Endothelial glycocalyx degradation has been implicated in the pathogenesis of sepsis. Previous studies linked elevated plasma syndecan-1, an established biomarker of glycocalyx disruption, to mortality in sepsis. We aimed to determine the association of plasma syndecan-1 levels with clinical outcomes and host response changes in patients with community-acquired pneumonia (CAP) with various disease severities. We included CAP patients upon presentation in three care settings: emergency department (ED), general ward, and intensive care unit (ICU). We stratified patients in a Normal-Syndecan-1 and an Elevated-Syndecan-1 group based on syndecan-1 levels measured in outpatient controls without infection, and measured 32 biomarkers reflective of five pathophysiological domains involved in sepsis immunopathology: coagulation activation, endothelial cell activation and dysfunction, cytokines, neutrophil degranulation, systemic inflammation and organ damage. We analyzed blood transcriptomes to obtain insight in changes in host response pathways in circulating leukocytes related with glycocalyx disruption. We included 50 non-infectious control patients and 384 CAP patients, with samples collected from 95 in the ED, 124 after admission to the general ward, and 165 after admission to the ICU. The Elevated-Syndecan-1 group showed significantly reduced 30-day survival compared to the Normal-Syndecan-1 group (log-rank p < 0.05). The relationship between syndecan-1 (continuous variable) and 30-day mortality was non-linear and independent of comorbidities and disease severity. Most biomarkers were already strongly elevated in the Normal-Syndecan-1 group relative to non-infectious controls, spanning all pathophysiological domains. All biomarkers showed further increases in the Elevated-Syndecan-1 group relative to non-infectious controls, which was also reflected in direct comparisons between the Normal-Syndecan-1 and Elevated-Syndecan-1 groups. Gene set enrichment analysis of blood leukocytes indicated a link between elevated syndecan-1 and increased expression of genes involved in extracellular matrix organization and hemostasis. Glycocalyx degradation, as measured by plasma syndecan-1, shows a non-linear association with mortality in patients with CAP. Key systemic host response changes implicated in sepsis pathogenesis occur prior to detectable glycocalyx degradation in this population.

BACKGROUND:Sepsis is a dysregulated host response to infection resulting in life-threatening organ failure. Although immune dysregulation is central to the sepsis definition, immunomodulation trials enrol participants based on clinical severity, not the extent of dysregulation, which could contribute to treatment heterogeneity. A pragmatic way to quantify immune dysregulation could improve prognostication, help to evaluate treatment responses, and identify individuals most likely to benefit from immunomodulation. We aimed to construct a parsimonious machine-learning tool that defines and quantifies immune dysregulation, thereby supporting biologically informed immunomodulation. METHODS:In this multicohort analysis and reanalysis of a randomised controlled trial, the primary objective was to derive and validate a categorical and continuous immune dysregulation score that is independent of clinical presentation or outcome. We measured 35 plasma biomarkers reflecting key host response domains in individuals with community-acquired pneumonia (CAP) across different care settings (emergency department, general ward, and intensive care unit) and disease severities using data from three independent cohorts. We applied unsupervised trajectory inference analysis to identify an immune dysregulation gradient captured as discrete immune dysregulation stages (Dysregulated Immune Profile [DIP]) and a continuous score (cDIP; 0-1). We developed two parsimonious machine-learning models to predict the DIP stages and cDIP scores based on 35 biomarkers, and validated their ability to capture immune dysregulation and predict clinical outcomes in five independent cohorts. On the basis of our hypothesis that only individuals with severe immune dysregulation benefit from immunomodulation, we carried out a post-hoc analysis of a randomised trial evaluating hydrocortisone in severe CAP (CAPE COD trial, NCT02517489), assessing treatment effects across DIP stages and the cDIP continuum, and how hydrocortisone influenced dysregulation trajectories over time. FINDINGS:We organised 398 participants with CAP along a continuum of immune dysregulation from mild to severe on the basis of 35 plasma biomarkers, yielding three dysregulation stages (DIP1-3) and a continuous score (cDIP). Clinical severity proved to be an inadequate proxy for immune dysregulation. A three-biomarker machine-learning framework (procalcitonin, soluble TREM-1, and IL-6) accurately predicted the degree of dysregulation derived from 35 biomarkers (DIP stage accuracy 91·2%; cDIP root mean square error 0·056). Although the framework was not designed for outcome prediction, increased immune dysregulation-reflected in DIP and cDIP-was associated with a gradual rise in mortality (cDIP odds ratio [OR] 1·26 [95% CI 1·13-1·40] per 10% increase, p<0·0001) and secondary infections (OR 1·50 [1·22-1·93] per 10% increase, p=0·0005), independent of clinical severity. The three-biomarker tool was validated in five external cohorts of varying infections, severities, and care settings (n=1191). Reanalysis of the CAPE COD trial showed that hydrocortisone conferred a survival benefit only in participants classified as severely dysregulated by our model (30-day mortality: DIP3 OR 0·25 [0·05-0·85], p=0·042; cDIP ≥0·63 OR 0·21 [0·10-0·72], p=0·011), accompanied by faster immune recovery (time × treatment interaction, p<0·0001). No such effect modification was observed when stratifying participants by clinical severity. INTERPRETATION:We have provided a publicly available three-biomarker framework to determine the extent of host response dysregulation with potential value for precision-guided immunomodulatory therapy. FUNDING:EU Horizon 2020.

