Sphingolipid Profiling May Help Distinguish IPF From Fibrotic HP

Sphingolipid profiling may offer patients with fibrotic interstitial lung disease (f-ILD), particularly those with idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (f-HP), a noninvasive biomarker to help classify disease and assess severity.¹

Data recently presented at the CHEST 2026 Annual Meeting found that sphingolipid signatures, when evaluated in plasma and exhaled breath condensate (EBC), differed between healthy adults and those with fibrotic ILD. There were also distinct differences between those with IPF when compared with those who had f-HP. Although the 2 diseases require different therapeutic approaches, they often share overlapping clinical, radiographic, and pathologic features. Being able to differentiate between the 2 could help clinicians address the severity of patients' disease sooner and help them access treatment in a timely manner so as to reduce the rate of disease progression.

Sphingolipids are bioactive lipids involved in membrane structure, immune regulation, and fibrogenic signaling, and they have been implicated in ILD pathobiology.¹ The findings were presented on October 19 during the ILD: Clinical Roundup rapid-fire original investigation session.¹

“Differentiating IPF from fibrotic hypersensitivity pneumonitis remains a major clinical challenge,” Jon Mullholand, MD, CHEST 2026 presenting author, said in a statement. “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.”²

How Researchers Measured Sphingolipids in Plasma and Breath Samples

The study used patients' plasma and EBC samples stored in an institutional biorepository. All participants provided informed consent, and the study was approved by the VCU Institutional Review Board.¹ There were 101 participants included in the analysis. Of them, 33 were diagnosed with IPF, 40 with f-HP, and 28 healthy adults served as controls. Diagnoses were confirmed through multidisciplinary ILD conference review.¹

High-performance liquid chromatography–tandem mass spectrometry was used to perform targeted sphingolipid profiling, which included assessing ceramides, hexosylceramides, sphingomyelins, and sphingosine species.

Clinical data, such as pulmonary function testing and gender-age-physiology (GAP) indices, were pulled from electronic medical records. Associations between sphingolipid species and clinical parameters were assessed using multivariable regression modeling.¹

The lipid analysis was performed on all participants included in the study. However, the EBC analysis was only conducted on a subset of individuals, specifically 18 patients with f-HP, 20 with IPF, and 11 healthy adults who served as controls.

Distinct Sphingolipid Signatures Separate IPF From f-HP

Sphingolipid profiles differed significantly between those with fibrotic ILD when compared with healthy adults in both plasma and EBC. Researchers also observed additional subtype-specific signatures that distinguished those with IPF from those with f-HP.

When comparing ILD with healthy controls, plasma hexosylceramide C24:0 and ceramide C24:1 were significantly altered. Whereas in EBC, sphingomyelin C24:0 and ceramide C24:1 also demonstrated significant differences between groups. In plasma, dihydrosphingosine (DHSo) and ceramide C24:0 were significantly different between disease subtypes. In EBC, sphingomyelin C24:1, ceramide C24:0, and sphingomyelin C18:0 similarly distinguished f-HP from IPF.

Sphingolipid Levels Tied to Lung Function and Disease Severity

Several sphingolipid species were associated with disease severity. In IPF, plasma hexosylceramide C18:0 (R² = 0.15; P = .025) and hexosylceramide C14:0 (R² = 0.18; P = .016) correlated with GAP score. In IPF EBC, hexosylceramide C18:1 also 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). In f-HP, plasma sphingosine-1-phosphate (S1P) correlated with GAP-ILD (R² = 0.20; P = .001).

EBC sphingolipids demonstrated additional physiologic associations. In f-HP, hexosylceramide C16:0 correlated with GAP-ILD (R² = 0.31; P = .014) and FVC (R² = 0.31; P = .014), while hexosylceramide C18:0 also correlated with FVC (R² = 0.25; P = .036).

The researchers concluded that plasma and EBC sphingolipid profiles differ between IPF and f-HP and correlate with physiologic markers of disease severity, supporting sphingolipid profiling as a noninvasive biomarker approach for disease characterization in fibrotic ILD.¹ According to CHEST, the findings support further study of the approach, and the associations with physiologic measures of disease severity may also provide additional information about disease characteristics.²

References

1. Mullholand J, Camus S, Reyna J, et al. Noninvasive sphingolipid profiling distinguishes IPF from fibrotic hypersensitivity pneumonitis. Presented at: CHEST 2026 Annual Meeting; October 18-21, 2026; Phoenix, AZ. doi:10.1016/j.chest.2026.07.2677

2. Noninvasive sphingolipid profiling may help differentiate fibrotic interstitial lung diseases. News release. CHEST. October 12, 2026. [URL NEEDED]