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Discipline of Small Animal Internal Medicine, Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, PO Box 57 (Viikintie 49), Helsinki 00014, Finland
Discipline of Small Animal Internal Medicine, Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, PO Box 57 (Viikintie 49), Helsinki 00014, Finland
Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial lung disease of unknown etiology affecting mainly middle-aged and old West Highland white terriers.
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Typical findings are cough, exercise intolerance, Velcro crackles, abdominal breathing pattern, and hypoxemia.
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Diagnosis is often requires either high-resolution computed tomography (HRCT) or histopathology of the lung tissue, which is seldom performed on live dogs.
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CIPF shares several clinical findings with human idiopathic pulmonary fibrosis, but in HRCT and histopathology, CIPF has features of human idiopathic pulmonary fibrosis as well as nonspecific interstitial pneumonia.
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No curative treatment exists, and clinical treatment trials are lacking in dogs. Symptomatic treatment with corticosteroids and theophylline may alleviate clinical signs.
Introduction
Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with no known cure. It is chronic, is inevitably progressive, and leads to death. IPF is recognized in humans and in their animal companions, cats and dogs.
published the first case series describing the clinical features of this disease in WHWTs. More reports of CIPF in a WHWT and other dog breeds were described around the same time.
CIPF was found to carry striking similarities to human IPF. The key feature of both diseases is the abnormal accumulation of collagen in the lung parenchyma for no known reason.
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
This hampers gas exchange causing cough, exercise intolerance, and, finally, respiratory failure. In humans, IPF diagnosis signifies a worse prognosis than most cancers. During the past 2 decades, CIPF has been the subject of several studies.
The possibility that dogs could serve as a spontaneous animal model for human IPF has increased interest in CIPF.
Currently, CIPF is the best-described ILD affecting dogs. Studies on CIPF have focused on detailed clinicopathologic findings, histopathologic features, concomitant pulmonary hypertension (PH), high-resolution computed tomography (HRCT) findings, and outcome and prognostic factors.
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
Comparison between sedation and general anesthesia for high resolution computed tomographic characterization of canine idiopathic pulmonary fibrosis in West Highland white terriers.
Further characterization of computed tomographic and clinical features for staging and prognosis of idiopathic pulmonary fibrosis in West Highland white terriers.
Thoracic high resolution CT using the modified VetMousetrap™ device is a feasible method for diagnosing canine idiopathic pulmonary fibrosis in awake West Highland White Terriers [published online ahead of print, June 7, 2019].
Potential blood and bronchoalveolar lavage fluid (BALF) biomarkers of CIPF have been targeted, namely procollagen type III amino-terminal propeptide (PIIINP), endothelin-1 (ET-1), serotonin, vascular endothelial growth factor, serum Krebs von den Lungen-6, and matrix metalloproteinases (MMPs).
Heikkilä HP, Krafft E, de Lorenzi D, et al. Matrix metalloproteinase -2 and -9 in bronchoalveolar lavage fluid of dogs with idiopathic pulmonary fibrosis and chronic bronchitis. Proceedings of the 21st ECVIM-CA Congress. Seville, Spain, September 8-10, 2011. p. 213.
Procollagen type III amino terminal propeptide concentrations in dogs with idiopathic pulmonary fibrosis compared with chronic bronchitis and eosinophilic bronchopneumopathy.
Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis.
New insight has been brought to the pathogenesis and etiology by investigating surfactant protein C, BALF proteome, transforming growth factor ß (TGF-ß) signaling pathway, gene expression profiles, chemokine concentrations, respiratory microbiota, presence of reflux aspiration, association with herpesvirus infection, and potential fungal etiology and by surveying the environment and care of WHWTs with and without CIPF.
Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis.
Proteomic analysis of bronchoalveolar lavage fluid samples obtained from West Highland White Terriers with idiopathic pulmonary fibrosis, dogs with chronic bronchitis, and healthy dogs.
Upregulation of alveolar levels of activin B, but not activin A, in lungs of West Highland white terriers with idiopathic pulmonary fibrosis and diffuse alveolar damage.
Assessment of CCL2 and CXCL8 chemokines in serum, bronchoalveolar lavage fluid and lung tissue samples from dogs affected with canine idiopathic pulmonary fibrosis.
The correlation between CIPF and human IPF is only partially understood at present. Even though CIPF is not identical to human IPF, as a disease model, it is likely superior to models of induced fibrosis in the mouse used today.
