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Systemic inflammation

Systemic inflammation refers to a widespread, body-wide inflammatory response orchestrated by the immune system, characterized by the activation of immune cells such as macrophages and lymphocytes, along with the release of pro-inflammatory mediators like cytokines (e.g., IL-6, TNF-α) and acute-phase proteins (e.g., C-reactive protein), in reaction to systemic stressors including infections, trauma, tissue damage, or chronic conditions.^[1]^[2] Unlike localized inflammation confined to a specific tissue or organ, systemic inflammation involves diffuse microcirculatory disturbances and can lead to multi-organ involvement if unresolved.^[3] This process can occur in acute or chronic forms, with acute systemic inflammation typically arising rapidly from severe insults like sepsis or major injury, manifesting as a cytokine storm, fever, elevated heart rate, and potential progression to multiple organ dysfunction syndrome (MODS), which carries high mortality rates (e.g., up to 71% in septic shock cases).^[3]^[4] In contrast, chronic systemic inflammation is a low-grade, persistent state lasting months to years, often driven by ongoing factors such as obesity, autoimmune disorders, or environmental irritants, and is marked by sustained elevation of biomarkers like high-sensitivity C-reactive protein (hsCRP) and fibrinogen.^[2]^[5] Key triggers of systemic inflammation include microbial pathogens detected via pattern recognition receptors (e.g., Toll-like receptors), sterile damage signals (e.g., damage-associated molecular patterns from injured cells), oxidative stress, and metabolic dysregulation, which activate signaling pathways like NF-κB and MAPK to amplify the response.^[1]^[5] Common markers for detection include interleukins (IL-1β, IL-6, IL-8), tumor necrosis factor-α (TNF-α), D-dimer, and cortisol, with clinical scales such as the Systemic Inflammation (SI) scale or SOFA score used to assess severity, particularly in acute settings.^[3]^[4] Systemic inflammation plays a pivotal role in the pathogenesis of numerous diseases, contributing to cardiovascular disorders (e.g., atherosclerosis), metabolic conditions (e.g., type 2 diabetes), neurodegenerative diseases (e.g., Alzheimer's), cancers, and autoimmune conditions (e.g., rheumatoid arthritis) by promoting tissue fibrosis, endothelial dysfunction, and immune dysregulation.^[2]^[1] In chronic forms, it underlies "inflammaging," the age-related increase in inflammatory markers that exacerbates frailty and disease susceptibility.^[5] Management strategies focus on addressing underlying causes, anti-inflammatory therapies (e.g., corticosteroids, JAK inhibitors), and lifestyle interventions like exercise and anti-inflammatory diets to mitigate its detrimental effects.^[2]^[3]

Definition and Overview

Definition

Systemic inflammation is defined as a widespread inflammatory response that extends beyond a localized site to affect multiple organ systems throughout the body, involving the coordinated activation of innate and adaptive immune mechanisms.^[1] This process represents an escalated defense mechanism where immune cells and signaling molecules disseminate via the bloodstream, potentially leading to diffuse physiological alterations.^[6] The concept of systemic inflammation gained formal recognition in the early 1990s in relation to sepsis, with the 1992 American College of Chest Physicians/Society of Critical Care Medicine consensus conference introducing the Systemic Inflammatory Response Syndrome (SIRS) criteria to describe the host's systemic reaction to infection or other insults.^[7] Over time, the understanding has broadened to include chronic low-grade systemic inflammation, which contributes to the pathogenesis of contemporary diseases such as cardiovascular disorders and metabolic syndrome.^[8] Key characteristics of systemic inflammation include the elevated circulation of pro-inflammatory mediators, notably cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which orchestrate immune cell recruitment and amplify the response across distant tissues.^[9] In contrast to local inflammation—restricted to the injury site and characterized by cardinal signs such as redness, swelling, heat, and pain—systemic inflammation propagates through vascular dissemination, risking multi-organ dysfunction if unchecked.^[10] It manifests in both acute and chronic forms, with the latter involving persistent, low-level activation.^[2]

