of injury”), and the
similarities in patterns of injury between ILDs makes disease
discrimination challenging when interpretation relies solely on a
histopathological description (Leslie, 2009). For example, a
histopathologic pattern of “diffuse alveolar damage” (DAD) can
be seen in acute respiratory distress syndrome, acute interstitial
pneumonia (AIP), and acute exacerbation of idiopathic pulmonary
fibrosis (IPF) (Marchioni et al., 2018; Mukhopadhyay and Parambil,
2012). Histopathology of the lung in ILDs is frequently inadequate
by itself for clinical diagnosis and thus mandates a clinical context
(Leslie, 2009); this is in direct contrast to long-held beliefs by
clinicians that histopathology should provide a definitive answer
for ILDs, as it generally does with infectious pneumonia or
pulmonary neoplasia.
The role of histopathology for many ILDs is to provide a pattern
of disease that, in conjunction with clinical and imaging features,
can be used to narrow the differential list. Pathologists may be
challenged to provide useful information when biopsies are small
and from a single site (usually the most severely affected), in
which examined areas fail to either be representative or, in the
case of end-stage lung/fibrosis, provide meaningful information
about the underlying disease process. Assuming veterinary
medicine adopts parallel descriptions used in human medicine,
an additional point of confusion is that many names of specific
disease entities are also histopathological patterns (e.g. non-
specific interstitial pneumonia (NSIP) as an IIP and NSIP as a
histopathological pattern as described in other ILDs of known
cause; Table 1 and Fig. 2) (Travis et al., 2013). To advance in our
understanding of ILDs and add to the classification proposed in
this article, cross-talk between clinicians, radiologists and
pathologists will be required.
Idiopathic interstitial pneumonias (IIPs)
In humans, major IIPs include IPF, NSIP, AIP, cryptogenic
organizing pneumonia (COP), the smoking related IIPs (respiratory
bronchiolitis-ILD, desquamative interstitial pneumonia (DIP)), and
rarely, lymphocytic interstitial pneumonia (LIP) (Travis et al., 2013,
2002). As both prognosis and survival depend on the subtype of IIP,
international and multidisciplinary efforts to classify the human
IIPs has led to refinement of definitions and descriptions.
Terminology in veterinary medicine is confusing, inconsistent
and often based on proposal by a single specialty with a
comparatively narrow focus instead of a multidisciplinary
collaboration. As diagnostic evaluation for pulmonary disease in
dogs and cats is generally substantially less comprehensive than in
humans (Maher, 2012), many veterinary ILDs remain “idiopathic”
because exhaustive evaluations were not performed, not neces-
sarily because a potentially identifiable underlying cause was not
present. The IIPs refer to very specific disease entities in humans
and for comparative purposes of potential One Health relevance,
the term “idiopathic” should be used cautiously when meant to
reflect parallel human diseases. If an underlying cause is found
with careful historical and clinical evaluation, the disease is
classified as a “Known Cause ILD” (see Interstitial Lung Diseases in
Dogs and Cats Part II: Known Cause and Other Discrete Forms).
Fig. 1. Suggested classification of canine and feline diffuse parenchymal lung diseases, more commonly known as interstitial lung diseases (ILDs). As there is no clear
consensus on human classification schemes, this classification is modified from humans (Maher, 2012; Travis et al., 2013) and adapted to syndromes described in dogs and
cats. This review focuses on the IIPs.
IIPs – idiopathic interstitial pneumonias; ILD – interstitial lung disease; NSIP – non-specific interstitial pneumonia; LIP – lymphocytic interstitial pneumonitis; AIP – acute
interstitial pneumonia; COP – cryptogenic organizing pneumonia; HP-like ILD – hypersensitivity-like interstitial lung disease; EP – eosinophilic pneumonia; PAP – pulmonary
alveolar proteinosis; DAH – diffuse alveolar hemorrhage; LP – lipid/lipoid pneumonia; PH – pulmonary hyalinosis; LCH/PLCH – Langerhans’ cell histiocytosis/pulmonary
Langerhans’ cell histiocytosis; PAM – pulmonary alveolar microlithiasis.
