Intersticial Lung Disease II

1. Review
Interstitial lung diseases in dogs and cats part II: Known cause and
other discrete forms
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:
Alveolar filling disorders
Bronchiolocentric lesions
Eosinophilic pneumonia
Inhalational exposure
Multidisciplinary collaboration
A B S T R A C T
In addition to idiopathic interstitial pneumonias, interstitial lung diseases (ILDs) can occur secondary to
known causes or be classified as discrete syndromes. Also known as diffuse parenchymal lung diseases,
the ILDs represent a heterogenous group of non-infectious, non-neoplastic disorders characterized by
varied patterns of inflammation and fibrosis. Characteristically associated with the true interstitium (i.e.
the anatomic space lined by alveolar epithelial cells and capillary endothelial cells and the loose-binding
connective tissue), it is important to understand ILDs are associated with pathology of the distal lung
parenchyma and thus lesions can be bronchiolocentric or resemble alveolar filling disorders. Injury to the
distal lung can occur via inhalation or hematogenous routes. This review will build on a proposed
classification scheme adapted from human medicine to describe known cause and discrete forms of ILDs
in dogs and cats.
© 2018 Elsevier Ltd. All rights reserved.
Introduction
Classification of canine and feline ILDs, modified from a human
classification of diffuse parenchymal lung diseases and as proposed
in part I of the companion article, consists of three major groups:
idiopathic interstitial pneumonias (IIPs), ILDs secondary to known
causes, and miscellaneous ILDs (Travis et al., 2002). The
pathogenesis of ILDs results from an inciting injury to resident
cells leading to a cascade of inflammatory events, dysregulated
repair, and in many instances, fibrosis. The focus of this review is on
the latter two categories in dogs and cats.
ILDs of “known cause”
Known cause of ILDs are not clearly defined in humans, but
include those that develop from inhalational, drug, biological
agent, and radiation exposure along with various collagen vascular
diseases and connective tissue disorders. In dogs and cats, ILDs
have been described as a result of exposures via inhalational routes
and secondary to drugs, radiation, and immune-mediated dis-
orders (Fig. 1). Searching for an identifiable trigger is important
both in ILD classification and removal or avoidance of the trigger as
a part of therapy.
Pneumoconiosis
Pneumoconiosis is an inflammatory and fibrotic ILD caused by
environmental exposure to mineral dusts and fibers including
silica, coal dust, asbestos and other small particulates (Jp et al.,
2017). Anthracosis, a milder type of pneumoconiosis, results from
accumulation of black dust particles from chronic exposure to air
pollution or inhalation of coal dust or smoke (Mirsadraee, 2014).
These disorders are somewhat unique among ILDs as they are
preventable. Furthermore, halting exposure may lead to substan-
tial clinical improvement. Histopathologic features reflect a
spectrum of accumulation of retained mineral particles, inflam-
mation and interstitial fibrosis (Cohen et al., 2016). With continued
exposure, massive progressive fibrosis may dominate (Laney et al.,
2017).
Experimental berylliosis and coal dust exposure have been
investigated in the dog (Haley et al.,1989; Morrow and Yuile,1982).
Naturally developing silicosis was described in two dogs; one died
from aspiration pneumonia and the other was healthy but died
under anesthesia for a routine ovariohysterectomy (Canfield et al.,
1989). Birefringent crystalline material within macrophages and
surrounding fibrosis was noted in the latter dog (Canfield et al.,
1989). A terrier living in an asbestos factory having cough and
labored respiration for two years developed pulmonary asbestosis
(Schuster, 1931). In a study assessing risk of environmental
asbestos exposure, lung tissue from urban dogs dying of natural
causes documented ferruginous bodies suggestive of respirable
environmental asbestos fibers significantly more commonly in
E-mail address: reineroc@missouri.edu (C. Reinero).
https://doi.org/10.1016/j.tvjl.2018.11.011
1090-0233/© 2018 Elsevier Ltd. All rights reserved.
The Veterinary Journal 243 (2019) 55–64
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2. older (81%) compared to younger dogs (13%) (Trosic et al., 1993).
Anthracosis has been linked to lung cancer in dogs (Bettini et al.,
2010). Interestingly, in this study 66% of dogs in the control group,
i.e. adult dogs that had died due to reasons other than lung cancer,
had anthracosis with 20% of those also having “acute or chronic
pneumonia”. It is unknown if any of these cases of “pneumonia”
represented pneumoconiosis. To the author’s knowledge, feline
pneumoconiosis has not yet been described.
Hypersensitivity pneumonitis (HP)
HP results from repetitive inhalation of small particulate
antigens leading to diffuse inflammation of the small airways
and pulmonary parenchyma (Miller et al., 2018). Genetic
susceptibility and environmental contributions lead to acute,
subacute and chronic forms of human HP (Miller et al., 2018).