Types

Systemic inflammation is primarily classified into two types: acute and chronic, distinguished by their duration, intensity, and underlying physiological processes.^[3] Acute systemic inflammation features a rapid onset, typically developing within hours to days in response to acute stressors such as infection or injury.^[10] This high-intensity response aims to eliminate the threat and restore homeostasis, often resolving spontaneously if the trigger is addressed, though it can escalate to life-threatening conditions like systemic inflammatory response syndrome (SIRS) or multiple organ dysfunction.^[4] It is characterized by neutrophil dominance, where these cells rapidly infiltrate tissues to phagocytose pathogens and debris, accompanied by systemic signs such as fever driven by proinflammatory cytokines.^[11] For instance, sepsis exemplifies acute systemic inflammation, involving a cytokine storm and widespread vascular permeability changes.^[3] In contrast, chronic systemic inflammation manifests as a persistent, low-grade state lasting weeks to years, fueled by unresolved or recurrent stimuli that evade complete clearance.^[8] This form promotes ongoing tissue remodeling and fibrosis rather than acute resolution, with monocyte and macrophage activation playing central roles in sustaining the inflammatory milieu through prolonged cytokine production and immune cell recruitment.^[11] Unlike its acute counterpart, it rarely induces fever but contributes to insidious progression in age-related pathologies. An example is the low-grade inflammation observed in metabolic syndrome, where adipose tissue-derived signals perpetuate a smoldering response.^[12] Key differences between the two types lie in their timelines, cellular orchestration, and outcomes: acute inflammation is neutrophil-led with intense, short-lived effects often marked by fever and potential for self-limitation or rapid deterioration, whereas chronic inflammation involves macrophage-driven persistence, emphasizing low-intensity remodeling over acute defense.^[3]^[13]

Causes and Triggers

Infectious Causes

Systemic inflammation often arises from infectious agents that breach local barriers and trigger a widespread immune response, particularly in the context of acute inflammation. Bacterial infections are primary initiators, with Gram-negative bacteria such as Escherichia coli releasing lipopolysaccharide (LPS), also known as endotoxin, a potent immunostimulant that binds to Toll-like receptor 4 (TLR4) on immune cells, leading to massive cytokine production and systemic effects like sepsis.^[14]^[15] Similarly, Gram-positive bacteria like Streptococcus species expose peptidoglycan and lipoteichoic acid (LTA) components of their cell walls, which activate TLR2 and other pattern recognition receptors, provoking proinflammatory cytokine storms that amplify inflammation beyond the infection site.^[16]^[17] Viral infections, especially respiratory pathogens, contribute significantly to systemic inflammation through mechanisms akin to cytokine release syndrome (CRS). Influenza viruses induce excessive release of cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) from infected lung epithelial cells and immune responders, resulting in vascular leakage and multi-organ involvement.^[18] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, similarly drives CRS by triggering hyperactivation of the innate immune system, with elevated levels of IL-1β, IL-6, and interferon-gamma leading to acute respiratory distress and systemic coagulopathy in vulnerable patients.^[19]^[18] Fungal and parasitic pathogens also elicit systemic inflammation, predominantly in immunocompromised individuals where host defenses are impaired. Candida species, particularly Candida albicans, can disseminate from mucosal sites into the bloodstream, releasing β-glucan and mannoproteins that stimulate inflammatory pathways via dectin-1 and TLRs, culminating in invasive candidiasis with high mortality rates.^[20]^[21] Parasitic infections like malaria, caused by Plasmodium species, provoke systemic responses through hemozoin and glycosylphosphatidylinositols, which induce TNF-α and IL-1 production, contributing to fever, anemia, and endothelial dysfunction in endemic regions.^[22]^[23] The spread of these pathogens often involves invasion of the bloodstream, transforming localized infections into sepsis, a life-threatening condition characterized by dysregulated host responses. This dissemination can activate the systemic inflammatory response syndrome (SIRS), defined by the 1992 American College of Chest Physicians/Society of Critical Care Medicine consensus criteria, which include abnormalities in temperature, heart rate, respiratory rate, and white blood cell count (from any cause, including infection).^[24]^[4]

