Interstitial Lung Disease in the United States: CDC Mortality Trends (1999–2024)

1. Introduction

ILD encompasses a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lung parenchyma, with TGF-β–mediated fibrogenesis playing a central role in progressive fibrotic subtypes. The overall prevalence of ILD is estimated at 6.3–76.0 cases per 100,000 people globally, with substantial geographic variation.[1] In the United States, the GBD 2019 study estimated approximately 654,841 patients had ILD, corresponding to a prevalence of 179.7 per 100,000 in males and 218.9 per 100,000 in females. [2,3] The rising incidence is attributed to improved diagnostic precision (including HRCT availability), incidental detection through lung cancer screening and cardiac/abdominal CT, increasing disease awareness, and evolving population demographics. [3]

Sarcoidosis, Connective Tissue Disease-ILD, and Idiopathic Pulmonary Fibrosis (IPF are the three most common fibrotic ILDs, with estimated prevalences of 30.2, 12.1, and 8.2 per 100,000, respectively. [4] Idiopathic pulmonary fibrosis occurs in people aged over 60 years, and it affects men more than women. In the United States, IPF prevalence ranges from 14–63 per 100,000 and was as high as 494 per 100,000 among adults over 65 in one study. [5] Males consistently have higher incidence and mortality rates than females across all regions. [5] Globally, ILD-related deaths totaled 169,833 in 2019, with a 166.6% increase in deaths from 1990 to 2019. [6] Connective tissue-induced ILD occurs in individuals aged 40-60 years. [1] It is more common in females than in males. CTD-ILD prevalence varies by underlying disease: 65% of patients with systemic sclerosis and up to 80% of those with diffuse cutaneous systemic sclerosis develop ILD, while 36–45% of patients with idiopathic inflammatory myopathy develop ILD (up to 80% in those with specific antisynthetase antibodies). [1] Incidence estimates for individual non-IPF subtypes are lower: Idiopathic NSIP 0.8 per 100,000/year, CTD-ILD ~2.7–4.3 per 100,000/year, fibrotic hypersensitivity pneumonitis 1.1 per 100,000/year, and sarcoidosis with ILD 4.9 per 100,000/year. [5]

Pirfenidone and nintedanib can slow the progression of the condition. Nintedanib, a small molecule inhibitor of tyrosine kinase receptors, Platelet Derived Growth Factor Receptor (PDGFR) and Vascular Endothelial Growth Factor Receptor (VEGFR), was recently approved by the FDA to treat patients with chronic fibrosing interstitial lung disease (ILD). [7] Pirfenidone is another antifibrotic medication used to treat IPF. It reduces fibrosis and inflammation by inhibiting TGF beta, a cytokine involved in fibroblast proliferation. [8] Nerandomilast is a phosphodiesterase 4B inhibitor with immunomodulatory effects, approved for IPF and IF ILD. [9] Pamrevlumab is a monoclonal antibody that binds to and inhibits connective tissue growth factor, studied for IPF management. [10]

We aimed to (1) characterize temporal trends in ILD mortality, (2) quantify sex and racial disparities, and (3) compare mortality rates before and after the 2014 FDA approval of antifibrotic agents.

2. Materials and Methods

Study Design and Data Source

This was a retrospective, population-based cross-sectional study of mortality trends and demographic disparities in ILD in the United States from 1999 to 2024. Mortality data were obtained from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) Underlying Cause of Death databases.

Two databases were queried: the 1999–2020 series (bridged-race population estimates) and the 2018–2024 Single Race series (single-race population estimates).

The underlying cause of death, defined by the World Health Organization as “the disease or injury which initiated the train of morbid events leading directly to death,” was used for case identification. Because the study used publicly available, de-identified data, institutional review board approval was not required.

Case Identification

Deaths attributable to ILD were identified using the International Classification of Diseases, Tenth Revision (ICD-10) codes listed as the underlying cause of death J84. J84 does not capture all ILD deaths (e.g., sarcoidosis is coded under D86, hypersensitivity pneumonitis under J67), and some J84-coded deaths may represent non-fibrotic conditions.

Database Reconciliation

Because CDC WONDER maintains two separate database series with a three-year overlap (2018–2020), death counts from both databases were compared for the overlap years to verify consistency. Death counts were identical across all overlap years (2018: 20,492; 2019: 21,221; 2020: 19,530), confirming full concordance.

For the merged 1999–2024 dataset, data from 1999–2017 were drawn from the 1999–2020 series, and data from 2018–2024 were drawn from the 2018–2024 Single Race series. The 1999–2020 series uses bridged-race population estimates, while the 2018–2024 series uses single-race estimates; this methodological difference is noted as a limitation for race-stratified analyses spanning both databases.