Humoral and cell-mediated immune responses cause alveolitis
that can either improve/heal or evolve into fibrosis; thus, HP is an
important differential for fibrotic lung disease (Churg et al., 2018;
Miller et al., 2018). In people, thoracic radiographs can be normal
and CT scans are preferred. Lesions on CT include patchy or diffuse
ground-glass opacities (GGO) and/or consolidation, micronodules,
mosaic attenuation, and with fibrosis, reticular patterns, architec-
tural distortion and traction bronchiectasis. Histopathology shows
non-necrotizing, granulomatous, interstitial, bronchiolocentric
pneumonitis (Churg et al., 2018). A recent international consen-
sus-based approach suggested the following criteria for the
diagnosis of HP: identification of a causative antigen, temporal
relationship between antigen exposure and disease, mosaic
attenuation on imaging, bronchoalveolar lavage (BAL) lymphocy-
tosis 40% and poorly formed non-necrotizing granulomas on
histopathologic examination (Morisset et al., 2017).
Experimental canine HP has been described (Reijula et al.,
1995). Hypersensitivity pneumonitis-like ILD is probably a more
appropriate term to describe spontaneous disease in dogs
(Alenghat et al., 2010; Buckeridge et al., 2011; Norris et al.,
2002b; Rubensohn, 2009; Whitney et al., 2013). In one pet dog,
histopathologic features were bronchiolocentric with alveolar
involvement; however, classic non-necrotizing granulomas were
not reported, nor was an antigen identified and associated
temporally with disease (Norris et al., 2002b). Inhalation of
puffball mushroom spores (Lycoperdon spp. and Geastrum triplex)
causes a canine pulmonary hypersensitivity reaction similar to HP
(Alenghat et al., 2010; Buckeridge et al., 2011; Rubensohn, 2009;
Whitney et al., 2013). The major difference is the canine disease is
generally associated with a single large inhalation of spores,
compared to human HP caused by repetitive exposure to mush-
rooms (Alenghat et al., 2010). Interstitial lung patterns predomi-
nate on radiography. Outcome was fatal in two dogs, allowing
documentation of histopathologic changes (Alenghat et al., 2010).
Other dogs survived with supportive care and corticosteroids
(Buckeridge et al., 2011; Rubensohn, 2009; Whitney et al., 2013).
Optimal therapy is unknown. A hypersensitivity reaction termed
“pneumonitis” may result from potentiated sulfonamides admin-
istration in dogs (Trepanier, 2004; Trepanier et al., 2003). It should
not be confused with HP as this is not a repetitive inhalational
injury and is better characterized as a drug-induced ILD.
Other inhalational ILDs
Two dogs exposed to a commercial hydrocarbon waterproofing
spray acutely developed tachypnea progressing to respiratory
distress and hypoxemia (Young et al., 2007). Both dogs had a
radiographic interstitial lung pattern, with radiographic improve-
ment in one dog and long-term survival without respiratory
clinical signs in both (Young et al., 2007). Neither had additional
advanced respiratory diagnostics to characterize lesions; thus, they
remain a presumptive inhalant toxin-induced ILD (Young et al.,
2007). A dog and its owner spending considerable time in a poorly-
ventilated workshop exposed to toxic fumes developed similar
respiratory signs suggestive of inhalational injury; the dog was
diagnosed with histopathologic lesions of organizing pneumonia
(OP) making this more likely secondary OP than cryptogenic OP, an
idiopathic interstitial pneumonia (Phillips et al., 2000).
Aspiration-related pulmonary syndromes provide credence to
the concept of a link between aspiration and respiratory tract
injury (Hu et al., 2015; Nafe et al., 2018). In humans, chronic
microaspiration is thought to lead to airway-centered fibroblastic
foci in idiopathic pulmonary fibrosis (IPF) (Bois et al., 2016), with
87% of IPF patients having acid reflux in one study (Raghu et al.,
2006). Other bronchiolocentric ILDs affecting the small airways
and radiating out to the interstitium are thought to be related to
Fig.1. Suggested classification of canine and feline interstitial lung diseases (ILDs), also known as diffuse parenchymal lung diseases. The ILDs exclude primary neoplastic and
infectious causes. As there is no clear consensus on human classification schemes, this classification is modified from humans (Maher, 2012) and adapted to syndromes
described in dogs and cats. The idiopathic interstitial pneumonias (IIPs) are described in the companion article “Interstitial Lung Diseases in Dogs and Cats Part I: Idiopathic
Interstitial Pneumonias” [The Veterinary Journal 243(2019) 48–54]. This manuscript focuses on the “Known Cause” and “Other Forms of ILD”.
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
*Common
56 C. Reinero / The Veterinary Journal 243 (2019) 55–64

3. repetitive microaspiration (Virk and Fraire, 2015). Pulmonary
granulomas suggestive of chronic aspiration (periodic acid-Schiff
positive macrophages and multinucleated giant cells that were
birefringent in polarized light), have been described as incidental
findings at necropsy in dogs (Billups et al., 1972). ILDs related to
repetitive microaspiration are likely underdiagnosed in veterinary
medicine.
ILD from drugs and radiation
Iatrogenic ILDs can arise secondary to exposure to drugs,
biologics and radiation (Camus et al., 2004). Various respiratory
disorders including ILD are a documented sequel to hundreds of
drugs and biologics (Camus, 2011). Respiratory disease may result
from an idiosyncratic reaction during treatment at recommended
dose ranges in an unpredictable fashion. Many histopathologic
patterns can be observed making an adverse drug reaction an
important differential for nearly all ILDs and warranting a
thorough medication history (Camus, 2011). A drug holiday with
resolution of disease supports diagnosis.