Several aspects of the disease remain, however, unanswered. The incidence and prevalence of CIPF are not known. A better understanding of the etiology and pathogenesis could help find new therapeutic agents. Finally, the role of genetics in this disorder is still poorly understood but is under active research.
Definition
CIPF and IPF belong to a heterogenous group of ILDs, which consist of several noninfectious and nonmalignant pulmonary diseases with overlapping clinicopathologic and radiographic features. A majority of the ILDs have an unknown etiology. More than 200 ILDs are recognized in humans, but many fewer are reported in dogs.
Because diagnosing ILD requires a thorough clinical work-up, histopathologic examination of lung tissue, and a multidisciplinary approach, it is likely that cases are undiagnosed.
A classification scheme modified from human medicine was proposed for canine and feline ILDs recently. It divides ILDs into (1) idiopathic interstitial pneumonias (IIPs), (2) ILDs of known cause, and (3) miscellaneous ILDs.
CIPF belongs to IIPs. In humans, the IIPs are a group of non-neoplastic disorders that result from damage to the lung parenchyma with varying patterns of inflammation and fibrosis.
An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
Canine and feline IIPs are further classified into sporadic and familial fibrotic ILD, nonspecific interstitial pneumonia (NSIP) and lymphocytic interstitial pneumonitis, acute interstitial pneumonia, cryptogenic organizing pneumonia, and other IIPs.
CIPF in WHWTs is a familial fibrotic ILD. For the details of the proposed classification and the description of the other IIPs and ILDs affecting dogs and cats, readers are referred to reviews.
CIPF is not the only term that has been used to describe this disease affecting WHWTs. Other names include IPF, chronic IPF, canine pulmonary fibrosis, chronic pulmonary disease in WHWTs, and ILD in WHWTs.
By CIPF, the authors refer to a chronic, progressive, familial fibrotic ILD of unknown cause, limited to the lungs, and occurring mainly in older WHWTs.
Histopathological features
CIPF is characterized histopathologically by 2 different patterns of interstitial fibrosis. All affected dogs have diffuse and mature uniform fibrosis of the alveolar wall.
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
These areas of fibrosis occur with pronounced alveolar epithelial and luminal changes, interstitial smooth muscle hyperplasia, proliferating myofibroblasts, and occasional honeycombing (Fig. 1C, D).
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
Fibrosis appears accentuated either adjacent to the bronchioli or under the pleura. Only mild to moderate interstitial lymphoplasmacytic inflammation is present.
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
Fig. 1Histopathologic features of CIPF in WHWTs. (A) Lung histology of a healthy WHWT (hematoxylin-eosin [HE]); bar, 200 μm. (Inset) Vessel of a healthy WHWT (Masson trichrome). (B) Mild diffuse mature interstitial fibrosis (HE); bar 200 μm. (Inset) Perivascular concentric fibrosis (Masson trichrome). (C) Focus of accentuated disease with severe interstitial fibrosis and type II pneumocyte hyperplasia (HE); bar, 200 μm. (D) Subpleural area of honeycombing and severe interstitial fibrosis (HE); bar, 1 mm. (Inset) Cystic fibrotic airspace within areas of honeycombing (Masson trichrome).
(From Laurila HP. Canine idiopathic pulmonary fibrosis - clinical disease, biomarkers and histopathological features. [PhD]. Helsinki, Finland: University of Helsinki; 2015: 3-76; with permission.)
When compared with human diseases, CIPF in WHWTs shares features of both human usual interstitial pneumonia (UIP), the histopathologic pattern of human IPF, and NSIP. The diffuse, mature fibrosis closely resembles the fibrosis pattern of NSIP whereas the accentuation areas are more characteristic of human UIP.
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
Whether there are differences in the histopathologic picture between CIPF, the familial fibrotic ILD affecting WHWTs, and a sporadic fibrotic ILD affecting other dog breeds remains to be investigated.
Pathogenesis and etiology
As the word idiopathic implies, the etiology of CIPF and IPF is unknown and pathologic processes are incompletely understood. The early idea of IPF as an inflammatory disease has been negated by recent research and the current hypothesis focuses on a repetitive insult to distal lung parenchyma followed by an aberrant wound healing process.
The injured alveolar epithelium seems to be the key player in the fibrotic lung response. Increased epithelial cell death, abnormal re-epithelialization, pneumocyte type II hyperplasia, and activation of alveolar epithelial cells participate in creating a profibrotic microenvironment.