INTRODUCTION:Monocytes play a pivotal role in the regulation of inflammation and pathogen clearance during infection. Knowledge of the human monocyte proteome during infection is limited. We present a comprehensive proteome profile of blood monocytes from patients with community-acquired pneumonia (CAP), one of the most common infectious diseases, and controls without infection. METHODS:Monocytes were purified from blood of patients with CAP within 16 h of admission to a general hospital ward and from controls matched for sex, age and comorbidities. Monocyte proteins were measured using liquid chromatography/mass spectrometry. The transcriptome was analysed in the same samples by RNA sequencing. Monocytes were stimulated with lipopolysaccharide for 24 h, after which cytokines were measured in the supernatant. RESULTS:We analysed the monocyte proteome of 34 CAP patients and 23 controls. Out of 7315 annotated proteins, 1340 (18.3%) were differentially abundant between groups. Functional enrichment analyses revealed a marked downregulation of mitochondrial respiration processes in patient monocytes; pathways pertaining to cell cycle, cytokine signalling and cell death were upregulated in patient monocytes. Monocyte mRNA levels correlated poorly with the abundance of corresponding proteins and associated functional pathways, raising caution regarding interpretation of functionality estimates based on transcriptome analyses. Differential expression of monocyte proteins had functional and clinical implications as indicated by associations with cytokine production capacity, disease severity and time to clinical stability. CONCLUSION:This study provides a publicly available monocyte protein atlas that can serve as a resource for future research on monocyte functions during infection.

Rationale: Community-acquired pneumonia (CAP) represents a significant health burden. Objectives: We aimed to map the plasma proteome in patients with CAP and associate protein abundance with pathophysiology, tissue source, and outcome. Methods: We measured the plasma proteome of patients with CAP upon admission to a general ward using Olink technology (derivation cohort). Additional Olink measurements were performed in patients with CAP admitted to the ICU and patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia across care settings (validation cohorts). Measurements and Main Results: Of 2,676 proteins analyzed in 93 ward patients with CAP and 21 healthy control subjects, 904 (33.8%) were higher in CAP, 396 (14.8%) lower, and 1,376 (51.4%) not different. More abundant proteins were associated with innate immune and mitosis pathways and mainly originated from lung and cardiac tissue. A total of 131 proteins associated with time to clinical stability (TCS), of which 124 (primarily related to monocyte and macrophage and RNA processing) were connected with a long TCS. Most TCS-associated proteins were differentially abundant in nonsurvivors versus survivors among 88 patients with ICU-CAP (1.4- to 3.5-fold higher) and 305 patients with SARS-CoV-2 pneumonia (1.16- to 1.35-fold lower or 1.14- to 2.65-fold higher; all P < 0.05). In the general population (UK Biobank), 115 of 124 (92.7%) proteins correlated with long TCS were associated with an increased risk of pneumonia during a 10-year follow-up, whereas 6 of 7 (85.7%) proteins correlated with shorter TCS were associated with a lower risk of pneumonia. Conclusions: This now publicly available CAP plasma proteome provides information on pathophysiological mechanisms and tissue involvement and may support development of personalized therapies.

