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Pulmonary hypertension due to unclassified interstitial lung disease in a Pembroke Welsh corgi


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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), diffuse lung alveolar infiltration, and severe pulmonary hypertension (tricuspid regurgitation pressure gradient was 81 mmHg) were identified. 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 unclassified interstitial lung disease based on histopathological findings.
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Internal Medicine
Pulmonary hypertension due to unclassied
interstitial lung disease in a Pembroke
Welsh corgi
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), diuse lung alveolar inltration, and severe
pulmonary hypertension (PH) (tricuspid regurgitation pressure gradient was 81 mmHg) were
identied. 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 unclassied 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) [16]. 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 unclassied 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 rell 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.) identied systemic hypertension (170/88 mmHg). Blood pressure
was not measured repeatedly.
The complete blood count was within the normal range. Signicant ndings from the serum biochemical prole 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
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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 specic 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 [29]]). 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 [12]. 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.
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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 [28]]) was identied. 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 [8]]. 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
[21]]; RV longitudinal strain derived from speckle tracking echocardiography, −11.5% [reference range, −16.4– −21.6% [22]]).
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 decit, 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 leaets 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 inltrations 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 inltrated moderately to severely into the alveolar space,
and there were also occasional foamy macrophages. There was no honeycombing, obliteration alveolar architecture, eosinophilic
inltration, 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 inammatory 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 inltration
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).
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regions of the thickened glomerular basement membrane by
immunouorescent 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
unclassied ILD.
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 [16]. 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 underlling 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 conrmed.
Although systemic hypertension can cause chronic LV diastolic
dysfunction and PH due to elevated LV lling pressure [23],
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 inammation and
hemorrhage in both kidneys and lungs were also not suspected in the present case because of the lack of characteristic hemorrhagic
lesions [11].
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 unclassied ILD. Indeed, in dogs, a denitive classication of ILD is currently difcult 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 claried in dogs. The prevalence of PH was 14% in human patients from a
heterogeneous group with ILD [2]. 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.
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specic therapy (e.g. sildenal) has not been recommended [10]. However, there are some reports on the effects of sildenal 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 efcacy of sildenal in dogs with PH. Kellum et al. reported that sildenal treatment resulted in clinical
improvement in 22 dogs with PH due to several causes, including respiratory disease (n=11) [18]. Bach et al. [3] and Kellihan et
al. [17] reported the efcacy of sildenal 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-specic
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 unclassied ILD in a dog. Further studies are needed to reveal the incidence rate and to
establish optimal therapy of PH due to ILD.
1. American Thoracic Society European Respiratory Society 2002. American Thoracic Society/European Respiratory Society International
Multidisciplinary Consensus Classication of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS),
and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June
2001. Am. J. Respir. Crit. Care Med. 165: 277–304. [Medline]
2. Andersen, C. U., Mellemkjær, S., Hilberg, O., Nielsen-Kudsk, J. E., Simonsen, U. and Bendstrup, E. 2012. Pulmonary hypertension in interstitial
lung disease: prevalence, prognosis and 6 min walk test. Respir. Med. 106: 875–882. [Medline] [CrossRef]
3. Bach, J. F., Rozanski, E. A., MacGregor, J., Betkowski, J. M. and Rush, J. E. 2006. Retrospective evaluation of sildenal citrate as a therapy for
pulmonary hypertension in dogs. J. Vet. Intern. Med. 20: 1132–1135. [Medline] [CrossRef]
4. Campbell, F. E. 2007. Cardiac effects of pulmonary disease. Vet. Clin. North Am. Small Anim. Pract. 37: 949–962, vii. [Medline] [CrossRef]
5. Choi, E., Shin, I., Youn, H. and Lee, C. 2004. Development of canine systemic lupus erythematosus model. J. Vet. Med. A Physiol. Pathol. Clin.
