Idiopathic Pulmonary Fibrosis: Description of Clinical Presentation
ACVIM 2008
Brendan M. Corcoran, MVB, PhD, MRCVS
University of Edinburgh
Scotland, UK

Introduction

Idiopathic pulmonary fibrosis (IPF) (also known in human medicine as cryptogenic fibrosing alveolitis in the UK and Europe) has been suggested to exist in the dog in recent years and some clinical and pathological evidence exists to support that assertion.1-4 However, the data are not entirely convincing as most of the information has been obtained from retrospective clinical studies and investigation of archived pathological material. The clinical impression is that an IPF-like clinical entity does exist in the dog and this appears to be particularly prevalent in the West Highland whiter terrier.4 For many years there have been anecdotal reports of a progressive debilitating respiratory condition in this breed characterised by profound crackles on thoracic auscultation, a marked interstitial pattern on thoracic radiographs and unresponsiveness to therapy. A similar clinical presentation can also be found with chronic bronchitis, although such patients often show a response to glucocorticosteroid therapy. The condition probably is present in other breeds of dogs, but the WHWT appears to be over-represented.

Clinical Presentation & Diagnosis

Previously, a retrospective study of 32 WHWTs had described the clinical appearance of a chronic respiratory presentation in this breed characterised by middle-age (median 9 yrs) onset of respiratory signs that progressed over many months, resulting in significant respiratory disability, coughing and exercise intolerance4. Although these dogs remained bright and alert throughout, eventually respiratory failure ensured. The main finding on physical examination was inspiratory crackles, and the suggestion was made that this clinical presentation might be analogous to IPF in humans. An additional observation was that these dogs had no bronchoscopic evidence of chronic bronchitis, the main other cause of chronic inspiratory crackles in dogs. Subsequently, IPF-like disease had been reported in other breeds and the consensus developed that an IPF-like entity probably does exist in dogs and that it appears to be particularly prevalent in the WHWT.1-3 However, definitive pathological proof of canine IPF is still lacking and furthermore the accuracy of clinical diagnosis has not been determined.5 Recently, a prospective study has been carried out in the USA and UK to better clarify the clinical features of WHWT IPF, and the data is in preparation for publication.

WHWTs with this clinical presentation appear to fall into three categories; chronic bronchitis alone, a combination of IPF and chronic bronchitis, and lone IPF. Approximately 40% of dogs will have lone IPF. For all three clinical presentations the clinical history is indistinguishable and no distinction can be made on physical examination or routine haematology and biochemistry profiles. Bronchoscopy is crucial in the identification and confirmation of chronic bronchitis, either as the sole condition or in combination with IPF. Analysis of bronchoalveolar lavage samples suggests a low cellular response is more typical of pure IPF, and this, not surprisingly, coincides with the absence of bronchoscopic changes. However, the BAL cell differential count does not assist diagnosis. Interestingly, bronchoscopy also identifies mild changes in some IPF cases suggesting co-existence of the other diseases or possible bronchial changes secondary to IPF. In these cases, the clinical disability, and in particular the presence of inspiratory crackles is best explained by the presence of IPF alone, with the mild airway changes making no significant contribution. A further interesting finding is that many WHWTs will have tracheal collapse, but to what degree this might contribute to their respiratory disability is currently unknown.

Thoracic radiography and high resolution computed tomography (HRTC) seem to be equally effective in identifying the presence of interstitial lung changes, but radiography is less sensitive in identifying bronchial changes. However, such changes can be identified on bronchoscopy suggesting HRCT is not necessary to obtain a reasonably complete picture of the bronchial and interstitial changes seen with IPF. HRCT does allow better discrimination of subtle lung changes and localisation of lesion changes. Additionally, the use of HRCT improves confidence in diagnostic interpretation of radiographic changes, but does not appear to appreciably affect the final diagnosis. If this imaging technique was more readily available it would probably be the technique of choice. Some dogs will have arterial hypoxia at rest, and this will correlate with the severity of lung disease. The concurrent existence of significant cardiac diseases needs to be considered in IPF cases as they may contribute to the clinical picture, but the most likely cardiac consequence of IPF is right sided heart failure in those patients that have significant tricuspid regurgitation. A significant proportion of dogs with IPF-like disease will have pulmonary hypertension, and in addition to increasing the risk of right sided heart failure, this will contribute to the dogs exercise intolerance.6

