In this study, we examined in-hospital mortality trends in patients with IPF from 2013 and 2017, which spanned the years immediately preceding and after the approval of anti-fibrotic therapy to treat IPF. We found that while in-hospital mortality was 10.9%, mortality was higher among patients admitted to academic hospital (11.6%) and even significantly higher in those with respiratory failure (20.5%), and those requiring mechanical ventilation (41.8%) who are admitted to academic centers. While in-hospital mortality did not significantly change over time for all-comers, mortality did significantly decrease in patients admitted to academic hospitals, including those with respiratory failure and those requiring mechanical ventilation. We reported no significant change in all-cause mortality in patients admitted to a non-academic institution. While respiratory failure associated mortality decreased significantly in IPF patients admitted to non-academic centers, mechanical ventilation-associated mortality increased significantly in this group. Subgroup analysis showed that mortality did significantly decrease in patients admitted with respiratory failure and in those requiring mechanical ventilation. These observations might suggest that the early referral to academic centers may reduce IPF mortality.
Our data demonstrate increasing all-cause hospitalizations for patients with IPF from 2013-2017, which may reflect previously reported increasing incidence and prevalence of IPF in the US.[27, 28] Despite this increase in hospitalizations, our data suggest a relatively static in-hospital mortality for patients admitted during this timeframe. These findings are supported by others using the NIS dataset, who reported similar all-cause mortality in patients with IPF admitted to the hospital 2006 to 2012[29] and others using a similar dataset, who reported IPF mortality during index admission from 2011 and 2014 to be 10.3%. [30] These findings stand in contrast to those published using the online CDC national death certificate database, which showed IPF-related mortality to be increasing over this timeframe.[31, 32] Besides, others reported decline in IPF all-cause mortality and hospitalizations using NIS dataset. [33] With different case finding methodologies employed by each study, these observations highlight the difficulties with capturing accurate IPF data using claims databases.
During the study period, when IPF hospitalizations were stratified by hospital academic status, we found a significant decline in all-cause mortality, respiratory failure associated mortality and mechanical ventilation associated mortality in IPF patients admitted to teaching hospitals. Interestingly, we found a significant increase in mechanical ventilation associated mortality in IPF patients hospitalized in a non-academic institution. No significant changes in all-cause mortality in IPF patient admitted to a non-academic hospital while respiratory associated mortality decreased significantly in the same group. The reasons underpinning these observations remain unclear but may suggest a stronger adherence of IPF guidelines at academic centers. We also hypothesize that multidisciplinary discussion for IPF diagnosis would be conducted in academic centers, and unlikely to be performed in non-academic institutions. Early access to lung transplant service and anti- fibrotic therapy might explain this observation as well. Others have shown that early referral of IPF patients to tertiary care centers is associated with reduced mortality, supporting an added benefit provided at these centers.[15]
We observed a significant decline in respiratory failure-associated mortality over the years assessed. Additionally, despite the plateau in mechanical ventilation associated mortality in the whole cohort, mechanical ventilation therapy and mechanical ventilation associated mortality in the respiratory failure group declined significantly. The mortality rate in IPF patients with respiratory failure receiving mechanical ventilation therapy has been reported to range from 50% to 90%.[2, 29, 34] Others reported mortality of 55.7% in intubated IPF patients between 2009 and 2011 using a different case definition for IPF codes (ICD9, 516.3). [34]Another study showed declining mortality between 2006 and 2013 from 58.4% to 49.3% using the same database, but different case definition.[29] In our cohort, the decline in the respiratory failure associated mortality, mechanical ventilated associated mortality and mechanical ventilation therapy is likely multifactorial and might reflect evolving and increased adherence to evidence-based pharmacological and non- pharmacological management strategies. [35]
The influence of comorbid conditions and interventions on IPF mortality has been increasingly studied over the last decade.[23] Our study supports the findings of others who have shown age, sex [30, 36-38], race and smoking history[36, 37, 39] to confer differential mortality risk. We found that admission to an academic center was associated with higher mortality risk, which is similar to previous studies[34] and may reflect a higher acuity of illness. Respiratory failure and need for mechanical ventilation therapy were the strongest predictors of in-hospital mortality, which supports prior findings.[7, 30] It is unclear why elective admission has been associated with increased mortality. One theory would be that elective admissions might be related to referrals from non-academic hospitals or urgent admissions from the outpatient clinic. In our assessment of comorbid conditions, our findings supported the work of other showing mortality risk to be increased in patients with pneumonia,[34, 40] low body mass index,[41] and thromboembolic disease,[42]. We found that those with concurrent obesity, GERD, diabetes and sleep apnea had lower mortality risk, which adds to mixed results with these conditions.[24, 25, 43-45] Finally, long term oxygen therapy was associated with decreased in-hospital mortality in our analysis. It is unclear if this is a true effect or this result is confounded by the presence of other diseases in which oxygen use is associated with improved survival. Further studies need to evaluate the impact of long-term oxygen use on IPF patients’ survival.
This study has several limitations. First, we used an administrative database, in which coding and documentation errors are inherent limitations. In attempts to mitigate the potential errors, multiple internal quality control measures are conducted to validate the NIS.[17] In addition, ICD-coding for IPF patients is challenging, given the complexity of the IPF diagnosis process, and might be another source of error. Therefore, we adopted a conservative approach which may result in missed cases and lower sensitivity at the expense of increased specificity. We included only patients with IPF specific codes (ICD-9, 516.31; ICD-10, J84.112), and we did not include less precise codes (ICD9, 516.3 or 515; ICD10, J84.1 or J84.9) used in previous studies.[29-31, 34]. Vu et al.[18] showed in a USA population- based study that only 4% of patients with IPF ICD9 code 515 had definite or probable IPF by 2018 Fleischner criteria. A Finnish study showed that 20-30% of patients with ICD10 codes J84.1 or J84.9 met IPF criteria.[46] We also excluded any patients who had a concomitant diagnosis of environmental exposure or CTD.[47] Second, our study is a retrospective observational study based on discharge data, and it is liable to selection bias and can only assess association and not assess causation. Finally, we were not able to retrieve antifibrotic treatment data for our analysis, therefore our results may or may not reflect the impact of the 2014 approval of anti-fibrotic therapy for the treatment of IPF. However, our data do potentially support the work of others, who have shown antifibrotic therapy to be associated with decreased mortality, respiratory hospitalization and AE-IPF. [6, 10, 48]