Med. 51: 375–383. [Medline] [CrossRef]
6. Clercx, C., Peeters, D., Snaps, F., Hansen, P., McEntee, K., Detilleux, J., Henroteaux, M. and Day, M. J. 2000. Eosinophilic bronchopneumopathy in
dogs. J. Vet. Intern. Med. 14: 282–291. [Medline] [CrossRef]
7. Corcoran, B. M., Cobb, M., Martin, M. W., Dukes-McEwan, J., French, A., Fuentes, V. L., Boswood, A. and Rhind, S. 1999. Chronic pulmonary
disease in West Highland white terriers. Vet. Rec. 144: 611–616. [Medline] [CrossRef]
8. Cornell, C. C., Kittleson, M. D., Della Torre, P., Häggström, J., Lombard, C. W., Pedersen, H. D., Vollmar, A. and Wey, A. 2004. Allometric scaling
of M-mode cardiac measurements in normal adult dogs. J. Vet. Intern. Med. 18: 311–321. [Medline] [CrossRef]
9. Fournel, C., Chabanne, L., Caux, C., Faure, J. R., Rigal, D., Magnol, J. P. and Monier, J. C. 1992. Canine systemic lupus erythematosus. I: A study
of 75 cases. Lupus 1: 133–139. [Medline] [CrossRef]
10. Galiè, N., Humbert, M., Vachiery, J. L., Gibbs, S., Lang, I., Torbicki, A., Simonneau, G., Peacock, A., Vonk Noordegraaf, A., Beghetti, M.,
Ghofrani, A., Gomez Sanchez, M. A., Hansmann, G., Klepetko, W., Lancellotti, P., Matucci, M., McDonagh, T., Pierard, L. A., Trindade, P. T.,
Zompatori, M., Hoeper M., ESC Scientic Document Group 2016. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension. Eur. Heart J. 37: 67–119. [Medline] [CrossRef]
11. Gibelin, A., Maldini, C. and Mahr, A. 2011. Epidemiology and etiology of wegener granulomatosis, microscopic polyangiitis, churg-strauss
syndrome and goodpasture syndrome: vasculitides with frequent lung involvement. Semin. Respir. Crit. Care Med. 32: 264–273. [Medline]
12. Guglielmini, C., Civitella, C., Diana, A., Di Tommaso, M., Cipone, M. and Luciani, A. 2010. Serum cardiac troponin I concentration in dogs with
precapillary and postcapillary pulmonary hypertension. J. Vet. Intern. Med. 24: 145–152. [Medline] [CrossRef]
13. Han, M. K., Bach, D. S., Hagan, P. G., Yow, E., Flaherty, K. R., Toews, G. B., Anstrom, K. J., Martinez F. J., IPFnet Investigators 2013. Sildenal
preserves exercise capacity in patients with idiopathic pulmonary brosis and right-sided ventricular dysfunction. Chest 143: 1699–1708. [Medline]
14. Heikkilä, H. P., Lappalainen, A. K., Day, M. J., Clercx, C. and Rajamäki, M. M. 2011. Clinical, bronchoscopic, histopathologic, diagnostic imaging,
and arterial oxygenation ndings in West Highland White Terriers with idiopathic pulmonary brosis. J. Vet. Intern. Med. 25: 433–439. [Medline]
15. Johnson, L., Boon, J. and Orton, E. C. 1999. Clinical characteristics of 53 dogs with Doppler-derived evidence of pulmonary hypertension: 1992-
1996. J. Vet. Intern. Med. 13: 440–447. [Medline]
16. Kellihan, H. B. and Stepien, R. L. 2010. Pulmonary hypertension in dogs: diagnosis and therapy. Vet. Clin. North Am. Small Anim. Pract. 40:
623–641 Elsevier Ltd. [Medline] [CrossRef]
17. Kellihan, H. B., Waller, K. R., Pinkos, A., Steinberg, H. and Bates, M. L. 2015. Acute resolution of pulmonary alveolar inltrates in 10 dogs with
pulmonary hypertension treated with sildenal citrate: 2005-2014. J. Vet. Cardiol. 17: 182–191. [Medline] [CrossRef]
18. Kellum, H. B. and Stepien, R. L. 2007. Sildenal citrate therapy in 22 dogs with pulmonary hypertension. J. Vet. Intern. Med. 21: 1258–1264.
