Prevalence, Clinical Features, and Outcomes of Young Patients with Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology associated with a histopathological or radiologic pattern of usual interstitial pneumonia [1, 2]. It is characterized by irreversible deterioration in lung function due to continuous scarring and fibrosis of lung parenchymal tissue, presenting with worsening respiratory symptoms such as exertional dyspnea and chronic cough [3]. These symptoms eventually cause a decline in quality of life, exercise intolerance, and physical disability [4, 5]. The prevalence and incidence of IPF are increasing over time globally, with rate estimated between 3 and 45 per 100,000 for prevalence and 1 to 13 per 100,000 persons per year for incidence [6‒9]. The prognosis for IPF patients is highly unfavorable, with an estimated median survival time of 2–5 years from the initial diagnosis [10]. Acute exacerbation (AE) can occur in the natural course of IPF, characterized by rapid deterioration of respiratory symptoms without an obvious cause. Furthermore, it is associated with increased mortality. The annual risk of AE-IPF has been reported to be 4%–20%, with an inhospital mortality of 50% and a median survival of less than 3 months [11, 12]. There is no proven effective treatment to improve survival for AE of IPF. Lung transplantation is a potentially lifesaving therapy [13, 14].

The incidence of IPF is recognized to rise with age, typically manifesting symptoms such as shortness of breath in individuals in their sixties or seventies. Instances of this disease in people under 50 years of age are relatively uncommon [4, 15‒18]. In 2000, American Thoracic Society (ATS), European Respiratory Society (ERS), and the American College of Chest Physicians (ACCP) issued an international consensus statement on the diagnosis of IPF, specifically listing being over the age of 50 as a minor criterion [19]. However, guidelines revised by the ATS/ERS/Japanese Respiratory Society (JRS)/Asociación Latinoamericana de Tórax (ALAT) in 2011 [4] underscore the necessity of considering IPF in the differential diagnosis of unexplained respiratory symptoms in adult patients, irrespective of age. Consequently, it is imperative to comprehend clinical features of IPF in younger patients for precise diagnosis and effective treatment.

Research on IPF in young patients has been extremely limited, with few available studies. In addition, such studies often focused solely on mortality rate with a limited number of patients. Therefore, there is a significant need for detailed information about clinical characteristics and prognosis for this particular group of patients. Thus, the objective of this study was to investigate not only differences in clinical characteristics and mortality but also the risk of AE and the composite outcome of lung transplantation and death across different age groups.

This was a population-based retrospective cohort study based on the National Health Insurance Service (NHIS) database. This compulsory health insurance system covers almost 97% of the Korean population [20]. Health Insurance and Review Assessment (HIRA), an affiliate of the government, provides appropriate healthcare provisions by reviewing medical expenses for reimbursement decisions and evaluating quality of healthcare services. It serves as a repository of claims data collected from hospitals during the reimbursement process to healthcare providers. HIRA data provide comprehensive information on all subscribers including sociodemographic characteristics, diagnosis using International Classification of Disease, tenth Revision (ICD-10) codes, as well as inpatient and outpatient healthcare services such as examinations, procedures, and treatments.

The definition of IPF was established utilizing both ICD-10 codes for IPF (J84.1 and J84.18) and the Rare Intractable Diseases (RID) code V236. In 2009, the Korean NHI introduced the RID registration system, offering up to a 90% copayment reduction for certain rare diseases, including IPF. To ensure registration quality, uniform diagnostic criteria must be met, and diagnoses are reviewed by healthcare institutions before submission to the NHI. Thus, the RID database is considered reliable [21]. For IPF registration, clinical assessment on radiologic exams, abnormal pulmonary function tests, and/or histologic findings were required [22]. Moreover, we also excluded other ILDs to ensure a clear IPF diagnosis (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000541692).

