2. whereas restrictive lung disease is associated with decreased lung
volume (Gold and Koth, 2016). The major differences in pulmonary
function underlying obstructive or restrictive phenotypes have
relevance both for diagnosis as well as therapy; these phenotypes
can be extrapolated to dogs. In people with RD/H, PH is associated
with a significantly worse prognosis versus those without PH
(Finlay et al., 1983; Arcasoy et al., 2001; Nadrous et al., 2005;
Hamada et al., 2007; Baughman et al., 2010; Andersen et al., 2012a,
b; Seeger et al., 2013) and the adverse impact of PH on outcome
correlates with PH severity (Nadrous et al., 2005; Leuchte et al.,
2006; Hamada et al., 2007).
There is a paucity of information regarding clinical and
diagnostic characteristics, prognostic variables, and long-term
survival in dogs with RD/H and concurrent PH, despite RD/H being
the second leading cause of PH in dogs. Therefore, this study had
three primary objectives in dogs with RD/H and PH: (1) to describe
clinical features, and results of thoracic radiography and computed
tomography (CT), fluoroscopy, tracheobronchoscopy, bronchoal-
veolar lavage, and histopathology; (2) to characterize distribution
of RD/H phenotypes (i.e., into obstructive or restrictive lung
disease categories); (3) to describe long-term survival and
investigate the association of potential prognostic variables (i.e.,
estimated sPAP, severity of PH, phosphodiesterase 5 (PDE5)
inhibitor treatment, and RD/H phenotype) with survival.
Materials and methods
Case selection and classification
A retrospective records study was performed. Dogs with an echocardiographic
diagnosis of PH and without concurrent pulmonic stenosis presented at the
University of Missouri Veterinary Health Center between August 2017–July 2018
were identified. Dogs were categorized according to main cause of PH, in a similar
manner to the human classification scheme (Simonneau et al., 2013). Only dogs
with PH due to RD/H had data retrieved from medical records, including
signalment, presenting complaint, medications, and diagnostic results (echocardi-
ography, thoracic radiographs and/or CT, respiratory fluoroscopy, videofluoroscopic
swallow study, tracheobronchoscopy, bronchoalveolar lavage fluid (BALF) cytology,
and lung histopathology). Specific types of RD/H were identified and sub-
categorized as either obstructive airway/lung disease (OALD) or restrictive lung
disease (RLD), and further characterized as either definitive or suspected based on
diagnostic evaluation (Table 1). OALD refers to disorders affecting the extra and
intra-thoracic trachea, bronchi, and/or bronchioles that obstruct airflow (e.g.,
tracheal or main stem bronchial collapse, bronchomalacia, obstructive sleep apnea,
brachycephalic obstructive airway syndrome, bronchiolar diseases, diffuse bron-
chiectasis, and emphysema; Gold and Koth, 2016). RLD consists of pleural or
parenchymal disorders that restrict lung expansion on inspiration (e.g., pulmonary
fibrosis, pulmonary neoplasia, pneumocystis pneumonia, aspiration-related
respiratory syndrome, and uncharacterized parenchymal disease; Gold and Koth,
2016). Bronchiolectasis is defined as the luminal dilatation of the small airways, or
bronchioles. They can be air or fluid (mucus, exudate, other debris) filled and
frequently have thickening of their walls (Edwards et al., 2015). Dilatation allows
visualization of this pathology on thoracic CT; normal bronchioles are cannot be
seen on thoracic radiography or CT (Edwards et al., 2015).
Echocardiography
Transthoracic echocardiography was performed using an Artida Aplio (Toshiba
Medical Systems Corporation, Otawara, Japan) and standard imaging planes
(Thomas et al., 1993) by a board-certified cardiologist or a directly-supervised
cardiology resident. Color Doppler evaluated presence of intra or extra-cardiac
shunting and valvular regurgitation. When present, tricuspid regurgitation (TR) was
interrogated; a peak velocity 2.8 m/s was indicative of PH (Kellihan and Stepien,
2012). Using the modified Bernoulli equation (Dp = 4V2
), the sPAP was estimated
(Kellihan and Stepien, 2012). Pulmonary hypertension was considered mild if the
estimated sPAP was 30–49 mmHg, moderate if 50–75 mmHg, and severe if 75
mmHg (Serres et al., 2006). Spectral Doppler interrogation of the pulmonic valve
evaluated the pulmonary arterial systolic flow profile and peak velocity, and
interrogated pulmonic insufficiency. In the absence of TR, PH was diagnosed based
on pulmonic insufficiency peak velocity (PIPV) 2.2 m/s (Kellum and Stepien,
2007), presence of a type II or type III mid-systolic pulmonary arterial flow profile
(MSPAFP; Kellum and Stepien, 2007) or a right pulmonary artery distensibility
(RPAD) index 34.6% (Visser et al., 2016). In the absence of TR, PH was considered
severe if there was a type III MSPAFP. Additional parameters included subjective
evaluation of the right heart size, the presence of septal flattening, and pulmonary
trunk to aortic root (PT:Ao) ratio (Kellihan and Stepien, 2010). Degenerative valve
disease was diagnosed and staged as previously described (Atkins et al., 2009). Left
atrial size was assessed as previously described (Rishniw and Erb, 2000). A
component of PH was at least partially attributed to left-sided heart disease if
moderate to severe left atrial enlargement was present.
Table 1
Types of respiratory disease identified in dogs with respiratory disease and/or hypoxia and pulmonary hypertension including obstructive or restrictive phenotype and
diagnostic requirements for confidence in disease category classification. Major disease categories were listed as definitive or suspect, based on comprehensive evaluation of
specific clinical and diagnostic test results.