Non-infectious Causes

Systemic inflammation can arise from non-infectious triggers, where tissue damage or dysregulated immune responses initiate a sterile inflammatory cascade without microbial involvement. These causes often involve the release of damage-associated molecular patterns (DAMPs), which activate innate immune pathways similar to pathogen-associated molecular patterns.^[4] Trauma and injury, including surgical procedures, burns, and accidents, are major non-infectious inducers of systemic inflammation. In these scenarios, cellular necrosis releases DAMPs such as high-mobility group box 1 (HMGB1), a potent proinflammatory mediator that binds to receptors like Toll-like receptor 4 (TLR4), triggering cytokine production and immune cell recruitment. For instance, major trauma or burns leads to a systemic inflammatory response syndrome (SIRS) in up to 50% of severe cases, characterized by elevated levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Post-surgical patients exhibit SIRS in a significant proportion, with studies reporting mortality rates of 12.7% in those meeting SIRS criteria compared to 0.4% without.^[4]^[25] Autoimmune and autoinflammatory disorders drive persistent systemic inflammation through aberrant recognition of self-antigens or innate immune dysregulation. In rheumatoid arthritis (RA), an autoimmune condition, self-antigens like citrullinated proteins elicit autoantibodies such as anti-citrullinated protein antibodies (ACPAs), present in 50-80% of patients, which perpetuate inflammation via synovial macrophage activation and release of cytokines including TNF-α, IL-1, and IL-6. These cytokines contribute to systemic effects beyond joints, such as cardiovascular complications. Autoinflammatory disorders, like familial Mediterranean fever (FMF) caused by MEFV gene mutations, involve inflammasome hyperactivation leading to excessive IL-1β production and recurrent sterile inflammatory episodes, affecting multiple organs.^[26]^[26]^[27] Environmental and lifestyle factors, including obesity, smoking, and poor diet, promote chronic low-grade systemic inflammation. In obesity, visceral adipose tissue produces proinflammatory cytokines like IL-6 and TNF-α due to adipocyte hypertrophy, hypoxia, and immune cell infiltration, elevating circulating inflammatory markers and increasing risks for metabolic diseases. Smoking induces oxidative stress and xenobiotic exposure, activating NF-κB pathways and elevating C-reactive protein levels. High-sugar diets exacerbate this by increasing gut permeability via mechanisms like zonulin upregulation, allowing bacterial endotoxins to translocate and trigger TLR-mediated inflammation.^[5]^[5]^[5] Ischemia-reperfusion injury, as seen in myocardial infarction, represents another key non-infectious cause, where restoration of blood flow paradoxically amplifies inflammation. During reperfusion, cardiomyocytes release DAMPs that activate TLRs and NLRP3 inflammasomes, leading to neutrophil infiltration, reactive oxygen species production, and cytokine storms involving IL-1β and TNF-α. This process contributes to up to 50% of the final infarct size and systemic responses, including elevated peripheral leukocytes and adhesion molecule expression.^[28]^[28]^[29]

Pathophysiology

Molecular Mechanisms

Systemic inflammation involves a complex network of cytokines that amplify the inflammatory response through key signaling pathways. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) play central roles in this process by activating the nuclear factor kappa B (NF-κB) pathway. These cytokines bind to their respective receptors on target cells, triggering a cascade that leads to the phosphorylation and degradation of the inhibitory protein IκB, thereby allowing NF-κB dimers to translocate to the nucleus and induce transcription of genes encoding additional inflammatory mediators.^[30]^[31] This amplification sustains and propagates the systemic response, particularly in response to triggers like infections.^[32] The complement system contributes to systemic inflammation through its activation via classical, alternative, and lectin pathways, culminating in the generation of anaphylatoxins C3a and C5a. In the classical pathway, antigen-antibody complexes initiate a proteolytic cascade involving C1 through C4 and C2, leading to C3 cleavage into C3a and C3b. The alternative pathway, triggered by spontaneous C3 hydrolysis or pathogen surfaces, bypasses early components and directly amplifies C3 convertase activity to produce C3a. Both C3a and C5a act as potent chemoattractants, binding to G-protein-coupled receptors on immune cells to induce degranulation, histamine release, and further cytokine production, thereby enhancing vascular permeability and leukocyte recruitment.^[33]^[34]^[35] Arachidonic acid metabolites, including prostaglandins and leukotrienes, are synthesized via cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) enzymes, respectively, and mediate key inflammatory effects such as fever and increased vascular permeability. COX-2, inducible by pro-inflammatory stimuli, converts arachidonic acid to prostaglandin H2 (PGH2), which is further metabolized to prostaglandin E2 (PGE2); PGE2 acts on hypothalamic neurons to elevate body temperature and on endothelial cells to promote vasodilation and edema. Similarly, 5-LOX catalyzes leukotriene production, with leukotriene B4 (LTB4) serving as a neutrophil chemoattractant that exacerbates tissue damage and permeability.^[36]^[37]^[38] Feedback mechanisms regulate the cytokine network to prevent excessive inflammation, with anti-inflammatory cytokines like interleukin-10 (IL-10) providing negative control by suppressing NF-κB activity and pro-inflammatory gene expression. IL-10 inhibits the production of TNF-α, IL-1β, and IL-6 through STAT3-dependent pathways that block inflammatory signaling in monocytes and macrophages. Dysregulation of these loops can lead to a cytokine storm, characterized by uncontrolled amplification of pro-inflammatory mediators. A key step in NF-κB activation is the phosphorylation of the inhibitor IκB by the IκB kinase (IKK) complex, followed by its ubiquitination and proteasomal degradation, enabling NF-κB nuclear translocation:

\text{IκB phosphorylation} \rightarrow \text{NF-κB nuclear translocation}

This process is tightly controlled, but in cytokine storms, persistent activation overwhelms regulatory mechanisms like IL-10.^[39]^[40]^[41]^[42]

Cellular Involvement

Innate immune cells are central to the initiation and amplification of systemic inflammation, with neutrophils serving as first responders that engulf pathogens through phagocytosis and deploy neutrophil extracellular traps (NETs) via NETosis to trap and kill microbes, thereby containing infection but potentially exacerbating tissue damage when dysregulated.^[43] Macrophages, another key innate player, polarize toward an M1 phenotype in response to microbial signals, releasing pro-inflammatory cytokines such as TNF-α and IL-6 to orchestrate broader immune activation and sustain the inflammatory cascade.^[44] These cells interact with molecular signals like cytokines to propagate responses across the body.^[45] Adaptive immune cells further modulate systemic inflammation, particularly in prolonged responses; T cells, including Th1 and Th17 subsets, amplify the reaction by producing IFN-γ and IL-17, respectively, which enhance macrophage activity and neutrophil recruitment to perpetuate inflammation.^[46] In chronic systemic inflammation, B cells contribute by differentiating into plasma cells that produce autoantibodies, such as anti-nuclear antibodies in conditions like systemic lupus erythematosus, which form immune complexes that trigger ongoing immune activation.^[47] Non-immune cells, including endothelial and epithelial cells, actively participate by undergoing barrier dysfunction during systemic inflammation, releasing alarmins like HMGB1 and IL-33 that alert immune cells and promote leukocyte adhesion and extravasation through upregulated expression of selectins and integrins on endothelial surfaces.^[48] Dysregulation of these cellular components can prolong systemic inflammation; for instance, excessive M1 macrophage activation in chronic states leads to persistent cytokine storms, while elevated circulating monocytes indicate heightened monocytic infiltration and contribute to sustained pro-inflammatory signaling.^[49]

Clinical Manifestations

Symptoms and Signs

Systemic inflammation manifests through a range of subjective symptoms and objective signs that reflect the body's widespread immune activation. Common symptoms include fever, often induced by interleukin-1 (IL-1) binding to receptors on brain endothelial cells in the preoptic hypothalamus, leading to prostaglandin E2 synthesis and elevated body temperature.^[50] Hypothalamic inflammation triggered by IL-1 and tumor necrosis factor-alpha (TNF-α) also contributes to fatigue, malaise, and anorexia, as these cytokines disrupt energy balance and appetite regulation in the brain.^[51] Observable signs of systemic inflammation include tachycardia, with heart rate exceeding 90 beats per minute, and leukocytosis, defined as a white blood cell count greater than 12,000/μL.^[4] In severe cases, hypotension may develop as part of the inflammatory cascade, particularly when progressing to conditions like septic shock.^[4] Additionally, elevated levels of acute-phase proteins, such as C-reactive protein, occur as the liver responds to proinflammatory cytokines like IL-6, marking the systemic acute-phase response.^[52] The presentation of systemic inflammation varies between acute and chronic forms. Acute systemic inflammation often involves dramatic symptoms like chills and rigors, accompanying rapid-onset fever as the body attempts to elevate temperature through shivering.^[53] In contrast, chronic systemic inflammation typically presents more subtly, with low-grade fever and gradual weight loss due to persistent anorexia and metabolic alterations.^[2] These symptoms and signs were historically codified in the 1992 Systemic Inflammatory Response Syndrome (SIRS) criteria, established by the American College of Chest Physicians and Society of Critical Care Medicine, which include core temperature greater than 38°C or less than 36°C and heart rate greater than 90 beats per minute, among others.^[54]

