Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology that occurs particularly in West Highland White Terriers (WHWTs).[1, 2] The disease causes collagenous thickening of the pulmonary interstitium[3, 4] and impairs gas exchange. Histologically, IPF in WHWTs shares features of the 2 most common subtypes of human idiopathic interstitial pneumonia, usual interstitial pneumonia (UIP), the pathologic counterpart of IPF, and nonspecific interstitial pneumonia (NSIP). The median survival of WHWTs with IPF has been reported in a retrospective study to be 16 months from onset of clinical signs and 7 months from diagnosis, but speculated not to shorten life expectancy as the disease affects middle-aged to older WHWTs. In humans, median survival of IPF patients from diagnosis is only 2–3 years, whereas fibrotic NSIP has a better prognosis of 6–13.5 years.[6, 7]
No studies have reported prognostic factors in any interstitial lung disease in dogs. In human IPF, the search for prognostic factors has been extensive as the course of the disease can vary greatly among patients, from rapidly to slowly progressive to a step-like process. Several factors have been associated with poor survival in humans, including decreased walking distance in 6-minute walk test (6MWT), increasing grade of interstitial fibrosis on thoracic radiographs, fibrosis score and traction bronchiectasis in thin-section computed tomography, increased bronchoalveolar lavage (BAL) neutrophilia, and presence of pulmonary hypertension. In human IPF with a step-like progression, periods of relative stability are interrupted by acute exacerbations (AEs), which are associated with high mortality and a histopathologic pattern of diffuse alveolar damage (DAD). In WHWTs with IPF, DAD has been demonstrated along with consequent organizing luminal fibrosis, suggesting a more rapid progression of the fibrosis through organizing DAD in some dogs.
The 6MWT is a submaximal exercise test that measures the distance an individual is able to walk over 6 minutes (6MWD) and is widely used in clinical practice to evaluate and monitor human patients with IPF.[5, 14] The 6MWT has been assessed in a limited number of studies with healthy dogs,1, 2,  dogs with induced congestive heart failure, and dogs with various pulmonary diseases, and has been found to be an easy and reproducible test for screening exercise tolerance.
Our objective here was to describe the clinical course of IPF in WHWTs and assess survival of affected dogs compared with controls. In addition, prognostic factors for the disease, and use of 6MWT in WHWTs were evaluated.
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- Materials and Methods
As IPF is a disease occurring in older WHWTs, and the magnitude of its effect on lifespan has been unclear, as no prospective studies with controls have been published previously. In this study, we have shown that IPF has significant negative impact on life expectancy in WHWTs. This finding is supported by both our age-adjusted survival models, risk from birth being 4.6 times higher and from study inclusion 4.4 times higher in diseased animals than in controls. The age alone was a significant predicting factor in multivariate Cox proportional hazards model from study inclusion, emphasizing the importance of using an age-adjusted model in survival comparison. The HR for age in Cox model from birth was, however, less than one, although not significant, implying that age would reduce the risk of death. This unexpected finding is attributable to the different ages of dogs at the time of inclusion when the follow-up time was kept similar, creating an artificially low HR for age in the Cox model from birth.
Even though the median survival time from onset of clinical signs in the IPF-related death group was quite high, being 2.7 years, it varied greatly, from only 2 months to 4.3 years. This variation indicates that IPF in WHWTs may have a rapid or slow disease progression, as also seen in human IPF. However, the time frame for detection of clinical signs is highly owner-dependent and might be delayed for several reasons, eg, reduced exercise tolerance because of aging. The median survival after diagnosis in WHWTs with IPF was 1 year, but some dogs lived up to 3 years. In human IPF patients, the median survival after diagnosis is 2–3 years.
No significant prognostic factors were identified among the chosen variables. However, a slight indication of high PaO2 having a protective effect on survival and high P(A-a)O2 being a risk factor were noted. This indicative finding further supports the use of arterial blood gas measurement in IPF follow-up. In humans, an increase in P(A-a)O2 is associated with earlier IPF mortality. In addition, we detected no significant effects of change in repeated-measure variables on the risk of IPF-related death. However, some slight indication of a higher risk of IPF-related death can be seen in the increase of hematocrit, hemoglobin, and erythrocyte values. In human IPF, high red cell distribution width (RDW), not available in our study, and an increase in RDW have been suggested to have prognostic value.