BACKGROUND:Gut microbiota play a protective role against pneumonia in mice, probably by producing the immunomodulatory short-chain fatty acid butyrate. Yet, butyrate has limited potential for clinical use due to its challenging handling in practice. We performed mouse experiments and translational analyses to determine whether butyrate-producing gut commensals, Faecalibacterium prausnitzii and Anaerobutyricum soehngenii, could provide protection against bacterial pneumonia and serve as next-generation probiotics. METHODS:We pre-treated C57BL/6J mice with butyrate, F. prausnitzii (recently reclassified as F. duncaniae) or A. soehngenii, and subsequently infected them intranasally with Klebsiella pneumoniae. To assess the relevance in humans, we assessed associations between rectal levels of Faecalibacterium, immune responses and clinical outcomes in 115 patients with community-acquired pneumonia (CAP) and in a separate validation cohort. RESULTS:Pre-treatment with F. prausnitzii, but not A. soehngenii, protected mice against bacterial pneumonia, as reflected by reduced bacterial growth and dissemination, lessened organ damage, and dampened inflammation. Similar to butyrate pre-treatment, F. prausnitzii resulted in reduced pulmonary interleukin (IL)-6 and CXCL1. In humans, gut Faecalibacterium was decreased during CAP compared to matched controls. CAP patients with higher gut Faecalibacterium levels had lower IL-6-producing capacity and downregulated inflammatory gene expression. Higher intestinal Faecalibacterium levels were associated with better clinical outcomes in independent cohorts of CAP and critically ill patients, which remained significant when controlled for potential confounders. CONCLUSION:This is the first study showing that the gut commensal F. prausnitzii provides protection against bacterial pneumonia and has translational potential. This motivates future studies investigating the clinical potential of F. prausnitzii as a novel probiotic for pneumonia.

Background Gut microbiota play a protective role against pneumonia in mice, probably by producing the immunomodulatory short-chain fatty acid butyrate. Yet, butyrate has limited potential for clinical use due to its challenging handling in practice. We performed mouse experiments and translational analyses to determine whether butyrate-producing gut commensals, Faecalibacterium prausnitzii and Anaerobutyricum soehngenii, could provide protection against bacterial pneumonia and serve as next-generation probiotics. Methods We pre-treated C57BL/6J mice with butyrate, F. prausnitzii (recently reclassified as F. duncaniae) or A. soehngenii, and subsequently infected them intranasally with Klebsiella pneumoniae. To assess the relevance in humans, we assessed associations between rectal levels of Faecalibacterium, immune responses and clinical outcomes in 115 patients with community-acquired pneumonia (CAP) and in a separate validation cohort. Results Pre-treatment with F. prausnitzii, but not A. soehngenii, protected mice against bacterial pneumonia, as reflected by reduced bacterial growth and dissemination, lessened organ damage, and dampened inflammation. Similar to butyrate pre-treatment, F. prausnitzii resulted in reduced pulmonary interleukin (IL)-6 and CXCL1. In humans, gut Faecalibacterium was decreased during CAP compared to matched controls. CAP patients with higher gut Faecalibacterium levels had lower IL-6-producing capacity and downregulated inflammatory gene expression. Higher intestinal Faecalibacterium levels were associated with better clinical outcomes in independent cohorts of CAP and critically ill patients, which remained significant when controlled for potential confounders. Conclusion This is the first study showing that the gut commensal F. prausnitzii provides protection against bacterial pneumonia and has translational potential. This motivates future studies investigating the clinical potential of F. prausnitzii as a novel probiotic for pneumonia.