Radiation-induced pulmonary toxicity depends on nature of the
ionizing radiation, dose, fractionation schedule, beam trajectory,
and concurrent other therapies and may also manifest as an ILD
such as OP or eosinophilic pneumonia (EP) (Camus et al., 2004).
Many changes are reversible over time, although in some cases,
fibrosis can occur (Camus et al., 2004).
Drug-induced ILD has been presumptively documented in dogs
treated with potentiated sulfonamides (Trepanier, 2004; Trepanier
et al., 2003), cytarabine/prednisone (Hart and Waddell, 2016),
bleomycin (Fleischman et al., 1971), lomustine (Van Meervenne
et al., 2008), rabacfosadine (Saba et al., 2018), and in a cat treated
with nitrosurea (Skorupski et al., 2008). Inhalant chemotherapy
can also induce lung fibrosis in dogs (Hershey et al., 1999; Selting
et al., 2011). Radiation-induced lung injury has been reported in
research dogs (Forrest et al., 1998; Yin et al., 2016), pet dogs (Laing
et al., 1989; McEntee et al., 1992), and pet cats (Cohen et al., 2001;
Cronin et al., 1998).
ILD associated with immune-mediated diseases
In humans, autoimmunity associated with hematologic (e.g.
immune-mediated thrombocytopenia (Fontana et al., 2007)),
intestinal (e.g. ulcerative colitis (Xu et al., 2014)), hepatic (e.g.
primary biliary cirrhosis (Shen et al., 2009)), and connective tissue
disorders (e.g. polymyositis/dermatomyositis (Sharma et al.,
2017)), may have ILD as a pulmonary manifestation. Immunosup-
pression is the first-line treatment. In veterinary patients with
immune-mediated disease, ILDs are not generally recognized. Even
with clinical or radiographic evidence of respiratory involvement,
focus is on extra-pulmonary disease because of (1) fear or cost of
sampling the lung in a meaningful fashion (i.e. lung biopsy), (2)
treating the primary disorder may resolve pulmonary abnormali-
ties without need for a separate diagnostic workup and (3) scant
veterinary literature documenting ILD secondary to immune-
mediated disorders, thus they are not “on the radar” of most
clinicians.
Systemic infectious disease can trigger immune-mediated
interstitial pneumonitis/ILD as in dogs naturally infected with
Leishmania (Goncalves et al., 2003). Collagen and inflammatory
cells were noted in inter-alveolar septa, with absence of
intracellular Leishmania amastigotes in the lungs, despite being
readily found in other tissues (Goncalves et al., 2003). It is unclear
if immune-complex deposits in the vascular endothelium or
interstitium or another not yet described mechanism caused
lesions. Immune-mediated ILD should be discriminated from
primary infectious interstitial pneumonia in which direct presence
of the organism within lung tissue causes pathologic changes (e.g.
Ehrlichia canis inducing pulmonary vasculitis) (Reardon and Pierce,
1981; Toom et al., 2016).
A dog with diffuse thoracic radiographic abnormalities meeting
criteria for systemic lupus erythematosus with thrombocytopenia,
polyarthritis, and a positive anti-nuclear antibody titer had BAL
cytology showing lupus erythematosus cells (Black et al., 2017). ILD
is not a major or minor sign of systemic lupus erythematosus in
dogs or cats (Black et al., 2017) but likely should be. One of the
immune-mediated vasculitides, granulomatosis with polyangiitis,
was reported in a dog with erosive rhinitis, thoracic CT diffuse GGO
and a positive antineutrophil cytoplasmic antibody test (Bohm and
Basson, 2015). While lung biopsies were not obtained in this case
(Bohm and Basson, 2015), diffuse GGO on CT are considered to be
consistent with pulmonary hemorrhage described in humans with
this disease (Marten et al., 2005). A young cat was diagnosed via
necropsy with systemic non-infectious necrotizing vasculitis
called periarteritis nodosa affecting the lungs and multiple other
organs (Campbell et al., 1972). Periarteritis nodosa bears some
similarities to granulomatosis with polyangiitis without a positive
antineutrophil cytoplasmic antibody test result. A canine steroid-
responsive ILD described in two dogs but lacking histopathologic
characterization could perhaps reflect an underlying immune-
mediated pathogenesis, although there was speculation of
cryptogenic OP based on clinicopathologic features (Koster and
Kirberger, 2014).
Other forms of ILDs (specific entities)
ILDs not easily fitting into the aforementioned schematic but
having distinct features can be placed in an “other” category
(Fig. 1). As a starting point for future refinement, veterinary ILDs in
this category include eosinophilic pneumonia (EP), pulmonary
alveolar proteinosis (PAP), diffuse alveolar hemorrhage syndromes
(DAH), lipid/lipoid pneumonia (LP), pulmonary hyalinosis (PH),
histiocytic disorders (systemic and pulmonary Langerhans’ cell
histiocytosis, LCH and PLCH respectively), and pulmonary alveolar
microlithiasis (PAM). Of note, while infectious agents may be
described as triggers of some of these ILDs, it is important to
distinguish a primary infectious interstitial pneumonia from an ILD
due to infection causing resident cell injury, sustained inflamma-
tion, dysregulated repair, and in some cases, fibrosis. With
infectious pneumonia, organisms engage the immune system
leading to inflammation; the inflammation is an appropriate
response to help contain and resolve infection. Primary infectious
interstitial pneumonia and infection triggering an ILD can have
similar clinicopathologic features and are generally discriminated
by identification of organisms and their expected responding
inflammatory cells and lack of sustained disease with appropriate
antimicrobial/anthelmintic therapy in the former.