Table 1
Identical histologic patterns of disease may be seen with idiopathic and known cause ILDs. This underscores the importance of cross-talk between clinicians, radiologists and
pathologists to put the meaning of microscopic changes in the appropriate clinical context.
Histologic pattern of disease UIP NSIP OP DAD
Idiopathic clinical syndrome IPF NSIP COP AIP
Clinical syndrome of known cause Fibrotic ILDa
Fibrotic ILDa
Secondary OPa
ARDS
UIP = usual interstitial pneumonia, NSIP = non-specific interstitial pneumonia, OP = organizing pneumonia, DAD = diffuse alveolar damage, IPF = idiopathic pulmonary fibrosis,
COP = cryptogenic organizing pneumonia, AIP = acute interstitial pneumonia, ARDS = acute respiratory distress syndrome.
a
Secondary to drugs, radiation, immune-mediated disease, etc.
C. Reinero / The Veterinary Journal 243 (2019) 48–54 49

3. Fibrotic ILD: revisiting the term idiopathic pulmonary fibrosis (IPF) in
veterinary medicine
In humans, IPF is the most common and severe type of fibrotic
ILD and is rising in incidence in most western societies (Nalysnyk
et al., 2012). Presentation is usually in older (>60 years) adults with
an insidious onset and median survival of <3 years (Bjoraker et al.,
1998; Larsen et al., 2017). It is diagnosed via multidisciplinary
collaboration between clinicians, radiologists and pathologists
with specific requirement for a pattern of fibrosis called usual
interstitial pneumonia (UIP) on high-resolution CT or histopathol-
ogy (Raghu et al., 2011). Histopathologically, the UIP pattern
demonstrates lesions with geographic and temporal heterogeneity
showing marked fibrosis and architectural distortion with or
without honeycomb change, in a predominant subpleural or
paraseptal location, with fibroblastic foci and absence of features
suggesting an alternative diagnosis (Raghu et al., 2011). However,
there are at least two other common and distinct histopathologic
patterns of pulmonary fibrosis in humans (reviewed in Smith,
2016). These include the fibrotic nonspecific interstitial
pneumonia pattern (fNSIP) and the airway-centered fibrosis
(ACF) pattern (Smith, 2016). Importantly, the distribution of
fibrosis as either diffuse or patchy and the anatomic location of the
fibrosis as subpleural/paraseptal, interstitial or airway centered is
suggestive of the underling etiology. While the UIP pattern has
diverse mechanisms for its development (e.g. infection, autoim-
mune disease, inhalational damage, idiopathic etc.), the fNSIP
pattern is believed to result from a hematogenous insult and the
ACF pattern reflects inhalational injury (Smith, 2016). Although
there may be overlap in patterns of fibrosis in humans, identifying
the predominant pattern has relevance for differential diagnoses,
treatment and prognosis. Pathologic classification systems in
veterinary medicine are a high priority future need; it is
substantially less helpful for clinicians to have a ‘yes’ or ‘no’
answer to the presence of fibrosis if the intent is to find a treatable
disease. When fibrosis is identified, less affected adjacent and non-
adjacent areas must be carefully examined for an underlying
disease process driving fibrosis (Fig. 3a and b). While end stage
fibrosis is minimally responsive to treatment, early recognition of
the underlying disease process driving fibrosis could allow for
Fig. 2. Hematoxylin and eosin stained lung specimens from dogs demonstrating histologic lesions of organizing pneumonia (OP; panel A) or diffuse alveolar damage (DAD;
panel B) at 10X magnification. These histologic lesions can be identified in the absence (“idiopathic”) or presence (known cause) of an etiology identified via a thorough
clinical evaluation. Thus histologic appearance does not by itself elucidate the underlying clinical disorder.