Objectives: Lymphopenia at hospital admission occurs in over one-third of patients with community-acquired pneumonia (CAP), yet its clinical relevance and pathophysiological implications remain underexplored. We evaluated outcomes and immune features of patients with lymphopenic CAP (L -CAP), a previously described immunophenotype characterized by admission lymphocyte count < 0.724 x 10 9 cells/L. Methods: Observational study in 149 patients admitted to a general ward for CAP. We measured 34 plasma biomarkers reflective of inflammation, endothelial cell responses, coagulation, and immune checkpoints. We characterized lymphocyte phenotypes in 29 patients using spectral flow cytometry. Results: L -CAP occurred in 45 patients (30.2%) and was associated with prolonged time-to-clinical-stability (median 5 versus 3 days), also when we accounted for competing events for reaching clinical stability and adjusted for baseline covariates (subdistribution hazard ratio 0.63; 95% confidence interval 0.45-0.88). LCAP patients demonstrated a proportional depletion of CD4 T follicular helper cells, CD4 T effector memory cells, na & iuml;ve CD8 T cells and IgG+ B cells. Plasma biomarker analyses indicated increased activation of the cytokine network and the vascular endothelium in L -CAP. Conclusions: L -CAP patients have a protracted clinical recovery course and a more broadly dysregulated host response. These findings highlight the prognostic and pathophysiological relevance of admission lymphopenia in patients with CAP. (c) 2024 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The lipidome of immune cells during infection has remained unexplored, although evidence of the importance of lipids in the context of immunity is mounting. In this study, we performed untargeted lipidomic analysis of blood monocytes and neutrophils from patients hospitalized for pneumonia and age- and sex-matched noninfectious control volunteers. We annotated 521 and 706 lipids in monocytes and neutrophils, respectively, which were normalized to an extensive set of internal standards per lipid class. The cellular lipidomes were profoundly altered in patients, with both common and distinct changes between the cell types. Changes involved every level of the cellular lipidome: differential lipid species, class-wide shifts, and altered saturation patterns. Overall, differential lipids were mainly less abundant in monocytes and more abundant in neutrophils from patients. One month after hospital admission, lipidomic changes were fully resolved in monocytes and partially in neutrophils. Integration of lipidomic and concurrently collected transcriptomic data highlighted altered sphingolipid metabolism in both cell types. Inhibition of ceramide and sphingosine-1-phosphate synthesis in healthy monocytes and neutrophils resulted in blunted cytokine responses upon stimulation with lipopolysaccharide. These data reveal major lipidomic remodeling in immune cells during infection, and link the cellular lipidome to immune functionality.

Neutrophils are potent immune cells with key antimicrobial functions. Previous in vitro work has shown that neutrophil effector functions are mainly fueled by intracellular glycolysis. Little is known about the state of neutrophils still in the circulation in patients during infection. Here, we combined flow cytometry, stimulation assays, transcriptomics, and metabolomics to investigate the link between inflammatory and metabolic pathways in blood neutrophils of patients with community-acquired pneumonia. Patients' neutrophils, relative to neutrophils from age- and sex- matched controls, showed increased degranulation upon ex vivo stimulation, and portrayed distinct upregulation of inflammatory transcriptional programs. This neutrophil phenotype was accompanied by a high-energy state with increased intracellular ATP content, and transcriptomic and metabolic upregulation of glycolysis and glycogenolysis. One month after hospital admission, these metabolic and transcriptomic changes were largely normalized. These data elucidate the molecular programs that underpin a balanced, yet primed state of blood neutrophils during pneumonia.

