Sphingolipid Profiles May Distinguish IPF from Fibrotic HP

Plasma and exhaled breath condensate (EBC) sphingolipid profiles differed between patients with idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (fHP) and correlated with markers of disease severity, according to a single-center study presented at the American College of Chest Physicians (CHEST) 2026 Annual Meeting, held October 18 to 21 in Phoenix, Arizona.^1,2

IPF and fHP require different treatment strategies but often share clinical, radiographic, and pathologic features, leaving multidisciplinary discussion as the diagnostic standard.¹ Sphingolipids, bioactive lipids involved in membrane structure, immune regulation, and fibrogenic signaling, have been implicated in interstitial lung disease (ILD) pathobiology.¹ The findings are from a conference abstract and have not yet been published in a peer-reviewed journal.

"Noninvasive sphingolipid profiling in plasma and exhaled breath condensate may complement multidisciplinary evaluation by improving disease classification and providing biologically relevant markers of severity in fibrotic ILD," said Jon Mullholand, MD, pulmonary and critical care medicine, Virginia Commonwealth University (VCU) Health.²

Plasma and exhaled breath sphingolipid differences in IPF and fHP

Investigators analyzed plasma from 40 patients with fHP, 33 with IPF, and 28 healthy controls, all drawn from a VCU institutional biorepository.¹ EBC was analyzed in a subset of 18 patients with fHP, 20 with IPF, and 11 controls.¹ Diagnoses were confirmed at multidisciplinary ILD conference, and targeted profiling of ceramides, hexosylceramides, sphingomyelins, and sphingosine species used high-performance liquid chromatography–tandem mass spectrometry.¹

Sphingolipid profiles differed significantly between patients with fibrotic ILD and healthy controls in both sample types.¹ Compared with controls, plasma hexosylceramide C24:0 and ceramide C24:1 were significantly altered in ILD, as were EBC sphingomyelin C24:0 and ceramide C24:1.¹

Subtype-specific signatures also emerged. In plasma, dihydrosphingosine (DHSo) and ceramide C24:0 differed significantly between fHP and IPF, and in EBC, sphingomyelin C24:1, ceramide C24:0, and sphingomyelin C18:0 distinguished the 2 diseases.¹ The abstract did not report the direction or magnitude of these differences or any measure of diagnostic accuracy.

Sphingolipid associations with GAP score, DLCO, and FVC

In IPF, plasma hexosylceramide C18:0 (R² = 0.15; P = .025) and hexosylceramide C14:0 (R² = 0.18; P = .016) correlated with gender-age-physiology (GAP) score.¹ EBC hexosylceramide C18:1 correlated with GAP score (R² = 0.28; P = .014), diffusing capacity of the lungs for carbon monoxide (DLCO; R² = 0.40; P = .002), and forced vital capacity (FVC; R² = 0.25; P = .02).¹

In fHP, plasma sphingosine-1-phosphate correlated with GAP-ILD score (R² = 0.20; P = .001).¹ EBC hexosylceramide C16:0 correlated with both GAP-ILD (R² = 0.31; P = .014) and FVC (R² = 0.31; P = .014), and hexosylceramide C18:0 correlated with FVC (R² = 0.25; P = .036).¹

Associations were assessed with multivariable regression, and the abstract did not describe adjustment for multiple comparisons across the sphingolipid species tested.¹ The EBC analyses included 11 to 20 participants per group, and the findings have not been validated in an external cohort.

"Differentiating IPF from fibrotic hypersensitivity pneumonitis remains a major clinical challenge," Mullholand said.²

The investigators concluded the results support further study of sphingolipid profiling as a noninvasive biomarker approach for characterizing fibrotic ILD.¹

References

1. Mullholand J, Camus S, Reyna J, et al. Noninvasive sphingolipid profiling distinguishes IPF from fibrotic hypersensitivity pneumonitis. CHEST. 2026;170(4S). doi:10.1016/j.chest.2026.07.2677

2. American College of Chest Physicians. Noninvasive sphingolipid profiling may help differentiate fibrotic interstitial lung diseases. News release. October 12, 2026. Accessed October 18, 2026.