Idiopathic pulmonary fibrosis in the UK: analysis of the British Thoracic Society electronic registry between 2013 and 2019

Discussion

Patient registries offer a unique opportunity to collect longitudinal data on uncommon diseases, such as IPF. They may help to identify specific clinical phenotypes and understand current practices in diagnosis and treatment stratification, ultimately leading to a more personalised medicine approach to individual patient care. Over the 6 years since it was established, the UK IPF Registry has collected baseline clinical data on over 2400 patients, which is the largest single-country IPF registry reported to date. Unlike clinical trials, which exclude patients based upon lung function impairment, comorbidities and concurrent medications, this retrospective analysis provides a more “real world” overview of patients with IPF in the UK.

Our baseline demographics are similar to other reported registries [5, 19, 21–26] as well as the inclusion criteria for the Assessment of Pirfenidone to Confirm Efficacy and Saftey in IPF (ASCEND) [3] and Efficacy and Safety of Nintednaib in IPF (INPULSIS) [4] clinical trials with patients being predominantly male, over the age of 60 years and ex-smokers. However, our mean±sd age at enrolment is higher than that reported by a number of worldwide registries (67–71±8 years) [5, 19–25] but comparable to the FinnishIPF Registry (73±9.0 years) [27]. This may be explained, in part, by an increase in the number and proportion of individuals aged 79 years or more diagnosed with IPF in our Registry. It may also reflect delays in presentation to primary care, referral to a respiratory physician or diagnosis as ∼40% of patients had symptoms for at least 2 years at time of inclusion to the UK IPF Registry. Delays in diagnosis may arise due to lack of awareness regarding IPF [28] and misdiagnosis with another respiratory disorder, as well as the complexities of the diagnostic pathway for IPF [29], although these cannot be evaluated using our Registry data.

The baseline lung function is analogous to that reported in the Australian IPF Registry (AIPFR) [5], The Belgian and Luxembourg Prospective IPF Registry (PROOF) [22], Spanish National IPF Registry (SEPAR) [26] and European Multipartner IPF Registry (EMPIRE) [24] registries as well as the INPULSIS study [4]. Although the gas transfer measurement was comparable, the mean FVC reported in our Registry was higher than that from the European IPF Registry (eurIPFreg) [23], United States IPF National Registry (IPF-PRO) [19] and ASCEND study [3]. Moreover, our cumulative data show that whilst the per cent predicted FVC at inclusion is relatively unchanged, the T_LCO value has reduced. From our data, the higher FVC and lower gas transfer values cannot be explained by an increase in the proportion of patients with coexisting emphysema. It may reflect more severe pulmonary fibrosis as supported by an increase in the proportion of patients in GAP stage II or more over this time. But other factors, such as pulmonary hypertension, can contribute to a reduction in gas transfer. However, Registry data concerning the presence of pulmonary hypertension are insufficient to draw any conclusions. Only a third of patients had performed a 6MWT at time of enrolment to the Registry. Given the limited data, we are unable to interpret these results. The Registry does not collect information about why the 6MWT was not performed. It may be due to lack of resources for testing and/or patient choice.

We identified a family history of IPF in <10% of cases, which is similar to that reported by the Finnish IPF Registry (FinnishIPF) [27], SEPAR [26] and PROOF [22] registries. However, a higher percentage of an affected first-degree relative has been observed in other registries [5, 23].

Data from patient registries have confirmed the presence of comorbidities in IPF and their association with poorer quality of life [30]. Our findings show that the majority of patients with IPF have a mean of 1.8 comorbidities. The most prevalent comorbidities were cardiovascular, including hypertension and ischaemic heart disease, and gastro-oesophageal reflux disease. These results are similar to those from the AIPFR [5], PROOF [22], eurIPFreg [23] and German IPF Registry (INSIGHTS) [21] IPF registries. In contrast, the prevalence of diabetes mellitus was greater (38%) in the FinnishIPF Registry [27] versus 15–22% as described by BTS, as well as European and Australian registries [5, 21–23, 26]. These comorbidities were collected at time of enrolment to the UK IPF Registry, and longitudinal data are required to determine their impact on treatment strategies, hospitalisations and mortality.