The abnormally activated alveolar epithelial cells secrete growth factors, such as TGF-ß, cytokines, and other chemotactic mediators, inducing fibroblast proliferation, migration, and recruitment of fibroblast progenitor cells. After epithelial injury, the coagulation cascade is activated, which in turn has profibrotic effects. Exposure to different stimuli, including TGF-ß and wound clotting, transforms epithelial cells into fibroblasts in a process called epithelial mesenchymal cell transition. In humans, fibroblasts form small clusters, the so-called fibroblast foci, and differentiate to myofibroblasts.
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
The final result is an abnormal accumulation of fibroblasts and myofibroblasts and exaggerated production of collagen and other extracellular matrix components, leading to architectural distortion characteristic of IPF lung.
The trigger for this fibrosis cascade is not known. In human IPF, research has revealed several potential epidemiologic risk factors that might contribute to the epithelial injury and apoptosis, such as cigarette smoking, exposure to environmental and occupational agents, gastroesophageal reflux leading to microaspiration, and chronic viral infections, in particular, herpesviruses.
Considering the histopathologic aspect of CIPF, the proximity of the fibrosis accentuation areas to bronchioli could indicate that an inhaled etiologic factor is involved in the pathogenesis of CIPF.
The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man.
An epidemiologic survey for owners of WHWTs with CIPF revealed that living in an old house, lack of ventilation system, and frequent grooming in dedicated grooming facilities were associated with increased risk for CIPF.
detected bile acids in BALF of WHWTs with CIPF and healthy WHWTs but not in BALF of healthy dogs of other breeds. The results suggest that microaspiration due to gastroesophageal reflux could be a predisposing factor for CIPF in WHWTs.
Although a majority of human IPF cases are sporadic, several genetic mutations are known to increase the risk for IPF; however, none of these has consistently been associated with IPF.
In dogs, accumulation of diseased individuals within one breed suggests that CIPF is hereditary in WHWTs. Genetic relationship to another WHWT with CIPF was associated with CIPF in the recent epidemiologic survey.
Despite ongoing studies, a unifying genetic factor has not yet been discovered and the strong breed predisposition of WHWTs to CIPF requires further research. One factor predisposing WHWTs to CIPF could be an increase in serum TGF-ß concentration detected both in diseased and healthy WHWTs.
The diffuse mature, uniform fibrosis detected in the CIPF lung is characteristic of human NSIP. In addition to being an idiopathic disease in humans, NSIP occurs in conjunction with other conditions, such as systemic connective tissue diseases.
An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
Such a disease, however, has not been reported in WHWTs to date.
It is likely that CIPF is the result of a complex puzzle of environmental insults, a specific genetic background, and other host factors contributing to the development of the disease.
Signalment and clinical signs
CIPF affects mainly WHWTs. Dogs of other breeds, mainly terriers, occasionally can be affected; however, it is unclear whether the fibrotic ILD in these dogs is similar to that of WHWTs. WHWTs tend to be middle-aged or old when they first display signs. The median age at the time of clinical diagnosis varies between 8 years and 13 years in different studies,
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
Comparison between sedation and general anesthesia for high resolution computed tomographic characterization of canine idiopathic pulmonary fibrosis in West Highland white terriers.
Further characterization of computed tomographic and clinical features for staging and prognosis of idiopathic pulmonary fibrosis in West Highland white terriers.
Commonly, dogs already suffer from advanced disease when they are presented to the veterinarian. The clinical signs develop slowly and at first the affected dogs probably appear normal. The duration of clinical signs varies but usually is between 8 months and 13 months prior to diagnosis.
The most common clinical sign is the combination of cough and exercise intolerance, but not all the dogs cough. Other described clinical signs are respiratory difficulty, cyanosis, tachypnea, orthopnea, and collapse.
and the authors are aware of some cases of pulmonary carcinoma in WHWTs with CIPF.
Diagnosis and clinical examinations
Diagnosis of CIPF is based on signalment, anamnestic information, findings in clinical examination, and HRCT as well as exclusion of other respiratory diseases. The typical signalment of a middle-aged to older WHWT improves diagnostic confidence. A definitive diagnosis is provided only by histopathologic examination of lung tissue, but lung biopsies are seldom obtained due to the invasiveness of the procedure; therefore, diagnosis often is confirmed at necropsy. Diagnosing a fibrotic ILD without histopathology in a non-WHWT breed is challenging.
Dogs with CIPF usually are bright and alert due to adaptation to slowly developing respiratory impairment. Some severely affected dogs can be cyanotic and in distress, and an abdominal breathing pattern commonly is present. Lung auscultation reveals bilateral, inspiratory Velcro crackles and sometimes also wheezes.
