Determinants and outcomes of prolonged anxiety and depression in idiopathic pulmonary fibrosis

To the Editor:

We have recently shown that anxiety and depression are common comorbidities for people with interstitial lung disease (ILD). In a cross-sectional single-centre study, the prevalence of anxiety was 31% and the prevalence of depression was 23% [1]. Anxiety and depression were not related to physiological parameters; however, dyspnoea and number of comorbidities were important contributors. The aims of this study were to determine the frequency of prolonged anxiety and depression among sufferers of idiopathic pulmonary fibrosis (IPF), and factors contributing to their persistence.⇓

Using the Australian IPF Registry, we obtained data from all individuals who had completed the self-reported Hospital Anxiety and Depression Scale (HADS) at baseline and at 12 months of follow-up [2, 3]. HADS scores were classified according to standard criteria where a score >10 indicates a probable case of clinically significant anxiety or depression and a score of 8–10 indicates borderline probability. We defined prolonged anxiety and depression as being present when subjects had HADS scores ≥8 at baseline and at 12 months follow-up. We defined worsening risk of anxiety and depression as moving from “no case” to “borderline” or “case”, or moving from “borderline” to “case”, at 12 months.

Analysis included demographic and physiologic data, and patient-reported medical comorbidities. Breathlessness was measured using the UCSD shortness of breath questionnaire (UCSDSOBQ) which, like the HADS scale, explores symptoms over the preceding week [4]. Cough severity was rated using an unvalidated visual analogue scale (VAS), measured between 0 and 100 mm, with anchors of “no cough” and “worst cough imaginable” The persistence of anxiety and depression over 12 months of follow-up was evaluated using the Fisher's exact test. Univariate relationships were tested using Pearson's Chi-squared test for categorical variables and one-way analysis of variance for continuous variables. Variables with a relationship to prolonged anxiety or depression (p<0.1) were entered into a logistic regression model. Model fit and the proportion of participants correctly classified by the model were evaluated using the Chi-squared test.

At the time of analysis, the Australian IPF registry included 435 participants with probable or definite IPF (table 1). All 102 participants who had completed the HADS questionnaire at baseline and follow-up (12±3 months) were included. Comparison of this group with those excluded from analysis at baseline demonstrated no differences with respect to demographic or physiologic features. At the 12-month follow-up 96 participants had completed the HADS anxiety domain and 98 had completed the HADS depression domain.

20 participants (21%) had prolonged anxiety, of whom 15 participants (75%) were not taking an anxiolytic. There was no association between prolonged anxiety and mortality (p=0.31). On univariate analysis, prolonged anxiety was associated with more severe baseline dyspnoea (p=0.008), supplemental oxygen use at baseline (p=0.035), suffering more comorbidities (p=0.005) and more severe baseline cough (p=0.07). There was no relationship with forced vital capacity (FVC) decline. On multivariate analysis, supplemental oxygen use was the only independent predictor of prolonged anxiety, and was associated with a 4.3 times greater odds of its presence (95% CI 1.142–15.636). There was a trend for association with cough severity (OR 1.023, 95% CI 0.997–1.049). The model correctly classified participants in 77% of cases.

13% of participants had a change in their HADS score to suggest worsening risk of anxiety over 12 months. On univariate analysis, worsening risk of anxiety was associated with change in cough severity over 12 months (mean increase 26 mm versus 2 mm, p=0.009), and worse dyspnoea at 12 months (UCSDSOBQ 94 versus 49 units, p=0.013). There was a trend for association with change in dyspnoea over 12 months (mean increase in UCSDSOBQ 37 versus 11 units points, p=0.06) and fall in FVC (mean −129 mL versus −30 mL, p=0.07). Multivariate analysis showed that only an increase in cough severity was an independent predictor of worsening risk of anxiety over 12 months (OR 1.056, 95% CI 1.011–1.104). A 10-mm increase on the cough severity scale was associated with a worsening risk of anxiety by 56%. This model correctly classified 93% of cases.

14 participants (14%) demonstrated prolonged depression, of whom 10 participants (71%) were not taking an antidepressant. On univariate analysis, prolonged depression was associated with worse baseline dyspnoea (p=0.004), worse baseline cough (p=0.03), more comorbidities (p=0.002), younger age (p=0.06) and worsening dyspnoea (p=0.07). There was no relationship with FVC decline. Multivariate analysis showed that prolonged depression was independently predicted by baseline cough severity (OR 1.045, 95% CI 1.012–1.080). A 10 mm increase in baseline cough severity increased the odds of prolonged depression by 45%.

7% of individuals had a worsening risk of depression over 12 months. Univariate analysis revealed associations with worse baseline dyspnoea (UCSDSOBQ mean 55 versus 36 units, p=0.046), worse dyspnoea at 12 months (80 versus 46 units, p=008) and change in dyspnoea (mean worsening 28 versus 10 units, p=0.006). 82% of individuals with a worsening risk of depression had two or more cormorbidities (p=0.017) and there were trends for association with greater worsening cough (41 versus 2 mm, p=0.08) and use of oxygen at 12 months (p=0.06). A change in FVC was not associated with worsening risk of depression. On multivariate analysis, only worsening dyspnoea was associated with a worsening risk of depression (OR 1.042, 95% CI 1.00–1.085). For each 1-unit increase in UCSDSOBQ over 12 months, the odds of a worsening risk of depression increased by 4%. This model correctly classified 89% of cases.

While previous cross-sectional research has demonstrated that depression is common among IPF sufferers, this study demonstrates that the tendency to anxiety and depression is retained over a 12-month period [5]. Pharmacologic therapy for anxiety and depression was being received in only approximately a quarter of cases, suggesting a large proportion are untreated. Further research is required to determine why this should be, with possibilities including that anxiety and depression are unrecognised, considered a normal response to IPF or thought refractory to treatment.

Our research confirms that dyspnoea is a major contributor to anxiety and depression and that another key IPF symptom, cough, is also an important contributor. The link between prolonged anxiety and depression and both cough and dyspnoea is demonstrated in a number of ways. On multivariate analysis, prolonged depression and cough were linked. While only oxygen usage was associated with anxiety on multivariate analysis, it has been previously demonstrated that ILD participants using oxygen perceive greater dyspnoea, and therefore in this study those variables are likely to demonstrate collinearity [6]. Finally, as cough and dyspnoea worsened, so too did the risk of anxiety and depression. The strong linkage seen between IPF symptoms and anxiety and depression raises the question of the direction of that relationship. Oxygen therapy was commonly added to our participants' therapy during the 12 months of longitudinal follow-up, but this did not appear to lessen the risk of anxiety. Whether the treatment of anxiety and depression might provide a route to the palliation of cough or dyspnoea remains an important question to explore.

This study has several limitations. We use the HADS scale at two time points to infer persistence of anxiety and depression rather than more thorough assessment as defined in current guidelines [7]. The validity of this instrument in detecting anxiety and depression is well established, but this has not been tested specifically in IPF [8, 9]. We used an unvalidated VAS measure of cough severity, potentially leading to imprecision. Additionally, we do not have a matched control population to determine the rates of prolonged anxiety and depression seen in the normal population.

Further research should examine the basis to prolonged anxiety and depression among sufferers of IPF. Any under recognition of anxiety and depression, or nihilism about their therapy should be addressed, given its strong linkage with IPF symptoms and health-related quality of life [10, 11]. Given the incomplete response of dyspnoea and cough to current palliative approaches, our findings suggest a further avenue for symptom control research via the treatment of anxiety and depression [12].

Disclosures