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J Transl Med. 2019 Nov 11;17(1):365. doi: 10.1186/s12967-019-2112-z.

Decreased plasma phospholipid concentrations and increased acid sphingomyelinase activity are accurate biomarkers for community-acquired pneumonia.

Author information

1
Research Group "Biomarkers for Infectious Diseases", TWINCORE Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625, Hannover, Germany.
2
Department of Systems Immunology and Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Brunswick, Germany.
3
Department of Chemical Biology, Helmholtz Centre for Infection Research and German Center for Infection Research (DZIF), Brunswick, Germany.
4
Clinic for Pneumology, Otto-von-Guericke University, Magdeburg, Germany.
5
Helmholtz Centre for Infection Research, Brunswick, Germany.
6
Department of Clinical Microbiology, Biomedical Diagnostic Centre (CDB), Hospital Clinic, School of Medicine, University of Barcelona, Institute of Global Health (ISGlobal), Barcelona, Spain.
7
Institute for Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
8
UMG-Laboratory, University Medicine Göttingen, Göttingen, Germany.
9
DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, University Medicine, Greifswald, Germany.
10
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Paris, France.
11
Paris Descartes University, Imagine Institute, Paris, France.
12
Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, USA.
13
Clinical Microbiology, GlaxoSmithKline, Collegeville, PA, USA.
14
Clinical Development, ViiV Healthcare, Brentford, UK.
15
Hannover Unified Biobank, Hannover Medical School, Hannover, Germany.
16
Research Group "Biomarkers for Infectious Diseases", TWINCORE Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Str. 7, 30625, Hannover, Germany. frank.pessler@twincore.de.
17
Helmholtz Centre for Infection Research, Brunswick, Germany. frank.pessler@twincore.de.
18
Centre for Individualised Infection Medicine, Hannover, Germany. frank.pessler@twincore.de.

Abstract

BACKGROUND:

There continues to be a great need for better biomarkers and host-directed treatment targets for community-acquired pneumonia (CAP). Alterations in phospholipid metabolism may constitute a source of small molecule biomarkers for acute infections including CAP. Evidence from animal models of pulmonary infections and sepsis suggests that inhibiting acid sphingomyelinase (which releases ceramides from sphingomyelins) may reduce end-organ damage.

METHODS:

We measured concentrations of 105 phospholipids, 40 acylcarnitines, and 4 ceramides, as well as acid sphingomyelinase activity, in plasma from patients with CAP (n = 29, sampled on admission and 4 subsequent time points), chronic obstructive pulmonary disease exacerbation with infection (COPD, n = 13) as a clinically important disease control, and 33 age- and sex-matched controls.

RESULTS:

Phospholipid concentrations were greatly decreased in CAP and normalized along clinical improvement. Greatest changes were seen in phosphatidylcholines, followed by lysophosphatidylcholines, sphingomyelins and ceramides (three of which were upregulated), and were least in acylcarnitines. Changes in COPD were less pronounced, but also differed qualitatively, e.g. by increases in selected sphingomyelins. We identified highly accurate biomarkers for CAP (AUC ≤ 0.97) and COPD (AUC ≤ 0.93) vs. Controls, and moderately accurate biomarkers for CAP vs. COPD (AUC ≤ 0.83), all of which were phospholipids. Phosphatidylcholines, lysophosphatidylcholines, and sphingomyelins were also markedly decreased in S. aureus-infected human A549 and differentiated THP1 cells. Correlations with C-reactive protein and procalcitonin were predominantly negative but only of mild-to-moderate extent, suggesting that these markers reflect more than merely inflammation. Consistent with the increased ceramide concentrations, increased acid sphingomyelinase activity accurately distinguished CAP (fold change = 2.8, AUC = 0.94) and COPD (1.75, 0.88) from Controls and normalized with clinical resolution.

CONCLUSIONS:

The results underscore the high potential of plasma phospholipids as biomarkers for CAP, begin to reveal differences in lipid dysregulation between CAP and infection-associated COPD exacerbation, and suggest that the decreases in plasma concentrations are at least partially determined by changes in host target cells. Furthermore, they provide validation in clinical blood samples of acid sphingomyelinase as a potential treatment target to improve clinical outcome of CAP.

KEYWORDS:

Biomarkers; Chronic obstructive pulmonary disease; Community-acquired pneumonia; Glycerophospholipids; Infection; Lipidomics; Lung disease; Mass spectrometry; Metabolism; Metabolomics; Sphingomyelinase

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