Fig. 3. Thoracic computed tomographic images obtained from two cats with histologic evidence of pulmonary fibrosis confirmed with Masson’s trichrome staining. Both cats
presented in respiratory distress and had cardiac disease ruled out as a cause of their clinical signs. (a) A ventilator breath-hold inspiratory CT transverse image from a 7-year-
old spayed female domestic shorthair cat. Changes consistent with fibrosis include subpleural thickening, architectural distortion, traction bronchiectasis and an associated
reticular patternwith multifocal ground glass opacities (thick black arrow); subpleural honeycombing (thin black arrow) is also noted. There is subtle overinflation of the right
lung compared to the left with a mediastinal shift towards the left, mostly in the dorsal aspect. Importantly, changes consistent with bronchiolar disease such as
bronchiolectasis are noted in areas with minimal increases in opacity/architectural distortion (white arrows) and support bronchiolar disease as the underlying cause of
fibrosis. Histopathology in this cat confirmed airway-centered interstitial fibrosis. (b) A sedated CT transverse image from an 8-year-old spayed female domestic shorthair cat.
Despite some motion artifact, patchy regions of ground glass opacity in areas of architectural distortion with traction bronchiectasis are noted (thick black arrow). No
subpleural honeycombing was appreciated. Histopathology showed evidence of vascular pathology/unclassified pulmonary vascular disease in addition to the pulmonary
fibrosis.
50 C. Reinero / The Veterinary Journal 243 (2019) 48–54

4. targeted intervention. Using this information and in conjunction
with input from clinicians and radiologists, discrete veterinary
syndromes of fibrotic ILD may be characterized.
For the purposes of this review, in small animals the term
fibrotic ILD will be used to describe a heterogenous group of
clinicopathologic syndromes sharing fibrosis as the terminal
consequence of a variety of injuries. There are familial and
sporadic forms. Idiopathic pulmonary fibrosis (IPF) in the West
Highland White terrier (WHWT), representing a familial fibrotic
ILD, will be excluded from further discussion in this article as it is a
subject of a complementary review in this journal. While IPF has
been used as a “catch all” term to describe fibrotic lung disease in
dogs and cats, this is inappropriate and needs to be revisited.
Analogous to hepatic cirrhosis, pulmonary fibrosis is not a single
disease entity but the end stage of known and unknown disease
processes, at least some of which if recognized and directly treated
early on may alter the course of fibrosis.
As fibrotic ILD represents the end stage of progressive damage
and reparative processes from diverse causes, it ultimately
culminates in a common clinical phenotype of restrictive lung
disease (Larsen et al., 2017). Clinically this manifests as rapid,
shallow breathing with diminished thoracic excursions. Regardless
of cause, once extensive enough to compromise respiratory
function, it has high morbidity and mortality. Pulmonary
hypertension is an important co-morbid condition that has been
documented in dogs and cats (Evola et al., 2014). Destruction of
lung tissue and replacement with collagen leads to impaired
respiratory function, hypoxemia and eventually respiratory failure
(Cohn et al., 2004; Corcoran et al., 1999b; Lobetti et al., 2001).
In a case report and a small case series of various breeds of dogs,
exclusive of the WHWT, fibrotic ILD was confirmed on histopa-
thology in Staffordshire bull terriers and a Schipperke (Corcoran
et al.,1999b; Lobetti et al., 2001). Clinical signs included respiratory
distress, cough, exercise intolerance and cyanosis with crackles
frequently noted on physical examination. Radiographs were non-
specific with diffuse mixed patterns (interstitial, alveolar and
bronchial) and outcome was uniformly fatal within hours to, at
most, a few months of presentation. Importantly, although these
were all termed IPF, they did not fit the current rigorous criteria of
UIP in humans (Corcoran et al., 1999b; Lobetti et al., 2001). While
there is no doubt these dogs had severe pulmonary fibrosis with
fatal outcomes, use of the term IPF is a disservice as it implies that
all the dogs had the same “idiopathic” disease process analogous to
the well characterized human disorder of the same name.