The date of diagnosis was identified based on the initial entry of the IPF code into the database. As multidisciplinary approach is considered crucial for the diagnosis and treatment of IPF, this study was conducted using only claims data from referral hospitals, excluding claims from primary care centers. Patients with the diagnosis code of IPF from 2016 to 2020 were initially selected. These individuals had also undergone a chest computed tomography (CT) scan and Pulmonary Function Test (PFT) within 1 year of IPF diagnosis.

To date, pirfenidone and nintedanib are the only drugs that have obtained FDA approval for the treatment of IPF. Unlike pirfenidone, nintedanib is not covered by medical insurance in South Korea. This lack of coverage presents a significant financial barrier, constraining its usage. As a result, nintedanib is limited to approximately 2% of patients in South Korea [23]. Therefore, the primary treatment for IPF has largely revolved around pirfenidone, owing to its coverage under medical insurance in October 2015. Identifying nintedanib users was not possible in the HIRA database because it depended solely on reimbursement claims. For this reason, this study contained only pirfenidone prescriptions identified by codes 620301ATB, 620302ATB, and 620303ATB, with the inclusion criterion being at least two prescriptions within a year. Maintenance steroid therapy dosage was calculated based on the equivalent dose to prednisolone. It is presented as a daily dosage.

In this study, the primary outcome measure was AE of IPF. The definition of AE of IPF was made primarily by aligning with the operational definition of AE proposed by the International Working Group in 2016 [12]. Additionally, it included the use of systemic steroids as a therapeutic intervention for AE, as outlined in the guidelines for IPF [4, 12, 24]. Hence, we established criteria for identifying AE of IPF among hospitalized patients with IPF based on their primary or secondary diagnosis. These patients should have undergone a chest CT scan within 1 month of admission or during hospitalization and have received systemic steroid therapy within 3 days after admission. Additionally, we employed diagnostic codes to exclude patients experiencing worsened respiratory symptoms due to heart failure or fluid overloads. As other outcome measures, lung transplantation (Z94.2 or Z94.3) and lung cancer (C34) were assessed using ICD-10 codes. Death was delineated as the absence of claim data for more than 1 year.

Study participants were categorized into three groups based on their age: <50, ≥50 and <65, and ≥65 years. Continuous variables within each group are presented as mean ± standard deviation, while categorical variables are expressed in frequencies and percentages. Comparisons between groups were performed using one-way analysis of variance with Tukey’s post hoc test, Kruskal-Wallis test, or χ² test, as appropriate. The risk of exacerbation and a composite endpoint comprising both death and lung transplantation were assessed using Kaplan-Meier method. In addition, the logrank test was applied to evaluate the cumulative incidence across age groups. To determine associations between covariates and composite outcome of lung transplant or death, Cox proportional hazards regression model was utilized. Initially, univariate analysis examined each covariate separately, including age, sex, type of insurance (NHI or medical aid), comorbidity index (modified Charlson comorbidity index [mCCI]), previous exacerbation, and use of pirfenidone or steroids. Consequently, adjusted models were designed using multivariate analysis. A p value of less than 0.05 was considered statistically significant. All analyses were performed using SAS software version 9.2 (SAS Institute Inc., Cary, NC, USA).

Among 44,688 patients diagnosed with IPF between October 2016 and September 2020, 39,991 were excluded due to the absence of PFT or chest CT scans within 1 year of the diagnosis. Additionally, this research excluded 358 patients with a concurrent diagnosis of connective tissue disease and 76 patients diagnosed with various other diffuse lung parenchymal diseases. A total of 4,243 subjects were categorized into three age groups (91 patients with age under 50 years, 834 with age ≥50 and <65 years, and 3,318 with age ≥65 years) based on their age at the time of IPF diagnosis (online suppl. Fig. S1). During the study period, the prevalence of IPF by age showed a consistent distribution year over year, with young patients under the age of 50 being identified at a range from 1.4% to 2.2% (Fig. 1).