Velcro crackles are hypothesized to result from sudden opening or closing of distorted distal airspaces. In humans, Velcro crackles can be the first sign of IPF.
If a WHWT with CIPF is breathing very shallowly, Velcro crackles might not be audible even in advanced CIPF, although in some dogs, crackles can be heard without a stethoscope when the dog is breathing with an open mouth.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
The authors pay special attention to lung auscultation in older WHWTs even if they do not have clinical signs indicating respiratory disease to provide early detection of potential disease. A soft right-sided murmur is heard in some dogs with tricuspid regurgitation due to PH. CIPF does not cause weight loss.
CIPF is not associated with changes in serum biochemistry or hematology, but these analyses are performed to rule out other reasons for exercise intolerance.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
The lack of polycythemia in CIPF is interesting and, in humans, polycythemia is not linked to IPF as it is to other chronic hypoxemic diseases. The reason for this is not known.
Fecal examinations, including the flotation and Baermann sedimentation methods, are performed to rule out pulmonary parasites.
Arterial oxygenation
Arterial blood gas (ABG) analysis is used to estimate lung function objectively and to determine the severity of CIPF. Repeated ABG analyses also are an easy tool for evaluating disease progression in dogs.
Hypoxemia is a key clinical consequence of CIPF. An ABG analysis can reveal a surprisingly low Pao2 and high alveolar-arterial oxygen gradient (Pao2 - Pao2) in a WHWT with CIPF (Table 1). Despite this, most dogs are not in respiratory distress, indicating adaptation to a chronic, slowly progressing disease. Elevation of Paco2 is not a feature of CIPF.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
Comparison between sedation and general anesthesia for high resolution computed tomographic characterization of canine idiopathic pulmonary fibrosis in West Highland white terriers.
Thoracic high resolution CT using the modified VetMousetrap™ device is a feasible method for diagnosing canine idiopathic pulmonary fibrosis in awake West Highland White Terriers [published online ahead of print, June 7, 2019].
Table 1Arterial blood gas analysis in older West Highland white terriers with canine idiopathic pulmonary fibrosis (40 dogs) and healthy West Highland white terriers (32 dogs, all >7 y)
West Highland White Terriers with Canine Idiopathic Pulmonary Fibrosis
Healthy West Highland White Terriers
Pao2
60.1 ± 10.2 (33.5–87.4) mm Hg
97.1 ± 6.7 (86.1–113.0) mm Hg
(Pao2 - Pao2)
55.0 ± 12.2 (28.0–84.7) mm Hg
18.7 ± 5.3 (9.8–29.9) mm Hg
Paco2
29.2 ± 3.6 (21.2–35.7) mm Hg
29.2 ± 4.3 (19.9–36.8) mm Hg
In CIPF dogs, ABG analysis was performed at the time of diagnosis. CIPF was confirmed by HRCT and/or histopathology. Healthy WHWTs had no clinical signs or HRCT findings indicating respiratory disease. Dogs participated in research projects at the Veterinary Teaching Hospital of the University of Helsinki, Finland. Results are given as mean ± SD and range.
A 6-minute walk test is a submaximal exercise test that measures the distance an individual is capable of walking over 6 minutes. It is used to evaluate exercise capacity in human IPF and can be used in CIPF as well without any special equipment or training.
Comparison between sedation and general anesthesia for high resolution computed tomographic characterization of canine idiopathic pulmonary fibrosis in West Highland white terriers.
It is not a diagnostic tool, instead, repeated P(a-a)o2 measurements of the distance walked in 6 minutes can be used to monitor the changes in exercise tolerance of WHWTs with CIPF and, therefore, the progression of the disease. The median distance walked was significantly lower in WHWTs with CIPF (398 m, range 273 m–519 m) compared with healthy aged WHWTs (492 m, range 420 m–568 m).
PH develops in many WHWTs with CIPF. Different studies have documented echocardiographic findings indicating PH in approximately 20% to 60% of diseased WHWTs.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
Comparison between sedation and general anesthesia for high resolution computed tomographic characterization of canine idiopathic pulmonary fibrosis in West Highland white terriers.
Further characterization of computed tomographic and clinical features for staging and prognosis of idiopathic pulmonary fibrosis in West Highland white terriers.
