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. Author manuscript; available in PMC: 2026 Jan 6.
Published in final edited form as: Adv Biomark Sci Technol. 2025 Aug 15;7:238–247. doi: 10.1016/j.abst.2025.08.002

Lung-Brain Axis-Generated Inflammatory Biomarkers in Traumatic Brain Injury and Acute Respiratory Distress Syndrome: Role of Mechanical Ventilation/Stress

Nathan H Johnson 1, Nancy G Casanova 1, Susannah Patarroyo White 1, Jason Canizales 1, Sara M Camp 1, Jon Perez Barcena 2, Juan Pablo de Rivero Vaccari 3, Bellal Joseph 4, Joe G N Garcia 1,§
PMCID: PMC12768522  NIHMSID: NIHMS2127714  PMID: 41497388

Abstract

RATIONALE:

The unmet need for effective therapeutic strategies to address the bidirectional perturbation of the lung-brain axis following traumatic brain injury (TBI) or associated with Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is increasingly recognized. Contributing to this unmet need is the absence of reliable biomarkers that reflect the severity of lung-brain axis disruption. We assessed specific potential lung-brain axis biomarkers in TBI and ALI/ARDS subjects and explored the specific influence of exposure to mechanical ventilation.

METHODS:

Serum biomarker levels from TBI (n=97) and ARDS subjects (n=39) and healthy controls (n=46) were analyzed (MesoScale Discovery ELISA) utilizing a critical illness lung-brain axis biomarker panel (CILBA) that included DAMPS (eNAMPT, S100A8), inflammatory cytokines (IL-6, IL-1β, IL-1RA, TNF-α), vascular biomarkers (PSGL-1, ANG-2), and neurotrauma biomarkers (GFAP or Glial fibrillary acidic protein, NFL or neurofilament light chain, Tau).

RESULTS:

TBI and ARDS subjects demonstrated significant elevations in each biomarker (compared to controls) with two exceptions: PSGL-1 was exclusively elevated in ARDS and GFAP exclusively elevated in TBI. Mechanically ventilated subjects exposed exhibited significantly DAMP, vascular and neurotrauma biomarker elevations compared to unexposed subjects. With the exception of GFAP, Ang-2, and S100A8, biomarker elevations were linked to ICU days or mortality.

CONCLUSIONS:

These results highlight overlapping innate immunity dysregulation as a manifestation of lung-brain axis disruption in both TBI- and ARDS-exposed subjects with amplified dysregulation with mechanical ventilation. Additional longitudinal studies of well-phenotyped TBI and ARDS subjects may substantiate the prognostic value of biomarker analyses in assessing the severity of bidirectional lung-brain axis injuries.

Keywords: eNAMPT, DAMP, TLR4, Tau, CILBA (Critical Illness Lung-Brain Axis Biomarker Panel)

INTRODUCTION

Traumatic Brain Injury (TBI), affects 1.4 million Americans annually1 with over 30% of patients developing Acute Respiratory Distress Syndrome (ARDS), a critical illness responsible for more than 10% of ICU admissions with greater than 30% mortality2. When TBI subjects are placed on mechanical ventilation (MV) they are at major risk for developing ventilator-associated pneumonia (VAP) pneumonia (40% incidence)3. Recent studies focusing on potential pathological mechanisms of neurological and respiratory crosstalk, dubbed the lung-brain axis3,4, have demonstrated that TBI induces activation of the innate immune system to promote development of acute lung injury or ALI4,5

Inflammation is an essential pathobiological component of both TBI and ARDS, with inflammatory cytokines such as IL-1β and IL-6 representing metrics of TBI and ARDS pathological severity and progression6–9 Damage-associated molecular patterns (DAMPs), such as SA100A8/9 and eNAMPT, are potent activators of innate immunity released from stressed or pyroptotic/necroptotic cells, and serve to either initiate or further amplify innate immunity-mediated inflammatory responses. inflammatory cytokines and DAMPS influence systemic vascular and blood brain barrier integrity and pathophysiologic responses such as reduced respiratory compliance and cognition6,8,10–15, reflected by increases in vascular-associated biomarkers such as PSGL-1 and Ang-2 in both ARDS and TBI16–18.

