Trends and seasonal variation of hospitalization and mortality of interstitial lung disease in the United States from 2006 to 2016

Interstitial lung disease (ILD) is a group of lung disorders characterized by abnormalities within the interstitium with or without extensive alteration of alveoli and airways [1]. There have been multiple forms of interstitial lung disease described, most of which lead to progressive lung scarring and dyspnea if left untreated [2, 3]. Idiopathic pulmonary fibrosis (IPF) is one of the most well described ILD with overall very poor prognosis and median survival of 3 to 5 years [4‐6]. ILD remains still one of the most challenging respiratory entities to fully understand effectively treat and requires high healthcare utilization. In the past decade, there have been multiple new treatments and knowledge of this complex group of lung disorder. However, study on the overall trend of hospital admission and mortality over the last decade is still needed.

Seasonal variations can play a major role in the general health and wellbeing of patients with respiratory conditions. Winter season can impact lung function and increase the risk of acute exacerbations [7]. The mechanisms of this observation are complex and not fully understood [8]. Pulmonary conditions other than interstitial lung disease such as chronic obstructive pulmonary disease (COPD) have been well studied showing significant seasonal variation [9‐11]. Understanding how respiratory diseases change with seasonal variation could guide medical professionals in more effective health resource allocation and to direct future studies on the pathogenesis of this complex entity.

Using a large administrative database, we aimed to analyze the trends and seasonal association of hospital admission and all-cause mortality of ILD in the past 10 years.

We obtained the study population from Nationwide Inpatient Sample (NIS) of Agency for Healthcare Resource and Quality (AHRQ) Healthcare Cost and Utilization Project, years 2006 to 2016. All data contained in these database files have previously been de-identified and are off public record, therefore, our institutional review board decided no approval for the study was necessary.

Appropriate weighting was used to produce accurate nation-wide estimates.

Study population was limited to adult patients (age ≥ 18), admitted with the primary diagnosis of interstitial lung disease (ILD) of all causes excluding the identifiable external causes (drug, asbestos, silicosis, pneumoconiosis, hypersensitivity pneumonitis due to organic dusts). (International Classification of Diseases, ninth revision, clinical modification (ICD-9-CM) diagnostic codes 516.30 through 516.37 and 515); ICD-10-CM codes J84.1 through J84.117). A complete list of used ICD codes with description is available in the Appendix. Annual population estimates were obtained from U.S Census Bureau, to account for growing U.S population.

To the best of our knowledge, our study is the first to describe both seasonal variations of hospital admission and in-hospital mortality for IPF and non-IPF ILD in the United States in the 11 year- period from 2006 to 2016. Our primary findings are that from 2006 to 2016, all-cause hospital admission rate of patients with interstitial lung disease (all interstitial lung disease and IPF-only subgroup) declined but their overall mortality remained unchanged (except IPF subgroup). Acute respiratory failure related admission account for 23% of all causes and pneumonia 17.6%. Mortality of ILD in general and ILD with acute respiratory failure is highest in winter, up to 8.13% ± 0.60 and 26.3% ± 10.2% respectively. Admission rate for all cause admissions are highest in months from January to April. Subgroup analysis also showed seasonal variations with highest hospitalization rates for all subgroups (IPF, ARF, pneumonia) in the months from December to April (winter to early Spring).

Our finding of highest all-cause mortality for all causes of admissions and subgroup of acute respiratory failure in the winter was similar to the findings by Olson et al. which used a different database for analysis [12]. Seasonal variations were observed in hospitalization rates across all subgroups (acute respiratory failure, IPF, pneumonia) as well. The two most common explanations for winter and early Spring increase in admission rates are respiratory infection and cold temperature. Cold air could hypothetically induce hyperpnoea, subsequently cause drying of the airways [13] and inducing proinflammatory substances production leading to epithelial injury [8]. Infectious etiology was suggested because strong seasonal variations have been reported in COPD, pneumonia and recognized viral illness [14]. There is some evidence that a colder environment could also prolong the life span of viruses. Many viruses such as influenza A, RSV and mycoplasma pneumonia which cause infections in humans almost exclusively in winter to early spring [15, 16]. One interesting findings is that although winter has highest admission rate for all subgroups (IPF, ARF, pneumonia and ILD in general), the mortality does not have strong seasonal variations in idiopathic pulmonary fibrosis and pneumonia only subgroup. One hypothesis could be the severity of IPF related admissions and pneumonia has no weather association. We could not find literature to explain this finding thoroughly and it could be a topic for future research.