Disease RD phenotype Definitive Suspect
Tracheal/MSB collapse Obstructive Cervical/thoracic radiography,
fluoroscopy, CT, tracheoscopy
Breeda
, clinical signsb
Bronchomalacia Obstructive Inspiratory/expiratory CT,
bronchoscopy, histopathology
Clinical signs (expiratory pushc
)
OSA/BOAS Obstructive Breed with associated defects,
compatible signs and absence
of other disordersf
Bronchiolar diseaseg
Obstructive Histopathology CT
Diffuse bronchiectasis Obstructive Thoracic radiography, CT,
histopathology
Emphysema Obstructive Histopathology CT
Pulmonary fibrosis Restrictive Histopathology Breedd
, audible crackles on PE, thoracic radiography/CTe
Pulmonary neoplasia Restrictive Cytology or histopathology Masses/nodules on thoracic imaging with systemic signs
Pneumocystis pneumonia Restrictive Cytology, histopathology, PCR
Aspiration-related respiratory
syndromeh
Restrictive Predisposing defecti
/chronic regurgitation, VFSS documented
GER, and respiratory clinical signs
Uncharacterized parenchymal
disease
Restrictive Respiratory clinical signs, thoracic radiography or CT
parenchymal abnormalities with no definitive diagnosis
RD, respiratory disease; MSB, mainstem bronchial collapse; CT, computed tomography; PE, physical examination; PCR, polymerase chain reaction; OSA, obstructive sleep
apnea; BOAS, brachycephalic obstructive airway syndrome; VFSS, video-fluoroscopic swallow study; GERD, gastroesophageal reflux.
a
Yorkshire terriers, Miniature poodles, Pugs, Maltese, Chihuahua, and Pomeranians.
b
Paroxysmal, dry harsh cough, described as ‘goose-honking’ or wheeze.
c
In the absence of other disorders explaining expiratory push/intrathoracic airway collapse.
d
West Highland white terrier, Staffordshire terrier.
e
Radiography showing underinflation and an interstitial pattern or CT demonstrating architectural distortion with or without traction bronchiectasis, parenchymal bands.
f
Stertor or stridor (no wheeze or expiratory distress); typical brachycephalic defects.
g
Bronchiolar disease can either be obstructive (constrictive bronchiolitis obliterans) or restrictive or a combination of both.
h
Diffuse aspiration bronchiolitis, recurrent aspiration pneumonia, pulmonary fibrosis.
i
Megaesophagus or other functional esophageal motility defect, hiatal hernia, laryngeal paralysis.
2 J.A. Jaffey et al. / The Veterinary Journal 251 (2019) 105347
3. Other imaging
All imaging studies were interpreted by a board-certified radiologist and/or
internist with expertise in pulmonology. Metrics for respiratory fluoroscopy studies
can be found in Supplementary Document D1 Part A. Videofluoroscopic studies were
performed utilizing an unrestrained free-feeding protocol (Harris et al., 2017).
Thoracic CT (64-detector row Toshiba Aquilion, Toshiba America Medical Systems,
Tustin, CA) scans were interpreted using lung and soft tissue windows, and compared
inspiratory, expiratory and contrast series when available (Supplementary Document
D1 Part B; illustrative examples of lesions shown in Figs. 2–5). Inspiratory and
expiratory breath holds were ventilator-assisted (Engstrom Carestation ventilator, GE
Healthcare) and performed in tandemwith CTscans. Positive end-expiratory pressure
was set to 0 cm H20 for the expiratory breath hold. Using CT scans, RD/H was
considered obstructive (Gold and Koth, 2016) if there was tracheal or mainstem
bronchial collapse (Stadler et al., 2011), bronchomalacia (Fig. 2), air trapping on the
expiratoryseries (Fig. 2) (Berniker and Henry, 2016), ‘direct’ bronchiolar signs without
architectural distortion and with associated decreased attenuation (Edwards et al.,
2015), or emphysema (Edwards et al., 2015). Disease was considered restrictive if
inspiratory images were suggestive of underinflation with multifocal or diffuse
ground-glass opacity(GGO; Fig. 5A), consolidation or if there was multifocal ordiffuse
nodular or linear patterns with architectural distortion (Fig. 3B) (Thierry et al., 2017;
Roels et al., 2017; Schiborra et al., 2018). The metrics for evaluation of endoscopic
tracheobronchial features can be found in Supplementary Document D1 Part C.
Tracheobronchial abnormalities were graded using a modification of a published
scoring system (Mercier et al., 2011).
Bronchoalveolar lavage fluid cytology and bacterial culture
Twenty mL aliquots of 0.9% sterile saline were instilled into 1 sublobar
bronchus, followed by manual suction through the endoscopic biopsy channel.
Recovered BALF was immediately processed for cytopathology and aerobic and
anaerobic bacterial culture. Differential cell counts performed by board-certified
clinical pathologists were based on evaluation of 200 nucleated cells.
Lung histopathology
Lungs were obtained shortly after death and processed as previously described
to avoid fixation artifacts, disruption of lung structures and prevent deflation (Jaffey
et al., 2017). In short, each lobar bronchus was cannulated with a 3 French red
rubber catheter and inflated with 10% formalin. Following sufficient inflation, the
bronchus was ligated and the lungs were placed in jars containing 10% formalin.
Histopathologic assessments were made by a board-certified anatomical patholo-
gist.
Statistical analysis
Statistical analysis was performed using commercial software (SigmaPlot, Systat
Software). Shapiro-Wilk test was used to assess normality. Categorical data were
presented as proportions and percentages. Non-normally distributed data were
described using median, Q1, Q3, and range. Non-survival was defined as death or
euthanasia. Survival time was counted from day of PH identification to either day of
non-survivalorcessationofstudy(October17,2018).Dogsalive attheendofthestudy,
dogs in which cause of non-survival was not RD/H related, and dogs lost to follow-up
were right-censored as non-events. Date of non-survival was determined from a
combination of medical records and phone communication with owners or referring
veterinarian. Survival analyses were performed on dogs with RD/H excluding those
with hemodynamically relevant MMVD (i.e., MMVD stage B2) (Keene et al., 2019). A
receiver-operating characteristic (ROC) curve was used to determine area under the
curve (AUC) and select the optimum cut-off value of estimated sPAP for detection of
non-survival maximizing Youden’s J statistic for sensitivity and specificity. Variables
potentially associated with survival time [i.e., estimated sPAP, age at PH identification,
severity of PH (mild/moderate/severe), PDE5 inhibitor treatment (yes/no), OALD only
(yes/no), RLD only (yes/no), mixed OALD and RLD (yes/no), estimated sPAP cutoff 47
mmHg (47 mmHg or 47 mmHg] were examined using univariate Cox proportional
hazard analysis. The estimated sPAP cutoff value of 47 mmHg was generated from the
ROC-curve. Variables significantly associated with survival time at the 10% (i.e., 0.10)
level were then included in a multivariable Cox proportional hazards model. Median
survival time was determined by the Kaplan–Meier method. Kaplan–Meier survival
curves were constructed to explore differences using log-rank-statistics of dogs
stratified byabove or below estimated sPAP 47 mmHg cutoff. The association between
PDE5 inhibitor treatment (yes/no) and severity of estimated sPAP (47 mmHg or
47 mmHg)wasexaminedwithaChi-squaretest.P 0.05was consideredsignificant.