In addition to trauma and infection, lung injury and DAMP release is triggered by excessive increases in mechanical stress via exposure to mechanical ventilation (MV) which directly contributes to profound activation of innate immunity19, a process known as ventilator-induced lung injury (VILI)20 21. Ventilator-associated brain injury (VABI)22,23 has been also described in cardiac arrest and COVID patients exposed to MV24,25 with cognitive complications such as delirium persisting beyond removal from mechanical ventilation23, presumably via a pathobiology involving MV-induced DAMPs and cytokines. To date, there are no FDA-approved therapies to reduce the severity of either TBI10 or ARDS with current standard of care being primarily palliative.

The present study was designed to provide preliminary insights into inflammatory signaling as a key component of lung-brain axis crosstalk by linking elevations in specific serum biomarkers of innate immune activation, lung injury, and neurotrauma6,8,26 in cohorts of TBI and ARDS subjects with and without MV exposure. Utilizing a Critical Illness Lung-Brain Axis (CILBA) biomarker panel comprised of inflammatory DAMPs (eNAMPT, S100A8), cytokines (IL-1β, IL-6, IL-1RA, TNF-α), vascular markers (Ang-2, PSGL-1) and neurotrauma-associated biomarkers (GFAP, NFL, total tau), we observed innate immunity dysregulation in both TBI- and ARDS-exposed subjects with an amplified dysregulation in MV patients. These results underscore inflammatory signaling as a manifestation of lung-brain axis disruption and identifies potential therapeutic targets for reducing pathological crosstalk between the brain and lungs after injury.

METHODS

Participants.

Serum samples were isolated from whole blood as previously described27 from healthy controls (46) and from three patient cohorts from the University of Arizona (Tucson, AZ) (n=39, ~52y/o), the University of Florida (Gainesville, FL) (n=39 ARDS, ~53y/o), and jointly through the University of Miami (Miami, FL) and the Son Espases University Hospital (Palma de Mallorca, Spain) (n=63, ~47y/o). Material transfer agreements were approved by the UF and UA IRBs and the Comite Etico de las Islas Baleares, Balearic Islands, Spain (IRB protocol number 3127/15). Table 1 details the demographic of the participants with 97 TBI patients, 39 ARDS patients and 63 TBI/ARDS patients receiving MV. UM TBI participant samples were collected within 36 hours of injury with all UA and UF patients collected from the first or second blood draw after diagnosis or hospital admission with patient data collected by hospital staff and from medical records. The injury severity for TBI from the University of Arizona was measured utilizing the Abbreviated Injury Scale (AIS)28 with a score of 3, 3, 3 (mean, median, mode) for the non MV patient cohort and 4, 5, 5 for the MV cohort. Injury severity for the University of Miami cohort was measured via Glasgow Coma Scale (GCS) with a score of 10, 11, 14 (mean, median, mode) for the complete TBI cohort. ARDS severity was composed of 5 unreported, 6 moderate, and 33 severe patients with APACHE II scores of 22, 22, 8 (mean, median, mode) for the 25 patients with reported scores (2 moderate, 23 severe).

Table 1:

Cohort Demographics

Type (n) Sex Age (years) Mortality ICU (days)
Healthy (46) M11/F8/U27 53 +/− 2 NA NA
TBI (97) M52/F11/U34 49 +/− 2 12D/49A/36U 8 +/− 1
ARDS (39) M17/F22/U0 53 +/− 2 15D/24A/0U 14 +/− 2
Location (n) TBI alone (n) TBI + vent (n) TBI + NVD (n) ARDS + vent (n)
U. Arizona 15 19 0 5
U. Florida 0 0 0 39
U. Miami 0 0 63 0
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Legend: M: Male, F: Female, U: Not Reported, D: Dead, A: Alive, NVD: No Vent Data.

Critical Illness Lung-Brain Axis (CILBA) Biomarker Panel.

Patient serum was analyzed for concentrations of inflammatory DAMPs (eNAMPT, S100A8), cytokines (IL-1β, IL-6, IL-1RA, TNF-α), vascular biomarkers (Ang-2, PSGL-1) and neurotrauma-associated biomarkers (GFAP, NFL, Tau) utilizing the Meso Scale Discovery (MSD; Rockville, MD, USA) R-Plex and U-Plex platforms as we previously described8,14. The assay consisted of the R-Plex plates for GFAP, NFL, S100A8 and Tau measurements and a U-Plex plate for eNAMPT, IL-1β, IL-6, IL-1RA, TNF-α, Ang-2, and PSGL-1. All assays were conducted in accordance with the manufacturer’s suggested protocols utilizing supplied reagents and buffers. Briefly, serum was thawed and diluted at a 1:4 ratio prior to addition to the plate. Plates were incubated at room temperature for 1 hour on a plate shaker prior to being placed at 4°C overnight. The following day plates were washed and incubated in secondary detection antibodies for 1 hour on a plate shaker at room temperature while protected from light. Plate was then washed and read solution was added. Plates were immediately read on the MSD Quick-Plex instrument. Raw data was interpreted utilizing MSD Discovery Workbench software and Microsoft Excel.