Outcome Measures

The primary outcome was the age-adjusted mortality rate (AAMR) per 100,000 population, standardized to the 2000 U.S. standard population using the direct method.

Secondary outcomes included absolute annual death counts, crude mortality rates per 100,000 population, and mortality rate ratios with 95% confidence intervals for demographic comparisons.

Demographic Variables

Deaths were stratified by the following variables as recorded on the death certificate:

- Sex: Female and male.

- Race: For the 1999–2020 series, race was categorized as White, Black or African American, American Indian or Alaska Native, and Asian or Pacific Islander. For the 2018–2024 series, the Single Race 6 classification was used: White, Black or African American, Asian, Native Hawaiian or Other Pacific Islander, American Indian or Alaska Native, and More than one race.

Race of the decedent was reported by the funeral director as provided by an informant, often the surviving next of kin, or on the basis of observation. To the extent that race reporting is inconsistent between death certificates and census self-report, death rates may be biased.

- Census Region: Northeast (Region 1), Midwest (Region 2), South (Region 3), and West (Region 4), as defined by the U.S. Census Bureau.

Statistical Analysis

Four pre-specified analyses were performed:

- Analysis 1 - Temporal Trend: Deaths grouped by calendar year (1999–2024), with annual AAMR to assess temporal trends. The estimated average annual percent change (AAPC) was calculated as [(AAMRfinal / AAMRinitial)^(1/n) − 1] × 100, where n is the number of year intervals.

- Analysis 2 - Sex Disparities: Deaths grouped by year and sex, with annual AAMR comparison and male-to-female mortality rate ratio.

- Analysis 3 - Racial Disparities: Deaths grouped by year and race, with AAMR comparison across groups.

- Analysis 4 -Deaths were divided into a pre-antifibrotic period (1999–2014) and a post-antifibrotic period (2015–2024), defined by the October 2014 FDA approval of nintedanib and pirfenidone for idiopathic pulmonary fibrosis. Aggregate AAMRs, mean annual death counts, and crude rate ranges were compared between eras. The year 2020 was flagged as a potential COVID-19 confounder.

Mortality rate ratios were calculated by dividing the AAMR of the comparison group by the AAMR of the reference group. All confidence intervals for age-adjusted rates were calculated using the gamma method as implemented by CDC WONDER. Cells with fewer than 10 deaths were suppressed per CDC confidentiality standards and were excluded from rate calculations. Rates based on fewer than 20 deaths were flagged as statistically unreliable per NCHS convention. All analyses were performed using CDC WONDER query tools.

3. Results

Overall Mortality Burden

From 1999 to 2024, a total of 505,816 deaths were attributed to interstitial lung disease (ICD-10 J84.0, J84.1, J84.8, J84.9) as the underlying cause of death in the United States (356,270 from 1999–2020; 149,546 from 2018–2024, with 61,243 in the 2018–2020 overlap). Annual ILD deaths doubled from 11,358 in 1999 to 22,849 in 2024, representing a 101% increase in absolute death counts over 26 years. The crude mortality rate rose from 4.1 per 100,000 in 1999 to 6.7 per 100,000 in 2024.

Analysis 1 - Temporal Trend

Despite the doubling of absolute death counts, the age-adjusted mortality rate remained remarkably stable over the 26-year study period. The AAMR rose from 4.2 per 100,000 in 1999 to a plateau of approximately 4.9–5.1 per 100,000 by 2005, and remained at that level through 2024 (Table 1). The overall AAMR for the full 1999–2024 period was approximately 5.0 per 100,000. The estimated AAPC for the full period was +0.78% per year.

The widening gap between crude rate and AAMR quantifies the accelerating contribution of population aging: the crude-AAMR difference was 0.0 in 1999 (crude 4.1, AAMR 4.2), 0.7 in 2014 (crude 5.7, AAMR 5.0), and 1.6 in 2024 (crude 6.7, AAMR 5.1).

Analysis 2 - Sex Disparities

Males accounted for approximately 53–55% of ILD deaths throughout the study period, with the male proportion rising from 51.2% in 1999 to 54.8% in 2024. The male AAMR was consistently higher than the female AAMR across all years (Table 2).

In the 1999–2020 period, the male AAMR ranged from 5.4 to 6.8 per 100,000, while the female AAMR ranged from 3.4 to 4.1 per 100,000. In the 2018–2024 period, the male AAMR ranged from 6.1 (2020) to 6.9 (2021) per 100,000, while the female AAMR ranged from 3.7 (2020) to 4.2 (2023 and 2024) per 100,000.