Results
Animal population
From August 2017 to July 2018, echocardiography was
performed on 507 dogs; 174 (34.3%) of these were diagnosed
with PH. Forty-seven of 174 (27.0%) dogs had PH due to RD/H
(Fig.1). The median age and weight were 12 years (Q1, Q3, range; 9,
13, 1–18 years) and 6.9 kg (Q1, Q3, range; 4.1, 9.6, 1.7–29.4 kg),
respectively. There were 44 purebred and three mixed breed dogs,
with 26 males (23 castrated) and 21 females (20 spayed).
Ninety-one percent (43/47) of dogs had at least one respiratory
clinical sign described by owners at the time of PH identification.
These included: cough 72.0% (31/43); increased respiratory effort
30.0% (13/44); tachypnea 21.0% (9/44), syncope 16.2% (7/43); acute
respiratory distress 7.0% (3/43); wheezing 7.0% (3/43); cyanosis
7.0% (3/43); hemoptysis 2.3% (1/43); and exercise intolerance 2.3%
(1/43). Many dogs exhibited more than one respiratory sign.
Seventy percent (33/47) of dogs were treated with 1
medication at the time of PH identification with the most common
including prednisone, hydrocodone, sildenafil, furosemide, and
enalapril. The most common medications recommended at
discharge in 38 dogs were prednisone, hydrocodone, sildenafil,
omeprazole, and tadalafil. The complete list of medications
recommended at the time of diagnosis and discharge can be
found in Supplementary Tables S1 and S2.
Echocardiography
Pulmonary hypertension was mild in 42.6% (20/47), moderate
in 12.8% (6/47), and severe in 46.8% (22/47). Descriptive
echocardiographic criteria in Table 2 (all RD/H dogs) and Table 3
(RD/H excluding dogs with MMVD ACVIM Stage B2); in dogs that
exhibited mixed MSPAFP, the higher profile was selected for
categorization. For all dogs with PH due to RD/H, subjective right
heart enlargement was present in 43.5% (n = 20/46) where it was
assessed; 14 of these dogs had severe PH. Septal flattening was
Fig. 1. Flowchart illustrating features of included dogs as well as the number of
excluded dogs and the reason for exclusion. During the study period, a total of 507
dogs had echocardiography performed. Dogs with increased tricuspid regurgitation
flow velocity secondary to causes other than pulmonary hypertension (one double
chambered right ventricle; one pulmonic stenosis)a
were excluded. Dogs with
pulmonary hypertension were categorized according to main cause, in a similar
manner to the human classification scheme (Simonneau et al., 2013); dogs other
than those in with pulmonary hypertension due to respiratory disease and/or
hypoxia were excluded leaving 47 dogs with pulmonary hypertension due to
respiratory disease/hypoxia. Purebred breeds with pulmonary hypertension
attributable to respiratory disease and/or hypoxia included Yorkshire terrier
(n = 6), Pomeranian (n = 4), Shih tzu (n = 4), Miniature Dachshund (n = 4), West
Highland white terrier (n = 4), Miniature poodle (n = 3), Chihuahua (n = 2), Miniature
Schnauzer (n = 2), Toy Poodle (n = 2), and one each of the following American cocker
spaniel, Beagle, Brussels Griffon, Cairn terrier, Cavalier King Charles spaniel, English
bulldog, Italian greyhound, Japanese chin, Papillion, Pug, Shetland sheepdog,
Miniature pinscher and Soft-coated wheaten terrier.b
Dogs in Group 3 with
degenerative mitral valve disease ACVIM Stage B2 (Keene et al., 2019) were
excluded (n = 8),c
leaving 39 dogs in the survival analysis.
J.A. Jaffey et al. / The Veterinary Journal 251 (2019) 105347 3
4. assessed in 31; of the nine dogs with septal flattening, eight had
severe PH. The RPAD index was measured in 26 dogs: 11/12 dogs
(91.7%) with severe PH had RPAD index 29.5%, and 9/12 had RPAD
index 10%. The PT:Ao ratio was obtained in 33 dogs; of the 18 dogs
with PT:Ao 0.98 13 (72.2%) had severe PH.
Other imaging
Thoracicradiographswereperformedin28dogs(Supplementary
document D1 part D). The most common abnormalities were
cardiomegaly (n = 20), abnormal pulmonary parenchyma (n = 20),
abnormal pulmonary vasculature (n = 10), and tracheal collapse (n
= 10). Fourteen dogs had respiratory fluoroscopy. Upper airways
could not be evaluated in one dog. Dynamic nasopharyngeal
collapse present in 2/13 dogs (mild and moderate in one each). An
elongated soft palate was present in 6/13 dogs (overlapping in four
and entrapping the epiglottis in two). Tracheal collapse was
intrathoracic (n = 7; grade 3 in five dogs; grade 2 and grade 4 in
one dog each), intra-and extra-thoracic (n = 1) or extrathoracic (n
= 1). Five dogs had no tracheal collapse. Tracheal collapse occurred
onlyduring cough (n = 5), with bothcough and breathing (n = 2), and
only during breathing (n = 2). Dynamic MSB collapse was noted in
tendogs(with coughalone in five, both cough/breathing in four, and
breathing alone in one), and lobar collapse or both MSB and lobar
collapse in one dog each. Lung lobe herniation was noted in eight
dogs, tracheal kinking or bowing at the thoracic inlet in nine dogs,
and hiatal hernia in one dog. Videofluoroscopic swallow studies
were performed in four dogs. Two dogs had no abnormalities
identified during oral, pharyngeal, or esophageal phases of
deglutition. One dog each had mild proximal esophageal hypo-
motility with kibble only and moderate gastroesophageal reflux.