Dogs of the Pekingese breed in Hong Kong have been described
to have an ILD with features of fibrotic ILD (Koster and Kirberger,
2016). Thirty-five dogs, middle aged to older, had a history of mild
chronic cough, exercise intolerance and syncope. Respiratory
distress and cyanosis, and audible crackles were common on
examination. Radiographs most commonly demonstrated a diffuse
interstitial pattern, although 20% of dogs had no abnormalities
noted. Thoracic CT in a small subpopulation of affected dogs
showed changes associated with fibrosis including subpleural
interstitial thickening, parenchymal bands, traction bronchiectasis
and honeycombing. All dogs had pulmonary hypertension. Median
survival was 60 days, with no dog receiving antemortem or
postmortem histopathologic examination of lung tissue. It is
unclear if this disorder is a hereditary form of IPF or another type of
ILD.
In the author’s opinion, it is not only feasible, but likely, that
some forms of what are currently recognized as fibrotic ILD may
have underlying etiologies that could be modified earlier in the
course of disease. This will require an understanding of triggers of
fibrosis and detection of lung lesions prior to the terminal stages
of fibrosis. Recognized triggers in humans include inhalational
injury (e.g. repetitive microaspiration, organic and inorganic
dusts, air pollution, etc.), infection, adverse drug reactions, toxin-
induced injury, immune-mediated disease, and radiation (Meyer,
2017). Experimentally in dogs, injected oleic acid (Derks and
Jacobovitz-Derks, 1980), infused bleomycin (Fleischman et al.,
1971), and targeted aerosol delivery of gemcitabine and cisplatin
(Selting et al., 2011) have led to fibrotic ILD. In pet dogs, oral
ingestion of the toxin paraquat (Darke et al., 1977) and
intravenous infusion of cytarabine (Hart and Waddell, 2016)
have led to an acute lung injury with a healing fibrotic phase.
Rabacfosadine, a nucleotide analog used to treat lymphoma, has
been reported to cause severe pulmonary fibrosis (up to grade 5
adverse event, defined as death) (Saba et al., 2018). However,
careful review of the pulmonary histopathology from the single
dog in this report with a grade 5 adverse event attributed to drug-
induced pulmonary fibrosis revealed mild fibrosis along with
pulmonary lymphoma; this casts some doubt on the specificity of
the adverse event grading scheme if guided by radiography and
underscores the need for careful histopathologic examination
(Saba et al., 2018). A familial form of acute respiratory distress
syndrome in Dalmatian dogs, caused by a mutation in an anillin
actin binding protein important for integrity of epithelial cell
organization (Holopainen et al., 2017), has been associated with
fibrosis (Jarvinen et al., 1995). Importantly, at least until there are
well characterized correlates between CT and histopathology for
fibrotic ILD in veterinary medicine, histopathology should be used
as a reference standard for diagnosis as descriptions of “IPF” in the
absence of biopsy confirmation may be misleading (Corcoran
et al., 1999a; Johnson et al., 2005).
Fibrotic ILD of unknown etiology in cats resembles human IPF
with a UIP histopathologic pattern of disease (Cohn et al., 2004;
Williams et al., 2004). In the largest case series of feline IPF-like
disease, cats were mostly middle-aged to older, usually present-
ing with respiratory distress and/or cough (Cohn et al., 2004).
Notably, in comparison to human IPF, some cats are outliers:
while uncommon, cats can be young (Cohn et al., 2004; Evola
et al., 2014), and some cats had no obvious evidence of respiratory
clinical signs (Cohn et al., 2004). Radiographic abnormalities
mimic a host of other feline respiratory conditions and are
considered non-specific (Cohn et al., 2004; Evola et al., 2014).