[Medline] [CrossRef]
19. Lettieri, C. J., Nathan, S. D., Barnett, S. D., Ahmad, S. and Shorr, A. F. 2006. Prevalence and outcomes of pulmonary arterial hypertension in
advanced idiopathic pulmonary brosis. Chest 129: 746–752. [Medline] [CrossRef]
20. Lobetti, R. G., Milner, R. and Lane, E. 2001. Chronic idiopathic pulmonary brosis in ve dogs. J. Am. Anim. Hosp. Assoc. 37: 119–127. [Medline]
21. Morita, T., Nakamura, K., Osuga, T., Lim, S. Y., Yokoyama, N., Morishita, K., Ohta, H. and Takiguchi, M. 2016. Repeatability and reproducibility
of right ventricular Tei index valves derived from three echocardiographic methods for evaluation of cardiac function in dogs. Am. J. Vet. Res. 77:
715–720. [Medline] [CrossRef]
22. Morita, T., Nakamura, K., Osuga, T., Yokoyama, N., Khoirun, N., Morishita, K., Sasaki, N., Ohta, H. and Takiguchi, M. 2017. The repeatability and
characteristics of right ventricular longitudinal strain imaging by speckle-tracking echocardiography in healthy dogs. J. Vet. Cardiol. 19: 351–362
Elsevier B.V. [Medline] [CrossRef]
23. Mukherjee, M., Mehta, N. K., Connolly, J. J., Dusaj, R. S., Choi, B. G., Katz, R. J. and Lewis, J. F. 2014. Pulmonary hypertension in hypertensive
patients: association with diastolic dysfunction and increased pulmonary vascular resistance. Echocardiography 31: 442–448. [Medline] [CrossRef]
do i: 10.1292/ jvms.17- 0716
24. Norris, C. R., Griffey, S. M. and Walsh, P. 2002. Use of keyhole lung biopsy for diagnosis of interstitial lung diseases in dogs and cats: 13 cases
(1998–2001). J. Am. Vet. Med. Assoc. 221: 1453–1459. [Medline] [CrossRef]
25. Phillips, S., Barr, S., Dykes, N., Scrivani, P., Kraus, M., Rishniw, M. and Valentine, B. 2000. Bronchiolitis obliterans with organizing pneumonia in
a dog. J. Vet. Intern. Med. 14: 204–207. [Medline]
26. Raya, A. I., Fernández-de Marco, M., Núñez, A., Afonso, J. C., Cortade, L. E. and Carrasco, L. 2006. Endogenous lipid pneumonia in a dog. J.
Comp. Pathol. 135: 153–155. [Medline] [CrossRef]
27. Reinero, C. R. and Cohn, L. A. 2007. Interstitial lung diseases. Vet. Clin. North Am. Small Anim. Pract. 37: 937–947, vi–vii. [Medline] [CrossRef]
28. Rishniw, M. and Erb, H. N. 2000. Evaluation of four 2-dimensional echocardiographic methods of assessing left atrial size in dogs. J. Vet. Intern.
Med. 14: 429–435. [Medline] [CrossRef]
29. Serres, F., Chetboul, V., Gouni, V., Tissier, R., Sampedrano, C. C. and Pouchelon, J. L. 2007. Diagnostic value of echo-Doppler and tissue Doppler
imaging in dogs with pulmonary arterial hypertension. J. Vet. Intern. Med. 21: 1280–1289. [Medline] [CrossRef]
30. Silverstein, D., Greene, C., Gregory, C., Lucas, S. and Quandt, J. 2000. Pulmonary alveolar proteinosis in a dog. J. Vet. Intern. Med. 14: 546–551.