Table 1 shows demographic and clinical characteristics of study subjects. Males accounted for 46.2% in the under 50 group and about 75% in both the 50–65 group and the ≥65 group (p < 0.001). Pirfenidone was used by 16.5%, 37.9%, and 40.2% of subjects in the <50, between 50 and 65, and ≥65 age groups, respectively, showing a significant increase with age (p < 0.001). Systemic steroids were given to 68.8%, 50.1%, and 51.6% of subjects in the three groups, showing a significant difference between the <50 age group and the other two age groups (p = 0.0029). There was a notably low occurrence of AE events over the previous year (range, 1%–2%) in all three age groups, showing no statistically significant differences.

Comorbidities in IPF patients across three age groups are presented in Table 1. Comorbidity index, mCCI, showed an increasing trend with age, indicating more comorbidities in older groups (p < 0.001). Cardiovascular diseases including myocardial infarction, congestive heart failure, atrial fibrillation, hypertension, and peripheral vascular disease were more common in older patients, with prevalence increased across age groups (p < 0.001 for all, except peripheral arterial disease, for which the p value = 0.015). Prevalence of other chronic diseases, such as chronic kidney disease and cerebrovascular disease, also increased with age groups. Although the prevalence and incidence of lung cancer following a diagnosis of IPF were higher in individuals over the age of 50, differences across age groups did not reach statistical significance (Table 1; online suppl. Fig. S2).

The risk of AE within the first year following diagnosis showed an age-related increase without showing a statistical significance (age ≥50 and <65, hazard ratio [HR]: 1.12, 95% confidence interval [CI]: 0.74–1.69; age ≥65, HR: 1.29, 95% CI: 0.87–1.92) as shown in Table 2. Findings remained consistent after adjusting for sex, history of previous AE, and comorbidities. Moreover, when further adjustments were made for treatment with pirfenidone, no significant differences were noted, resulting in HR of 1.05 (95% CI: 0.69–1.61) for age group of ≥50 and <65 years and 1.16 (95% CI: 0.77–1.74) for individuals aged 65 years and older.

In this study, individuals under 50 years were used as a reference group to assess the risk of a composite endpoint consisting of death and/or lung transplantation (Fig. 2). A notable increase in risk was observed in the age group of ≥50 and < 65 (HR: 1.52, 95% CI: 0.93–2.49) and the ≥65 years group (HR: 2.44, 95% CI: 1.51–3.93). Meanwhile, individuals aged 65 years and older displayed a significantly higher composite risk, which remained substantial after adjusting for covariates such as sex, previous AE history, comorbidities, and treatment with pirfenidone. Combining the endpoints of death and lung transplantation, the Kaplan-Meier survival estimates over a 4-year follow-up period revealed a significant disparity between age groups, with a p value of <0.001, indicating significantly higher event-free survival rates – defined as no lung transplantation or death – in the younger IPF group under 50 years.

In the univariate analysis, the following factors were significantly associated with the composite outcome of mortality and/or lung transplantation: age over 65 years (HR: 2.44, 95% CI: 1.51–3.93), male gender (HR: 1.39, 95% CI: 1.22–1.57), higher comorbidity index (HR: 1.09, 95% CI: 1.07–1.12), previous history of AE (HR: 3.66, 95% CI: 2.76–4.86), and systemic steroid use (HR: 2.88, 95% CI: 2.57–3.22) (Table 3; Fig. 3). Conversely, treatment with pirfenidone was associated with a lower risk (HR: 0.85, 95% CI: 0.77–0.95) of the composite of mortality and lung transplantation. In the subsequent multivariable analysis, adjustments were made for covariates including sex, history of AE, mCCI, and pirfenidone treatment in model 1 with systemic steroid use further adjusted in model 2. Both models affirmed independent associations of these factors with the composite outcome. The incidence of lung cancer following an IPF diagnosis was significantly associated with an increased risk of composite outcome, with an HR of 1.57 (95% CI: 1.37–1.81). Consequently, the incidence of lung cancer was considered an additional covariate in the assessment of risk factors, which yielded consistent results (online suppl. Table S2).