Thoracic CT provides more specific detail (Evola et al., 2014; Le
Boedec et al., 2014). Universally, there is poor response to therapy
with most cats dying within days to months reflective of end-
stage disease (Cohn et al., 2004; Evola et al., 2014; Le Boedec et al.,
2014; Secrest et al., 2008). Of interest, pulmonary neoplasia was
detected in 26% of cats in one study, although these lesions were
believed incidental encompassing only a small portion of the total
lung mass with fibrosis being the primary lesion (Cohn et al.,
2004). This is similar to humans with IPF where neoplasia is seven
times more common than control populations (Hubbard et al.,
2000). While pulmonary neoplasia was considered an incidental
finding in cats (i.e. not substantially contributing to clinical signs
in comparison to wide-spread severe fibrosis), it is of note that
prognosis for IPF rivals that of many malignancies. Reports on
known causes of fibrotic ILD in pet cats are sparse, with high
cumulative doses of nitrosourea (Evola et al., 2014; Skorupski
et al., 2008) and paraquat poisoning (Johnson and Huxtable, 1976)
suspected as triggers.
Non-specific interstitial pneumonia (NSIP) and lymphocytic
interstitial pneumonitis (LIP)
Idiopathic NSIP in humans is a distinct clinical disorder with a
highly heterogenous clinical course that may manifest as cellular
or fibrotic forms (Travis et al., 2013, 2008). Idiopathic NSIP overall
is considered to have a better prognosis than IPF, as patients with
the cellular form may improve or stabilize with therapy (Bjoraker
C. Reinero / The Veterinary Journal 243 (2019) 48–54 51

5. et al., 1998; Travis et al., 2013, 2008). Importantly, NSIP is also a
histopathologic pattern of disease that can occur secondary to
drugs, hypersensitivity pneumonitis, and collagen vascular disease
among others (Travis et al., 2013). Similarly, LIP can be idiopathic or
secondary to other diseases, and with revised diagnostic criteria
many cases of LIP have been reclassified into cellular NSIP (Travis
et al., 2013).
In dogs, NSIP has been described as a histopathologic pattern of
disease in West Highland White terriers (see companion article for
additional details) (Syrja et al., 2013). In cats, LIP was diagnosed
secondary to natural infection with feline immunodeficiency virus,
via lymphocytic bronchoalveolar lavage (BAL) and accumulation of
lymphocytes in the alveolar walls on histopathological examina-
tion of pulmonary tissue, in five (Cadore et al.,1997). Of note, three
of these five cats had lesions resembling NSIP seen with human
immunodeficiency virus. The author is not aware of any studies in
cats documenting NSIP or LIP as an IIP.
Acute interstitial pneumonia (AIP)
Unique in terms of its time course, AIP has been termed
“idiopathic ARDS” because of its indistinguishable clinicopatho-
logic features to ARDS (Bonaccorsi et al., 2003). AIP is characterized
by respiratory disease 60 days duration; bilateral, diffuse
infiltrates on imaging studies; the histopathologic lesion of diffuse
alveolar damage (DAD); lack of an inciting event or predisposing
condition; and no prior abnormal thoracic radiograph (Vourlekis
et al., 2001). Humans with AIP develop acute respiratory failure,
often necessitating mechanical ventilation, and mortality is high
(Vourlekis et al., 2001). As AIP begins with acute lung injury and
progresses to fibrotic lesions, it has been confused with acute
exacerbations of IPF. Lesions in AIP have temporal homogeneity
compatible with a single insult; however, IPF has temporal
heterogeneity compatible with repetitive insults (Vourlekis
et al., 2001).