Therefore, Doppler echocardiography is required to search for PH, especially if the dog has a soft right-sided murmur or if thoracic radiographs raise suspicion of right-sided cardiac enlargement. PH is thought to result from an imbalance between pulmonary arterial vasoconstriction and vasodilatation, vascular remodeling due to an advanced lung disease, and chronic hypoxemia. Nevertheless, the pathogenesis of PH is likely much more complex than this and is not yet thoroughly understood.
Thoracic radiographs of WHWTs with CIPF commonly show a bronchointerstitial pattern, which is already moderate to severe when the animal is presented to the veterinarian.
Changes in thoracic radiographs are neither sensitive nor specific for CIPF, and the main reason for taking them is to rule out other lung diseases, such as neoplasia.
Identifying early radiographic changes of CIPF is problematic, because healthy older WHWTs also can have mild bronchial or bronchointerstitial patterns in thoracic radiographs.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
Additionally, the thick skin typical for WHWTs can make the interpretation of subtle changes difficult. Thoracic radiography is not helpful in evaluating the progression of CIPF, because the changes vary independently of clinical signs (Fig. 2).
Cardiac and pulmonary arterial enlargement can be present in thoracic radiographs, caused mainly by PH.
Fig. 2Thoracic radiography is not a sensitive tool to evaluate the severity of CIPF as demonstrated by these images. Right lateral and ventrodorsal radiographs from a 12-year-old WHWT with moderate CIPF (Pao2 82 mm Hg) (A, B) and from another 12-year-old WHWT with more severe CIPF (Pao2 64 mm Hg) (C, D). The images show moderate (B) to severe (A, C, D) generalized bronchointerstitial lung patterns and a large cardiac shadow. Extreme skin folds increase the overall opacity of the lungs.
([A, B] From Laurila HP. Canine idiopathic pulmonary fibrosis - clinical disease, biomarkers and histopathological features. [PhD]. Helsinki, Finland: University of Helsinki; 2015: 3-76; with permission; and [C, D] Courtesy of Anu K. Lappalainen, DVM, PhD, University of Helsinki, Finland.)
HRCT provides superior evaluation of the lung compared with conventional radiographs. If HRCT findings are characteristic, lung biopsy is not necessary to confirm IPF in humans.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
Comparison between sedation and general anesthesia for high resolution computed tomographic characterization of canine idiopathic pulmonary fibrosis in West Highland white terriers.
Further characterization of computed tomographic and clinical features for staging and prognosis of idiopathic pulmonary fibrosis in West Highland white terriers.
Thoracic high resolution CT using the modified VetMousetrap™ device is a feasible method for diagnosing canine idiopathic pulmonary fibrosis in awake West Highland White Terriers [published online ahead of print, June 7, 2019].
The most frequent finding is ground-glass opacity (GGO) described as a hazy increased opacity of the lungs, with preservation of bronchial and vascular margins. Mosaic attenuation pattern also is frequently observed
Comparison between sedation and general anesthesia for high resolution computed tomographic characterization of canine idiopathic pulmonary fibrosis in West Highland white terriers.
Further characterization of computed tomographic and clinical features for staging and prognosis of idiopathic pulmonary fibrosis in West Highland white terriers.
Further characterization of computed tomographic and clinical features for staging and prognosis of idiopathic pulmonary fibrosis in West Highland white terriers.
Linear and reticular opacities are common, whereas traction bronchiectasis and honeycombing are detected more rarely. Consolidation can occur, and, in some dogs, bronchial wall thickening or nodules have been described (Fig. 3).
Fig. 3A transverse HRCT image at the level of caudal lung lobes in an 11-year-old WHWT with CIPF and a Pao2 of 57 mm Hg. Areas of GGO (arrow) and traction bronchiectasis (arrowhead) are seen dorsally. The images were obtained under general anesthesia.
(Courtesy of Anu K. Lappalainen, DVM, PhD, University of Helsinki, Finland.)
In humans, extensive GGO points toward an alternative diagnosis, such as NSIP, whereas honeycombing, traction bronchiectasis, coarse reticulation, and architectural distortion are characteristic of IPF.
Challenges in pulmonary fibrosis. 1: use of high resolution CT scanning of the lung for the evaluation of patients with idiopathic interstitial pneumonias.
When lung tissue attenuation is evaluated quantitatively by measuring computed tomography values, values are significantly higher in WHWTs with CIPF than in healthy WHWTs.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
Further characterization of computed tomographic and clinical features for staging and prognosis of idiopathic pulmonary fibrosis in West Highland white terriers.
