Underlying and immediate causes of death in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common form of the idiopathic interstitial lung diseases [1]. The most common cause of death in IPF patients has been reported to be the disease itself followed by cardiac disorders and lung cancer [2‐5]. A rapid deterioration of the disease may be caused by pulmonary embolism, pneumothorax, infections or heart failure [6]. Nearly half of all patients (47%) dying primarily from IPF had experienced a deterioration of their lung disease prior to their death [7]. A new definition and revised diagnostic criteria for acute exacerbation of IPF have been proposed recently; exclusion of infection or other potential triggers is no longer required, the only qualifier is that the clinician should determine that cardiac failure or fluid overload does not fully explain the radiological findings of new bilateral ground glass opacification or consolidation [8].

Global mortality from IPF has been increasing, with males being reported to have higher mortality than females [9‐12]. It seems that mortality varies between countries depending on the definition and diagnosis codes used [9]. In the years 2011–2013 in the European Union (EU), the highest IPF mortality rates were reported in the United Kingdom while the lowest rates were in Lithuania [12]. In Finland, the median mortality rate for males was 7.36 per 100,000 and 3.62 per 100,000 for females, these values being the second highest in the EU [12].

The aim of this study was to examine the mortality rates of patients with IPF in the Kuopio University Hospital (KUH) area located in eastern Finland. The underlying and immediate causes of death from the patients’ death certificates were gathered. All data was explored in the whole study group as well as separately for females and males. Smoking history, disease progression categorized according to the life span into rapid (0–2 years), moderate (2–5 years) and slow (> 5 years) as well as gender-age-physiology (GAP) stage were taken into account. Furthermore, the total numbers of deaths due to pulmonary fibrosis (PF) according to the ICD-10 code J84 were investigated in Finland between the years 1998–2015 from the national registry database of Statistics Finland and this data was compared to that from the local area served by KUH.

As far as we are aware, this is the first detailed clarification of the causes of death in patients with IPF taking into account differences between genders and smoking histories as well as disease progression. Even in this relatively small patient cohort, differences in the causes of death were detected between females and males. Moreover, by examining the smoking histories, we observed that more males and ex-smokers as well as more current smokers died of triggered exacerbations of IPF. Furthermore, more patients with a rapid disease progression died from an acute exacerbation compared to the other disease progression subtypes.

Depending on the methods and diagnostic codes used, the mortality rates have been shown to vary globally and in different countries in the EU [9, 12]. Data from death certificates using ICD-10 codes J84 mortality in 2012 have been reported to be 4.25 per 100,000 in Sweden, 8.88 per 100,000 in Scotland and 8.22 per 100,000 in England and Wales [15]. In Finland, the mortality rate was 5.1 per 100,000 in 2012, being rather similar to the value from Sweden. When classified according to code J84.1, mortality in England and Wales was reported to be 6.90 per 100,000 in 2012 which is higher than our value i.e. 4.7 per 100,000 in the period from 2008 to 2012 [15]. A recent publication based on World Health Organization (WHO) mortality data revealed that the median IPF mortality rate has been rising between the years 2001 and 2013 in 10 out of 17 EU countries, being highest in the United Kingdom (12.01 and 5.63 per 100,000 for males and females, respectively) [12]. The mortality rates in Finland were the second highest i.e. 7.36 and 3.62 per 100,000 for males and females, respectively [12]. Our results are in line with the above-mentioned study revealing that mortality of PF and IPF has risen during the twenty-first century in Finland [12].

The number of PF deaths in Finland has doubled in the last 15 years; in addition, a gender difference has become more apparent since currently more males than females die from PF “http://​www.​stat.​fi/​til/​ksyyt/​2015/​ksyyt_​2015_​2016-12-30_​tau_​001_​en.​html”. It could be argued that the changes in the death certificates’ disease classification in the years 2005–2006 may have had some effect on the rising number of PF deaths in Finland “http://​www.​stat.​fi/​til/​ksyyt/​2015/​ksyyt_​2015_​2016-12-30_​tau_​001_​en.​html”. This argument, however, was not supported by the results of our study on KUH patient cohort, since the numbers of the patients with pneumonia as the underlying cause of death have not changed after the year 2006; in fact, only three patients had pneumonia as the underlying cause of death during the complete study period. However, the diagnostic methods have improved in the past 10–20 years after the appearance of ATS guidelines for IPF in 2000 [16]. It is possible that more of the other types of interstitial lung diseases such as non-specific interstitial pneumonia were included with IPF at the beginning of the twenty-first century. Since IPF is the most common form of idiopathic PF, the numbers of deaths for PF coded as J84 are likely to reflect the actual number of IPF deaths. The rising trend was also seen in the mortality rate in the KUH cohort. This proposal is supported by the recent data from the WHO mortality database, from which it can be estimated that in the year 2001 the mortality rates in males were 4.7 and 5.0 per 100,000 for the narrow (ICD-10 code J84.1) and the broad (ICD-10 code J84) definitions, respectively, while in females, the rates were around 3.0 per 100,000 with both definitions [12]. In the year 2013, the estimated mortality rates were 7.9 and 8.6 per 100,000 for males, and 3.5 and 3.9 per 100,000 for females, with the narrow and broad definitions, respectively [12]. Thus, it can be concluded that most of the cases coded as J84 represented code J84.1. Moreover, since 30% of IPF patients in the KUH area died for reasons other than IPF, one can estimate from the statistics that approximately 350–400 IPF patients die every year in Finland.