Our results demonstrate that the majority of patients had symptoms of exertional breathlessness and/or cough for 12 months or more, prior to diagnosis and enrolment on the UK IPF Registry. Similar findings have been reported by other registries, such as eurIPFreg where the average time between the onset of symptoms and diagnosis of IPF was 21.8 months [23]. Determining the time from onset of symptoms to diagnosis of IPF can be confounded by several factors. It is well recognised that there may be a prolonged period, up to 4–5 years, between symptom onset and diagnosis [31]. In addition, patients may be at different stages in their disease course at the time of enrolment, and it may be difficult to ascertain precisely when their symptoms first started. Although patients may have been diagnosed with IPF by local physicians prior to referral to a specialist ILD centre, the time taken to refer to an ILD service can be very variable. Overall 90% of Registry cases were submitted from specialist centres, where patient referral may be delayed until the FVC is within the treatment criteria defined by NICE. Hence the date of assessment or MDM is unlikely to be equivalent to the date of diagnosis. Furthermore, we have not observed an increase in the proportion of patients presenting with shorter symptom duration over the course of the UK IPF Registry. This suggests that there is a need for education and raising awareness about the condition to promote earlier diagnosis, especially amongst primary care physicians who frequently undertake the initial patient assessment.

The gold standard for diagnosis of IPF is MDM [6]; however, not all patients were reviewed at MDM. This may reflect that patients can be enrolled by secondary care teams without evaluation in a specialist centre MDM. In comparison to other registries, the UK IPF Registry has a higher number of cases being reviewed at MDM. This difference may be due to easier access to a specialist ILD MDM as the majority of the patients were enrolled from ILD centres who have regular MDMs. In comparison, limited access to local ILD multidisciplinary meetings was a major concern for the Australian IPF Registry who implemented a central MDM review to overcome this barrier [5].

Since the UK IPF Registry was established, there has been an update to the clinical practice guidelines [32], which reflects changes in the radiological diagnostic criteria for IPF [33]. However, the data presented have been collected using the previous ATS/ERS/JRS/ALAT guideline [18]. They show an increase in the number of cases reported with a possible UIP pattern on thoracic HRCT scan over this time. As the Registry does not independently evaluate the thoracic HRCT scans, these results suggest an increased awareness of the spectrum of radiological characteristics and clinical predictors of IPF [33, 34] amongst ILD physicians and MDM in the UK. From late 2019 onwards, the UK IPF Registry dataset was modified to reflect the newer clinical practice guidelines [32].

In the setting of possible UIP pattern pulmonary fibrosis, the clinical guideline advises lung biopsy provided there are no contraindications. Despite these recommendations, the surgical lung biopsy rate (<10%) was lower than the 20–30% reported by the IPF-PRO, PROOF, FinnishIPF, AIPFR and Swedish IPF registries [5, 19, 22, 25, 27]. Furthermore, we observed a reduction in surgical lung biopsy rates over this time. This could not be explained by an increase in bronchoalveolar lavage or use of cryobiopsy, as this was not routinely available at most enrolling sites. A similar decline in open or thoracoscopic lung biopsy procedures has been observed by the eurIPFreg [23]. The UK IPF Registry does not collect information as to why investigations such as surgical lung biopsy or bronchoalveolar lavage were not performed. We speculate that the decline in lung biopsy indicates a growing awareness and recognition of the risk of acute exacerbation and progression of pulmonary fibrosis associated with the procedure [35] amongst specialist ILD MDMs in the UK. In addition, the rates of bronchoscopy and analysis of bronchoalveolar lavage fluid (BALF) vary widely across registries, with analysis of BALF conducted in 85% of patients in eurIPFreg [23], 62% of patients in INSIGHTS-IPF [21], about 20% of patients in AIPFR [5] and 10% of patients in the IPF-PRO Registry [19]. This is in contrast to the lower number of bronchoalveolar lavage (4%) reported here. Although bronchoscopy is available at most UK IPF Registry enrolling sites, not all services can provide differential cell count analysis of the BALF. Furthermore, other factors such as comorbidities and patient and/or physician preference may influence a lower uptake of bronchoscopy in the diagnostic pathway for IPF in the UK.