Nineteen dogs had thoracic CT, 16 with paired inspiratory and
expiratory series. Fifteen dogs had single phase CTangiography and
four had triphasic CT angiography. Each dog had multiple lesions
on CT with illustrative examples in Figs. 2–5. Airway collapse,
diagnosed or highlighted on expiratory series, was common with
mainstem bronchial (MSB) collapse in 15 dogs, bronchomalacia in
11 dogs, and tracheal collapse in nine dogs. Bronchiectasis affected
the medium (n = 5) and large (n = 4) airways with traction
bronchiectasis in two dogs. Bronchiolectasis with (n = 13) or
without (n = 3) architectural distortion was common. Parenchymal
lesions were present in each of the seven lobes in all dogs (and by
definition, bilateral); 14 dogs had asymmetric lesions. On
transverse images, only one dog had sparing of the upper region;
all 19 dogs had some lesions in the mid and lower zones. Moving
exterior to interior, dogs had involvement in zone 1 (n = 3), zone 2
(n = 17) and zone 3 (n = 19). A mosaic attenuation pattern was
present in 13 dogs. Of dogs with increased attenuation, GGO (n
= 13), consolidation (n = 13) and attenuation greater than soft tissue
(n = 1) were noted. Of dogs with decreased attenuation, air
trapping occurred in three dogs, and hypoperfusion, a solitary
honeycomb cyst or emphysema in one dog each. Nodules were
interstitial (n = 14), airspace (n = 4) and density greater than soft
tissue (n = 1). Types of linear patterns included subpleural
interstitial thickening (n = 14), peribronchovascular interstitial
thickening (n = 12), parenchymal bands (n = 9), reticular pattern
(n = 7) and honeycomb pattern (n = 4). Anatomic localization of
lesions were parenchymal (n = 17) subpleural and bronchovascular
(n = 15 each), random (n = 3) and pleural (n = 1). Two dogs had hilar
lymphadenopathy. Evidence of a mixed obstructive and restrictive
disorder was noted in 12 dogs with a sole restrictive or obstructive
disorder identified in four and three dogs, respectively. Only one
dog with bronchiectasis had concurrent air trapping and was
classified as obstructive; all other dogs with bronchiectasis lacked
air trapping on expiratory series.
Tracheobronchoscopy
Seventeen dogs had tracheobronchoscopic examination (Sup-
plementary Fig. 1), with videos (n = 12) or reports (n = 5) available
Table 2
Descriptive echocardiographic criteria for all dogs with pulmonary hypertension attributable to respiratory disease and/or hypoxia, including breakdown of pulmonary
hypertension severity (when applicable), median, interquartile range, and total range.
Echo criteria Number of dogs with available parameter Dogs with PH Median Interquartile range Total range
Mild Moderate Severe
TRFV 43 23 11 9 3.5 m/s 3.17–4.08 m/s 2.67–5.37 m/s
sPAP 43 23 11 9 48.9 mmHg 40.1–66.4 mmHg 28.5–115.3 mmHg
PIPV 16 14 2.69 m/s 2.46–3.08 m/s 1.21–3.4 m/s
MSPAFP 40 10 13 18 – – –
RPAD index 26 6 20 20.5% 7.6–27.5% 1.16–43.24%
PT:Ao 33 18 1.0 0.86–1.07 0.51–1.17
Echo, echocardiography; PT:Ao, pulmonary trunk artery to aortic root ratio; MSPAFP, mid-systolic pulmonary arterial flow profile; PH, pulmonary hypertension; PIPV,
pulmonic insufficiency peak velocity; RPAD, right pulmonary artery distensibility; sPAP, systolic pulmonary arterial pressure; TRFV, tricuspid regurgitation flow velocity.
Table 3
Descriptive echocardiographic criteria for dogs with pulmonary hypertension attributable to respiratory disease and/or hypoxia excluding dogs with myxomatous mitral
valve disease ACVIM Stage B2, including breakdown of pulmonary hypertension severity (when applicable), median, interquartile range, and total range.
Echo criteria Number of dogs with
available parameter
Dogs with PH Median Interquartile range Total range
Mild Moderate Severe
TRFV 37 20 9 8 3.5 m/s 3.17–5.19 m/s 2.67–5.37 m/s
sPAP 37 20 9 8 48.8 mmHg 40.3–70.2 mmHg 28.5–115.3 mmHg
PIPV 15 14 2.66 m/s 2.43–3.07 m/s 1.21–3.4 m/s
MSPAFP 34 6 11 17 – – –
RPAD index 19 4 15 8.88% 7.0–26.4% 1.16–43.24%
PT:Ao 26 14 1.01 0.86–1.08 0.51–1.17
ACVIM, American College of Veterinary Internal Medicine; Echo, echocardiography; m, meter; mmHg, millimeter of mercury; PT:Ao, pulmonary trunk to aortic root ratio;
MSPAFP, mid-systolic pulmonary arterial flow profile; PH, pulmonary hypertension; PIPV, pulmonic insufficiency peak velocity; RPAD, right pulmonary artery distensibility;
sPAP, systolic pulmonary arterial pressure; TRFV, tricuspid regurgitation flow velocity.
4 J.A. Jaffey et al. / The Veterinary Journal 251 (2019) 105347
5. for review. The most common tracheobronchial abnormalities
included diffuse bronchomalacia (n = 15), tracheal collapse (n = 12),
mainstem bronchial collapse (n = 11), and diffuse bronchiectasis (n
= 10).