To date, there have been no reports in dogs or cats with disease
termed AIP. Attempts to screen for “idiopathic ARDS” cases in the
literature is not fruitful as one of the four current diagnostic criteria
of veterinary ARDS mandates a known risk factor (Balakrishnan
et al., 2017). Additionally, the use of the human definition of AIP is
challenging as histopathologic evidence of DAD is not a require-
ment for diagnosis of ARDS in veterinary medicine (Balakrishnan
et al., 2017). Diffuse alveolar injury of unknown cause leading to
“proliferative interstitial pneumonia” has been described in two
dogs (one a West Highland White terrier), which could represent
AIP (Cogan and Carpenter,1989). While the fatal juvenile disease in
Dalmatian dogs has some histologic similarities with AIP, there are
clear and important differences and it is now considered a familial
form of ARDS (Holopainen et al., 2017; Syrja et al., 2009). A
literature search identified a single case report of histologic DAD in
a young cat; however, clinical signs occurred over a 5-month time
frame and twice weekly treatments with supplemental oxygen for
hypoxia secondary to severe aortic stenosis could have contributed
to pulmonary pathology (Kobayashi et al., 2011). Veterinarians
should be on the lookout for AIP in dogs or cats with an ARDS-like
presentation without a known risk factor and in which DAD is
documented.
Cryptogenic organizing pneumonia (COP)
Organizing pneumonia (OP) is a term referring both to a
histopathologic pattern of disease as well as distinct clinical
syndromes; the latter is subdivided into the idiopathic form, COP,
and secondary OP (Baque-Juston et al., 2014; Drakopanagiotakis
et al., 2011). The former is an important distinction as
pathologists may use the descriptive term OP to describe a
reparative process to lung injury in cancer, vasculitis, other ILD,
etc., without the clinical diagnosis of OP (Baque-Juston et al.,
2014). The name bronchiolitis obliterans with organizing
pneumonia (BOOP) in human medicine has fallen out of favor
(Baque-Juston et al., 2014; Drakopanagiotakis et al., 2011), in part
because OP can occur without bronchiolar intraluminal polyps
and in part because it may be confused with the primary
bronchiolar disorder constrictive bronchiolitis obliterans (King,
2011). Secondary OP is associated with infection (viral, bacterial,
protozoal and fungal), drugs, radiation therapy, hematologic
malignancies, organ transplantation, aspiration and connective
tissue disorders in humans (Drakopanagiotakis et al., 2011; King,
2011; Travis et al., 2013). Recognition of underlying triggers is
important as treatment should directly target these. Importantly,
in contrast to many other ILDs, OP is not only treatable, but is
estimated to be curable in up to 80% of humans (Epler, 2011).
In one study of humans with OP, the mean age was 60 14
years, with malaise, cough, fever and dyspnea being common
clinical complaints; mean duration of symptoms before diagnosis
was 3 months with delays in diagnosis suspected because of rarity
of disease and under-recognition by physicians (Drakopanagiota-
kis et al., 2011). Lesion on CT scans vary, but the common patterns
are focal sub-pleural and/or peribronchovascular parenchymal
consolidations that are frequently asymmetrical and bilateral
(Baque-Juston et al., 2014). Nodules, masses and reverse halo signs
can also be seen (Baque-Juston et al., 2014). BAL lymphocytosis is a
frequent finding (Drakopanagiotakis et al., 2011). Treatment of
diffuse disease generally consists of steroids with a minority of
patients (those who are asymptomatic) receiving no treatment.
Roughly 6% and 9% of patients respectively died in hospital or
within 1 year (Drakopanagiotakis et al., 2011). Focal OP manifest-
ing as a solitary lesion can be managed with surgical resection in
humans (Huo et al., 2015).
Scant literature documents existence of biopsy confirmed OP
(under the term BOOP) in pet dogs and cats (Norris et al., 2002;
Phillips et al., 2000), with oleic acid and adenovirus inducing
lesions in research dogs (Castleman, 1985; Li et al., 2006). In one
dog presenting for exercise intolerance and respiratory distress,
radiographs showed a diffuse interstitial pattern; however, CT
documented subpleural asymmetric airspace consolidation (Phil-
lips et al., 2000). The same dog also had pulmonary hypertension.