Eosinophilic pneumonia (EP)
EP in humans are defined by eosinophils comprising a
prominent cell type infiltrating the pulmonary parenchyma on
histological examination (Cottin and Cordier, 2016). With clinical
and imaging features, the surrogate marker of BAL eosinophilia is
frequently used for diagnosis. EP manifests with mild to severe
phenotypes, and most have dramatic responses to corticosteroids
and minimal residual impairment of lung function. In humans, CT
features of chronic EP (CEP) include bilateral, usually peripheral,
GGO and consolidation (Cordier and Cottin, 2011). Importantly,
bronchiectasis is not a feature of CEP. Broadly, human EP can be
subdivided into undetermined causes, determined causes and a
miscellaneous category of other lung diseases associated with
eosinophilia (Table 1). Recognition of underlying causes allows
C. Reinero / The Veterinary Journal 243 (2019) 55–64 57

4. directed therapy. The human classification system has benefitted
from the study of a comparatively large numbers of patients to
identify characteristic features based on signalment, history,
physical examination, imaging and microscopic descriptions.
Overlapping clinicopathologic features, responsiveness to
corticosteroids, and infrequent histopathologic examination con-
tributes to the paucity of information on subtypes of canine EP. BAL
cytology helps rule out disease mimics like infection and
neoplasia; when interpreted with the entire clinical picture, BAL
eosinophilia is considered diagnostic. A proposed system (Table 1)
divides canine syndromes anatomically into eosinophilic bronchi-
tis (EB; disease confined to airways; not discussed further),
eosinophilic bronchopneumopathy (EBP; disease affecting airways
and parenchyma) and eosinophilic pneumonia (EP; disease
affecting parenchyma). Any can be idiopathic or secondary to an
identified cause. A thorough search for parasites, bacteria, fungi
(Norris and Mellema, 2004) and drugs (Trepanier, 2004) should be
undertaken before arriving at an “idiopathic” diagnosis. The term
pulmonary infiltrates with eosinophilia, originally used to describe
radiographic abnormalities with concurrent peripheral eosino-
philia, may encompass EB, EBP and EP, and should not be used
(Lord et al., 1975). Both EBP and EP likely represent a diverse group
of disorders with overlap. Canine EP can be subclassified as CEP or
its more severe subtypes, eosinophilic pulmonary granulomatosis
(EPG) and hypereosinophilic syndrome (HES).
The term canine idiopathic EBP was coined in 2000 by Clercx
et al. and describes a diagnosis based on radiographic and
bronchoscopic findings of airway and parenchymal involvement,
blood and airway eosinophilia, and exclusion of known causes
(Clercx et al., 2000). Idiopathic EBP may be secondary to a
hypersensitivity reaction to inhaled aeroallergens (Peeters et al.,
2005). Bronchiectasis is common in chronic cases (Clercx et al.,
2000). EBP responds well to corticosteroids. While the term EBP
was intended to reflect an idiopathic condition, other known
causes (often parasitic) can result in an identical disease
phenotype.
In contrast to EBP, canine CEP is poorly documented in the
literature. One dog with CEP had large bilateral pulmonary masses
extending to the periphery on radiography and a complete
sustained clinical remission of 2 years with immunosuppressive
doses of prednisone (Waddle et al.,1992). EPG describes a subset of
canine EP of known and unknown causes characterized by
pulmonary masses obliterating normal lung architecture, airway
eosinophilia and in general, a poor response to therapy (Confer
et al., 1983; Fina et al., 2014; Katajavuori et al., 2013; Neer et al.,
1986; von Rotz et al., 1986). One case report documented
prolonged remission of idiopathic canine EPG with immunosup-
pressive therapy (Katajavuori et al., 2013). The most common
identifiable cause of EPG is parasitic infection, especially heart-
worm disease (Confer et al., 1983; Neer et al., 1986). Hilar
lymphadenopathy is sometimes noted. Histopathologic features of
EPG secondary to Dirofilaria immitis include granulomas consisting
of large epithelioid cells, macrophages and eosinophils obliterating
the normal pulmonary architecture (Confer et al., 1983). Another
severe form of canine EP is HES, a multisystemic idiopathic
disorder of infiltrating mature eosinophils into organs commonly
including the lungs (Aroch et al., 2001; Goto et al., 1983; Madden
and Schoeffler, 2016; Perkins and Watson, 2001; Sykes et al., 2001).
It behaves somewhat similarly to eosinophilic leukemia. Breed
predisposition for HES includes the Rottweiler (James and Mans-
field, 2009; Sykes et al., 2001), and possibly the Boxer (Goto et al.,
1983; Madden and Schoeffler, 2016).