The male-to-female AAMR ratio ranged from 1.57 to 1.74 across the study period, with a mean ratio of approximately 1.65, indicating a persistent 65% higher age-adjusted mortality risk in males. This ratio remained stable across both the pre-antifibrotic and post-antifibrotic eras, with no evidence of narrowing or widening.

Analysis 3 - Racial Disparities

In the 1999–2020 period, White individuals accounted for the majority of ILD deaths (80–85% annually), followed by Black or African American (5–6%), Asian or Pacific Islander (2–3%), and American Indian or Alaska Native (1%) (Table 3).

Age-adjusted rates by race showed distinct patterns. White individuals had the highest AAMR, rising from 4.3 in 1999 to a peak of 5.5 in 2018–2019 before declining to 5.0 in 2020. Black or African American individuals had a stable AAMR ranging from 2.6 to 3.3 throughout the study period. Asian or Pacific Islander individuals had a stable AAMR ranging from 2.5 to 3.6. American Indian or Alaska Native individuals showed the widest fluctuation (range 4.3–10.6), reflecting the small population size and resultant statistical instability.

Unlike the overall trend, the White AAMR showed a modest upward trajectory (4.3 in 1999 to 5.5 in 2019), while the Black AAMR remained essentially flat (2.9 in 1999 to 2.8 in 2020). The White-to-Black AAMR ratio widened from 1.48:1 in 1999 to 1.79:1 in 2020, suggesting a growing racial disparity in ILD mortality.

Analysis 4 - Pre-Antifibrotic vs. Post-Antifibrotic comparison

The pre-antifibrotic period (1999–2014) encompassed 238,202 deaths with a mean of 14,888 deaths per year and an aggregate AAMR of 4.8 per 100,000 (range 4.2–5.1). The post-antifibrotic period (2015–2024) encompassed 206,371 deaths with a mean of 20,637 deaths per year and an aggregate AAMR of 5.1 per 100,000 (range 4.7–5.3) (Table 4).

The estimated AAPC was +1.17% per year in the pre-antifibrotic period (1999–2014) and +0.22% per year in the post-antifibrotic period (2015–2024, excluding 2020). No downward inflection in the AAMR was observed at or after the 2014 FDA approval of nintedanib and pirfenidone. The AAMR was 5.0 in 2014 and remained at 5.0 in 2015 and 2016, then drifted to 5.1–5.2 in 2017–2019. After the 2020 COVID dip (AAMR 4.7), the AAMR returned to 5.1–5.3 in 2021–2024.

The crude rate divergence from AAMR accelerated between eras. In the pre-antifibrotic time, the crude rate ranged from 4.1 to 5.7, while in the post-antifibrotic time it ranged from 5.8 to 6.8. The crude-AAMR gap widened from 0.7 in 2014 to 1.6 in 2024, reflecting the accelerating contribution of population aging to the absolute ILD mortality burden.

4. Discussion

This population-based analysis of CDC WONDER data spanning 26 years (1999–2024) reveals an interesting pattern in ILD mortality in the United States. Absolute death counts doubled from 11,358 to 22,849, yet the age-adjusted mortality rate remained remarkably stable, rising only modestly from 4.2 to 5.1 per 100,000. This dissociation between crude and age-adjusted trends quantifies the role of population aging in driving the ILD mortality burden and is consistent with the GBD 2021 analysis, which identified population growth and aging as the primary drivers of increasing ILD disease burden globally. [11]

As the 65 and older population expanded from approximately 35 million in 1999 to over 60 million by 2024, the absolute number of individuals at risk for ILD-related death increased substantially, even without a proportional increase in age-specific risk. This finding aligns with Spagnolo et al. (2025), who noted that ILD mortality rates are generally higher in people older than 55 years and that the burden on the elderly population is garnering growing attention as the global population ages. [3]

The 2020 dip likely reflects COVID-19 coded as the underlying cause in ILD patients and disrupted healthcare access, while the 2021 spike may reflect delayed ILD deaths, post-COVID fibrotic sequelae, and the established vulnerability of ILD patients to COVID-19. Drake et al. (2020) reported 49% mortality among hospitalized ILD patients with COVID-19, with a hazard ratio of 1.60 compared to matched controls without ILD. Wang et al. (2022) confirmed these findings in a meta-analysis of 16 studies encompassing 217,260 COVID-19 patients, demonstrating that pre-existing ILD was independently associated with higher COVID-19 severity (pooled effect 1.34, 95% CI 1.16–1.55) and mortality (pooled effect 1.26, 95% CI 1.09–1.46), with consistent results across subgroup analyses stratified by study design, sample size, and adjustment methods. [13,14]