Statistical Analysis.

All samples were analyzed utilizing GraphPad Prism version 10 (Boston, MA, USA) software. Samples were assigned to groups in accordance with phenotypic data such as the mechanism of injury/infection, patient outcome, and utilization of mechanical ventilation. Prior to analysis, all samples and groups were analyzed for outliers utilizing ROUT analysis with a Q set to 1%. After removal of outliers, sample groups were first tested for normality then compared utilizing nonparametric 2-tailed Mann-Whitney for comparison between two groups or Kruskal-Wallis with post hoc Dunn’s correction (multiple comparison correction) tests for comparisons between multiple groups. Receiver operating characteristics (ROC) curve was calculated for TBI vs ARDS, all patients alive vs dead (for TBI mortality was classified as a GOSE of 1), and TBI with mechanical ventilation vs non mechanical ventilation to determine biomarker specificity for the mechanism of injury/infection tested, or to clinical outcomes of interest. A spearman correlation was performed to test correlations between biomarkers and clinical measures. Patients missing pertinent phenotypic data related to a specific group/outcome (mortality, ICU length, or mechanical ventilation) were omitted from the respectively tested group or outcome.

RESULTS

Significant Elevation of CILBA Biomarkers in TBI and ARDS.

Compared to healthy controls (mean +/− standard error of mean [SEM], p value), ARDS subjects exhibited significantly elevated levels of each inflammatory cytokine (IL-6 [12.82+/−2.29, p<0.0001], IL-1RA [1328+/−190.7, p<0.0001], IL-1β [0.23+/−0.93, p<0.0001], TNF-α [3.57+/−0.34, p<0.0001]), each DAMP (eNAMPT [20.01+/−2.17, p<0.0001], S100A8 [1395+/−168.9, p<0.0001]), and the vascular biomarker Ang-2 [22507+/−2888, p<0.0001], but not PSGL1 [4656+/−279, p=0.27]. Both NFL [434.3+/−57.68, p<0.0001] and Tau [35.61+/−4.28, p<0.0001] neuro biomarkers, but not GFAP [157.3+/−16.68, p>0.99], were also significantly elevated (Figure 1A–K). Moreover, CILBA analysis of TBI subjects demonstrated significantly elevated levels of each DAMP (eNAMPT, S100A8), each inflammatory cytokine (IL-6 [22.29+/−2.11, p<0.0001], IL-1RA [689.2+/−51.37, p<0.0001], IL-1β [0.45+/−0.03, p<0.0001], TNF-α [2.14+/−0.15, p<0.0001]), the vascular marker, Ang-2 [8566+/−583.5, p=0.0004] (not PSGL1 [2905+/−116.7, p=0.0002]), and each neuro biomarkers (NFL [273.1+/−27, p<0.0001], Tau [49.32+/−4.42, p<0.0001], GFAP [13684+/−1605, p<0.0001]) compared to healthy controls (Figure 1A–K).

Figure 1: Significant Elevation of CILBA Biomarkers in TBI and ARDS.

Figure 1:

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Biomarker levels were measured in the serum of TBI and ARDS patients. All biomarkers were significantly different (p<0.05) in TBI and in ARDS except PSGL-1 and GFAP (A-K). Biomarkers eNAMPT (A), TNF-a (D), Ang-2 (G), PSGL-1 (H), and GFAP (I) all significantly differed between TBI/ARDS. ROC analysis of TBI vs ARDS patients demonstrated that eNAMPT, TNF-a, Ang-2, PSGL-1, and GFAP were pathology specific in sensitivity (L). Outliers removed via ROUT analysis then analyzed via Kruskal-Wallis w/ post hoc Dunn correction. Data shown as mean +/− SEM.