In human patients ante-mortem diagnosis without invasive lung biopsy is greatly improved by using High Resolution Computed Tomography (HRCT). IPF in human patients will show reticular opacities, traction bronchiectasis and honeycombing and this correlates well with the pathological changes allowing differentiation from other IPF-like diseases.7 However, the diagnostic accuracy of HRCT is closely linked to the radiologist's experience, which interestingly matches the accuracy of expert clinicians.8 Lower lobe honeycombing and upper lung irregular lines are most predicative of IPF. Nevertheless, there can be a noticeable proportion (varies between studies) of patients where HRCT is inaccurate in identifying IPF.8 An additional use of HRCT in human IPF is its predicative valve for prognosis.9 Used in conjunction with functional lung testing, HRCT findings can be a predictor of time to death and response to therapy, but longitudinal HRCT changes in the short to medium term are less useful in determining prognosis compared to physiological testing.10 More recently there has been a report of HRCT changes in a group of ten dogs (2 Cairn terriers and 8 WHWTs) with suspect IPF.11 An interesting finding was that the two severely affected dogs had traction bronchiectasis and honeycombing, which are common findings in human IPF, and which was not present in the mild or moderately affected cases. Other changes noted in some or all of the categories were ground-glass opacity (as the sole finding only seen in a mild case), sub-pleural interstitial thickening, sub-pleural lines, parenchymal bands and peri-bronchovascular interstitial thickening (in all categories).11 Despite the advances with HRCT use in human medicine, the limitations of imaging still necessitates the use of surgical lung biopsy to achieve a definitive diagnosis, but there is agreement that highly suggestive evidence from clinical presentation and imaging can suffice in making a likely diagnosis, thereby avoiding the inherent risk of biopsy.9,12

In humans and dogs with IPF, the severe respiratory pathology can result in pulmonary arterial hypertension (PAH), which may contribute to the development of right-sided congestive heart failure, and the presence of PAH can significantly compromise exercise ability and quality of life.6,13

Pathology

Pathology is crucial to determining if IPF exists in the dog or not. The diagnostic criteria for human IPF have been laid out in the International Consensus Statement (2000) of the American Thoracic Society and the European Respiratory Society, with subsequent modification in the light of advances in pathological description.12 It is now accepted that definitive diagnosis is dependent on pathological confirmation of Usual Interstitial Pneumonitis (UIP). UIP is described as fibrotic areas mainly localised to the peripheral sub-pleural parenchyma, associated with honeycombing, and focally distributed such that fibrotic areas are interspersed with relatively normal areas of lung.14-17 There are areas of chronic fibrosis as well as areas of more active fibrosis with accumulation of proliferating fibroblasts and myofibroblasts ("fibroblastic foci"). Thickening of alveolar walls with collagen, extra-cellular matrix, type II pneumocyte hyperplasia and mild to moderate infiltration with lymphocytes, plasma cells and histiocytes is also reported.9,16 UIP is pathologically distinguishable from other idiopathic interstitial pneumonias, such as desquamative interstitial pneumonitis (DIP) and non-specific interstitial pneumonia (NSIP).16 DIP was previously thought to be an earlier, more active and more responsive to therapy form of UIP, but is now recognised as a separate entity.16 DIP has been described in the cat, but not in the dog15, and UIP has also been described pathologically in the cat, where the characteristic finding of fibroblast/myofibroblast foci is described.18 In the dog, the difficulty with ascribing a UIP-like pathology to putative IPF cases is the paucity of pathology data for the dog. Coupled with this is the lack of clear criteria for defining the clinical features of canine IPF and so properly correlating the clinical and pathological phenotypes. Of the 30 WHWTs, four Staffordshire bull terriers, one bull terrier and one schipperke whose clinical signs have been reported in the literature, pathological assessment, either as full post mortem reports or assessment of lung biopsies, is available for only 10,. However there are some concerns about the accuracy of IPF diagnosis for some of these cases, making interpretation of the pathological reports problematic. Changes reported in dogs include severe alveolar septal fibrosis, alveolar epithelialisation and perivascular hyalinization, alveolar metaplasia, hyperplasia of type II pneumocytes, and interstitial and alveolar cellular infiltrates. However, proliferative fibroblast foci and activated myofibroblasts have not been reported to date in the dog, making accurate comparison with human (UIP) IPF difficult. What is needed is detailed post-mortem examination of cases where strict diagnostic criteria have been applied, to determine if UIP exists in the dog.

Therapy and Outcome

The prognosis for canine IPF is very poor with respiratory failure an inevitable outcome. This is similar to that reported for human IPF patients, where apart from heart-lung transplantation, there is no cure. Typically, both canine and human patients are administered glucocorticosteroids and immuno-suppressive drugs such as azathioprine on a trial and error basis. If there is a clinical response it is more likely to be due to the presence of chronic bronchitis in the dog or an inflammatory interstitial disease, such as DIP, in humans and not due to an effect on IPF. The use of anti-fibrotic drugs, such as colchicine also appears to be of little benefit. Sildenafil can provide some improvement in clinical signs in those patients with concurrent pulmonary hypertension.13 The survival of dogs with IPF from diagnosis can be between 1 and 36 months, but typically is less than 12 months.

Conclusion

On the basis of the available data, it can be stated with reasonable confidence that an IPF-like condition exists in the dog, and is particularly prevalent in the West Highland white terrier. Furthermore, it is a slowly progressive respiratory disease of middle aged dogs, presents with one or a combination of coughing, dyspnoea and exercise intolerance in otherwise healthy dogs, in which there is no evidence of chronic bronchitis on bronchoscopy, is likely to have a low cellularity in bronchoalveolar lavage samples, and has radiographic or HRCT evidence of an interstitial pattern. The condition is incurable and therapy is at best palliative and more typically ineffective. The definitive proof that canine IPF is analogous to human IPF will depend on more extensive pathology studies.

References

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Speaker Information
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Brendan Corcoran, MVB, PhD, MRCVS
The University of Edinburgh
Roslin, Midlothian, Scotland


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