As histopathologic examination, the gold standard for disease
classification, is rarely performed, surrogate imaging diagnostics
become important (Fig. 2). CT features of a series of dogs with EBP
and EPG have been published (Fina et al., 2014; Mesquita et al.,
2015). Mesquita et al. only used airway eosinophilia and exclusion
of parasites to define EBP; thus, the cases would have encompassed
many types of eosinophilic lung disease including EB, EBP and EP.
This was reflected in their diverse CT findings including bronchial
wall thickening, bronchiectasis/plugging of the bronchial lumen,
and peribronchial opacity reflective of EBP, as well as nodules/
masses reflective of the EPG form of EP (Mesquita et al., 2015). In
the other description of CT features of idiopathic EPG, severely
bronchiectatic airways were identified within masses of four of five
dogs (Fina et al., 2014), bringing up the question if non-parasitic
cases of EPG represent an advanced/terminal stage of EBP wherein
bronchiectasis is the primary contributor to peribronchial paren-
chymal changes (Meler et al., 2010). Bronchiectasis does not appear
to be a feature of canine EPG secondary to parasitic infection either
via imaging or histopathology (Confer et al.,1983; Neer et al.,1986).
Thus, while both are termed EPG, they are likely dramatically
different syndromes: one having bronchial inflammation, bron-
chiectasis, loss of mucociliary function and extension of
Table 1
Classification of eosinophilic lung disease with adaptation of a canine scheme from human medicine (Adamama-Moraitou et al., 2011; Berry et al., 1990; Confer et al., 1983;
Cottin and Cordier, 2016; Khanna et al., 1997; Norris and Mellema, 2004; Postorino et al., 1989; Sykes et al., 2001; von Rotz et al., 1986).
Man Dog (proposed)
Undetermined cause Undetermined cause
Acute eosinophilic pneumonia Idiopathic eosinophilic bronchopneumopathya
Chronic eosinophilic pneumonia Idiopathic eosinophilic pneumonia
Eosinophilic granulomatosis with polyangiitis Chronic eosinophilic pneumonia
Hypereosinophilic syndrome Eosinophilic pulmonary granulomatosis
Idiopathic hypereosinophilic obliterative bronchiolitis Hypereosinophilic syndrome
Determined cause secondary to Determined cause secondary tob
Infection (predominantly parasites; also fungal, bacterial, viral) Infection (predominantly parasites; also fungal, bacterial, viral)
Drug reactions Drug reactions
Toxins
Radiation
Allergic bronchopulmonary aspergillosis and related syndromes
Miscellaneous pulmonary syndromes with possible eosinophilia Miscellaneous pulmonary syndromes with possible eosinophilia
Asthma Asthma (exceedingly rare in dogs)
Organizing pneumonia Malignancies (including lymphomatoid granulomatosis)
IPF
Malignancies
Langerhans’ cell histiocytosis
a
Some cases of EBP in the veterinary literature outside of the original description (Clercx et al., 2000) are likely examples of EB, EP or EPG.
b
Can manifest as EBP, EP or EPG.
58 C. Reinero / The Veterinary Journal 243 (2019) 55–64

5. eosinophilic infiltrates outward from airways and the other, having
primary parenchymal lesions obliterating normal architecture
inclusive of entrapped airways.
In cats, a common eosinophilic pulmonary disease is allergic
asthma (Reinero, 2011); however, experimental and spontaneous
parasitic infections may induce eosinophilic granulomatous
pneumonia (Dennler et al., 2013; Hoover and Dubey, 1978; Maia
et al., 2011; Panopoulos et al., 2017; Parsons et al., 1989; Philbey
et al., 2014). Dying heartworms (D. immitis) in cats have been
reported to cause EP and EBP (Venco et al., 2015). Paraneoplastic
eosinophilic lung infiltrates (Gilroy et al., 2011) and HES with lung
involvement (Huibregtse and Turner, 1994; Muir et al., 1993) have
both been described in the cat. There is currently no classification
scheme for feline EP.
Pulmonary alveolar proteinosis (PAP)
A rare alveolar filling disorder, PAP is characterized by
accumulation of phospholipoproteinaceous material (surfactant)
from impaired clearance (Griese, 2017). It can be congenital or
acquired, and primary (from disrupted granulocyte-macrophage
colony-stimulating factor signaling) or secondary to inhalation
exposures, drugs, immune dysfunction, neoplasia, etc. (Papiris
et al., 2015). Radiographs show bilateral alveolar opacities and CT
scans classically demonstrate a “crazy-paving” pattern from GGO
superimposed over a reticular pattern (Griese, 2017). Whole lung
lavage has been the preferred treatment in humans (Griese, 2017),
although inhalation of GM-CSF may be beneficial (Papiris et al.,
2015).
Described in the dog (Cummings et al., 2013; Jefferies et al.,
1987; Silverstein et al., 2000) and cat (Szatmari et al., 2015), PAP is
a rare disorder. Respiratory signs range from subtle to severe;
radiographs demonstrate diffuse interstitial to alveolar patterns.