Organ System Effects

Systemic inflammation exerts profound effects on the cardiovascular system primarily through endothelial damage, which accelerates atherosclerosis and heightens the risk of thrombosis. Proinflammatory cytokines such as TNF-α and C-reactive protein (CRP) activate endothelial cells, reducing nitric oxide bioavailability by downregulating endothelial nitric oxide synthase expression, thereby impairing vasodilation and promoting leukocyte adhesion.^[55] This endothelial dysfunction facilitates the recruitment of inflammatory cells into the arterial wall, initiating and exacerbating atherosclerotic plaque formation.^[55] Furthermore, systemic inflammation enhances prothrombotic states by increasing the expression of tissue factor and plasminogen activator inhibitor-1, which weaken plaque stability and promote thrombus formation upon rupture, significantly elevating the risk of acute coronary events.^[56] Cytokines like IL-6 also elevate fibrinogen levels, contributing to a hypercoagulable environment that links chronic low-grade inflammation to cardiovascular disease progression.^[56] In the respiratory system, systemic inflammation can precipitate acute respiratory distress syndrome (ARDS) via widespread capillary leak and resultant ventilation-perfusion (V/Q) mismatch. Inflammatory mediators, including cytokines and chemokines released from activated alveolar macrophages and recruited neutrophils, disrupt the alveolar-capillary barrier, increasing permeability and leading to protein-rich edema fluid accumulation in the alveoli.^[57] This exudative phase impairs gas exchange by flooding airspaces, while concurrent endothelial injury causes microvascular thrombosis and heterogeneous lung collapse, particularly in dependent regions.^[57] The resulting V/Q mismatch manifests as intrapulmonary shunting and increased physiologic dead space, contributing to refractory hypoxemia that is often resistant to supplemental oxygen.^[58] Vascular changes from inflammation further exacerbate this by elevating pulmonary artery pressure and right ventricular strain, amplifying the mismatch and overall respiratory failure.^[58] Systemic inflammation impacts the renal and hepatic systems by inducing acute kidney injury through hypoperfusion and driving hepatic production of acute-phase reactants such as CRP. In the kidneys, proinflammatory cytokines and oxidative stress from systemic sources reduce renal blood flow via vasoconstriction and endothelial dysfunction, leading to ischemic hypoperfusion and tubular injury.^[59] This is compounded by systemic disturbances like elevated lactate levels, which correlate with worse outcomes in inflammatory contexts, highlighting hypoperfusion as a key mediator of AKI severity.^[60] Concurrently, the liver responds to inflammatory signals, primarily IL-6, by upregulating synthesis of CRP as part of the acute-phase response, with circulating levels rising dramatically within hours of onset.^[61] This hepatic production not only amplifies the inflammatory cascade but also reflects the organ's role in modulating systemic responses, though excessive inflammation can impair overall liver function.^[61] Neurological effects of systemic inflammation include encephalopathy arising from cytokines breaching the blood-brain barrier (BBB), which contributes to delirium and cognitive dysfunction. Proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 cross the BBB via circumventricular organs or disrupted tight junctions, activating microglia and triggering neuroinflammation within brain regions like the hippocampus.^[62] This leads to endothelial activation, reduced expression of junctional proteins like occludin and claudin-5, and increased permeability, allowing further influx of inflammatory mediators that cause neuronal excitotoxicity and metabolic stress.^[63] The resulting encephalopathy manifests clinically as delirium, affecting up to 70% of septic patients, with associated EEG changes and long-term cognitive deficits due to sustained neuroinflammatory damage.^[62]