[Medline] [CrossRef]
31. Tanabe, N., Taniguchi, H., Tsujino, I., Sakamaki, F., Emoto, N., Kimura, H., Takamura, K., Hanaoka, M., Nishimura, M., Tatsumi K., JRS Lung
Disease PH Study Group 2015. Multi-institutional retrospective cohort study of patients with severe pulmonary hypertension associated with
respiratory diseases. Respirology 20: 805–812. [Medline] [CrossRef]
32. Travis, W. D., Costabel, U., Hansell, D. M., King, T. E. Jr., Lynch, D. A., Nicholson, A. G., Ryerson, C. J., Ryu, J. H., Selman, M., Wells, A.
U., Behr, J., Bouros, D., Brown, K. K., Colby, T. V., Collard, H. R., Cordeiro, C. R., Cottin, V., Crestani, B., Drent, M., Dudden, R. F., Egan, J.,
Flaherty, K., Hogaboam, C., Inoue, Y., Johkoh, T., Kim, D. S., Kitaichi, M., Loyd, J., Martinez, F. J., Myers, J., Protzko, S., Raghu, G., Richeldi,
L., Sverzellati, N., Swigris, J., Valeyre D., ATS/ERS Committee on Idiopathic Interstitial Pneumonias 2013. An ofcial American Thoracic Society/
European Respiratory Society statement: Update of the international multidisciplinary classication of the idiopathic interstitial pneumonias. Am. J.
Respir. Crit. Care Med. 188: 733–748. [Medline] [CrossRef]
... pulmonary fibrosis(Johnson et al., 1999;Kellihan et al., 2015; Serres et al., 2007; Vezzosi et al., 2018a), uncharacterized 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 J o u r n a l P r e -p r o o f ...
Pulmonary hypertension (PH) is associated with substantial morbidity and if untreated, mortality. The human classification of PH is based on pathological, hemodynamic characteristics, and therapeutic approaches. Despite being a leading cause of PH, little is known about dogs with respiratory disease and/or hypoxia (RD/H)-associated PH. Therefore, our objectives were to retrospectively describe clinical features, diagnostic evaluations, final diagnoses and identify prognostic variables in dogs with RD/H and PH. In 47 dogs identified with RD/H and PH, chronic airway obstructive disorders, bronchiectasis, bronchiolar disease, emphysema, pulmonary fibrosis, neoplasia and other parenchymal disorders were identified using thoracic radiography, computed tomography, fluoroscopy, tracheobronchoscopy, bronchoalveolar lavage, and histopathology. PH was diagnosed using transthoracic echocardiography. Overall median survival was 276.0 days (SE, 95% CI; 216, 0-699 days). Dogs with an estimated systolic pulmonary arterial pressure (sPAP) ≥47mmHg (n=21; 9 days; 95% CI, 0-85 days) had significantly shorter survival times than those <47mmHg (n=16; P=0.001). Estimated sPAP at a cutoff of ≥47mmHg was a fair predictor of non-survival with sensitivity of 0.78 (95% CI, 0.52-0.94) and specificity of 0.63 (95% CI, 0.38-0.84). Phosphodiesterase-5 (PDE5) inhibitor administration was the sole independent predictor of survival in a multivariable analysis (hazard ratio: 4.0, P=0.02). Canine PH is present in a diverse spectrum of respiratory diseases, most commonly obstructive disorders. Similar to people, severity of PH is prognostic in dogs with RD/H and PDE5 inhibition could be a viable therapy to improve outcome.