IPF is known to have a higher incidence rate in older adults. However, it can also occur in younger individuals. Unfortunately, detailed information on younger populations with IPF is very limited. Nationwide database enabled us to access prevalence of IPF across different age groups and to conduct comprehensive analyses on several outcomes, from AE to death and lung transplantation, through diagnosis code and a logical operational definition. Although younger patients with IPF exhibited a lower risk of the composite endpoint of death and lung transplantation compared to older patients, particularly those aged 65 and above, they were more frequently treated with systemic steroids and less often with pirfenidone. This paradoxical treatment pattern converged toward increasing the risk of adverse outcomes. Furthermore, the risk of AE did not show any age-related differences, underscoring the importance of focusing on young patients with IPF and the necessity for more disease-oriented, appropriate treatments.

In 2005, Nadrous et al. [25] conducted a study on IPF patients under 50 years of age, enrolled from 1994 to 2000. The study revealed that the median survival was 2.1 years, with 1-year and 2-year survival rates of 69% and 53%, respectively. There were no significant differences in the clinical course as did older patients with the same disease. Ultimately, their findings underscored that the severity of the disease was a critical factor for outcome, regardless of age. However, it was a study with a small sample size, comprising only 22 patients under the age of 50. In addition, it was conducted in the pre-antifibrotic era when treatments primarily included prednisone, colchicine, azathioprine, methotrexate, and acetylcysteine. Since then, there have been significant advancements in evidence-based guidelines and multimodal management of IPF, particularly with the introduction of antifibrotic therapies. A more recent research on young patients with IPF was carried out in 2018 at a tertiary center in Germany [26], which targeted 30 patients aged 50 years or younger and 99 patients older than 50 years. Consistent with our findings, this study also demonstrated greater usage of antifibrotics among those over 50 years old, despite the younger patient group exhibiting a similar disease burden to the older group. Although statistically insignificant, treatment with corticosteroids and immunosuppressants was more prevalent in the younger age group, which again aligned with our results. Additionally, younger patients demonstrated significantly higher event-free survival compared to older IPF patients, consistent with the findings of our study. However, this improved survival may have been influenced by the significantly higher number of younger patients undergoing lung transplantation, given that the study was conducted in a referral center specializing in lung transplant. Moreover, the relatively small sample size limits the generalizability of these findings.

The prognosis for patients with IPF is extremely poor, with reported survival rates even lower than those with some malignancies [27]. Taking this into account, preventive strategies with prompt and accurate diagnosis of IPF should be followed by early and aggressive disease-specific interventions to improve prognosis. Regrettably, as of now, there is no definitive treatment to improve the mortality rate of IPF. Smoking cessation education, targeting a known risk factor, supplementary oxygen use if hypoxemic, managing comorbidities, along with the administration of antifibrotic agents to inhibit the progression of the disease have recently become crucial components of the treatment paradigm [9, 24].

Recent studies have suggested that the development of IPF is predominantly associated with micro-injuries to alveolar epithelial cells that trigger fibrosis [28, 29], contrasting with earlier beliefs that inflammatory process primarily leads to fibroblast activation and accumulation of extracellular matrix, prompting the 2000 ATS/ERS/ACCP consensus to recommend corticosteroids and immunomodulators as standard treatments [28, 30]. This shift in the conceptual understanding of the pathogenesis has significantly altered the approach to treatment from immunosuppressants to antifibrotic agents [31]. This strategy is supported by findings from the PANTHER-IPF study demonstrating that treatments combining prednisone, azathioprine, and N-acetylcysteine are associated with worse outcomes, including increased mortality and hospitalizations compared to placebo [32]. There are currently two antifibrotic agents available for use, pirfenidone and nintedanib. The efficacy of each drug has been established through sufficient clinical trials demonstrating their ability to slow the decline in lung function, reduce the risk of AE, improve disease-related symptoms, and improve exercise capacity [33‒38]. In light of this evidence, the current guideline advocates the use of two specific drugs as a pharmacological intervention in IPF [24]. In the present study, it appeared that, paradoxically, younger patients with IPF were treated with antifibrotics less frequently, while the use of systemic steroids was significantly higher in younger patients than in older IPF patients. This treatment pattern was identified as a significant risk factor for mortality composite endpoints, implying an inadequate focus on disease-centric treatment in younger patients. In fact, the mortality composite risk was higher in older IPF patients, presumably due to an inherent survival benefit associated with younger age. Moreover, the risk of AE did not differ by age group. These findings reflect a management landscape that excluding the beneficial impact of younger age itself may converge toward a more negative prognosis for younger patients.