BAL is opaque and milky (Cummings et al., 2013; Szatmari et al.,
2015). Macrophages and alveoli filled with PAS-positive material
and cholesterol clefts suggestive of lipid are noted on cytology and
histopathology. Lung lavage successfully treated a dog (Silverstein
et al., 2000).
Diffuse alveolar hemorrhage (DAH)
Alveolar hemorrhage is a shared common event in a diverse
group of disorders in humans (Lichtenberger et al., 2014). If
recurrent, it may lead to pulmonary fibrosis (Lichtenberger et al.,
2014). The clinical syndrome of DAH is characterized by
hemoptysis (not universally present), anemia, diffuse radiographic
pulmonary infiltrates and hypoxemic respiratory failure associated
with three histopathologic patterns: pulmonary capillaritis, bland
pulmonary hemorrhage and diffuse alveolar damage (Schwartz,
2017). Pulmonary capillaritis, most commonly seen with systemic
Fig. 2. The spectrum of eosinophilic lung diseases ranges from eosinophilic bronchitis (EB; pathology being airway centered) to eosinophilic bronchopneumopathy (EBP;
pathology involving airways and parenchyma) to eosinophilic pneumonia (EP; pathology being parenchymal centered). In lieu of histopathology, imaging can help localize
disease to airways and/or the parenchyma. All dogs had peripheral and airway eosinophilia, thoracic imaging abnormalities, negative testing for parasites, and no concrete
drug history linked to disease onset. (a) Right lateral thoracic radiograph obtained from a 7-year-old female spayed Cavalier King Charles Spaniel showing a severe diffuse
bronchial pattern with pronounced peribronchial cuffing (white arrows) consistent with EB. (b) In this dog with EB, transverse CT image highlights the bronchocentric nature
of the lesions with increases in peribronchovascular opacification that in cross-section appears as “donuts”. (c) Right lateral thoracic radiograph from a 4-month-old female
intact mixed breed puppy with EBP. Radiographic changes revealed similar evidence of peribronchial cuffing as the dog with EB, but with a marked patchy unstructured
interstitial pattern. Thoracic CT was not performed. Severe peripheral eosinophilia (36,194 cells/mL; reference range, 80–1,100 cells/mL) and airway eosinophilia (50%
eosinophils, reference range 5%) were both documented. Fecal float revealed a few coccidia and fecal Baermann’s was negative for larvae. Allergen-specific IgE testing
revealed a single low positive result for a storage mite, which was not believed to be clinically significant. The dog had clinical and radiographic resolution of disease in
response to fenbendazole, ponazuril and prednisone. (d) Transverse thoracic CT image from a 4-year-old female spayed Toy Poodle with EBP. CT changes include increases in
peribronchovascular opacification consistent with airway involvement (small arrows) and patchy regions of GGO consistent with parenchymal involvement (large arrows).
Clinical remission was induced with prednisone therapy. (e) Right lateral thoracic radiograph from a 19-month-old spayed female German Shepherd dog with
hypereosinophilic syndrome, a severe form of EP. A 23 24 13 cm multilobulated soft tissue mass was noted to occupy the caudal thorax, displacing other structures. Unlike
most cases of EP, HES is systemic, and this dog had involvement of the liver and gastrointestinal tract. Immunosuppression led to partial clinical remission but disease
progression led to euthanasia 1 year later.
C. Reinero / The Veterinary Journal 243 (2019) 55–64 59

6. vasculitides, immune-mediated disorders, and drugs, is associated
with neutrophilic inflammation and necrosis of vessels. Vascular
hemorrhage may arise from veins (e.g. pulmonary veno-occlusive
disease) or capillaries (e.g. pulmonary capillary hemangiomatosis)
(Rabiller et al., 2006; Tron et al., 1986). Bland pulmonary
hemorrhage arises without inflammation or alveolar destruction.
It is caused by connective tissue disorders, drugs including
anticoagulants, bleeding disorders, chronic pulmonary venous
hypertension, and others. Diffuse alveolar damage leading to
hemorrhage can be caused by infection, immune-mediated
disease, drugs, toxins, any cause of acute respiratory distress
syndrome (ARDS) etc. Radiographs may be normal with acute
pulmonary hemorrhage or show airspace opacities (Lichtenberger
et al., 2014). Treatment and prognosis depends on underlying
etiology.
A retrospective study of canine hemoptysis showed a myriad of
underlying causes (Bailiff and Norris, 2002); however, not all
hemoptysis can be classified as DAH, as it must follow the
definition above. Canine DAH with histopathologic evidence of
bland pulmonary hemorrhage has been described secondary to
antibodies against the glomerular basement membrane (Good-
pasture’s syndrome in humans) (Brown et al., 2008). Copper
sulfate powder has also led to hemoptysis, anemia, and hypoxemic
respiratory failure in a dog (Giudice et al., 2017). Although
envenomation can lead to alveolar hemorrhage in dogs (Abraham
et al., 2004; Jacoby-Alner et al., 2011; Oliveira et al., 2007)
envenomation is not considered a cause of DAH in humans unless
associated with ARDS. As in humans, DAH can occur in some dogs
and cats with ARDS (Balakrishnan et al., 2017). Infection, for
example leptospirosis, is a well-recognized cause of DAH in both
humans and dogs (Klopfleisch et al., 2010; Luks et al., 2003).
