Professor, Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Roslin, Scotland, UK
Introduction and Background
Idiopathic pulmonary fibrosis (IPF) is an emerging disease of importance in human medicine in the developed world. It is estimated that 150,000 people in the USA are affected and up to 6,000 new cases are identified in the UK each year. It is likely these figures are an underestimate not least because of the difficulty in achieving a definitive diagnosis and lack of awareness amongst primary care general practitioners. There is evidence for a range of chronic lung fibrotic conditions affecting veterinary species and credible reports have included dogs, cats, horses and donkeys. It is not clear that the veterinary diseases are directly analogous to human IPF, but this is a debatable point as there is changing opinion as to the exact definition of IPF in mammalian species.
It has been generally presumed that IPF represents a pathological phenotype referred to as usual interstitial pneumonia (UIP) and that other fibrotic lung diseases that do not have the correct pathological changes cannot be included in the IPF category. However, there is confusion as to what extent other forms of fibrotic or profibrotic lung diseases might be subsets of IPF or might contribute to the eventual IPF phenotype. Clearly there are fibrotic lung diseases that have no relationship to IPF. In the case of the asinine disease, which can affect up to 35% of donkeys, this has now been confirmed to be pleuroparenchymal fibroelastosis (PPFE) and not IPF. PPFE is reported to be a very rare condition in humans, but might be underdiagnosed. The equine form of IPF has reasonably close pathological correlates, but is invariably associated with infection the EHV1 virus, but a viral aetiology is not observed in humans. The dog form has been proposed as a potential model of the disease, not least because of the similar clinical presentation and the shared environment between dogs and humans. However, the pathology appears to be mixed with some evidence of UIP, but a predominance of nonspecific interstitial pneumonitis (NSIP). Lastly, the feline form is the most credible when it comes to comparison with human IPF, but is relatively rare, and cats also get desquamative interstitial pneumonitis (DIP) which is not part of the IPF phenotype.
What is interesting in discussion of disease phenotype and pathological correlates is the continual re-evaluation of the disease in humans. It can be decided that IPF is UIP, but what contribution might NSIP and DIP make to the disease is being reconsidered, particularly if two or more are found in the same patient. This re-evaluation of pathological phenotype in human IPF will have consequences for our understanding of IPF in veterinary species, particularly dogs.
Clinical Presentation and Diagnosis
Canine IPF (cIPF) is probably the best described of all the veterinary forms of the disease and has close clinical comparisons to that seen in human patients. Typically dogs are middle to old age (> 9 yrs), have a slowly progressing respiratory condition with exercise intolerance, coughing and dyspnoea with the severity of clinical signs matching the extent of disease. cIPF is most commonly seen in West Highland white terriers and is only rarely seen in other breeds. On physical examination distinct inspiratory pulmonary crackles are heard on auscultation, but there are few other specific signs. Affected dogs are very healthy, keen to exercise and have a good appetite. Some might show cyanosis during exercise, but if seen at rest indicates respiratory failure has occurred and that euthanasia is needed.
There are no specific diagnostic tests available, so tentative diagnosis is made on the basis of exclusion of other probable diseases. Lung biopsy for histological confirmation is not readily available, and even if it was, the patchy regional distribution of pathology and the small samples that might be collected would make confirmation difficult.
Diagnostic imaging is the main method used to identify affected dogs. In conjunction with bronchoscopy and BALF to exclude other possible diseases, high-resolution computed tomography (HRCT) is the best available option, and is widely used for the same purpose in human IPF. HRCT findings have been described for both the dog and human and there are definite differences suggesting the diseases are not exactly the same. For example, ground-glass opacity is commonly seen in dogs, but is presumed to represent NSIP in humans, so is not accepted as a criterion of IPF. More IPF-specific changes in both species include subpleural localisation, subpleural bands, parenchymal bands, honeycombing (very uncommon in dogs) and traction bronchiectasis, with or without some degree of ground-glass opacity. On BALF sampling there is some disagreement as to what should be found in dogs with IPF. UIP is characterised by a subpleural localisation, minimal cell infiltrates, presence of myofibroblasts, fibroproliferation with fibroblast foci and honeycombing. Some dogs, and most human patients, will have acellular BALF samples, while other dogs may have large cell numbers. In the latter group the coexistence of chronic bronchitis needs to be considered, or alternatively, might they be affected by NSIP?
Because of the difficulty in achieving a definitive diagnosis with HRCT, and the reluctance to take lung biopsy in these elderly and respiratory-compromised patients, work is ongoing to try and identify biomarkers for IPF. There is particular interest in BALF and serum levels of the chemokine CCL-2, levels of which correlate closely with disease phenotype and clinical severity in human IPF. Studies are ongoing to look for similar biomarkers in cIPF, and such tests would be invaluable in diagnosis considering the expense and limited availability of HRCT in canine medicine.
Because these dogs have severe and extensive pulmonary fibrosis, at least 50% will have clinically significant pulmonary arterial hypertension, which can be most easily identified using Doppler echocardiography if they have a tricuspid regurgitation or a combination of 2D echocardiographic examination of the right side of the heart and pulmonary artery and HRCT imaging.
Treatment, Management and Prognosis
Drug therapy is of little benefit in IPF, but most canine cases tend to be trialled on prednisolone and may show a response if chronic bronchitis or active inflammation is implicated, but not if the presentation is exclusively caused by fibrosis. Azathioprine is preferred in human patients over prednisolone, but there is no clear evidence to support its use in these patients. Because many patients, canine and human, have pulmonary hypertension, sildenafil (Viagra) is trialled to see if there is clinical benefit. Combination therapy of sildenafil with pimobendan has been reported in human patients with IPF in Japan (the only country where pimobendan is licensed for human use) and some reports suggest it is of clinical benefit, and this combination can be advocated for the dog. The antifibrotic drug pirfenidone has recently been licensed (restricted use) for human IPF in Europe and has shown some promise, but is not yet available for veterinary use.
As for human IPF, the canine condition is predictably progressive and results in terminal respiratory failure. Death can occur anytime between 2 to 50 months after diagnosis, but this survival prediction is dependent on the extent of disease at diagnosis (how severe) and if there are any comorbidities or any episodes of acute exacerbations. A median survival from the owner first noticing clinical signs can be about 15 months, but again this is dependent on owner observation bias as most owners confuse the onset of clinical signs with normal ageing changes. In human IPF there is an increasing awareness that survival is heavily dependent on the presence of comorbidities; lifestyle (obesity, cigarette smoking, etc.); whether or not the patient is being managed by a specialist centre; and the rapidity in which acute exacerbations are dealt with.
1. Syrja P, Heikkila HP, Lilja-Maula L, Krafft E, Clerx C, Day MJ, Ronty M, Myllarniemi M, Rajamaki MM. 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. J Comp Pathol. 2013;149:303–313.
2. Travis WD. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188:733–748.
3. Corcoran BM, King LG, Schwarz T, Hammond, G, Sullivan M. Further characterization of the clinical features of chronic pulmonary disease in the West Highland white terrier. Vet Rec. 2011;168:355.
4. Johnson VS, Corcoran BM, Wotton PR, Schwarz T, Sullivan M. Thoracic high-resolution computed tomographic findings in dogs with canine idiopathic pulmonary fibrosis. J Small Anim Pract. 2005;46:381–388.
5. Roman J, Brown KK, Olson A, Corcoran BM, Williams KJ. An official American Thoracic Society workshop report: comparative pathobiology of fibrosing lung disorders in humans and domestic animals. Ann Am Thorac Soc. 2013;10:S224–S229.