Bronchoalveolar fluid cytology and bacterial culture
BALF was collected in 17 dogs; total cell count was unavailable
in four dogs because of flocculant fluid. The median total cell count
in 13 dogs was 316 cells/mL (Q1, Q3, range; 145, 548, 20–1170 cells/
mL). Differential cell count results were available for 12 dogs;
cytologic descriptive results were available for other dogs. The
median macrophage, neutrophil, eosinophil, and lymphocyte
percentages were 77% (36, 83, 23–95%), 15% (8, 47, 2–74%), 0%
(0, 3, 0–16%), and 7% (3, 11, 1–35%), respectively. Two dogs had
bacteria within neutrophils, and Pneumocystis carinii was seen in
one dog. Aerobic and anaerobic bacterial culture was performed in
16 dogs; 1 bacterial isolates were identified in four dogs,
including two dogs with intracellular bacteria identified on
cytology. In two dogs each, Enterobacter cloacae and Stenotropho-
monas maltophila were cultured, with Pseudomonas putida,
Brevundimonas diminuta, Streptococcus spp. (alpha hemolytic),
Acinetobacter spp., Enterococcus hirae, and Escherichia coli cultured
in one dog each.
Lung histopathology
Nine dogs had 1 lung lobes submitted for histopathologic
evaluation shortly after death. Eight of nine dogs had multiple
pathologies identified. Final airway diagnoses included bronchial
cartilage degeneration consistent with bronchomalacia (n = 5);
constrictive (n = 4) or polypoid (n = 1) bronchiolitis obliterans, and
chronic bronchitis (n = 3). Final parenchymal diagnoses included
pulmonary fibrosis (n = 4), emphysema (n = 1), developmental lung
disease (n = 1), pulmonary hemorrhage (n = 1) and aspiration
pneumonia (n = 1). All dogs had widespread pulmonary arteriolar
Fig. 2. Paired inspiratory (A) and expiratory (B) breath-hold CT transverse images of a 13-year-old, female, spayed, Brussels Griffon dog. (A) Several ill-defined areas of ground
glass opacity are seen in the left caudal, right caudal and right middle lung lobes (white arrows). Focal consolidation is identified involving the cranioventral aspect of the right
caudal lung lobe (asterisk). The volume of the right lung is overall smaller than the left. (B) At exhalation, the low attenuation of the caudal part of the left cranial lung lobe is
accentuated in comparison to the adjacent left caudal lung lobe (white arrows with black outline). Bronchi ventilating the right caudal lung lobe, RB4 (right caudal lobe
bronchus) and RB4V1 (the first ventral segmental bronchus branching out from the right caudal lobar bronchus), are markedly collapsed during exhalation (black arrows).
Fig. 3. Inspiratory transverse CT images demonstrating airway lesions in a 13-year-old, male, castrated, soft-coated wheaten terrier. (A) There is marked dilation of medium
and small airways (bronchiectasis) involving the cranial part of the left cranial lung lobe and ventral aspect of the right cranial lung lobe (white arrows). Also present is
bronchiolectasis (a few dilated bronchioles) without associated architectural distortion identified at the periphery of the right cranial lung lobe (black arrowheads). (B) There
is bronchiectasis of LB1V1 (ventral segmental bronchus branching out from the left cranial lobar bronchus; double headed arrow) extending to the dependent portion of the
caudal part of the left cranial lung lobe. The dilated bronchus is surrounded by thickened small and medium-sized bronchi and linear opacities (area ventral to the arrowhead).
The entire right middle lung lobe is characterized by cylindrical to varicose dilation of all airways (lobar, segmental, sub-segmental, bronchioles) with loss of normal
parenchyma and reduction of overall lung volume (white thick arrows).
J.A. Jaffey et al. / The Veterinary Journal 251 (2019) 105347 5
6. smooth muscle hypertrophy/hyperplasia characterized as severe
(n = 2), moderate to severe (n = 2), moderate (n = 2), mild to
moderate (n = 2), and mild (n = 1).
Obstructive versus restrictive phenotype
Using all clinical and diagnostic information, the most common
RD/H phenotype was OALD (Table 4). Eighty-three percent (39/47)
of dogs had OALD either as a singular pathology (51%; 24/47) or
combined OALD/RLD (31.9%; 15/47). Nineteen percent (9/47) of
dogs had RLD alone.
Survival analysis
Of dogs with RD/H, 17% (8/47) were excluded because of
concurrent MMVD stage B2 leaving 39 dogs in survival analyses,
all with available follow-up (Fig. 1). Fifty-one percent (20/39) of
dogs were alive at the study end. Of 19 non-survivors, 63% (12/19)
were euthanized because of complications related to RD/H (i.e.
decreased quality of life and/or respiratory distress), 32% (6/19)
died suddenly, and 5% (1/19) were euthanized for non-respiratory
reasons. The median follow-up time was 118 days (Q1, Q3, range; 3,
236, 1–418 days). Median survival time was 276 days (SE, 95% CI;
216, 0–699; Fig.6A).
Thirty-seven dogs were included in the ROC curve investigating
estimated sPAP as a non-survival marker. Two dogs were excluded:
one without a measurable tricuspid regurgitation flow velocity
(TRFV) to estimate sPAP and one euthanized for non-respiratory
reasons. The area under the ROC curve for estimated sPAP in
relation to non-survival was 0.75 (95% CI, 0.58–0.91). The optimal
cutoff was 47 mmHg, with greater increases in estimated sPAP
consistent with non-survival. Using this cutoff, a sensitivity of 0.78
(95% CI, 0.52–0.94) and a specificity of 0.63 (95% CI, 0.38–0.84) for
detection of non-survival was achieved (Fig.7; Supplementary
Table S3).
Variables associated with survival time at the 10% level (P
0.10) in univariable cox regression analyses included estimated
sPAP (continuous variable), estimated sPAP 47 mmHg cutoff, and
PDE5 inhibitor treatment (Table 5). When these variables were
entered into the multivariable model, only PDE5 inhibitor
treatment remained significant (P = 0.02; Table 6). At any time-
point in the follow-up, dogs administered a PDE5 inhibitor were
four times more likely to survive versus dogs not treated with a
PDE5 inhibitor. Fifty-nine percent (23/39) of dogs were treated
with tadalafil (n = 12) or sildenafil (n = 11). The median dose of
tadalafil and sildenafil used was 2.0 mg/kg per os once every 24 h
(Q1, Q3, range; 1.9, 2.0, 0.9–2.0 mg/kg) and 0.5 mg/kg per os once
every 8 h (0.5, 1.1, 0.5–3.3 mg/kg), respectively. There was not a
significant association between PDE5 inhibitor treatment (yes/no)
and severity of estimated sPAP (47 mmHg or 47 mmHg;
P = 0.12).
