*Correspondence to: Nakamura, K.: email@example.com
©2018 The Japanese Society of Veterinary Science
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives (by-nc-nd)
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Pulmonary hypertension due to unclassied
interstitial lung disease in a Pembroke
Tomoya MORITA1), Kensuke NAKAMURA2)*, Tatsuyuki OSUGA1),
Atsushi KOBAYASHI3), Osamu ICHII4), Akira YABUKI5) and Mitsuyoshi TAKIGUCHI1)
1)Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Sciences, Graduate School of
Veterinary Medicine, Hokkaido University, N18 W9, Sapporo, Hokkaido 060-0818, Japan
2)Organization for promotion of Tenure Track, University of Miyazaki, 1-1 Gakuenkibanadai-nishi,
Miyazaki 889-2192, Japan
3)Laboratory of Comparative Pathology, Department of Veterinary Clinical Sciences,
Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Sapporo, Hokkaido 060-0818, Japan
4)Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine,
Hokkaido University, N18 W9, Sapporo, Hokkaido 060-0818, Japan
5)Laboratory of Veterinary Clinical Pathology, Joint Faculty of Veterinary Medicine, Kagoshima University,
1-21-24 Korimoto, Kagoshima 890-0065, Japan
ABSTRACT. A 12 year-old intact male Pembroke Welsh corgi weighing 10.8 kg was presented
for evaluation of a 3-month history of dyspnea, and a 1-week history of exercise intolerance
and anorexia. Severe hypoxemia (PaO2 56 mmHg), diuse lung alveolar inltration, and severe
pulmonary hypertension (PH) (tricuspid regurgitation pressure gradient was 81 mmHg) were
identied. A tentative diagnosis of severe PH due to lung disease or pulmonary thromboembolism
was made and treated intensively. After 5 days of hospitalization, the dog died despite oxygen
supplementation and anticoagulant therapy. This dog was diagnosed as unclassied interstitial
lung disease based on histopathological ndings.
KEY WORDS: canine, echocardiography, respiratory disease
Pulmonary hypertension (PH) is caused by several diseases and conditions, such as lung disease and/or hypoxia, left-sided
heart disease, and pulmonary thromboembolism (PTE) . PH due to lung disease and/or hypoxia is the second most common
in dogs [18, 29]. While many lung diseases have been reported to induce PH, interstitial lung disease (ILD) except for interstitial
pulmonary brosis (IPF) in West Highland Terriers, are uncommon in dogs [4, 7, 14, 15]. The authors report a case of severe PH
due to unclassied ILD in Pembroke Welsh corgi.
A 12 year-old intact male Pembroke Welsh corgi weighing 10.8 kg was presented for evaluation of a 3-month history of
dyspnea, and a 1-week history of exercise intolerance and anorexia. Three months prior to referral, the dog was treated by oral
furosemide, benazepril, prednisone, and theophylline were administered by the referring veterinarian. This resulted in transient
relief of dyspnea.
On presentation to our institution, physical examination revealed tachypnea (66 breaths/min), dehydration, and mucous
membranes were slightly pale and dry. There were no abnormalities on heart and lung auscultation. Heart rate was 156 bpm, and
capillary rell time was within the normal limit. Pulse oximetry (Life Scope A, Nihon Kohden Corp., Tokyo, Japan) demonstrated
a SpO2 on room air of 77%. Systolic and diastolic blood pressure measurement with an oscillometric blood pressure measurement
unit (PetMAP graphic, Ramsey Medical Inc., Tampa, FL, U.S.A.) identied systemic hypertension (170/88 mmHg). Blood pressure
was not measured repeatedly.
The complete blood count was within the normal range. Signicant ndings from the serum biochemical prole included
severe azotemia (blood urea nitrogen, 120.8 mg/dl [reference range, 9.2–29.2 mg/dl]; creatinine, 4.8 mg/dl [reference range,
0.4–1.4 mg/dl]), hyperphosphatemia (14.2 mg/dl [reference range, 1.9–5.0 mg/dl]), hypercalcemia (13.9 mg/dl [reference range,
9.3–12.1 mg/dl]), mild hyperkalemia (5.1 mEq/l [reference range, 3.8–5.0 mEq/l]), a slight increase in alanine aminotransferase
(158 IU/l [reference range, 17–78 IU/l]), and a slight increase in aspartate alkaline phosphatase (612 IU/l [reference range,
47–254 IU/l]). C-reactive protein (0 mg/dl [reference range, <1.0 mg/dl]) was within the normal range. Arterial blood gas
Received: 4 January 2018
Accepted: 12 April 2018
Published online in J-STAGE:
23 April 2018
J. Vet. Med. Sci.
80(6): 939 –944, 2018
do i: 10.1292 /jvms .17- 0716
T. MORITA ET AL.
do i: 10.1292/ jvms.17- 0716
analysis revealed hypoxemia (PaO2, 56 mmHg [reference range, 80–110 mmHg]), hypercapnemia (PaCO2, 51 mmHg [reference
range, 40–45 mmHg]), high alveolar-arterial oxygen gradient (65 mmHg [reference range, <15 mmHg]), low HCO3− (11.9 mM
[reference range, 19–24 mM]), low base excess (−13.9 mM [reference range, −5–5 mM]), and high anion gap (23.1 mM [reference
range, 12–20 mM]) on room air, and mild metabolic acidosis (pH, 7.32 [reference range, 7.35–7.45]). Urinalysis demonstrated
isosthenuria (urine specic gravity, 1.013 [reference range, 1.015–1.030]) and proteinuria (urine protein creatinine ratio, 2.5
[reference range, ≤0.2]). On standard 6-lead electrocardiogram, sinus rhythm and heart rate were 106 bpm.
Two-view thoracic radiographs revealed enlargement of the main pulmonary artery in the dorso-ventral (DV) view, and
unstructured interstitial and alveolar lung patterns in all lung lobes in the DV and right lateral view (Fig. 1A and 1B). Two-view
abdominal radiographs showed right kidney enlargement and renal mineralization in both kidneys.
Transthoracic echocardiography demonstrated increased left ventricular (LV) wall thickness (Fig. 1C) and main pulmonary
artery dilation (main pulmonary artery to aorta ratio, 1.19 [reference range, <0.98 ]). The mild interventricular septal
attening at end-diastolic was observed form the right parasternal short axis view (Fig. 1C). The velocity of tricuspid regurgitation
(maximum velocity, 4.4 m/sec; pressure gradient, 81 mmHg) and pulmonary regurgitation (maximum velocity, 3.5 m/sec; pressure
gradient 53 mmHg) was high (Fig. 1D), and the right atrial pressure was estimated as 10 mmHg because right atrial dilation was
present without right-sided congestive heart failure . The systolic and mean pulmonary arterial pressure were estimated 91
Fig. 1. A-Dorsoventral thoracic radiograph showing unstructured interstitial and alveolar lung patterns in all lung lobes, especially right middle
lobe (black dashed line), and main pulmonary artery enlargement (black arrow). B-Right lateral thoracic radiograph showing unstructured
interstitial lung patterns in all lung lobes, especially caudal lobe (black dashed line). C-Transthoracic echocardiography recorded from the right
parasternal short axis view at the level of the papillary muscles. Left ventricular free wall and septum were thickened, and interventricular septum
was mildly attened at end-diastole (white arrows). D-Continuous-wave Doppler image of tricuspid regurgitation in the apical 4-chamber view.
PULMONARY HYPERTENSION BY LUNG DISEASE
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and 63 mmHg. These ndings were consistent with severe PH. Mild mitral regurgitation without left atrium enlargement (left
atrium to aorta ratio, 1.38 [reference range, 0.86–1.57 ]) was identied. Left ventricular diameter in diastole was 22.3 mm,
and normalized left ventricular diameter in diastole was 1.11 [reference range, 1.35–1.73 ]. The transmitral ow pattern was an
impaired relaxation pattern (E velocity, 0.60 m/sec; A velocity, 0.89 m/sec; E/A, 0.67). The echocardiographic indices of the right
ventricular (RV) function were impaired (RV Tei index derived from dual-pulsed wave Doppler, 1.36 [reference range, 0.23–0.31
]; RV longitudinal strain derived from speckle tracking echocardiography, −11.5% [reference range, −16.4– −21.6% ]).
Abdominal ultrasound revealed increased echogenicity in the renal cortex, and irregular cortical margin of both kidneys. A tentative
diagnosis was PH due to diffuse parenchymal lung disease, which is also described as interstitial lung disease (ILD) or pulmonary
thromboembolism and chronic kidney disease with proteinuria.