DNA methyltransferase 3b (Dnmt3b) has been suggested to play a role in the host immune response during bacterial infection. Neutrophils and other myeloid cells are crucial for lung defense against Pseudomonas (P.) aeruginosa infection. This study aimed to investigate the role of Dnmt3b in neutrophils and myeloid cells during acute pneumonia caused by P. aeruginosa. Neutrophil-specific (Dnmt3bfl/flMrp8Cre) or myeloid cell-specific (Dnmt3bfl/flLysMCre) Dnmt3b-deficient mice and littermate control mice were infected with P. aeruginosa PAK via the airways. Bacteria burdens, neutrophil recruitment, and activation (CD11b expression, myeloperoxidase, and elastase levels), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF) were measured in bronchoalveolar lavage fluid (BALF) at 6 and 24 h after infection. Our data showed that the bacterial loads and neutrophil recruitment and activation did not differ in BALF obtained from neutrophil-specific Dnmt3b-deficient and control mice, whilst BALF IL-6 and TNF levels were lower in the former group at 24 but not at 6 h after infection. None of the host response parameters measured differed between myeloid cell-specific Dnmt3b-deficient and control mice. In conclusion, dnmt3b deficiency in neutrophils or myeloid cells does not affect acute immune responses in the airways during Pseudomonas pneumonia.

Tet methylcytosine dioxygenase 2 (Tet2) is an important enzyme in the demethylation of DNA. Recent evidence has indicated a role for Tet2 in the regulation of macrophage activation by lipopolysaccharide (LPS) and mice with a myeloid cell Tet2 deficiency showed enhanced lung inflammation upon local LPS administration. However, mice with a global Tet2 deficiency showed reduced systemic inflammation during abdominal sepsis. Here, we sought to determine the role of myeloid cell Tet2 in the host response during gram-negative bacterial pneumonia. To this end we infected myeloid cell specific Tet2 deficient and control mice with two common gram-negative respiratory pathogens via the airways: Pseudomonas aeruginosa (PAK, causing acute infection that remains confined in the lungs) or Klebsiella pneumoniae (causing a gradually evolving pneumonia with subsequent dissemination and sepsis) and compared bacterial loads and host response parameters between mouse strains. Bone marrow derived macrophages from myeloid Tet2 deficient mice released more interleukin-6 than control macrophages upon stimulation with PAK or K. pneumoniae. However, bacterial loads did not differ between mouse strains upon infection with viable PAK or K. pneumoniae, and neither did cytokine levels or neutrophil recruitment. In addition, in the K. pneumoniae pneumosepsis model myeloid Tet2 deficiency did not affect systemic inflammation or organ injury. Together these data strongly argue against a role for myeloid cell Tet2 in the host response during gram-negative bacterial pneumonia and pneumosepsis.

Background: Community-acquired pneumonia (CAP) is responsible for a high morbidity and mortality worldwide. Monocytes are essential for pathogen recognition and the initiation of an innate immune response. Immune cells induce intracellular glycolysis upon activation to support several functions.Objective: To obtain insight in the metabolic profile of blood monocytes during CAP, with a focus on glycolysis and branching metabolic pathways, and to determine a possible association between intracellular metabolite levels and monocyte function.Methods: Monocytes were isolated from blood of patients with CAP within 24 h of hospital admission and from control subjects matched for age, sex and chronic comorbidities. Changes in glycolysis, oxidative phosphoryla-tion (OXPHOS), tricarboxylic acid (TCA) cycle and the pentose phosphate pathway were investigated through RNA sequencing and metabolomics measurements. Monocytes were stimulated ex vivo with lipopolysaccharide (LPS) to determine their capacity to produce tumor necrosis factor (TNF), interleukin (IL)-18 and IL-10. Results: 50 patients with CAP and 25 non-infectious control subjects were studied. When compared with control monocytes, monocytes from patients showed upregulation of many genes involved in glycolysis, including PKM, the gene encoding pyruvate kinase, the rate limiting enzyme for pyruvate production. Gene set enrichment analysis of OXPHOS, the TCA cycle and the pentose phosphate pathway did not reveal differences between monocytes from patients and controls. Patients' monocytes had elevated intracellular levels of pyruvate and the TCA cycle intermediate alpha-ketoglutarate. Monocytes from patients were less capable of producing cytokines upon LPS stimulation. Intracellular pyruvate (but not alpha-ketoglutarate) concentrations positively correlated with IL-18 and IL-10 levels released by patients' (but not control) monocytes upon exposure to LPS.Conclusion: These results suggest that elevated intracellular pyruvate levels may partially maintain cytokine production capacity of hyporesponsive monocytes from patients with CAP.