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Pulmonary hypertension (PH), defined by increased pressure within the pulmonary vasculature, is a hemodynamic and pathophysiologic state present in a wide variety of cardiovascular, respiratory, and systemic diseases. The purpose of this consensus statement is to provide a multidisciplinary approach to guidelines for the diagnosis, classification, treatment, and monitoring of PH in dogs. Comprehensive evaluation including consideration of signalment, clinical signs, echocardiographic parameters, and results of other diagnostic tests supports the diagnosis of PH and allows identification of associated underlying conditions. Dogs with PH can be classified into the following 6 groups: group 1, pulmonary arterial hypertension; group 2, left heart disease; group 3, respiratory disease/hypoxia; group 4, pulmonary emboli/pulmonary thrombi/pulmonary thromboemboli; group 5, parasitic disease (Dirofilaria and Angiostrongylus); and group 6, disorders that are multifactorial or with unclear mechanisms. The approach to treatment of PH focuses on strategies to decrease the risk of progression, complications, or both, recommendations to target underlying diseases or factors contributing to PH, and PH‐specific treatments. Dogs with PH should be monitored for improvement, static condition, or progression, and any identified underlying disorder should be addressed and monitored simultaneously.
Dogs with respiratory disease can develop pulmonary hypertension (PH), a comorbid condition that can impact therapy and prognosis. Without confirmation using the criterion standard of echocardiography, this complication may be missed. Point-of-care ultrasound (POCUS) is a simple, non-invasive screening test that may suggest PH. It was hypothesized that in dogs POCUS right-sided cardiac markers (R-SCM) at the subxiphoid view would predict moderate to severe PH confirmed by echocardiography. Forty-three client-owned dogs that underwent respiratory evaluation with POCUS and echocardiography were included. POCUS R-SCM evaluated in the subxiphoid view included subjective caudal vena cava distention (CVCsx), CVCsx >1 cm, gallbladder wall edema and ascites. PH was defined by tricuspid regurgitation pressure gradient (TRPG) as mild (30–49.9 mmHg), moderate (50–74.9 mmHg) or severe (>75 mmHg). POCUS subxiphoid views were blindly evaluated post hoc and compared to echocardiography. Chi square test and one-way ANOVA were used to evaluate correlations between POCUS R-SCM and echocardiographic diagnosis of moderate to severe PH. Twenty-six dogs with PH, and 17 dogs without PH, were enrolled. There was no significant difference in the presence or absence of any R-SCM between dogs with and without PH. When dogs with no PH and mild PH were grouped and compared to dogs with moderate to severe PH (i.e., dogs for which treatment for PH would be recommended), no significant differences in R-SCM were noted. POCUS R-SCM using the CVCsx view was not a sensitive screening test to identify dogs with PH in this study population.
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Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate. 2015 ESC/ERS pulmonary hypertension guidelines incorporate changes and adaptations focusing on clinical management
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To describe clinical canine patients with naturally occurring pulmonary hypertension and radiographic pulmonary alveolar infiltrates before and after treatment with sildenafil. Ten client-owned dogs. A retrospective analysis of dogs with echocardiographically-determined pulmonary hypertension and pulmonary alveolar infiltrates on thoracic radiographs was performed before (PRE) and after (POST) sildenafil therapy. Clinical scores, pulmonary alveolar infiltrate scores and tricuspid regurgitation gradients were analyzed PRE and POST sildenafil. Pulmonary alveolar infiltrates associated with pulmonary hypertension developed in a diffusely patchy distribution (10/10). Sixty percent of dogs had a suspected diagnosis of interstitial pulmonary fibrosis as the etiology of pulmonary hypertension. Median PRE clinical score was 4 (range: 3-4) compared to POST score of 0 (0-2) (p = 0.005). Median alveolar infiltrate score PRE was 10 (5-12) compared to POST score of 4 (0-6) (p = 0.006). Median tricuspid regurgitation gradient PRE was 83 mmHg (57-196) compared to 55 mmHg POST (33-151) (p = 0.002). A subset of dogs with moderate to severe pulmonary hypertension present with diffuse, patchy alveolar infiltrates consistent with non-cardiogenic pulmonary edema. The typical clinical presentation is acute dyspnea and syncope, often in conjunction with heart murmurs suggestive of valvular insufficiency. This constellation of signs may lead to an initial misdiagnosis of congestive heart failure or pneumonia; however, these dogs clinically and radiographically improve with the initiation of sildenafil. Copyright © 2015 Elsevier B.V. All rights reserved.