The dog was treated in the intensive care unit, and oxygen therapy was initiated. To replace the volume decit, lactated Ringer’s
solution was intravenously administered at an infusion rate of 3 ml/kg/hr. Low molecular heparin (150 IU/kg SC q 8 hr, Fragmin,
Kissei Pharmaceutical Corp., Tokyo, Japan) was administered to prevent intravenous blood clotting. Respiratory status and
azotemia mildly improved during hospitalization. However, on day 4 of hospitalization, the dog exhibited dyspnea and C-reactive
protein was elevated (5.0 mg/dl). Thoracic radiographs revealed a severe alveolar pattern in the caudal lobes (Fig. 2A). The next
day (on day 5 of hospitalization), a severe alveolar pattern in all lung lobes was evident on thoracic radiographs (Fig. 2B), and
the dog became apneic with cyanotic mucous membranes and entered full cardiac arrest, for which cardiopulmonary resuscitation
was initiated. Cardiopulmonary resuscitation was unsuccessful, and the body was submitted for necropsy examination. The plasma
D-dimer concentration on day 1 (0.80 µg/ml [reference range, <1.0 µg/ml]) was within the normal range, and antinuclear antibody
test on day 1 was negative.
On necropsy, the lungs were solid with multiple dark red mottled or white foci diffusely located in all lung lobes. Pulmonary
thrombus was not detected in any lung lobes. The LV and septum were markedly thickened, and LV cavity was decreased. The RV
free wall was mildly thickened. The mitral and tricuspid valve leaets were mildly thickened. The right kidney was moderately
enlarged, and there were multiple white foci in the outer layer of the medulla in both kidneys.
Histological examination of the lung was performed on the right middle lobe and left caudal lobe, and demonstrated diffuse
interstitial pneumonia, characterized by a moderately thickened alveolar wall with inltrations of lymphocytes and macrophages,
and brosis (Fig. 3A). There was diffuse hyperplasia of type II pneumocytes with microvesicular cytoplasmic change (Fig. 3B).
Lymphocytes, plasma cells, macrophages, and multinucleated giant cells inltrated moderately to severely into the alveolar space,
and there were also occasional foamy macrophages. There was no honeycombing, obliteration alveolar architecture, eosinophilic
inltration, or eosinophilic proteinaceous material in the alveolar space. No bacteria or fungi were observed in the lung. Multiple
dark red mottled foci were consistent with hemorrhages, and white foci were consistent with inammatory cell clumps. Pulmonary
arteriolar wall was thickened, and intravascular space were narrowed. There was no plexiform lesion. The LV wall and septum
were markedly thickened, but cardiomyocyte disarray was not evident.
Histological examination of the kidney revealed severe chronic tubulointerstitial nephritis characterized by inltration
of lymphocytes, plasma cells, and macrophages, as well as interstitial brosis. Furthermore, we noted moderate
membranoproliferative glomerulonephritis characterized by the diffuse thickening of the glomerular basement membrane, and
increase of mesangial cells and their matrixes. The present case showed weak granular IgG-positive reactions along subendothelial
Fig. 2. A-Right lateral thoracic radiograph on day 4 of hospitalization showing a severe alveolar pattern in the caudal lobe (black dashed line).
B-Right lateral thoracic radiograph on day 5 of hospitalization showing a more severe alveolar pattern in all lung lobes (black dashed line).
T. MORITA ET AL.
do i: 10.1292/ jvms.17- 0716
regions of the thickened glomerular basement membrane by
immunouorescent microscopic observation, but clear immune
complex deposition was not detected with transmission electron
microscopy. Thus, we were not able to determine whether the
membranoproliferative glomerulonephritis in the present case was
an immune complex-mediated disease or not. The reason for this
result may be that the immune complex was masked by therapy or
degraded by postmortem changes.
Based on these ndings, the present case was diagnosed as
The present case had severe PH concurrent with severe hypoxia
and lung lesions. PH is caused by several diseases and conditions,
such as lung disease or hypoxia, left-sided heart disease,
congenital cardiovascular shunts, pulmonary thromboembolism,
heartworm disease, and idiopathic causes . The present
case had only mild mitral regurgitation without left heart
enlargement and did not have congenital cardiovascular shunts,
but had thickened LV wall. Thickened LV wall can be caused by
hypertrophic cardiomyopathy, dehydration (pseudohypertrophy),
or systemic hypertension. Hypertrophic cardiomyopathy was ruled
out by histological examination. The present case was treated
with furosemide, and dehydration was suspected by physical
examination and echocardiography (LV underlling based on
small left ventricular diameter in diastole). However, LV wall
was certainly thickened on histological examination. Therefore,
the thickening of the LV wall may be due to hypertension rather
than dehydration. However, in the present case, since repeatedly
blood pressure measurement and fundic examination were not
performed, systemic hypertension could not be conrmed.