Associated Conditions

Comorbidities

Systemic inflammation is strongly associated with several comorbidities, where chronic inflammatory processes exacerbate disease progression and increase mortality risk. In metabolic disorders, such as obesity and type 2 diabetes, adipose tissue becomes a major source of pro-inflammatory cytokines, linking low-grade systemic inflammation to insulin resistance. Obese individuals exhibit elevated levels of interleukin-6 (IL-6) derived from adipose tissue, which impairs insulin signaling by inhibiting tyrosine phosphorylation of insulin receptor substrates in adipocytes and hepatocytes, thereby promoting hyperglycemia and type 2 diabetes development.^[64] This adipose-derived IL-6 activates the JAK/STAT pathway, fostering a chronic inflammatory state that extends to skeletal muscle and liver, worsening systemic insulin resistance.^[65] Cardiovascular diseases, including atherosclerosis and heart failure, are significantly worsened by systemic inflammation, which drives endothelial dysfunction and plaque vulnerability. In atherosclerosis, inflammatory cells such as macrophages release matrix metalloproteinases that degrade the fibrous cap of plaques, increasing the risk of rupture and thrombosis, while T lymphocytes inhibit collagen synthesis by smooth muscle cells, further destabilizing lesions.^[66] Chronic inflammatory conditions, like rheumatoid arthritis, elevate the risk of cardiovascular morbidity and mortality by approximately 50%, highlighting the role of sustained inflammation in accelerating plaque instability and heart failure progression.^[67] Neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, involve systemic inflammation that activates microglia, amplifying neuroinflammation and neuronal damage. In Alzheimer's disease, peripheral inflammatory signals trigger microglial responses to amyloid-β plaques, leading to the formation of disease-associated microglia that release pro-inflammatory cytokines like IL-1β and TNF-α, which impair amyloid clearance and promote tau pathology.^[68] Similarly, in Parkinson's disease, systemic inflammation enhances microglial activation in response to α-synuclein aggregates, resulting in dopaminergic neuron loss through NLRP3 inflammasome-mediated cytokine release and peripheral monocyte infiltration via the CCL2-CCR2 axis.^[68] In cancer, systemic inflammation creates a pro-tumorigenic microenvironment that supports tumor growth, angiogenesis, and metastasis. Elevated C-reactive protein (CRP) levels, a marker of systemic inflammation, correlate with poor prognosis, as demonstrated in a 2019 study of patients receiving PD-1 inhibitors, where CRP >10 mg/L was associated with significantly shorter progression-free survival (3.0 months vs. 17.0 months) and overall survival (12.0 months vs. not reached).^[69] This inflammatory state fosters immune evasion and tumor progression across various cancers, including melanoma and non-small cell lung cancer.^[69] Systemic Inflammatory Response Syndrome (SIRS) is a clinical condition characterized by a widespread inflammatory response to various insults, including infections, trauma, or ischemia, and it often serves as a precursor to more severe states like sepsis. Diagnosis requires the presence of at least two of the following criteria: body temperature greater than 38°C (100.4°F) or less than 36°C (96.8°F); heart rate exceeding 90 beats per minute; respiratory rate greater than 20 breaths per minute or partial pressure of arterial carbon dioxide (PaCO₂) less than 32 mmHg; and white blood cell count greater than 12,000/mm³, less than 4,000/mm³, or more than 10% immature (band) forms.^[4]^[70] SIRS frequently precedes sepsis, particularly in infectious contexts, where it reflects the body's attempt to combat pathogens but can escalate to organ dysfunction if unchecked.^[71] Cytokine Release Syndrome (CRS) represents an acute and severe manifestation of systemic inflammation, driven by excessive cytokine production from activated immune cells, commonly observed in immunotherapies such as chimeric antigen receptor T-cell (CAR-T) therapy or severe infections. In CAR-T contexts, CRS arises from rapid T-cell expansion and cytokine storm, leading to symptoms like fever, hypotension, and organ hypoperfusion. Severity is graded using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria, where grade 3 involves hypotension requiring vasopressor support despite fluid resuscitation, alongside fever and potential hypoxia.^[72] Management focuses on supportive care and targeted cytokine blockade, such as with tocilizumab, to mitigate life-threatening complications.^[73] Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory syndrome triggered by uncontrolled macrophage and lymphocyte activation, resulting in cytokine overproduction and tissue damage, often secondary to infections, malignancies, or autoimmune disorders. The HLH-2024 diagnostic criteria (updated as of November 2024) require either a molecular confirmation of HLH-associated gene mutations or fulfillment of five out of seven clinical and laboratory features: fever for at least seven days; splenomegaly; cytopenias affecting at least two of three lineages (hemoglobin <9 g/dL, platelets <100,000/μL, neutrophils <1,000/μL); hypertriglyceridemia (≥265 mg/dL) or hypofibrinogenemia (≤1.5 g/L); hemophagocytosis in bone marrow, spleen, or lymph nodes; ferritin level ≥500 ng/mL; and elevated soluble CD25 (sIL-2 receptor) ≥2,400 U/mL. The update from HLH-2004 removes the requirement for low or absent natural killer cell activity to improve diagnostic accessibility.^[74]^[75] This core set of features, including fever, splenomegaly, cytopenias, hypertriglyceridemia or hypofibrinogenemia, and hemophagocytosis, underscores the syndrome's multisystem involvement.^[75] HLH demands prompt immunosuppression and etiological treatment to prevent fatal outcomes.^[76] In the context of viral infections like those seen in the COVID-19 pandemic, SIRS criteria have been applied to identify inflammatory responses, highlighting their relevance to non-bacterial triggers without formal redefinition in the 2020s.^[77]