Introduction: To assess the repeatability and characteristics of echocardiographic indices of the right ventricular (RV) function derived from speckle-tracking echocardiography. Animals: Fourteen laboratory Beagles and 103 privately owned dogs without cardiac disease were involved in this study. Materials and methods: Right ventricular longitudinal strain, strain rate, and a strain-related index for assessing RV dyssynchrony derived from speckle-tracking echocardiography were obtained by two different observers using five Beagles. Within-day, between-day, and interobserver coefficients of variation and the intraclass correlation coefficient of speckle-tracking echocardiography indices were determined. Both speckle-tracking echocardiography and conventional indices of RV function, including the peak velocity of systolic tricuspid annular motion, tricuspid annulus plane systolic excursion, fractional area change, and the Tei index, were obtained from 14 Beagles and 103 privately owned dogs. Relationships between echocardiographic indices and the body weight, heart rate, age, and sex were estimated by regression analysis. Results: Speckle-tracking echocardiographic indices showed good within-day repeatability, between-day and interobserver repeatability were moderate to good. In large dogs, RV longitudinal strain, strain rate, and fractional area change were significantly decreased, while the index of RV dyssynchrony, systolic tricuspid annular motion, tricuspid annulus plane systolic excursion, and the Tei index were increased. All speckle-tracking and conventional echocardiographic indices were correlated with the body weight. Discussion and conclusions: The speckle-tracking echocardiography indices were highly repeatable and body weight affected speckle-tracking echocardiography indices in dogs. Further studies are needed to apply speckle-tracking echocardiography indices in dogs with cardiac disease.
OBJECTIVE To evaluate repeatability and reproducibility of right ventricular Tei index (RTX) values derived from dual pulsed-wave Doppler, conventional pulsed-wave Doppler, and tissue Doppler echocardiography and to investigate relationships and repeatability among the 3 methods in healthy dogs. ANIMALS 6 healthy adult Beagles. PROCEDURE Echocardiography was performed on each dog on different days for 2 weeks (3 times/d) by 2 echocardiographers. Intraobserver within- and between-day and interobserver coefficients of variation (CVs) and intraclass correlation coefficients (ICCs) for RTXs derived from dual pulse-waved Doppler (RTX DPD ), conventional pulsed-wave Doppler (RTX PD ), and tissue Doppler (RTX TD ) methods were determined. Degrees of agreement among RTX values derived from the 3 methods were assessed by modified Bland-Altman analysis. RESULTS Least squares mean (95% confidence interval) RTX td was 0.50 (0.46 to 0.54), which was significantly higher than that for RTX DPD (0.27 [0.23 to 0.31]) and RTX PD (0.25 [0.21 to 0.29]). Agreement between RTX DPD and RTX PD was good (bias [mean difference], 0.04 [95% confidence interval, −0.03 to 0.10]). The RTX dpd had high within-day (CV, 6.1; ICC, 0.77) and interobserver (CV, 3.5; ICC, 0.83) repeatability, but between-day repeatability was not high. The RTX td had high within-day repeatability (CV, 6.0; ICC, 0.80), but between-day and interobserver repeatability were not high. Within-day, between-day, and interobserver repeatability of RTX PD were not high. CONCLUSIONS AND CLINICAL RELEVANCE RTX dpd measurement was a repeatable and reproducible method of cardiac evaluation in healthy dogs. The RTX TD values were significantly higher than the RTX DPD and RTX PD values; therefore, RTX values derived from different echocardiographic methods should be interpreted with caution.