Tet methylcytosine dioxygenase 2 (Tet2) mediates demethylation of DNA. We here sought to determine the expression and function of Tet2 in macrophages upon exposure to lipopolysaccharide (LPS), and in the host response to LPS induced lung and peritoneal inflammation, and during Escherichia (E.) coli induced peritonitis. LPS induced Tet2 expression in mouse macrophages and human monocytes in vitro, as well as in human alveolar macrophages after bronchial instillation in vivo. Bone marrow-derived macrophages from myeloid Tet2 deficient (Tet2fl/flLysMCre) mice displayed enhanced production of IL-1β, IL-6 and CXCL1 upon stimulation with several Toll-like receptor agonists; similar results were obtained with LPS stimulated alveolar and peritoneal macrophages. Histone deacetylation was involved in the effect of Tet2 on IL-6 production, whilst methylation at the Il6 promoter was not altered by Tet2 deficiency. Tet2fl/flLysMCre mice showed higher IL-6 and TNF levels in bronchoalveolar and peritoneal lavage fluid after intranasal and intraperitoneal LPS administration, respectively, whilst other inflammatory responses were unaltered. E. coli induced stronger production of IL-1β and IL-6 by Tet2 deficient peritoneal macrophages but not in peritoneal lavage fluid of Tet2fl/flLysMCre mice after in vivo intraperitoneal infection. Tet2fl/flLysMCre mice displayed enhanced bacterial growth during E. coli peritonitis, which was associated with a reduced capacity of Tet2fl/flLysMCre peritoneal macrophages to inhibit the growth of E. coli in vitro. Collectively, these data suggest that Tet2 is involved in the regulation of macrophage functions triggered by LPS and during E. coli infection.

Abstract Background Strongly elevated ferritin levels have been proposed to reflect systemic hyperinflammation in patients admitted to the intensive care unit. Knowledge of the incidence and pathophysiological implications of hyperferritinemia in patients with acute infection admitted to a non–intensive care setting is limited. Methods We determined the association between hyperferritinemia, defined by 2 cutoff values (500 and 250 ng/mL), and aberrations in key host response mechanisms among patients with community-acquired pneumonia (CAP) on admission to a general hospital ward (clinicaltrials.gov NCT02928367; trialregister.nl NTR6163). Results Plasma ferritin levels were higher in patients with CAP (n = 174; median [interquartile ranges], 259.5 [123.1–518.3] ng/mL) than in age- and sex-matched controls without infection (n = 50; 102.8 [53.5–185.7] ng/mL); P < .001); they were ≥500 ng/mL in 46 patients (26%) and ≥250 ng/mL in 90 (52%). Measurements of 26 biomarkers reflective of distinct pathophysiological domains showed that hyperferritinemia was associated with enhanced systemic inflammation, neutrophil activation, cytokine release, endothelial cell activation and dysfunction, and activation of the coagulation system. Results were robust across different cutoff values. Conclusions Hyperferritinemia identifies patients with CAP with a broad deregulation of various host response mechanisms implicated in the pathogenesis of sepsis. This could inform future therapeutic strategies targeting subgroups within the CAP population.

Human studies describing the immunomodulatory role of the intestinal microbiota in systemic infections are lacking. Here, we sought to relate microbiota profiles from 115 patients with community-acquired pneumonia (CAP), both on hospital admission and following discharge, to concurrent circulating monocyte and neutrophil function. Rectal microbiota composition did not explain variation in cytokine responses in acute CAP (median 0%, IQR 0.0%-1.9%), but did one month following hospitalization (median 4.1%, IQR 0.0%-6.6%, p = 0.0035). Gene expression analysis of monocytes showed that undisrupted microbiota profiles following hospitalization were associated with upregulated interferon, interleukin-10, and G-protein-coupled-receptor-ligand-binding pathways. While CAP is characterized by profoundly distorted gut microbiota, the effects of these disruptions on cytokine responses and transcriptional profiles during acute infection were absent or modest. However, rectal microbiota were related to altered cytokine responses one month following CAP hospitalization, which may provide insights into potential mechanisms contributing to the high risk of recurrent infections following hospitalization.