To further explore the effect of estimated sPAP on survival, we
compared the Kaplan–Meier survival of dogs by dividing the
population into two comparative cohorts based on the estimated
sPAP cutoff 47 mmHg (i.e., or 47 mmHg). The survival time of
dogs with an estimated sPAP 47 mmHg (n = 21; 9.0 days; 95% CI,
0–85.3 days) was significantly shorter than dogs with an estimated
sPAP of 47 mmHg (n = 16; P = 0.03; Fig.6b). The median survival
time for dogs with an estimated sPAP of 47 mmHg could not be
calculated because more than 50% of the dogs were alive at the end
of the study period.
Fig. 4. In a 10-year-old, male, castrated, Yorkshire terrier there is a large (16 mm
height x10 mm width x27 mm length), irregularly-marginated, soft tissue (47
Hounsfield units) nodule located along the costal pleural surface of the left caudal
lung lobe (*). Bronchovascular thickening with adjacent ground-glass opacity is
prominent in the accessory lung lobe (white arrows).
Fig. 5. Pre- and post-contrast CT images from a 15-year-old, female, spayed, Yorkshire terrier. (a) Using a lung window, the entire lung parenchyma in this transverse image is
increased in attenuation. In addition, marked ill-defined ground-glass opacity are seen (arrowheads) creating a mosaic pattern as well as few areas of consolidation (asterisk).
Several small, dilated bronchioles can also be identified (white thick arrows). An irregularly-marginated, ground-glass opacity nodule is also noted (black arrow). (B) Using a
soft-tissue window, a post-contrast inspiratory CT transverse image acquired during the arterial phase allows measurement of the pulmonary trunk and descending thoracic
aorta. The pulmonary trunk (double headed arrow) is enlarged in comparison to the descending thoracic aorta (dotted lines) resulting in an increased ratio of 2.1, supportive of
pulmonary hypertension.
6 J.A. Jaffey et al. / The Veterinary Journal 251 (2019) 105347
7. Discussion
Dogs with RD/H-associated PH had chronic large airway
obstructive disorders (tracheal and mainstem bronchial col-
lapse, bronchomalacia, brachycephalic obstructive airway syn-
drome), bronchiectasis, bronchiolar disease, emphysema,
pulmonary fibrosis, neoplasia and other parenchymal disorders.
Most (81%) dogs in this study with PH due to RD/H had OALD
rather than RLD. This study confirmed that the magnitude of PH
is prognostic in dogs with RD/H. Utilization of estimated sPAP at
a cutoff of 47 mmHg was a fair predictor of non-survival in dogs
with RD/H in our study. Dogs with estimated sPAP 47 mmHg
compared to those 47 mmHg had significantly shorter survival
times. Lastly, when evaluating predictors of survival benefit, the
sole factor to improve likelihood of survival was PDE5
inhibition.
Fig. 6. Kaplan–Meier survival curve for dogs with pulmonary hypertension and respiratory disease and/or hypoxia (A; n = 39). Estimated survival based on non-survival in
two groups of dogs with pulmonary hypertension and respiratory disease/hypoxia divided by estimated systolic pulmonary arterial pressure cutoff of 47 mmHg (red line,
n = 21) or 47 mmHg (blue line; n = 16; B). Dogs were censored from analysis if they were still alive at follow-up or if non-survival was non-respiratory related, and are
represented by small black stars on the graph.
Table 4
Distribution and breed of the 47 dogs with respiratory disease and/or hypoxia and associated pulmonary hypertension by primary respiratory diagnosis as obstructive airway/
lung disease or restrictive lung disease and as definitive or suspected.
Obstructive airway/lung disease
Definitive n
(%)
Suspected
n (%)
Breed
Tracheal collapse 27 (57) 0 (0) YST (n = 6), Pomeranian (n = 3), Miniature Dachshund (n = 2), Miniature poodle (n = 2), MBD (n = 2), Brussels
Griffon, Miniature schnauzer, ACS, Japanese chin, CKCS, Chihuahua, Cairn terrier, Shih tzu, Papillion,
Miniature pinscher, Toy poodle, Shetland sheepdog
MSB collapse 24 (51) 0 (0) YST (n = 4), Miniature Dachshund (n = 3), Pomeranian (n = 2), MBD (n = 2) Brussels Griffon, Miniature
schnauzer, ACS, Japanese chin, CKCS, Italian greyhound, Chihuahua, Cairn terrier, Shih tzu, Papillion,
Miniature poodle, Miniature pinscher, Shetland sheepdog
Bronchomalacia 18 (38) 0 (0) Pomeranian (n = 2), Miniature Dachshund (n = 2), YST (n = 2), MBD (n = 2), Brussels Griffon, Miniature
schnauzer, CKCS, Shih tzu, Papillon, Toy poodle, SCWT, WHWT, Pug, Shetland sheepdog
Bronchiectasis 9 (19) 0 (0) Miniature Dachshund (n = 2), Miniature schnauzer, CKCS, Pomeranian, Shih tzu, YST, MBD, SCWT
Bronchiolar disease 4 (10) 0 (0) Miniature poodle, Pomeranian, shih tzu, pug
Emphysema 1 (2) 0 (0) Shih tzu
BOAS 1 (2) 0 (0) English bulldog
Restrictive lung disease
Definitive
(%)
Suspected
(%)
Pulmonary fibrosis 4 (8) 10 (21) WHWT (n = 4), YST (n = 2), Brussels Griffon, Chihuahua, Miniature Dachshund, MBD, Pomeranian, Papillon,
Toy poodle, Pug
Pulmonary neoplasia 2 (4) 0 (0) Italian greyhound, Miniature schnauzer
ARRS 0 (0) 4 (8) Miniature Dachshund (n = 2), SCWT, Miniature pinscher
Uncharacterized parenchymal
disease
0 (0) 5 (10) MBD (n = 2), Beagle, Miniature poodle, Miniature Dachshund
Pneumocystis pneumonia 1 (2) 0 (0) Shih tzu
MBD, Mixed-breed dog; SCWT, Soft coated wheaten terrier; WHWT, West Highland white terrier; YST, Yorkshire terrier; CKCS, Cavalier King Charles spaniel; ACS, American
cocker spaniel; MSB, mainstem bronchial collapse; BOAS, brachycephalic airway syndrome; ARRS, aspiration-related respiratory syndrome.