A previous study reported that most IPF patients with CAD die from IPF and only 12% from CAD [17]. Here, the number of ischemic heart disease deaths among IPF patients with CAD was higher (28.3%) probably due to the large disease burden of CAD and other cardiovascular diseases in Finland “http://​urn.​fi/​URN:​NBN:​fi-fe2016111829194”. However, the total proportion of ischemic heart disease deaths was in line with published reports [3, 5]. In our previous study, we determined that 72.7% of the patients had one or more cardiovascular diseases (hypertension, CAD, cerebral infarction) as a comorbidity and CAD was diagnosed in 49.2% of the patients [13]. Lung cancer accounted for approximately 6% of the deaths in this study, which is somewhat less common than in the previous studies [4, 18].

One can speculate on the reasons for the relatively high number of pneumonias and the low number of acute exacerbations. The data of the current study was collected from the IPF patients diagnosed in KUH between the years 2002–2012 i.e. during the period when the first international perspectives including diagnostic criteria for acute exacerbation of IPF were published (2007) [19]. Since then, Finnish physicians specializing in respiratory medicine have gradually become aware of the exacerbation phenomenon. Since nearly 60% of the patients in our study died outside of tertiary centers, most of the death certificates had been prepared by primary health care physicians. Thus, it is possible that the acute exacerbations were not correctly identified due to the time point of the study and the places of death. Furthermore, HRCT, which would have been needed for diagnosing an acute exacerbation of IPF, is usually not available in the community hospitals in which most of the deaths occurred.

Never-smokers have been claimed to possess a higher risk for acute exacerbation of IPF, although this finding has not been confirmed in all studies [20‐22]. A recent study revealed no gender difference in the numbers of acute exacerbations [22]. We observed that few death certificates reported acute exacerbations whereas pneumonias were reported to be the second most common immediate cause of death. Pneumonias are likely to represent triggered acute exacerbations as defined in the recent statement [8]. Since we found significantly less mentions of pneumonia as the immediate cause of death in females than in males and in non-smokers than ex-smokers, it seems that males and ex-smokers experienced more acute pneumonia-triggered exacerbation-linked deaths than females and non-smokers. If that is the case, the exacerbation may be associated with smoking since non-smokers were also less likely to suffer pneumonia than current smokers.

A recently published study, which investigated causes of death associated with GAP scoring (using GAP points), detected no differences between the groups with different scores [23]. In our study, more patients in GAP stage III (GAP score 6) died from IPF (83.0% vs 46.2%) and fewer from infections (0 vs 30.8%). The other GAP stages are more difficult to compare due to their different study approach. However, our study confirms that acute exacerbation leading to death may develop at any stage of the disease. We also found that IPF patients living less than 2 years suffered from lethal acute exacerbations more often than patients with longer survival times.

The limitations of the study mainly result from the relatively small number of patients and the retrospective study protocol. Our data is, however, comparable with those of other studies and moreover, it was very thoroughly collected and re-evaluated. Since histological data was available from only a minority of patients, the diagnoses are mostly based on clinical and radiological investigations which reflect diagnostic procedures of true clinical practice. The percentage of histological diagnoses in this study, however, was comparable with most of the previous studies. Nevertheless, the radiological data of all patients has been carefully re-evaluated and re-classified. The decision to utilize the national death registry base of Finland and its ICD-10 code at the 3 character level i.e. J84, may mean that it includes other fibrotic lung diseases in addition to IPF. We aimed to reduce this potential inaccuracy by investigating the same ICD-codes in our local KUH cohort.

The mortality determined in this study population reflects the demographics of IPF since there has been a year-on-year increase in the numbers of males and smokers with IPF dying from this disease. Even though the overall mortality was higher in males, the disease-specific mortality for IPF was higher in females, with males having more commonly comorbidities as the underlying cause of death. An acute exacerbation of IPF may be associated with smoking and gender since females and non-smokers were less likely to develop pneumonia, an illness that is known to trigger acute exacerbations. Thus, we conclude that disease progression at the end of life may vary depending on smoking habits and gender in IPF patients.