Diagnosis

Clinical Assessment

The clinical assessment of systemic inflammation commences with a thorough history-taking to identify potential triggers and underlying predisposing factors. Clinicians inquire about recent infections, trauma, surgical interventions, medication exposures, or environmental allergens that could initiate a widespread inflammatory cascade. A systematic review of symptoms is conducted, encompassing constitutional complaints like fever and malaise, as well as organ-specific manifestations such as migratory joint pain indicative of autoimmune etiologies or persistent cough suggesting pulmonary involvement.^[4]^[78] The physical examination focuses on vital signs to detect derangements consistent with the Systemic Inflammatory Response Syndrome (SIRS) criteria, defined as two or more of the following: core body temperature exceeding 38°C or below 36°C; heart rate greater than 90 beats per minute; respiratory rate greater than 20 breaths per minute or PaCO₂ less than 32 mmHg; or leukocyte count greater than 12,000/μL, less than 4,000/μL, or greater than 10% immature (band) forms. These abnormalities signal an exaggerated host response and prompt evaluation for systemic spread. Additional findings, such as generalized lymphadenopathy, skin rashes, or hepatosplenomegaly, are documented to assess multi-organ involvement and guide suspicion toward specific inflammatory pathways.^[4]^[70] Risk stratification is performed using validated scoring systems, particularly the quick Sequential Organ Failure Assessment (qSOFA) in suspected sepsis-associated inflammation. This tool awards one point for each of three clinical parameters: respiratory rate ≥22 breaths per minute, altered mentation (e.g., Glasgow Coma Scale <15), and systolic blood pressure ≤100 mmHg. A qSOFA score ≥2 identifies patients at elevated risk for adverse outcomes, including prolonged hospital stays and mortality, necessitating intensified monitoring and resource allocation.^[79]^[80] Formulating a differential diagnosis requires excluding conditions that mimic systemic inflammation, such as malignancies that induce paraneoplastic syndromes with fever, cachexia, and elevated acute-phase reactants, or endocrine disorders like subacute thyroiditis presenting with painful swelling and systemic symptoms. Historical elements like unexplained weight loss, night sweats, or endocrine dysfunction (e.g., diabetes mellitus) are probed to differentiate inflammatory processes from these neoplastic or hormonal imbalances.^[4]^[81] The Surviving Sepsis Campaign international guidelines emphasize immediate clinical assessment upon suspicion of sepsis-related systemic inflammation, recommending initiation of the hour-1 bundle—encompassing recognition, vital sign evaluation, and risk scoring—within the first hour of presentation to optimize outcomes.^[82]

