Pneumonia-specific plasma metabolite profiles among patients hospitalised with infection in Southeast Asia

Abstract

Background: Community-acquired pneumonia (CAP) is a major public health threat globally but is understudied in regions with the highest burden. The host immune response during infection may differ based on the site of infection. We hypothesised that analysis of the plasma metabolome in patients hospitalised with suspected infection could identify host response pathways specific to CAP.

Methods: We analysed the plasma metabolomes of adults admitted to a tertiary care hospital in northeastern Thailand with suspected community-acquired infection. Multivariable linear regression was performed for differential metabolite analyses and the global test was used for pathway analysis comparing patients with CAP versus non-CAP infections and uninfected controls. The least absolute shrinkage and selection operator (LASSO) was used to identify a parsimonious metabolite prognostic signature that was tested on an internal validation set to predict mortality.

Results: 841 metabolites from 107 CAP patients and 152 non-CAP infected patients were analysed. 52 metabolites were differentially abundant between the CAP and non-CAP groups. CAP was characterised by increased metabolites involved in polyamine metabolism and decreased metabolites involved in lipid pathways. 13 pathways were differentially enriched between the CAP and non-CAP groups, consistent with individual metabolite analyses. 40 metabolites and four pathways were associated with CAP-specific mortality. A four-metabolite signature predicted 28-day mortality in CAP (area under the curve 0.79, 95% CI 0.62-0.97).

Conclusion: In a rural tropical setting, CAP induced a distinct metabolomic state compared to non-CAP presentations of infection that may reflect the activation of select host immune responses.

FIGURE 1

Differentially abundant metabolites comparing a) community-acquired pneumonia (CAP) (n=107) versus uninfected controls (n=50) and b) non-CAP infection (n=152) versus uninfected controls (n=50). c) Venn diagram of the differentially increased and decreased metabolites identified in these two comparisons. Models are adjusted for age, sex, body mass index, and diabetes. *: Significant metabolites with adjusted p-value<0.05 are highlighted. Red: increased abundance; blue: decreased abundance. GPC: glycerophosphorylcholine; GPE: glycerophosphorylethanolamine; GPG: glycerophosphorylglycerol.

FIGURE 2

Differentially abundant metabolites comparing community-acquired pneumonia (CAP) (n=107) versus non-CAP infected patients (n=152). a) Heatmap showing CAP versus non-CAP adjusted for age, sex, chronic lung disease, chronic kidney disease, infectious aetiology and modified SOFA (Sequential Organ Failure Assessment) score. b) Volcano plot showing the same comparison.

FIGURE 3

Differentially abundant metabolites comparing a) community-acquired pneumonia (CAP) nonsurvivors (n=55) versus CAP survivors (n=52) and b) non-CAP nonsurvivors (n=45) versus non-CAP survivors (n=107). c) Venn diagram of the differentially increased and decreased metabolites identified in these two comparisons. Models are adjusted for age, sex, chronic lung disease, chronic kidney disease and infectious aetiology. GPC: glycerophosphorylcholine.

FIGURE 4

a) Average selection frequency (y-axis) and coefficient estimates (x-axis) in the repeated sample splitting with LASSO (least absolute shrinkage and selection operator) for identifying fatal community-acquired pneumonia (CAP) cases in the derivation set (n=75). b) Receiver operating characteristic curve for identifying fatal CAP cases in the validation set (n=32) set using the four-metabolite signature (1-methylnicotinamide, 1,5-anhydroglucitol, heptanoate (7:0) and carboxyethyl-γ-aminobutyric acid (GABA)). Receiver operating characteristic curves are shown for CURB-65 (confusion, urea >19 mg·dL⁻¹, respiratory rate ≥30, systolic blood pressure <90 mmHg or diastolic blood pressure ≥60 mmHg, and age ≥65 years), modified Sequential Organ Failure Assessment (mSOFA) score and the four-metabolite model (area under the receiver operating curve (AUC) 0.57, 0.62 and 0.79, respectively). c) Receiver operating characteristic curves for CURB-65, mSOFA score, CURB-65 plus the four-metabolite model and mSOFA score plus the four-metabolite model (AUC 0.57, 0.62, 0.77 and 0.80, respectively).