Thoracic high resolution CT using the modified VetMousetrap™ device is a feasible method for diagnosing canine idiopathic pulmonary fibrosis in awake West Highland White Terriers [published online ahead of print, June 7, 2019].
To avoid the risks of general anesthesia, the authors use a modified VetMouseTrap positioning device (Universal Medical Systems Inc., Solon, OH) (Fig. 4). It limits the dog’s motion and enables HR CT imaging with no or only minimal sedation. The method was found feasible in discriminating healthy from diseased WHWTs.
Thoracic high resolution CT using the modified VetMousetrap™ device is a feasible method for diagnosing canine idiopathic pulmonary fibrosis in awake West Highland White Terriers [published online ahead of print, June 7, 2019].
When HR CT images obtained under sedation were compared with those obtained under anesthesia, both underestimation and overestimation of GGO and mosaic attenuation patterns were observed.
Comparison between sedation and general anesthesia for high resolution computed tomographic characterization of canine idiopathic pulmonary fibrosis in West Highland white terriers.
Fig. 4Photograph illustrating use of the modified VetMouseTrap™ (Universal Medical Systems Inc., Solon, OH.) The device is used without the lid, and padding is added inside the device.
(From Holopainen S, Rautala E, Lilja-Maula L, et al. Thoracic high resolution CT using the modified VetMousetrap™ device is a feasible method for diagnosing canine idiopathic pulmonary fibrosis in awake West Highland white terriers. Vet Radiol Ultrasound. 2019; 60(5):525-532; with permission.)
Bronchoscopy and BALF provide useful information about the lung and airways, but the findings are not specific for CIPF. Many dogs with CIPF have some degree of bronchial involvement (Fig. 5). It is not known whether this is an individual phenomenon, related to underlying CIPF, or connected to cough. The presence of bronchoscopic changes cannot be used to differentiate CIPF from CB. Bronchial changes, however, such as hyperemia, mucus accumulation, and mucosal irregularities, usually are more profound in CB than in CIPF.
Bronchoscopy requires general anesthesia. The decision to perform bronchoscopy must be considered from the perspective of benefits versus risks. Bronchoscopy should be pursued, especially when there is discrepancy between clinical data and HRCT findings or suspicion of infection or other disease process or if CIPF is suspected in a young WHWT or in a dog of a non-WHWT breed. The general condition and the severity of hypoxemia determine whether a dog is fit for the procedure. In the authors’ experience, careful planning of anesthesia with supplemental oxygen before, during, and after bronchoscopy make scoping possible even in severely hypoxemic WHWTs with CIPF.
Fig. 5Bronchoscopic images from WHWTs with CIPF. (A) Moderate bronchial mucosal irregularity in a 12-year-old WHWT with CIPF. (B) Grade II tracheal collapse viewed at the level of carina in a 12-year-old WHWT with CIPF.
(From Laurila HP. Canine idiopathic pulmonary fibrosis - clinical disease, biomarkers and histopathological features. [PhD]. Helsinki, Finland: University of Helsinki; 2015: 3-76; with permission.)
Bronchoscopic changes reported in CIPF are bronchial mucosal irregularity, mild to moderate increases in bronchial mucus, bronchomalacia, dynamic airway collapse, and bronchiectasis.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
Comparison between sedation and general anesthesia for high resolution computed tomographic characterization of canine idiopathic pulmonary fibrosis in West Highland white terriers.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
Comparison between sedation and general anesthesia for high resolution computed tomographic characterization of canine idiopathic pulmonary fibrosis in West Highland white terriers.
The significance of this finding and its possible relationship to the underlying ILD is unclear, and the authors have also detected tracheal collapse in clinically healthy old WHWTs.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
BALF analysis of WHWTs with CIPF usually shows an increase in the total cell count due to increased numbers of macrophages, neutrophils, and mast cells. Bacterial growth is uncommon.
Clinical, bronchoscopic, histopathologic, diagnostic imaging, and arterial oxygenation findings in West Highland white terriers with idiopathic pulmonary fibrosis.
BALF analysis is not routinely recommended in the diagnostic evaluation of human IPF, but it can be useful in excluding other ILDs or evaluating infection or malignancy.
In human IPF, increased total cell count, BALF neutrophilia, and mild to moderate eosinophilia are described. Lack of lymphocytosis supports the IPF diagnosis. In NSIP, BALF lymphocytosis is typical.
An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease.