We detected a declining trend in PaO2 values during disease progression. However, in some dogs, temporary increases in arterial oxygenation were noted, and some owners described a temporal improvement in clinical signs. The reason for these improvements remains unknown, but it is unlikely to be connected to the effect of medications on the fibrosis process; at least fibrosis in human IPF is unresponsive to medications used here. Our study design did not allow systematic evaluation of the treatment effect on survival or on clinical signs because of individual treatment protocols. The decrease between the first and last PaO2 values in dogs that died of IPF-related causes was significant, as was the increase in P(A-a)O2 values. Repeated measurements of arterial blood gas values seemed to be a good tool for evaluating disease progression, although it should be noted that some animals with very low PaO2 values survive quite long because of excellent adaptation and slow deterioration in oxygenation capacity.
Our study showed that IPF does not cause weight loss in dogs. Severe malnutrition is also not a feature of human IPF. Based on our findings, thoracic radiographs are not useful in evaluating disease progression, as the radiographic features varied during the disease independently of clinical signs. Evaluation of other possible emerging diseases, such as infections or neoplasms, is also challenging, as changes seen in radiographs already at the time of diagnosis are notable. None of the deceased WHWTs with IPF in our study had primary lung tumors detected postmortem. In humans, bronchogenic carcinoma occurs with increased frequency in lungs affected by IPF.
Exercise intolerance is a common clinical sign in WHWTs with IPF,[1, 2] but is difficult to evaluate reliably in older nonathletic pet dogs. Therefore, a noninvasive 6MWT was applied in the study. We showed that 6MWT is an easy and well-tolerated test also in WHWTs with IPF and the 6MWD in diseased animals was reduced relative to that in control dogs. Use of control dogs of same breed and age group is necessary to rule out confounding factors and to have more comparable results of exercise performance between diseased and healthy animals. Oxygen desaturation in 6MWT increases the risk of death in human IPF patients. Previous studies on dogs have reported a difference in oxygen saturation between healthy dogs and dogs with pulmonary disease as well as postwalking oxygen desaturation in a group of old healthy beagles. 1 In our study, we detected no significant difference in SpO2 between controls and WHWTs with IPF, nor did we find significant postwalking oxygen desaturation. Pulse oximeter seems to be a rather unreliable indicator of a decline in PaO2 in unanesthetized dogs, and its usefulness in 6MWT in WHWTs with IPF is questionable. In other variables measured pre- and postwalking, the only significant change was a higher postwalking heart rate in WHWTs with IPF; no changes were seen between any pre- and postwalking variables in control dogs. The short delay when taking the postwalking arterial sample may influence the arterial blood sample results. The PaO2 seemed to correlate positively with 6MWD, and therefore, 6MWD could serve as a noninvasive means of monitoring lung function in WHWTs with IPF. However, this finding needs further verification.
Four of the 5 WHWTs with IPF that were euthanized because of acute dyspnea had DAD in the lungs, in addition to chronic interstitial fibrosis. This finding is in line with human IPF, where DAD is reported as a common terminal histopathologic finding related to AEs. Human IPF patients with AEs have a very poor prognosis despite treatment efforts.[5, 6] One dog in the non-IPF–related death group also had DAD, but this is probably explained by the cause of death of this dog being drowning.
The main study limitation was the low number of animals. This is mainly attributable to disease being uncommon and the diagnosis, as well as verification of health, requiring invasive diagnostics. In addition, the median age of the control group was slightly younger, and only three deaths occurred in the control group. However, the median follow-up time was similar in both groups and the age was taken into account in the survival analysis. Because of low sample size, the results of prognostic factor analyses are mainly indicative, and should therefore be interpreted cautiously. In addition, some potentially interesting prognostic factors, such as 6MWD, altered BAL fluid cell counts, and presence of pulmonary hypertension, detected in WHWTs with IPF[1, 22] could not be included in the analysis.
In conclusion, the median IPF-specific lifetime expectancy after onset of clinical signs is 2.7 years, but this can vary greatly. IPF in WHWTs may therefore have both a rapid or slow disease progression. The WHWTs with IPF have a significantly higher risk of dying than control WHWTs. Acute worsening of the disease is characterized by dyspnea and is often associated with DAD in the lungs histologically. The 6MWD is an easy and noninvasive parameter to evaluate lung function and level of exercise intolerance in WHWTs with IPF.