Background and objectivePulmonary hypertension (PH) is often associated with respiratory diseases, but only a small number of patients present with severe PH defined as mean pulmonary arterial pressure ≥ 35 mm Hg. We here conducted a multicenter, retrospective study of patients with severe PH associated with respiratory diseases (R-PH) to reveal their demographics, treatment, prognosis and determinants of prognosis.Methods From 101 patients with severe R-PH collected by postal survey at the first stage, 70 patients with four major diseases (chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis with emphysema (CPFE), interstitial pneumonia associated with connective tissue disease (CTD-IP), interstitial pneumonia (IP)) and normal pulmonary arterial wedge pressure were studied for clinical characteristics, treatment and prognosis.ResultsThree-year survival rates were 50% for COPD (n = 18), 35.7% for IP (n = 19) and 68.1% for CTD-IP (n = 20), and the 2-year survival rate for CPFE (n = 13) was only 22.6%. Eighty-one per cent of patients had been treated with pharmacotherapy specific for pulmonary arterial hypertension. Those patients who had received phosphodiesterase-5 inhibitors (PDE-5I) displayed significantly better survival from the date of diagnosis than those who had not (3-year survival: 61.8% vs 20.0% P < 0.0001), especially in the IP, CTD-IP and CPFE groups. Multivariate analysis also revealed that treatment with PDE-5I was a positive prognostic factor.Conclusions We here demonstrated the dismal prognosis of patients with severe R-PH. The remarkably better survival in those patients who had received PDE-5I warrants and facilitates future prospective randomized studies in this particular population.
In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical "gold standard" of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs. PURPOSE: The objective of this statement is to update the 2002 ATS/ERS classification of IIPs. METHODS: An international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011. RESULTS: Substantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis-interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia is recognized to be heterogeneous. Acute exacerbation of IIPs is now well defined. A substantial percentage of patients with IIP are difficult to classify, often due to mixed patterns of lung injury. A classification based on observed disease behavior is proposed for patients who are difficult to classify or for entities with heterogeneity in clinical course. A group of rare entities, including pleuroparenchymal fibroelastosis and rare histologic patterns, is introduced. The rapidly evolving field of molecular markers is reviewed with the intent of promoting additional investigations that may help in determining diagnosis, and potentially prognosis and treatment. CONCLUSIONS: This update is a supplement to the previous 2002 IIP classification document. It outlines advances in the past decade and potential areas for future investigation.
Pulmonary hypertension (PH) in patients with systemic hypertension and preserved ejection fraction (PEF) has been described. However, the pathophysiology and consequences are not entirely clear. We sought to distinguish the clinical and anatomic features among hypertensive patients with or without coexistent PH. Echocardiograms and records of hypertensive patients with left ventricular (LV) hypertrophy and PEF from January 2009 to January 2011 were reviewed. We identified 174 patients, including 36 with PH (calculated pulmonary artery systolic pressure [PASP] ≥ 35 mmHg), and 138 with normal pulmonary pressures. Hypertensive patients with PH were older (76 ± 13 vs. 65 ± 13 years, P < 0.0001), more often female (91, 70%), had lower estimated glomerular filtration rate (eGFR) (63 ± 44 vs. 88 ± 48 mL/min, P = 0.002), and higher pro-BNP levels (3141 ± 4253 vs. 1219 ± 1900 pg/mL, P = 0.003). PH patients also had larger left atrial areas (23.7 ± 3.8 vs. 20.8 ± 4.6 cm(2) , P = 0.002), evidence of diastolic dysfunction (i.e., septal E/e' 17.6 ± 8.6 vs. 12.7 ± 4.4, P = 0.0005), and higher calculated peripheral vascular resistance (PVR) (2.3 ± 1.1 vs. 1.6 ± 0.4, P < 0.0001). Both PVR and septal E/e' showed strong linear correlation with PASP (P < 0.0001 and P < 0.0001, respectively). Hypertension in elderly patients is frequently complicated by LV diastolic dysfunction and secondary PH. These hypertensive patients tended to have reduced renal function and higher pro-BNP. Because of the known morbidity and mortality associated with PH, these observations have potentially important implications for target medical therapy.