Pulmonary histopathology of dogs with leptospiral pulmonary
hemorrhage syndrome (LPHS) shows marked alveolar hemorrhage
and edema without substantial inflammation (Schuller et al.,
2015). Deposition of IgG and IgM in lungs of dogs with LPHS
suggests an immune-mediated pathogenesis (Schuller et al., 2015).
While not an exhaustive list, respiratory viruses (Castleman et al.,
2010; Chvala-Mannsberger et al., 2009; Kumar et al., 2015; Monne
Rodriguez et al., 2014), bacteria (Handt et al., 2003; Highland et al.,
2009; Jaeger et al., 2013; Jang et al., 1973; Lobetti et al., 1993),
protozoa (Snider et al., 2010) and parasites (Brennan et al., 2004)
can cause alveolar hemorrhage. Many aforementioned causes have
multifactorial and poorly understood mechanisms leading to DAH.
Canine pulmonary veno-occlusive disease and canine and feline
pulmonary capillary hemangiomatosis are newly described, rare,
chronic disorders associated with the finding of pulmonary
hemosiderophages (Jaffey et al., 2017; Jenkins and Jennings,
2017; Williams et al., 2016). A cat with hemorrhagic BAL fluid
had histopathologic evidence of pulmonary fibrosis, an uncharac-
terized “histiocytic interstitial pneumonia” and chronic bronchitis;
it is unknown if this cat had chronic DAH leading to fibrosis or if the
underlying disease predisposed to both fibrosis and hemorrhage
(Norris et al., 2002a).
Lipid/lipoid pneumonia (LP)
LP results from accumulation of endogenous or exogenous lipids
inalveoli(HaddaandKhilnani,2010).Chronicrecurrent aspirationof
exogenous animal, vegetable and mineral sources of lipid triggers
inflammation and possibly fibrosis. Endogenous lipid accumulation
usually occurs secondary to airway obstruction in humans. Clinical
signs have an insidious onset and are non-specific, and radiographic
lesions may mimic other respiratory disorders. Cytologic or
histopathologic identification of lipid-laden macrophages helps
confirm diagnosis. Aside from removing lipid exposure in exogenous
LP, treatment protocols are not well defined.
Exogenous LP has been described in dogs (Carminato et al.,
2011; Hudson et al.,1994) and cats (Chalifoux et al.,1987; De Souza
et al., 1998) following inadvertent aspiration of mineral oil.
Endogenous LP is more common in cats (Jones et al., 2000) than
dogs (Corcoran et al.,1992; Leissinger et al., 2015; Raya et al., 2006).
In cats it is frequently secondary to obstructive pulmonary disease,
including inflammatory airway disease, similar to humans (Jones
et al., 2000). Endogenous LP has been described in a dog with
heartworm disease and chronic bronchitis and in another with
recurrent bronchopneumonia (Corcoran et al., 1992; Raya et al.,
2006). Lipid accumulations have also been described in dogs and
cat with Mycobacterium fortuitum pneumonia (Couto and Artacho,
2007; Leissinger et al., 2015; Turnwald et al., 1988). LP may be
asymptomatic or result in non-specific clinical signs (Jones et al.,
2000; Raya et al., 2006). There is no single pathognomonic
radiographic abnormality, with lesions mimicking or reflecting
another respiratory disease. In a case series of 24 cats with
endogenous LP diagnosed on necropsy, LP was not the cause of
death in any cat, although it was frequently a marker for severe
underlying respiratory disease (Jones et al., 2000). Surgical
resection of solitary lesions may be curative (Carminato et al.,
2011; Corcoran et al., 1992; Hudson et al., 1994).
Langerhans’ cell histiocytosis
Systemic Langerhans’ cell histiocytosis (LCH), localized LCH and
PLCH have been described in humans. PLCH rarely involves other
organs, is generally associated with tobacco use in young adults
and, without clear consensus, has been debated as a reactive, clonal
or neoplastic process (Vassallo et al., 2017). Thoracic CT in humans
with PLCH shows nodules, cavitated nodules and cysts in varying
combinations (Castoldi et al., 2014). Histopathology reflects
bronchiolocentric lesions, with progression to cysts when the
bronchiolar wall is destroyed and the lumen dilated (Vassallo et al.,
2017). Respiratory clinical signs are insidious or acute, and
incidental detection of radiographic lesions is not uncommon
(Vassallo et al., 2017). Acute clinical signs occur in 15–20% of cases
secondary to spontaneous pneumothorax as cysts rupture
(Vassallo et al., 2017).
Dogs may develop disease resembling human LCH, with
widespread dissemination of cutaneous lesions including to the
lungs (Moore, 2014). Feline PLCH has been described in three
cats with respiratory signs and miliary and/or bronchointer-
stitial patterns on radiography (Busch et al., 2008). Pulmonary
lesions center on peribronchial and perivascular regions, not
characteristically obstructing bronchioles as is seen in human
PLCH (Busch et al., 2008). Signs progressed despite glucocorti-
coid administration in two of the three cats. Gross lesions,
unlike in humans, failed to demonstrate cystic or cavitary
lesions, instead showing diffuse small nodules that in regions
coalesced to efface parenchymal tissue. Histopathology con-
firmed obstructive intraluminal histiocytic infiltrates of termi-
nal and respiratory bronchioles with extension into the
parenchyma. Immunohistochemistry and electron microscopy
were used to document Langerhans’ cells.