Clear guidelines regarding the optimal timing for initiating antifibrotic treatment in IPF have not been established yet. However, a previous study supports that initiating an antifibrotic agent as early as possible in the course of the disease may be the most effective strategy to maintain lung capacity [37]. In Korea, pirfenidone was included in the health insurance coverage in October 2015. However, it was restricted to patients who could satisfy specific criteria, composed of a predicted forced vital capacity of 50–90%, a DLCO of at least 35%, and a 6-min walk distance of more than 150 m. From January 2019, insurance coverage of pirfenidone has extended to IPF patients whose forced vital capacity and DLCO fall below 90% and 80% of the predicted value, respectively. However, this coverage does not encompass all IPF patients, especially those with mild IPF characterized by preserved lung function [39]. Hence, it was conceivable that this paradoxical treatment pattern was noted among comparatively young patients who might have relatively good lung functions. However, given the progressive nature of this intractable disease, delaying treatment until disease progression might result in irreversible lung function decrement and make outcomes worse. Further studies on these younger patients with early initiation of disease-directed treatment are mandatory.

Both respiratory and nonrespiratory comorbidities are common in IPF and may influence the survival outcomes [40, 41]. Comorbidities such as cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer are highly prevalent and share risk factors including smoking and older age [40, 42]. While the increased prevalence of comorbidities with age was anticipated, our study provides a quantitative analysis of these differences, showing a significant trend in the mCCI index across age groups (p < 0.001). These findings underscore the need for age-specific management strategies in IPF patients. Although the incidence of lung cancer did not vary significantly among different age groups, its occurrence notably increased the overall mortality risk in patients with IPF. Considering age and lung cancer together, each significantly elevated the risk of mortality. This underscores the necessity of focusing on the prognosis for younger patients. Many of the observations in baseline characteristics are consistent with previously established knowledge about IPF patients; however, our analysis revealed age-related differences among IPF patients, particularly in gender composition. It is well documented that IPF is not only more prevalent in older individuals but also more common in men than in women [43‒46]. Interestingly, IPF had a significantly higher prevalence in female IPF patients under the age of 50. This finding is particularly intriguing, given that the aforementioned studies have reported no discernible demographic differences between younger and older patients with IPF, aside from their age.

One of the most noteworthy aspects of this study was the clear definition of an AE of IPF we used. Given the absence of a specific ICD-10 code for AE-IPF, defining AE using claim databases poses considerable challenges. Previous studies have established definitions for AE-IPF cases where patients have received high-dose or pulse-dose corticosteroid pulse therapy during hospitalizations [47, 48]. Despite the latest ATS guideline offering a tentative recommendation for the use of systemic steroid in the AE-IPF setting, the effectiveness of high-dose steroid therapy remains controversial. In addition, guidelines do not provide details on the dosage or the duration of treatment [4]. The diagnostic criteria for AE-IPF, as proposed by the International Working Group in 2016, include the following: a confirmed diagnosis of IPF, an acute onset or worsening of dyspnea typically within a month, CT findings of new bilateral ground-glass opacities and/or consolidation superimposed on background pattern consistent with usual interstitial pneumonia pattern, and lastly, deterioration that cannot be fully attributed to cardiac failure or fluid overload. For the purposes of our study and to enhance inclusivity and practicality, we modified this definition by incorporating the use of systemic steroids, regardless of dosage, as part of the diagnostic criteria for acute exacerbation, in accordance with the latest guidelines.