Respiratory causes of death accounted for 64 -89% in patients with ILD [17‐19]. We found that acute respiratory failure accounts for 23% of admission of interstitial lung disease and this types of admission has high mortality rate of 26.3% ± 10.2%. This finding concurs with the results of Moua et al. that IPF and non-IPF interstitial lung disease both have very high and similar mortality rates after admission for respiratory distress [20]. Based on a study in Finland, ischemic heart disease, heart failure and lung cancer were the other causes of death [21]. All of those conditions also have been reported to have higher mortality in winter time in the general population [12, 22], which may explain the higher mortality in IPF and non IPF ILD patients in winter time.

Of note, the in-hospital mortality of interstitial lung disease was noted to be significantly higher than the similar study in chronic obstructive lung disease (COPD) and asthma patients using the same national database,8% vs 2, 8% vs 1% respectively [23, 24]. interestingly enough, the mortality rate was 14% higher in the winter compared to the summer, which was less pronounced than the seasonal variations of all cause of deaths of COPD patients (25 to 50% higher in the winter) [12, 25]. Although both COPD and interstitial lung disease are both progressive illnesses with the pathogenesis involving accelerated cellular senescence [26]. This finding suggests that the impact of weather and viral illness on mortality might not be as pronounced in ILD, compared to COPD.

One of the utmost important roles of physicians is to prevent hospital admission for ILD patients. ILD and especially IPF related admissions are significant events after which the lung function of patients will significantly deteriorate with the mean survival only from 2.8 months to 27.7 months [27]. From our study, we found that all cause admission rates in ILD patients, subgroup of only IPF, acute respiratory failure and only pneumonia in the last 11 years were highest in the months December to April (winter to early Spring). Spring in general had highest admission rates compared to the average of other seasons, even when infectious lung diseases were ruled out. Moineddin et al. in their study in the primary care settings found a higher office visits due to respiratory disease in the months from December to April [28].

In the period of 11 years from 2006 to 2016, we observed a decrease in admissions rate for all cause hospital admission for ILD (all types ILD and subgroup of IPF) with the rise in population taken into account. The sharp decrease in 2016 hospital admissions might be a result of incomplete report of administrative data possibly due to the transition from ICD-10 system in the third quarter of 2015. In addition, many advances have been introduced in diagnosis and treatment of interstitial lung disease [29] as well as in hospital management in reducing hospital admissions [30].

The all-cause mortality rate from interstitial lung disease from 2006 to 2016 has been unchanged. However, the all-cause mortality rate of idiopathic pulmonary fibrosis subgroup encouragingly decreased in this 11-year period. Anti-fibrotic treatment availability could be a possible explanation. A recent large database study by Demsey et al. reported a decreased mortality risk in IPF patients in the first 2 years of anti-fibrotic treatment [31]. However, it is challenging to pinpoint a single factor that lead to this encouraging result based on our study especially when antifibrotic therapies were only approved since 2014 [32].

Our study has limitations. We did not include all types of interstitial lung disease We excluded the interstitial lung disease group with identifiable external agents (organic dust, drug, asbestos, silicosis, pneumoconiosis) because of two reasons. Firstly, it is for the comparison with the results of the study by Olson et al. for the interstitial lung disease group from 1992 to 2003 [12] and secondly, including ILD group with identifiable external agents with different pathogenesis will create more heterogeneity to our population. IPF cases were identified based on a broad definition algorithm which has been commonly used in the epidemiology studies. However, this algorithm was sensitive but not specific [33], thus could overestimate the prevalence of IPF in our ILD population. We also did not include the analysis of ILD with and without lung cancer subgroups because it would require extensive analysis beyond the scope of this manuscript. Concomitant lung cancer and interstitial lung disease could be a topic for future studies. Although we have included all ICD-9-CM and ICD-10-CM codes for interstitial lung disease, the results are inevitably susceptible to errors from coding inaccuracies. Nevertheless, this study has provided with an important and objective overview on the seasonal variations and trends in admissions and mortality of this entity spectrum over a long period of time.

All cause hospital admission and mortality of interstitial lung disease have a strong seasonal variation in 11 years from 2006 to 2016. Hospital admissions are highest in the period from January to May, in-hospital death was highest in the winter. All- cause hospital admission of patients with interstitial lung disease declined but their mortality remained unchanged, with or without the presence of infectious pneumonia.