BACKGROUND:Community-acquired pneumonia (CAP) can be caused by a variety of pathogens, of which Streptococcus pneumoniae, Influenza and currently SARS-CoV-2 are the most common. We sought to identify shared and pathogen-specific host response features by directly comparing different aetiologies of CAP.METHODS:We measured 72 plasma biomarkers in a cohort of 265 patients hospitalized for CAP, all sampled within 48 hours of admission, and 28 age-and sex matched non-infectious controls. We stratified the biomarkers into several pathophysiological domains- antiviral response, vascular response and function, coagulation, systemic inflammation, and immune checkpoint markers. We directly compared CAP caused by SARS-CoV-2 (COVID-19, n=39), Streptococcus pneumoniae (CAP-strep, n=27), Influenza (CAP-flu, n=22) and other or unknown pathogens (CAP-other, n=177). We adjusted the comparisons for age, sex and disease severity scores.FINDINGS:Biomarkers reflective of a stronger cell-mediated antiviral response clearly separated COVID-19 from other CAPs (most notably granzyme B). Biomarkers reflecting activation and function of the vasculature showed endothelial barrier integrity was least affected in COVID-19, while glycocalyx degradation and angiogenesis were enhanced relative to other CAPs. Notably, markers of coagulation activation, including D-dimer, were not different between the CAP groups. Ferritin was most increased in COVID-19, while other systemic inflammation biomarkers such as IL-6 and procalcitonin were highest in CAP-strep. Immune checkpoint markers showed distinctive patterns in viral and non-viral CAP, with highly elevated levels of Galectin-9 in COVID-19.INTERPRETATION:Our investigation provides insight into shared and distinct pathophysiological mechanisms in different aetiologies of CAP, which may help guide new pathogen-specific therapeutic strategies.FUNDING:This study was financially supported by the Dutch Research Council, the European Commission and the Netherlands Organization for Health Research and Development.

OBJECTIVES: Plasma ferritin levels above 4,420 ng/mL have been proposed as a diagnostic marker for macrophage activation-like syndrome in sepsis and used for selection of sepsis patients for anti-inflammatory therapy. We here sought to determine the frequency, presentation, outcome, and host response aberrations of macrophage activation-like syndrome, as defined by admission ferritin levels above 4,420 ng/mL, in critically ill patients with community-acquired pneumonia. DESIGN: A prospective observational cohort study. SETTING: ICUs in two tertiary hospitals in the Netherlands. PATIENTS: One hundred fifty-three patients admitted with community-acquired pneumonia. MEASUREMENTS AND MAIN RESULTS: Patients were stratified in community-acquired pneumonia-macrophage activation-like syndrome (n = 15; 9.8%) and community-acquired pneumonia-control groups (n = 138; 90.2%) based on an admission plasma ferritin level above or below 4,420 ng/mL, respectively. Community-acquired pneumonia-macrophage activation-like syndrome patients presented with a higher disease severity and had a higher ICU mortality (46.7% vs 12.3% in community-acquired pneumonia-controls; p = 0.002). Twenty-three plasma biomarkers indicative of dysregulation of key host response pathways implicated in sepsis pathogenesis (systemic inflammation, cytokine responses, endothelial cell activation, and barrier function, coagulation activation) were more disturbed in community-acquired pneumonia-macrophage activation-like syndrome patients. Hematologic malignancies were overrepresented in community-acquired pneumonia-macrophage activation-like syndrome patients (33.3% vs 5.1% in community-acquired pneumonia-controls; p = 0.001). In a subgroup analysis excluding patients with hematologic malignancies (n = 141), differences in mortality were not present anymore, but the exaggerated host response abnormalities in community-acquired pneumonia-macrophage activation-like syndrome patients remained. CONCLUSIONS: Macrophage activation-like syndrome in critically ill patients with community-acquired pneumonia occurs more often in patients with hematologic malignancies and is associated with deregulation of multiple host response pathways.