Reaching CIPF diagnosis can require HRCT, which is expensive and not always applicable, or histologic investigation of lung tissue. The lack of CIPF-specific therapy, however, questions the benefits of surgical lung biopsy. Therefore, identification of a noninvasive fibrosis biomarker could be helpful. Both screening and targeted investigational approaches have been used in the biomarker search with promising results.
Biomarkers with the potential to discriminate WHWTs with CIPF from healthy WHWTs are serum and BALF ET-1, serum and BALF chemokine (C-C) ligand 2, BALF interleukin-8, BALF PIIINP, and BALF MMP-9.
Heikkilä HP, Krafft E, de Lorenzi D, et al. Matrix metalloproteinase -2 and -9 in bronchoalveolar lavage fluid of dogs with idiopathic pulmonary fibrosis and chronic bronchitis. Proceedings of the 21st ECVIM-CA Congress. Seville, Spain, September 8-10, 2011. p. 213.
Procollagen type III amino terminal propeptide concentrations in dogs with idiopathic pulmonary fibrosis compared with chronic bronchitis and eosinophilic bronchopneumopathy.
Assessment of CCL2 and CXCL8 chemokines in serum, bronchoalveolar lavage fluid and lung tissue samples from dogs affected with canine idiopathic pulmonary fibrosis.
Biomarkers with the potential to differentiate WHWTs with CIPF from dogs with chronic bronchitis (CB) are serum and BALF ET-1, BALF PIIINP, BALF MMP-9, and BALF MMP-2.
Heikkilä HP, Krafft E, de Lorenzi D, et al. Matrix metalloproteinase -2 and -9 in bronchoalveolar lavage fluid of dogs with idiopathic pulmonary fibrosis and chronic bronchitis. Proceedings of the 21st ECVIM-CA Congress. Seville, Spain, September 8-10, 2011. p. 213.
Procollagen type III amino terminal propeptide concentrations in dogs with idiopathic pulmonary fibrosis compared with chronic bronchitis and eosinophilic bronchopneumopathy.
Biomarkers that might be related to the predisposition of WHWT breed for CIPF are serum TGF-ß, serum interleukin-8, and possibly serum Krebs von den Lungen-6. The concentrations of these markers were higher in serum of WHWTs compared with other breeds.
Evaluation of chemokines CXCL8 and CCL2, serotonin, and vascular endothelial growth factor serum concentrations in healthy dogs from seven breeds with variable predisposition for canine idiopathic pulmonary fibrosis.
Further studies are necessary to confirm these findings, to find novel biomarkers, and to investigate combinations of these that have the highest predictive values. Ideally, a biomarker that differentiates WHWTs that will develop CIPF from those that will not would be available to select WHWTs for breeding.
Treatment
Currently, there are no effective treatments for CIPF. No treatment trials have been performed on dogs with CIPF, and the studies published on CIPF have not been designed to evaluate any treatment effect.
Pharmacologic treatment options for human IPF are scarce as well. No known treatment can stop the progression or reverse the fibrotic changes. IPF is the leading indication for lung transplantation in humans worldwide.
Knowledge about IPF pathogenesis has shifted treatment targets from inflammation toward the aberrant wound healing process. What used to be a standard-of-care combination therapy with prednisone, azathioprine, and N-acetylcysteine was revealed to be harmful in human IPF. At present, human IPF-specific therapy is based on 2 novel antifibrotics, pirfenidone and nintedanib. Both can slow the decline in lung function but do not result in cure.
An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. an update of the 2011 clinical practice guideline.
An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. an update of the 2011 clinical practice guideline.
It might be considered for treatment of CIPF. Although the pharmacokinetics of pirfenidone have been studied in dogs, the safety is not known and there are no clinical reports of its use in dogs.
Currently, pirfenidone is expensive: treating a WHWT would cost 12€ to 17€ ($13–$20) per day (July 2019) if the pirfenidone dose is extrapolated from humans.
Nintedanib is an intracellular inhibitor of multiple tyrosine kinases with potent antifibrotic and anti-inflammatory effects in animal models.
An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. an update of the 2011 clinical practice guideline.
reported that some dogs with CIPF seem to respond to corticosteroid treatment. Based on the authors’ experience, corticosteroids reduce cough in many dogs; however, the authors have not observed any clear long-term improvement in arterial oxygenation.
In NSIP, however, oral corticosteroids form the basis of the treatment alone or in combination with other immunosuppressive agents. Human patients with a less common, cellular NSIP respond well whereas patients with a more common, fibrosing NSIP do far worse but still survive longer than patients with IPF.