Spontaneous OP in dogs and cats is generally considered
idiopathic, with one case suspected secondary to inhalation of
toxic fumes described (Phillips et al., 2000). A steroid-responsive
ILD with clinical and CT features of COP was reported in two dogs;
however, histology was not performed to rule out other immune-
mediated ILD (Koster and Kirberger, 2014). All reported cases of OP
in the veterinary literature to date describe diffuse disease;
however, at the author’s institution, focal OP was diagnosed in a
dog following lung lobectomy for a suspected lung tumor (Fig. 4a
and b). Lung lobectomy was curative in that case. In the author’s
experience, COP in dogs is readily treatable with immunosuppres-
sive doses of steroids with a good to excellent prognosis if
diagnosed and treated before respiratory failure.
Other IIPs
Smoking-related IIPs in humans include respiratory-bronchiol-
itis ILD and DIP; of note, there are many other smoking related ILDs
outside of the group of IIPs (Margaritopoulos et al., 2015). Although
dogs and cats do not smoke, they may be exposed to tobacco smoke
in their environment. Environmental tobacco smoke has not yet
been linked to ILDs in dogs or cats and is only very rarely linked to
DIP in humans (Carrington et al.,1978). There is a single case report
of DIP in the cat with “no obvious exposure to airway irritants”
having the characteristic intra-alveolar accumulation of
52 C. Reinero / The Veterinary Journal 243 (2019) 48–54

6. macrophages along with interstitial fibrosis (Rhind and Gunn-
Moore, 2000).
The most current update of the international consensus group
reviewing terminology and diagnostic criteria of IIPs added
unclassifiable IIPs (Travis et al., 2013). In these circumstances, a
final diagnosis cannot be obtained even with multidisciplinary
collaboration. In many of these cases histologic examination
reveals mixed patterns of lung injury, preventing specific clinical
classification into a single disease category (Travis et al., 2013). As
multidisciplinary collaboration is not routinely employed in dogs
and cats with ILDs, existence of unclassifiable IIPs awaits
establishment, acceptance, and ultimately modification of ILD
classification.
Conclusions
Recognition of ILDs in veterinary medicine is becoming more
common; however, as disease phenotypes are diverse, careful
classification will be required to understand more about the
natural clinical course, treatment and prognosis. Classification of
IIPs in humans has benefitted from strong international multidis-
ciplinary collaborations. While it is unlikely that dogs and cats have
identical IIPs to each other or humans, they almost certainly have
important similarities. For all IIPs, a careful search for an
underlying trigger is essential since if an underlying cause is
found, the disease is classified as a “Known Cause ILD” (see
Interstitial Lung Diseases in Dogs and Cats Part II: Known Cause
and Other Discrete Forms). One major lesson is that in dogs and
cats fibrotic ILD is not a single “disease” but represents the end
stage of a variety of insults. As with the other IIPs, emphasis needs
to focus on identifying and classifying fibrotic ILDs using a
combination of careful history taking, clinical and imaging
findings, with final diagnosis supported by histopathologic
features. In the foreseeable future, histopathology will play a
central role, and it is important to recognize when possible, to
sample more than one affected lobe and to not sample just the
most visibly severe lesions. Severe lesions may confirm end stage
fibrosis, but may miss the underlying process that could be
treatable. Earlier recognition may provide a chance to intervene
before irreversible changes occur. Histopathology may also be used
to diagnose COP, which in contrast to other IIPs, has a good to
excellent response to immunosuppressive therapy in most
patients.
Conflict of interest
The author does not have a financial or personal relationship
with other people or organisations that could inappropriately
influence or bias the content of the paper.
Acknowledgements
The author would like to thank Dennis Chairman MD, Division
of Pulmonary and Critical Care Medicine, University of Missouri
and Cecile Clercx, DVM, DECVIM, PhD, University of Liege, Belgium
for review of this manuscript. The author would also like to thank
Dr. Isabelle Masseau DVM, DACVR, PhD, Université de Montréal,
Canada for review of radiographic and CT images and Dr. Kurt
Williams, DVM, DACVP, PhD, Michigan State University for
providing the histologic figures. The author would also like to
thank Karen Clifford, University of Missouri, for assistance with the
illustrations.
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