J.A. Jaffey et al. / The Veterinary Journal 251 (2019) 105347 7
8. Identification of RD/H in dogs with PH has prognostic value. The
median survival time of study dogs with RD/H-associated PH (276
days) is substantially shorter than that reported for dogs with
MMVD-associated PH (576 days; Borgarelli et al., 2015). This
difference in survival time substantiates the need for thorough
respiratory diagnostics (e.g., thoracic radiography/CT, fluoroscopy,
tracheobronchoscopy, BAL, and possibly histopathology if clinical-
ly warranted) in dogs with PH that have had MMVD excluded.
These diagnostics will help determine if RD/H is the cause for PH,
which will provide valuable prognostic information for dog
owners. In addition, results from respiratory diagnostics could
also identify RD/H phenotypes that would benefit from specific
interventional therapies potentially improving quality of life and
survival. Future prospective studies screening dogs with varying
severities and phenotypes of RD/H are needed to better understand
the role of PH in these dogs. The difference in survival time
between dogs with RD/H-associated PH in this study compared to
that reported in dogs with MMVD-PH is interesting (Borgarelli
et al., 2015). There are several potential explanations for this. It is
possible that the underlying RD/H pathology resulting in PH
progresses and impacts quality of life faster than MMVD
independent of the severity of PH. Alternatively, the severity of
PH in dogs with RD/H could be worse than that associated with
MMVD impacting morbidity and survival. Lastly, it is possible this
study was subjected to case selection bias because of its
retrospective design. Clinicians could have been more inclined
to screen dogs for PH in more severe cases of RD/H resulting in a
skewed population of more debilitated dogs.
In contrast to the previous literature in dogs with RD/H that
suggest RLD (e.g., pulmonary fibrosis (Johnson et al.,1999; Kellihan
Fig. 7. Receiver operating characteristic (ROC) curve and dot plot comparing diagnostic sensitivity and 1-specificity of estimated systolic pulmonary arterial pulmonary
pressure (sPAP) for determining non-survival in dogs with respiratory disease/hypoxia associated pulmonary hypertension. (A) The diagonal red line represents the reference
line. (B) The horizontal red line represents the optimal cutoff of estimated sPAP of 47 mmHg.
Table 5
Univariable cox regression analysis of potential variables associated with survival in dogs with pulmonary hypertension and respiratory disease and/or hypoxia.
Variable Hazard ratio 95% CI P
Age 0.88 0.76–1.03 0.13
Estimated sPAP 0.99 0.97–1.01 0.10
PDE5 inhibitor treatment (yes/no) 2.22 0.86–5.56 0.09
Estimated sPAP cutoff 47 mmHg ( or 47 mmHg) 3.13 1.03–10.00 0.04
Pulmonary hypertension severity
Severe (yes/no) 0.88 0.34–2.27 0.80
Moderate (yes/no) 0.55 0.13–2.40 0.43
Mild (yes/no) 0.70 0.25–2.00 0.50
Lung disease phenotype
Obstructive lung disease (yes/no) 2.00 0.73–5.26 0.18
Restrictive lung disease (yes/no) 0.68 0.23–2.10 0.51
Mixed lung disease (yes/no) 1.54 0.60–3.85 0.37
CI, confidence interval; sPAP, systolic pulmonary arterial pressure; PDE5, phosphodiesterase 5.
Table 6
Multivariable cox proportional hazards regression analysis of variables significantly associated with survival (i.e. P 0.10) in univariable analyses in dogs with pulmonary
hypertension and respiratory disease and/or hypoxia.
Variable Hazard ratio 95% CI P
Estimated sPAP 0.98 0.95–1.01 0.30
PDE5 inhibitor treatment (yes/no) 4.00 1.19–12.50 0.02
Estimated sPAP cutoff 47 mmHg ( or 47 mmHg) 2.56 0.57–11.11 0.22
CI, confidence interval; sPAP, systolic pulmonary arterial pressure; PDE5, phosphodiesterase 5.
8 J.A. Jaffey et al. / The Veterinary Journal 251 (2019) 105347
9. et al., 2015; Serres et al., 2007; Vezzosi et al., 2018a), uncharac-
terized parenchymal disease (Johnson et al., 1999; Kellihan et al.,
2011; Koster and Kirberger, 2016; Morita et al., 2018), and
infectious interstitial pneumonias (Toom et al., 2016; Okine
et al., 2018; Schiborra et al., 2018) as predominant etiologies of
PH, the current study documented OALD as the dominant
phenotype alone or with RLD. In humans, chronic obstructive
pulmonary disease (COPD) and obstructive sleep apnea represent
the most common RD/H phenotype with a prevalence ranging
from 38 to 62% (Hurdman et al., 2012; Brewis et al., 2015; Chebib
et al., 2018). Worldwide, COPD is the most common non-infectious
lung disease with PH in up to 70% of people (Lopez et al., 2006;
Chaouat et al., 2008; Chatila et al., 2008; Falk et al., 2008). While
the prevalence of PH in dogs with obstructive airway disease (not
the same disease as COPD) is unknown, a study of dogs with
bronchomalacia found a significant association with the presence
of PH (Bottero et al., 2013). Obstructive disorders previously
associated with canine PH include tracheal or mainstem bronchial
collapse (Kellum and Stepien, 2007; Serres et al., 2007; Tai and
Huang, 2013) and brachycephalic obstructive airway syndrome
(Tai and Huang, 2013). To our knowledge, bronchiectasis has not
been reported as the primary disease leading to PH in dogs, as in
people (Ocal et al., 2016). In our study, one dog with diffuse
bronchiectasis had air trapping on the expiratory CT diagnostic for
obstructive disease. Narrowing of the small airways (bronchioles)
by inflammation or fibrosis is considered an obstructive lung
disorder; bronchiolar disease was documented in five dogs in the
current study. Bronchiolitis obliterans, especially in hematopoietic
stem cell transplant recipients in people, is associated with PH
(Pate et al., 2016). Emphysema is another obstructive disorder
documented in one dog in this study.