Over the duration of the UK IPF Registry, there has been an increase in the use of anti-fibrotic therapies at time of enrolment supporting a change in patient management. Our data also show differences in prescribing practice which likely reflects the availability of these therapies in the UK, as pirfenidone was first approved for IPF in 2013 [11], but it was not until 2016 when access to nintedanib was granted by NICE [12]. Of note, not all eligible patients with IPF were receiving anti-fibrotic therapy. This may be due to several reasons including patient choice and contraindications to treatment. As only specialist ILD centres can prescribe anti-fibrotic therapies in England and Wales, any eligible patients enrolled by secondary care sites will not have access to these treatments until they are reviewed at a prescribing centre.

The UK IPF Registry confirmed that many patients are receiving supportive care. Approximately a quarter of patients have supplemental oxygen therapy at baseline, which is similar to that reported in the IPF-PRO Registry [19]. This has not significantly changed over the 6 years of the Registry. However, the observed increased use of pulmonary rehabilitation may reflect implementation of NICE Quality Standards for IPF [10] as well as the accumulating evidence that pulmonary rehabilitation improves quality of life and symptoms in patients with IPF [36]. As reported by other registries, the proportion of patients assessed and listed for lung transplantation remains small [19, 23]. Given the stringent suitability criteria, lung transplantation is only an option for a highly selected cohort of IPF patients.

The published registries have confirmed the high mortality associated with IPF. In support of this, the eurIPFreg reported a mortality rate of 38% during the follow-up period [23], the INSIGHTS-IPF Registry reported that 26.7% of patients died during follow-up [30] and 15% of patients died within 30 months as detailed by the IPF-PRO Registry [19]. Advanced age and worse lung function (FVC and T_LCO) have consistently been shown to be predictors of mortality in IPF registries [19]. A more recent analysis of data from 662 patients in the IPF-PRO Registry demonstrated that use of supplemental oxygen at rest was the strongest predictor of mortality over a follow-up period of 30 months [19]. Compared to other registries, the mortality rate reported here is lower. It is unlikely to be a true representation of IPF mortality in the UK as the survival data are incomplete. Longitudinal follow-up data are required for a more precise assessment of mortality. Hence we are not able to draw specific conclusions about IPF-related mortality in the UK in comparison to other worldwide registries.

The UK IPF Registry dataset has been modified in order to capture information relating to the NICE Quality Standards for IPF.

There are several limitations to these data, in particular incomplete datasets. In order to address this, the data have been presented as percentages and absolute numbers of patients shown where applicable.

In conclusion, we have reported the largest single-country IPF cohort, which may provide insights into the phenotypes and natural course of the disease as well as changes in the clinical management of these patients. Our results have identified key changes in the diagnostic evaluation of patients with suspected IPF in the UK between 2013 and 2019 suggesting a better understanding of the clinical and radiological predictors of IPF. We have also observed vital improvements in patient care. How these changes will impact longer-term outcomes such as hospitalisation and survival, as well as informing development of healthcare policies, remains to be determined. In addition, our findings have highlighted critical areas to target for research, especially the need for earlier diagnosis. Longitudinal data are essential to achieve these aims of the Registry. However ongoing challenges remain, in particular how to maintain the quality and completeness of the Registry data, which present both resourcing and administrative challenges.