Although systemic hypertension can cause chronic LV diastolic
dysfunction and PH due to elevated LV lling pressure ,
the normal left atrial size and unelevated transmitral E velocity
indicated low probability of LV diastolic dysfunction in the
present case. In addition, pulmonary thromboembolism was ruled
out by the D-dimer concentration and histological examination.
Heartworm disease was also ruled out by histological examination.
Therefore, the present case was diagnosed as PH due to lung
disease or hypoxia. In dogs, lung disease or hypoxia have been
reported to be the second most common cause of PH, with an
incidence rate of approximately 13 to 50% in dogs with PH
[18, 29]. Many respiratory diseases, including pneumonia, tracheobronchial disease, tumors, and IPF have been reported to induce
PH [4, 7, 14, 15]. Although the present case exhibited severe pneumonia, infectious pneumonia was ruled out because the present
animal was well vaccinated and histological examination detected no bacteria or fungi. Therefore, the present case was diagnosed
as PH due to ILD.
ILD can be caused by inhaled chemical fumes, mineral bers, dusts, or allergens, drugs, as well as connective tissue disease, and
idiopathic, involving the interstitium in human and dogs [1, 27, 32]. In the present case, there were few possibilities of inhalation
of these materials or exposure to toxins and drugs. In dogs, only systemic lupus erythematosus has been reported as the connective
tissue disease causing ILD [5, 9]. The present dog had glomerulonephritis, but there was no other nding supporting the diagnosis
of systemic lupus erythematosus. Microscopic polyangiitis and Goodpasture’s syndrome that can cause severe inammation and
hemorrhage in both kidneys and lungs were also not suspected in the present case because of the lack of characteristic hemorrhagic
Several types of ILD, including IPF, bronchiolitis obliterans with organizing pneumonia (cryptogenic organizing pneumonia),
eosinophilic pneumonia, endogenous lipid pneumonia, and pulmonary alveolar proteinosis, have been previously reported in dogs
[6, 14, 24–26, 30]. In this case, the histopathological ndings were inconsistent with those previously reported for ILD. Therefore,
the present case was diagnosed as unclassied ILD. Indeed, in dogs, a denitive classication of ILD is currently difcult because
little is known about comprehensive clinical data in dogs with ILD, except for IPF, which is one of the most common ILD
[7, 14, 20]. Further studies are needed to clarify the histological criteria of ILD in dogs.
The incidence rate of PH due to ILD has not been claried in dogs. The prevalence of PH was 14% in human patients from a
heterogeneous group with ILD . Furthermore, the presence of PH was associated with greater mortality in patients with ILD
[2, 19]. The standard treatment for human patients with PH due to lung disease or hypoxia is long-term oxygen therapy, and PH-
Fig. 3. A-Microscopic image of the middle lobe (200 ×) show-
ing that the alveolar wall was moderately thickened with in-
ltration of lymphocytes and macrophages (arrowheads), and
brosis (arrows). H&E staining, bar=100 µm, B-Microscopic
image of the middle lobe (400 ×) showing diffuse hyperpla-
sia of type II pneumocytes with microvesicular cytoplasmic
changes (arrows). H&E staining, bar=50 µm.
PULMONARY HYPERTENSION BY LUNG DISEASE
do i: 10.1292/ jvms.17- 0716
specic therapy (e.g. sildenal) has not been recommended . However, there are some reports on the effects of sildenal on
survival and exercise capacity in human patients with severe PH due to lung disease or hypoxia [13, 31]. Furthermore, the previous
reports demonstrated the efcacy of sildenal in dogs with PH. Kellum et al. reported that sildenal treatment resulted in clinical
improvement in 22 dogs with PH due to several causes, including respiratory disease (n=11) . Bach et al.  and Kellihan et
al.  reported the efcacy of sildenal on amelioration of the clinical signs and the velocity of tricuspid regurgitation in 13 and
10 dogs (included 5 and 7 dogs with respiratory disease), respectively. Although the present case was not treated with PH-specic
therapy, it may be an effective treatment.
In conclusion, this report describes the comprehensive clinical data, including physiological data, diagnostic imaging ndings,
and histological ndings, of PH due to unclassied ILD in a dog. Further studies are needed to reveal the incidence rate and to
establish optimal therapy of PH due to ILD.
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