Furthermore, ARDS subjects exhibited greater elevations of eNAMPT (p=0.006), TNF-α (p<0.0001), Ang-2 (p<0.0001), and PSGL1 (p<0.0001) compared to TBI subjects with only GFAP (p<0.0001) levels noted to be greater in TBI subjects (Figure 1A–K). Biomarker levels of S100A8 (p=0.44), IL-6 (p=0.08), IL-1β (p>0.99), IL-1RA (p=0.12), NFL (p=0.057), and Tau (p>0.99) were comparable between the two cohorts. ROC analysis of the biomarkers confirmed significant differences between TBI and ARDS subjects (Figure 1L) with eNAMPT (AUC=0.7296, p<0.0001), PSGL-1 (AUC=0.8182, p<0.0001) and GFAP (AUC=0.9230, p<0.0001) being more specific for TBI, while TNF-α (AUC=0.7378, p<0.0001) and IL-6 (AUC=0.66.96, p=0.005) were more specific for ARDS (Figure 1L).

Impact of Mechanical Ventilation Exposure on CILBA Biomarker Elevations in TBI and ARDS.

As MV is an emergency intervention utilized in both severe TBI and ARDS, we assessed the impact of MV on CILBA biomarker elevations and collapsed TBI and ARDS subjects into MV-negative and MV-positive cohorts. Interestingly, each DAMP (eNAMPT [p=0.002], S100A8 [p=0.012]), each vascular marker (Ang-2 [p=0.007], PSGL1 [p=0.0002]), and the neuro-inflammation markers, (NFL [p=0.001] and Tau [p<0.0001]) were significantly elevated in the MV-positive cohort, whereas no inflammatory cytokine or GFAP discriminated MV-positive from MV-negative cohorts (Figure 2A–K). Moreover, ROC analyses showed eNAMPT (AUC=0.7636, p=0.0025), S100A8 (AUC=0.7143, p=0.0136), Ang-2 (AUC=0.7251, p=0.0076), PSGL-1 (AUC=0.8023, p=0.0003), NFL (AUC=0.7712, p=0.0019), and total tau (AUC=0.8436, p=0.0002) to be strong biomarkers of MV exposure whereas each inflammatory cytokine failed to show significance (Figure 2A–K).

Figure 2: Impact of Mechanical Ventilation Exposure on Biomarkers in TBI and ARDS.

Figure 2:

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MV patients exhibited significantly increased serum levels of eNAMPT (A), NFL (F), S100A8 (G), total tau (H), PSGL-1 (I), GFAP (J), and ANG-2 (K) compared to non-MV TBI/ARDS patients. ROC analysis of MV vs non-MV patients indicated that elevated eNAMPT, NFL, S100A8, total tau, PSGL-1, GFAP, and ANG-2 levels implicated a higher chance of MV in TBI/ARDS (L). Outliers removed via ROUT analysis then analyzed via Kruskal-Wallis w/ post hoc Dunn correction. Data shown as mean +/− SEM.

Further sub-analyses of MV-negative and MV-positive TBI subjects showed only eNAMPT (p=0.017) and Tau (p=0.0001) to be significantly elevated in MV-positive TBI subjects according to ROC curves of eNAMPT (AUC=0.7444, p=0.0179) and Tau (AUC=0.8971, p=0.0003) (Figure 3A–M). Interestingly, GFAP was significantly elevated in non-MV patients compared to MV patients (Figure 2H). However, when considering that GFAP was only elevated in the TBI group, this result may be skewed by the fact that the majority of intubated patients were from the ARDS cohort. Additionally, GFAP was elevated in TBI patients regardless of intubation, further supporting that the results may be skewed phenotypically.

Figure 3: Increased levels of eNAMPT and total tau in TBI+MV patients.

Figure 3:

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MV significantly increased levels of eNAMPT and total tau in TBI patients compared to TBI alone (A,C). ROC analysis of TBI+MV vs TBI alone indicated that elevated eNAMPT, and total tau levels were associated with MV in TBI (B,D). No other tested biomarkers were significantly different between TBI+MV and TBI alone patients (E-M). Outliers removed via ROUT analysis then analyzed via Kruskal-Wallis w/ post hoc Dunn correction. Data shown as mean +/− SEM.

Linkage of CILBA Biomarker Elevations to TBI/ARDS Mortality and ICU Length.