Raghu et al. [43] analyzed US healthcare claims data (1996–2000) and found 12.1%–16.3% of IPF patients were under 55, with a similar range reported in an Italian study during 2000–2010 [49]. The higher proportion in these studies may be due to the inclusion of patients aged 50–54. In contrast, a nationwide study using HIRA dataset (2012–2016) showed that only 1.3% of IPF patients were under 50 [50], closely aligning with our findings of 2.1%, thus supporting the reliability of our study despite the small size of the younger IPF group.

Although we found clinical features and outcomes of younger patients with IPF in various aspects through a nationwide large sample study, this study had several limitations. First, the retrospective design of this study without randomization and the use of diagnostic codes for identification of disease case might have introduced bias. However, by focusing solely on reimbursement data from referral hospitals where a multidisciplinary approach – an essential component of the IPF diagnosis and management – is feasible, the risk of such biases has been mitigated. Second, while South Korea ranks among the countries with the highest incidence of IPF, alongside Canada and the USA [8], the exclusion of other ethnic and racial populations might have limited the generalizability. Moreover, restrictions on the reimbursement for antifibrotic medications in South Korea suggest that patients with mild disease with well-preserved lung function are less likely to receive these treatments, potentially leading to a study population that tended to have more severe cases. Third, this study did not include information regarding another antifibrotic agent, nintedanib, because it is a nonreimbursable drug. However, nintedanib is only given to 2% of IPF patients in Korea, imposing an economic barrier that limits access for IPF patients [23]. Fourth, HIRA database does not provide information on the severity of IPF itself, such as lung function value or the extent of disease observed through chest CT scans. It also lacks details on the severity of a patient’s subjective symptoms either. Lastly, socioeconomic factors such as patient’s education, occupation, and income, which could affect patients’ access to healthcare and health behaviors, could not be assessed due the inherent limitations of the HIRA database.

In conclusion, our study showed that younger patients with IPF experienced similar AE events and better survival compared to older patients. However, in the younger patient group, antifibrotic treatments were used less frequently, while systemic steroids were more commonly prescribed, both of which were risk factors that could increase the risk of mortality. Excluding age itself as a protective factor for prognosis, younger patients are apt to potentially harmful treatments. This necessitates increased attention and a shift toward more disease-centric, proactive treatments, irrespective of the age at diagnosis. To further support this approach, future studies should focus on comparing progression-free survival of younger patients with early-stage IPF who receive early treatment interventions.

The Institutional Review Board (IRB) of Seoul St Mary’s Hospital approved the study protocol (No. KC22ZASE0545) and has waived the need for informed consent due to the retrospective study. The study was performed in accordance with the principles of the Declaration of Helsinki concerning the ethical principles for medical research.

The authors declare no conflicts of interest in relation to the production of this manuscript.

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (Grant No. NRF-2022R1I1A1A01063654). None of the authors have any financial relationships with a commercial entity with an interest in the subject of this manuscript.

Y.S.J. is the guarantor of the content of the manuscript and conceived the study design. K.K.J. conducted data analysis, and K.K.J. and Y.S.J. interpreted the data. J.W.L. drafted the manuscript. J.W.L., K.K.J., J.H.N., J.Y.C., R.C.K., and Y.S.J. reviewed and edited the final draft of the manuscript.

The data that support the findings of this study are available from the Korean National Health Insurance Service (KNHIS) database, which provides access to researchers who meet the criteria for access to confidential data. Detailed information on accessing KNHIS data can be found at https://nhiss.nhis.or.kr/bd/ab/bdaba000eng.do. However, the specific data analyzed in this study cannot be shared publicly due to legal and confidentiality requirements.