If corticosteroids are chosen as an empirical therapy for CIPF, it is up to the veterinarian to decide whether to give it orally or via inhalation. No studies exist to support either use. Given the potential benefit of corticosteroids in human NSIP, an oral route might be elected. On the other hand, considering the lack of efficacy in human IPF, concurrent bronchial changes could be targeted instead of the interstation, and, therefore, inhaled steroids might be a better option, especially in old WHWTs with concomitant diseases.
Combination therapy with corticosteroids and theophylline has been recommended for treatment of CIPF and is also the authors’ choice.
WHWTs with CIPF might benefit from use of proton pump inhibitors or histamine H2 receptor blockers. This is supported by the finding of microaspiration in WHWTs with CIPF.
Gastroesophageal reflux with microaspiration is common in human IPF and predisposes to lung injury. Antiacid therapy is recommended for the treatment of all human patients with IPF
Because it is a low-cost treatment and unlikely harmful, it can be used in WHWTs with CIPF as well.
Treatment of PH usually focuses first on management of the underlying disease; however, because no effective treatment exists for CIPF, treatment of concurrent PH is directly targeted to reduce pulmonary arterial pressure. A recent meta-analysis in human medicine did not support the theoretic concern that hypoxemia could worsen with PH treatment because of deterioration in ventilation-perfusion mismatch.
Data on the use of sildenafil in human IPF-related PH are conflicting and the authors of the official management guidelines of human IPF do not take a stand for or against its use.
An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. an update of the 2011 clinical practice guideline.
Although no study has evaluated the benefits and adverse effects of sildenafil in CIPF-related PH, sildenafil therapy has been investigated in dogs with PH in general and has been reported to improve clinical signs and quality of life. The authors prescribe sildenafil to WHWTs with CIPF that have echocardiographic measurements suggesting PH.
WHWTs with CIPF can experience acute worsening of respiratory function during the disease course. The cause for such worsening, for example, a bacterial pneumonia, should be treated appropriately. If no cause is found, the dog could be suffering from an acute exacerbation (AE) of CIPF, histopathologically characterized by diffuse alveolar damage.
Upregulation of alveolar levels of activin B, but not activin A, in lungs of West Highland white terriers with idiopathic pulmonary fibrosis and diffuse alveolar damage.
The etiology of AE in human IPF is unknown, but it is likely triggered by an acute insult, for example, microaspiration, infection, or stress due to bronchoscopy or surgery, which then leads to severe acute lung injury. Despite empirical treatment with a high dose of corticosteroids and broad-spectrum antibiotics, the short-term mortality of AE of IPF in humans is very high.
The authors encourage the owners of WHWTs with CIPF to continue routine daily walks with their dogs, unless the dog shows signs of exhaustion. Long-term oxygen therapy is not feasible in dogs, although intermittent treatment might be possible in some dogs.
Clinical course and survival
Although diseased WHWTs usually are already old at the time of disease recognition, CIPF has a negative impact on survival. Median survival was reported to be 32 months (range 2–51 months) from the onset of clinical signs and 11 months (range 0–40 months) from diagnosis (Fig. 6).
Predicting the disease course for an individual WHWT is difficult, because of the lack of prognostic markers. Only high-serum chemokine (C-C) ligand 2 at the time of diagnosis and the severity of CT findings were found to be negatively associated with survival.
As in human IPF, CIPF in WHWTs can have either a slow or rapid disease progression. When diseased WHWTs were followed over time, 5 of 15 WHWTs with CIPF needed to be euthanized because of AE.
Further research into the etiopathogenesis and genetics of CIPF is needed, along with searches for viable biomarkers for disease as well as disease progression.
Fig. 6Kaplan-Meier survival curves for all-cause survival (dashed line) and CIPF-specific survival (solid line) of WHWTs with CIPF from onset of clinical signs. Circles indicate censored animals (all-cause survival: WHWTs alive at study endpoint; CIPF-specific survival: WHWTs alive and those who died of non–CIPF-related causes).
(From Lilja-Maula LIO, Laurila HP, Syrjä P, et al. Long-term outcome and use of 6-minute walk test in West Highland white terriers with idiopathic pulmonary fibrosis. J Vet Intern Med 2014;28:379-85; with permission.)
The authors thank the funding sources: Orion-Farmos Research Foundation, Finnish Veterinary Association, Finnish Veterinary Research Foundation, and the Finnish West Highland White Terrier Breeding Club.
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An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. an update of the 2011 clinical practice guideline.
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