Pulmonary hyalinosis
Pulmonary hyalinosis is another rare alveolar filling disorder,
described in research Beagles exposed to inhaled air of uranium
mines and as an unexplained finding in a Boxer with an intestinal
anaplastic sarcoma (Amand et al., 1973; Dagle et al., 1976). While
small foci of hyalinosis are incidental findings in older dogs, when
widespread and severe, they can lead to hypoxemic respiratory
failure (Fig. 3).
60 C. Reinero / The Veterinary Journal 243 (2019) 55–64

7. Pulmonary alveolar microlithiasis (PAM)
Considered a rare autosomal recessive genetic disease in
humans, PAM presents with diffuse intra-alveolar accumulations
of small calculi (Castellana et al., 2015). Defects in a sodium-
phosphate cotransporter impairs ability of type II alveolar
epithelial cells to clear phosphorous ions from alveolar spaces,
contributing to microliths (Ferreira Francisco et al., 2013). Clinical
course ranges from asymptomatic to fatal (Castellana et al., 2015).
Pulmonary fibrosis may result from large microliths exerting
pressure and causing damage to alveolar walls (Ferreira Francisco
et al., 2013). Thoracic imaging showing micronodular mineraliza-
tion and BAL showing microliths is generally diagnostic; lung
biopsy is rarely needed (Castellana et al., 2015). There is no
effective medical or gene therapy and lung transplantation is used
for end stage disease (Castellana et al., 2015; Ferreira Francisco
et al., 2013).
Reported in pet dogs (Brix et al., 1994; de Brot and Hilbe,
2013; Liu et al., 1969; O’Neill et al., 2006), research Beagles
(Caceres and Genta, 1988) and a cat (Brummer et al., 1989), the
cause of PAM remains unknown. Unlike in humans where
microliths lack and inflammatory response, inflammation has
been associated with microliths in some veterinary cases
(Brummer et al., 1989; Liu et al., 1969). Pulmonary mineraliza-
tion manifesting as a miliary pattern has been described in dogs
with respiratory clinical signs (Brix et al., 1994; Liu et al., 1969);
however, as in humans, PAM may be an incidental finding on
thoracic imaging (O’Neill et al., 2006) (Fig. 4). PAM should be
discriminated from dystrophic and metastatic calcification,
which have underlying causes that need to be addressed and
where mineral deposits are found in regions of necrosis or in
the interstitium (Crawford et al., 1987; de Brot and Hilbe, 2013).
It also differs from broncholithiasis in which mineralized
concretions fill the airways, not alveoli (Talavera et al., 2008).
Interstitial fibrosis in varying degrees has been reported in all
canine and feline cases of PAM (Brix et al., 1994; Brummer et al.,
1989; Caceres and Genta, 1988; de Brot and Hilbe, 2013; Liu
et al., 1969; O’Neill et al., 2006).
Fig. 4. Right lateral and dorsoventral thoracic radiographs from an 11-year-old spayed female Dachshund with pulmonary alveolar microlithiasis. The dog was asymptomatic
for respiratory disease and had imaging for another medical reason. Mineralized opacities sparing but surrounding the airways are noted on both radiographic views. Images
courtesy of Tekla Lee-Fowler, DVM, DACVIM (SAIM).
Fig. 3. Thoracic imaging from a 12-year-old castrated male Jack Russell terrier presenting for exercise intolerance and labored respiration ultimately diagnosed with
pulmonary hyalinosis. Post-mortem examination of lung tissue revealed effacement of alveoli with aggregates of extracellular brown-gold material surrounded by collagen,
vacuolated macrophages and multinucleated giant cells. (a) Right lateral thoracic radiograph showing air bronchograms, rounding of the lung lobe margins with thickened
pleural fissure lines, and border effacement between pulmonary lesions, the cardiac silhouette and the diaphragm. While the distribution is predominantly ventral, the dorsal
aspect of the lesions demonstrates a severe unstructured interstitial pattern. (b) Transverse thoracic CT scan supports an alveolar filling disorder with increased opacification
of the parenchyma surrounding air-filled bronchi/bronchioles (black arrows). Images courtesy of Christine Cocayne, DVM, DACVIM (SAIM).
C. Reinero / The Veterinary Journal 243 (2019) 55–64 61

8. Conclusions
Knowledge of ILDs in dogs and cats remains in its infancy.
Improved imaging tools, specifically thoracic CT scans, will likely
increase awareness of ILDs, and provide a rationale for lung biopsy
earlier in the disease course where intervention could better
impact outcome. Multidisciplinary collaboration between clini-
cians, radiologists and pathologists remains key to advancing the
field.
Conflict of interest statement
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 and Dr. Isabelle Masseau DVM,
DACVR, PhD, Université de Montréal, Canada for review of
radiographic and CT images. The author would also like to thank
Karen Clifford, University of Missouri, for assistance with the
illustrations.
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