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with pulmonary vasculopathy. The purpose of this study was to determine whether sildenafil improves 6-min walk distance (6MWD) in subjects with IPF and right ventricular dysfunction. The IPFnet, a network of IPF research centers in the United States, conducted a randomized trial examining the effect of sildenafil on 6MWD in patients with advanced IPF, defined by carbon monoxide diffusing capacity < 35% predicted. A substudy examined 119 of 180 randomized subjects where echocardiograms were available for independent review by two cardiologists. Right ventricular (RV) hypertrophy (RVH), right ventricular systolic dysfunction (RVSD), and right ventricular systolic pressure (RVSP) were assessed. Multivariable linear regression models estimated the relationship between RV abnormality, sildenafil treatment, and changes in 6MWD, St. George's Respiratory Questionnaire (SGRQ), the EuroQol instrument, and SF-36 Health Survey (SF-36) from enrollment to 12 weeks. The prevalence of RVH and RVSD were 12.8% and 18.6%, respectively. RVSP was measurable in 71 of 119 (60%) subjects; mean RVSP was 42.5 mm Hg. In the subgroup of subjects with RVSD, subjects treated with sildenafil experienced less decrement in 6MWD (99.3 m; P = .01) and greater improvement in SGRQ (13.4 points; P = .005) and EuroQol visual analog scores (17.9 points; P = .04) than subjects receiving placebo. In the subgroup with RVH, sildenafil was not associated with change in 6MWD (P = .13), but was associated with greater relative improvement in SGRQ (14.8 points; P = .02) vs subjects receiving placebo. Sildenafil treatment in those with RVSD and RVH was not associated with change in SF-36. Sildenafil treatment in IPF with RVSD results in better preservation of exercise capacity as compared with placebo. Sildenafil also improves quality of life in subjects with RVH and RVSD.
Pulmonary hypertension (PH) is an important complication to interstitial lung disease (ILD). The aim of the present study was to investigate the prevalence and impact of PH on prognosis and exercise capacity in ILD patients. 212 ILD patients were screened for PH by echocardiography. Criteria for PH were either a tricuspid pressure regurgitation gradient >40 mmHg, a tricuspid annular plane systolic excursion <1.8 cm or right ventricular dilatation. If possible, PH was confirmed by right heart catheterisation. Pulmonary function tests and 6 min walk tests (6MWT) were performed. 29 patients (14%) had PH, 16 (8%) had mild and 13 (6%) had severe PH (mean pulmonary artery pressure ≥ 35 mmHg). Compared to patients without PH, lung function parameters were lower in PH patients, a larger proportion had idiopathic pulmonary fibrosis (IPF) (41 vs 21%, p = 0.006), and the hazard ratio for death was 8.5 (95% CI: 4-17). After correction for lung function parameters and the presence of IPF, 6MWT was significantly lower in patients with PH compared to non-PH patients (difference ± SEM: 58 ± 22 m, p = 0.01). PH occurred in 14% of a cohort of patients with ILD and was associated to IPF and lower lung function parameters. Mortality was markedly higher in PH patients, and the presence of PH reduced 6MWT independently of lung function and the presence of IPF. The present results emphasize the need for intensified treatment of patients with ILD and PH.
This review focuses on the epidemiological characteristics and etiologies of four primary systemic vasculitides with frequent lung involvement, namely Wegener granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and Goodpasture syndrome (GPS). Elucidation of the mechanisms underlying these vasculitides with frequent lung involvement is complicated by their rarity, which hampers the undertaking of large-scale studies; difficulties in classification; and their multifaceted clinical presentations, which infer the existence of several etiologic pathways. Notwithstanding, epidemiological research showed some evidence for international, interethnic, and temporal variations of the frequencies of these four vasculitides; led to the identification of several genetic and environmental risk factors; and provided insight on the extent to which genes and environment might contribute to their development. Available data support the concept that WG, MPA, CSS, and GPS have unique and shared risk determinants. Although the precise causes of these vasculitides are not yet fully understood and the development of prevention strategies is out of our reach at present, current knowledge enables the formulation of etiologic hypotheses to provide caregivers and their patients with valuable information on the nature of these rare entities.