The persistent male predominance in ILD mortality (male-to-female AAMR ratio 1.55–1.74, mean 1.65) is consistent with global data. [15] The GBD 2019 analysis reported higher ILD mortality rates in men across all regions, and the JAMA review by Maher (2024) noted that IPF, the most common ILD subtype, has a male-to-female prevalence ratio of approximately 3:1. [1,2,3] Causes include potentially relevant inhalational exposures, with occupational exposures present in 66% of men versus only 14% of women. The INSIGHTS-ILD registry (2026) provides context for the observed male predominance. Among 883 patients with non-IPF ILD, men reported more occupational and environmental exposures and had higher rates of fibrotic idiopathic interstitial pneumonia, whereas women more frequently had autoimmune-related ILD. Although unadjusted survival was shorter in men (HR 1.51, 95% CI 1.03–2.21), this association disappeared entirely after adjustment for age. [15]

Racial disparities in ILD mortality showed a concerning pattern. White individuals had the highest AAMR throughout the study period (rising from 4.3 in 1999 to 5.5 in 2019), while the Black individuals remained essentially flat (2.9 in 1999 to 2.8 in 2020). The widening White-to-Black AAMR ratio (1.48:1 in 1999 to 1.79:1 in 2020) appears opposite given the well-documented health disparities affecting Black populations. [15] However, this pattern is consistent with the findings of Leary et al. (2025), who reported the lowest ILD mortality rates in the non-Hispanic African American population.[15]

The two-period comparison (pre-antifibrotic 1999–2014 vs. post-antifibrotic 2015–2024) revealed no discernible population-level mortality reduction attributable to the 2014 FDA approval of nintedanib and pirfenidone. [7,8] The AAMR was 5.0 in 2014 and remained at 5.0–5.1 through 2016, with no downward inflection. The estimated AAPC decelerated from +1.17% per year in the pre-antifibrotic era to +0.22% per year in the post-antifibrotic period (excluding 2020), suggesting a possible attenuation of the upward trend but not a reversal. This finding contrasts with individual-level evidence: a meta-analysis by Petnak et al. (2021) of 12,956 patients across 26 studies found that antifibrotic treatment was associated with a pooled RR of 0.55 (95% CI 0.45–0.66) for all-cause mortality. [16] Dempsey et al. (2019), however, showed the mortality benefit was present only through the first 2 years of treatment, with no sustained long-term survival advantage. [17] Several factors may explain the disconnect between individual-level antifibrotic efficacy and the absence of a population-level mortality reduction. Limited benefit combined with suboptimal treatment uptake and intolerable side effect profile dilutes the mortality benefit.

This study has several limitations that should be considered when interpreting the findings. First, the analysis relies on the underlying cause of death as recorded on death certificates, which captures only cases where ILD was designated as the initiating cause of the fatal sequence. Patients with ILD who died from other causes (e.g., cardiovascular disease, lung cancer, or COVID-19) would not be captured, likely leading to underestimation of the true ILD mortality burden. Second, the use of the ICD-10 code J84 does not capture all ILD subtypes. Sarcoidosis (D86), hypersensitivity pneumonitis (J67), and certain connective tissue disease–associated ILDs coded under their primary rheumatologic diagnosis would be excluded. Conversely, J84 encompasses heterogeneous conditions, and some coded deaths may represent non-fibrotic or misclassified entities.

Thirdly, CDC WONDER data do not contain information on treatment status, disease severity, comorbidities, or healthcare utilization. Therefore, the two-period comparison cannot determine whether individual patients received antifibrotic therapy, and the ecological design precludes causal inference about treatment effects at the population level. Fourth, the AAPC was calculated using a geometric mean formula rather than regression-based methods such as Joinpoint analysis, which limits the ability to detect statistically significant inflection points in the mortality trend. Finally, race as recorded on death certificates is reported by funeral directors or informants rather than by self-identification, which may introduce misclassification, particularly for American Indian/Alaska Native and multiracial individuals.

5. Conclusions

ILD mortality in the United States has increased in numbers, largely due to an aging population and improved detection. Despite this increase, age-adjusted mortality remained relatively stable, indicating no major rise in overall risk. Men are more susceptible than women, likely due to environmental factors like occupation and smoking. White non-Hispanic individuals accounted majority of deaths in number but the age-adjusted mortality across ethnicities remained stable, suggesting population growth rather than increased susceptibility explains the rise in deaths.