Elevated levels of DAMPs and inflammatory cytokines are well recognized metrics of severity and probable mortality in TBI4,16 and ARDS subjects6–9,14. When compared to survivors, TBI non-survivors exhibited significantly higher levels of each inflammatory cytokine (IL-6 [p=0.008], Il-1β [p=0.015], IL-1RA [0=0.0004], TNF-α [p=0.0002]), the DAMP eNAMPT (p=0.02), the vascular marker PSGL-1 (p=0.036), and neurotrauma biomarkers NFL (p=0.001) and total tau (p=0.003) (Figure 4A–K) with ROC analysis confirming significant association with mortality (Figure 4M).

Figure 4: Linkage of Biomarkers Mortality and ICU Length.

Figure 4:

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Elevations in each biomarker with the exception of ANG-2, GFAP, and S100A8, were associated with increased patient mortality in a collapsed TBI and ARDS dataset (A-K). ROC analysis of patient outcomes (alive vs dead) indicated that elevated eNAMPT, Il-6, IL-1b, TNF-a, IL-1RA, total tau, PSGL-1, and NFL were all associated with greater chance of mortality in TBI/ARDS (L). Spearman correlation of biomarkers with length of ICU stay indicated that levels of IL-6, IL-1RA, TNF-a, and NFL were positively correlated with days in the ICU (M). Outliers removed via ROUT analysis then analyzed via Kruskal-Wallis w/ post hoc Dunn correction. Data shown as mean +/− SEM.

We next determined CILBA biomarker correlation with ICU length of stay. Accordingly, Spearman correlation analysis identified the neuroinflammation biomarker, NFL with the strongest correlation (0.378, p=0.001) with ICU length of stay, followed by the inflammatory cytokines TNF-α (0.333, p=0.001) and IL-1RA (0.209, p=0.041) (Figure 4L, Supplementary Figure 1A–C). In addition, subjects with elevated levels of NFL, TNF-α and IL-1RA showed longer ICU stays and mortality.

DISCUSSION

The absence of reliable clinically useful biomarkers is a major contributing factor to the unmet need for FDA-approved TBI and ARDS therapies. We examined the utility of a panel of clinically relevant biomarkers as a strategy to gain insights into lung-brain axis pathobiology. Our results examining inflammatory cytokine, DAMP, vascular and neurotrauma biomarkers indicate common TBI and ARDS pathobiological mechanisms involving innate immune activation/dysregulation and interactions via lung-brain axis crosstalk, particularly in TBI/ARDS patients on MV.

These results are consistent with multiple TBI/ARDS studies which have underscored the importance of altered host-defense mechanisms, inflammatory signaling and participation of inflammatory cytokines and DAMPs in driving disease severity4,8,12,29. TLR4, a highly prominent pathogen recognition receptor in ARDS and TBI, is activated by multiple DAMPs including S100 calcium binding protein 8 and 9 (S100A8/9), high-mobility group box1 (HMGB1), hyaluronan, and extracellular nicotinamide phosphoribosyltransferase or eNAMPT14,30,31. S100A8 inhibition reduces neuroinflammation in preclinical TBI mouse models31,32 and S100A8 actively contributes to VILI and systemic inflammation33,34. Similarly, robust elevations in plasma eNAMPT levels were noted in clinical and preclinical ARDS and VILI studies and correlated with disease severity including mortality8,14,20,35. Our current study findings support these findings as eNAMPT and S100A8 were significantly elevated in ARDS and TBI with amplified expression in MV-treated patients. The therapeutic efficacy eNAMPT neutralization in multiple preclinical models of severe inflammatory and fibrotic disease14,36 and in current Phase 2A clinical trials for ARDS (NCT05938036), suggests eNAMPT and IL-6 as potential druggable targets23,37 in mitigating TBI inflammatory pathology.

Our results support ongoing evidence that levels of NFL, GFAP, and Tau (total tau) may contribute to or be effective indicators of neurotrauma severity, neurodegeneration38 and prognosis in TBI and respiratory patients39. GFAP, a monomeric filament cytoskeletal protein strongly associated with activated astrocytes, is associated to worsened CT imaging and a negative TBI prognosis38,40,41. NFL is a component of myelinated axons and an effective biomarker of axonal injury in TBI38 and Tau is a microtubule-associated protein in axons with elevated levels following repeated TBIs and Alzheimer’s disease10,38. Interestingly, the vascular-centric biomarker, Ang-2, was significantly elevated in ARDS and TBI subjects16–18. PSGL-1, a cell adhesion molecule that binds P and E selectins, was elevated in ARDS but reduced in TBI subjects, potentially reflecting tissue-specific release42. Importantly, levels of assessed biomarkers was linked to clinical parameters including the length of intensive care unit (ICU) stay (NFL, TNF-α) and patient outcomes levels including mortality (NFL, TNF-α, eNAMPT, IL-6, IL-1β, PSGL-1, Tau)6–8,20,38,43.