A univariate cox regression analysis indicated presence of
estimated sPAP 47 mmHg was predictive of survival in dogs with
RD/H but lost significance when incorporated into a multivariable
analysis that included estimated sPAP (continuous variable) and
PDE5 inhibitor treatment. Despite lack of significance in the
multivariable analysis, we investigated how an estimated sPAP
cutoff of 47 mmHg impacted survival independently via ROC-
curve and Kaplan–Meier analyses because PAP is the most
clinically applicable variable utilized in dogs with PH. As expected,
dogs with estimated sPAP 47 mmHg versus 47 mmHg had
significantly shorter survival times. Utilization of estimated sPAP at
a cutoff of 47 mmHg was a fair predictor of non-survival with a
sensitivity and specificity of 0.78 and 0.63, respectively. A cutoff of
95 mmHg yielded an excellent specificity (0.95) but poor
sensitivity (0.17) for predicting non-survival. Collectively, our
results indicate that PH in dogs with RD/H, like people, conveys a
worse prognosis with outcomes correlating with PH severity
(Finlay et al., 1983; Arcasoy et al., 2001; Nadrous et al., 2005;
Baughman et al., 2010; Seeger et al., 2013). Future prospective
studies are necessary to investigate if PH impacts survival
differently within various respiratory diseases in dogs.
A multivariable analysis indicated that PDE5 inhibitor admin-
istration was the sole independent variable predictive of survival in
dogs in our study. Compared to untreated dogs, dogs treated with a
PDE5 inhibitor were four times more likely to survive. Currently,
there is no consensus on use of vasodilatory drugs in people with
PH due to RD/H (Galie et al., 2016). Several small studies have
demonstrated mixed results with regards to the clinical benefit of
PDE5 inhibition in people with RD/H but is beyond the scope of this
discussion. Hypoxemia in people with PH due to RD/H is treated
with long-term oxygen therapy irrespective of underlying etiology
(Barbera and Blanco, 2015). However, long-term oxygen therapy is
impractical in dogs highlighting the importance that PDE5
inhibition could improve outcome in dogs with advanced RD/H
and PH. Study results provide the prerequisite rationale for future
clinical trials to investigate the clinical utility of PDE5 inhibition in
dogs with PH due to RD/H.
Echocardiographic diagnosis of PH can be difficult in the
absence of adequate TR and screening patients for this study
utilized other echocardiographic indices including subjective right
heart enlargement, septal flattening, RPAD index 35.4%, and PT:
Ao 0.98. Although not the focus of the study, it is worthwhile
noting that in patients with severe PH, nearly all dogs had RPAD
index 29.5% (majority had RPAD index 10%) and PT:Ao 0.98;
additionally, septal flattening was nearly exclusively present in
conjunction with severe PH. Further studies helping to elucidate
the ideal combination of these echocardiographic findings to
reliably categorize severity of PH in the absence of TR are
warranted.
There were several limitations of this retrospective study.
Tracheal collapse could have been underestimated as thoracic CT
generally only included a portion of the cervical trachea and the
endotracheal tube could have obscured the presence of collapse.
Using echocardiography to estimate sPAP is influenced by operator
skill and patient compliance (Denton et al., 1997; Fisher et al.,
2009). Both under- and overestimation of PAP is noted when using
echocardiography as a surrogate for right heart catheterization, the
criterion standard test (Soydan et al., 2015). The latter is invasive
and contraindicated in dogs and people with advanced RD/H
(Klinger, 2016). Additionally, underestimation of TRFV due to
inadequate signal may have mis-categorized PH severity; dogs
with poor quality signals were still enrolled in this study, reflecting
real-world evaluation of patients in respiratory distress with less-
than-ideal imaging conditions. Another study limitation was co-
morbid cardiac disease. Survival analyses excluded dogs with
MMVD stage B2 in dogs with primary RD/H. Without right heart
catheterizations, contributions of left-sided heart disease to
outcome could not be determined. A small number of dogs in
this study had positive BALF bacterial cultures (n = 4) and one dog
was diagnosed with pneumocystis pneumonia at the time of PH
diagnosis. Four of these five dogs (one dog was lost to follow-up)
were alive at the end of the study period. While it was not seen in
this study, it is possible the presence of respiratory pathogens
could influence survival in dogs with RD/H and PH. In addition, this
study was not designed to adequately assess the impact of
antimicrobial therapy on the severity of PH in dogs with
respiratory pathogens. It is possible that antimicrobial interven-
tion could improve or resolve PH in dogs with RD/H and PH. Future
studies are needed to explore the long-term role respiratory
pathogens and antimicrobial intervention have on dogs with RD/H
and PH. A final limitation was the study was not designed to
evaluate the overall prevalence of PH within dogs with RD/H.
Conclusions
This study provides a comprehensive description of clinical
features, diagnostic evaluations and prognostic variables in dogs
with RD/H-associated PH. In dogs, PH was most common with
obstructive disorders, some previously described and others
(bronchiectasis, bronchiolar disorders and emphysema) newly
documented. Similar to people with RD/H-associated PH, in-
creased severity of PH is predictive of non-survival in dogs.
Importantly, PDE5 inhibition provided a survival benefit. Future
clinical trials with large numbers of dogs within disease
subcategories of RD/H are needed to more clearly define clinical
recommendations.
Conflict of interest statement
The authors have no financial or personal relationships that
could inappropriately influence of bias the content of the paper.
J.A. Jaffey et al. / The Veterinary Journal 251 (2019) 105347 9
10. Acknowledgement
We thank Kate Anderson for her editorial review.
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.tvjl.2019.105347.
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