A specific focus of the current study was to examine biomarker composition in TBI and ARDS patients exposed to the mechanical stress produced by MV. MV induces the release of DAMPs20, cytokines, and both vascular44 and neuro-inflammatory markers22,45 and contributes to brain injury22,23,46,47. Our study demonstrates that MV-treated TBI and ARDS patients exhibit significant plasma elevations of eNAMPT, PSGL-1, Ang-2, S100A8, NFL and Tau when compared with patients unexposed to MV. Although eNAMPT and S100A8 were both elevated in ARDS and TBI subjects, only eNAMPT8,20,48–50 and total tau were significantly elevated in MV-treated TBI patients compared to TBI patients unexposed to MV. Considering the role of tau in TBI10 and eNAMPT in ALI8, our results suggest the possibility that eNAMPT and Tau may represent reliable biomarkers of ventilator-induced brain injury or potential contributors to lung-brain axis crosstalk.

Despite the new insights into lung-brain axis crosstalk in TBI and ARDS, several limitations need to be noted including the single time point for data acquisition and the incomplete phenotypic data available on study subjects. This can be addressed in future studies utilizing a longitudinal cohort of well-phenotyped TBI and ARDS patients with careful analysis of severity of injury, time from injury to assessment, and presence or absence of specific clinical interventions, comorbidities, or health history, information not fully contained in the present study, a major limitation. Careful delineation of MV parameters such as duration and magnitude of ventilatory support, linked to biomarker levels would be a major focus in such a study. Finally, the present study did not include supporting biomarker data from preclinical models of TBI, ARDS, and MV, a future goal given the complexity and heterogeneity of TBI and ARDS pathobiology’s and capacity to delineate underlying signaling mechanisms involved in lung-brain axis signaling.

CONCLUSION

Our results demonstrate that innate immune activation is an overlapping pathological hallmark of both TBI and ARDS patients, further amplified in MV-treated patients, and may represent a mechanism of crosstalk in lung-brain axis signaling, Importantly, the biomarkers assessed in the current study are potentially druggable therapeutic targets with several currently FDA-approved therapeutics or under active investigation and development47,51–55. Future studies that include longitudinal assessments of well-phenotyped TBI and ARDS patients (with and without MV) are required to fully substantiate the utility of these biomarkers in measuring bidirectional lung-brain axis pathology and to begin to address the unmet need for novel TBI/ARDS therapeutics.

Supplementary Material

Supplemental Figure 1

Supplemental Figure 1 – Spearman correlation of all tested biomarkers with q values shown (A). Significant (p<0.05) values highlighted in yellow (B). N values for each group after ROUT analysis for each group (C).

Funding:

This work was supported by NIH R01-HL141387 (JGNG), P01-HL126609 (JGNG), U01-HL125208 (JGNG), R42-HL164300 (JGNG), R01NS113969 (JPdRV), RF1NS125578 (JPdRV)

Footnotes

Conflicts of Interest: JGNG is CEO and Founder of Aqualung Therapeutics Corporation. JPdRV is a co-founder and managing members of InflamaCORE, LLC and has licensed patents on inflammasome proteins as biomarkers of injury and disease as well as on targeting inflammasome proteins for therapeutic purposes. JPdRV is a Scientific Advisory Board Members of ZyVersa Therapeutics. All other authors declare no competing financial interests.

Ethics Approval: Research was performed in accordance with the Declaration of Helsinki. Material transfer agreements were approved by the UF and UA IRBs and the Comite Etico de las Islas Baleares, Balearic Islands, Spain (IRB protocol number 3127/15).

Data Availability Statement:

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Figure 1

Supplemental Figure 1 – Spearman correlation of all tested biomarkers with q values shown (A). Significant (p<0.05) values highlighted in yellow (B). N values for each group after ROUT analysis for each group (C).

NIHMS2127714-supplement-Supplemental_Figure_1.eps (6.3MB, eps)

Data Availability Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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