Biomarkers and Tests

Diagnosis of systemic inflammation relies on a variety of laboratory biomarkers and imaging modalities to objectively quantify inflammatory processes and differentiate underlying causes. C-reactive protein (CRP) is a widely used acute-phase reactant that rises rapidly in response to interleukin-6 (IL-6) stimulation during inflammation, with levels exceeding 10 mg/L indicating moderate to marked systemic inflammation often associated with acute conditions such as infections or autoimmune flares.^[83] Similarly, the erythrocyte sedimentation rate (ESR) measures the rate at which red blood cells settle in a tube over one hour, serving as a non-specific indicator of inflammation; values greater than 20 mm/hr are typically elevated and correlate with increased fibrinogen and other plasma proteins in inflammatory states.^[84] Procalcitonin (PCT), a precursor to calcitonin, is particularly valuable for distinguishing bacterial infections from non-infectious systemic inflammation, as its levels rise more selectively in bacterial sepsis (often >0.5 ng/mL) compared to viral or sterile inflammatory responses.^[85] Cytokine profiling provides deeper insights into the inflammatory cascade but is not routinely employed in clinical practice due to high costs and technical complexity associated with assays like enzyme-linked immunosorbent assays (ELISA) or multiplex platforms. Plasma levels of IL-6, a key pro-inflammatory cytokine, can exceed 100 pg/mL in severe systemic inflammation, such as in sepsis or cytokine release syndromes, reflecting intense immune activation; however, routine measurement is limited to research or specialized settings where it aids in prognostic assessment.^[86] Imaging techniques complement laboratory tests by visualizing organ-specific inflammatory involvement. Computed tomography (CT) and magnetic resonance imaging (MRI) are essential for detecting structural changes, such as ground-glass opacities on chest CT, which represent alveolar inflammation and are commonly observed in systemic conditions like acute respiratory distress syndrome or interstitial lung diseases.^[87] Positron emission tomography (PET) scans, often combined with CT, excel in assessing chronic or occult inflammatory activity by capturing metabolic uptake of tracers like 18F-fluorodeoxyglucose in affected tissues, proving useful in vasculitis or large-vessel inflammation.^[88] Emerging diagnostic approaches integrate multi-omics data for more personalized assessment of systemic inflammation. Recent 2025 studies have developed multi-omics approaches integrating metabolomics, proteomics, and transcriptomics to identify metabolite signatures, such as altered lipid profiles or amino acid imbalances, that enhance diagnostic accuracy in conditions like sepsis, enabling tailored interventions beyond traditional markers.^[89] These approaches hold promise for early detection but require validation in larger clinical cohorts before widespread adoption.^[90]

Management and Treatment

Acute Management

Acute management of systemic inflammation prioritizes rapid stabilization to prevent organ dysfunction and mortality, particularly in conditions like sepsis or trauma-induced responses where inflammation escalates to life-threatening levels. Initial interventions focus on restoring hemodynamic stability, controlling the inflammatory source, and mitigating complications such as shock or acute respiratory distress syndrome (ARDS).^[82]^[4] Supportive care begins with fluid resuscitation to address hypoperfusion, administering at least 30 mL/kg of intravenous crystalloids (such as balanced solutions) within the first 3 hours for patients with sepsis-induced hypotension or elevated lactate levels (≥4 mmol/L). If mean arterial pressure remains below 65 mmHg despite fluids, vasopressors like norepinephrine are initiated as the first-line agent to maintain perfusion. For respiratory failure, mechanical ventilation employs lung-protective strategies, including low tidal volumes of 6 mL/kg predicted body weight and plateau pressures ≤30 cm H₂O in cases of sepsis-induced ARDS.^[82]^[82]^[82] Standardized protocols, such as the Surviving Sepsis Campaign's Hour-1 Bundle, guide immediate actions: measure lactate level, obtain blood cultures before antibiotics, administer broad-spectrum intravenous antibiotics within 1 hour for suspected infection, deliver the 30 mL/kg crystalloid bolus for hypoperfusion, and apply vasopressors if hypotensive. These steps aim to interrupt the inflammatory cascade early.^[82] Source control is essential to eliminate the inflammatory trigger, involving prompt administration of empiric broad-spectrum antibiotics (e.g., vancomycin combined with piperacillin-tazobactam for coverage against methicillin-resistant Staphylococcus aureus and gram-negative organisms) within 1 hour of recognition in infectious cases, followed by de-escalation based on cultures. In trauma-related systemic inflammation, surgical debridement of necrotic or infected tissue and drainage of abscesses are performed as soon as feasible, ideally within 6 hours, to halt ongoing cytokine release and bacterial dissemination.^[82]^[91]^[4]^[92] Anti-inflammatory agents like corticosteroids are reserved for refractory septic shock, with intravenous hydrocortisone at 200 mg/day suggested only for patients requiring ongoing vasopressor support despite adequate fluid resuscitation, as routine use is not recommended per 2021 guidelines due to limited evidence of benefit in non-refractory cases.^[82]

Chronic Management

Chronic management of systemic inflammation focuses on sustained strategies to mitigate persistent inflammatory processes, particularly in individuals with underlying conditions such as metabolic disorders or autoimmune diseases. Lifestyle interventions form the cornerstone of these approaches, emphasizing modifiable behaviors that reduce pro-inflammatory cytokines and oxidative stress.^[93] A key recommendation is adherence to an anti-inflammatory diet, such as the Mediterranean diet, which is rich in fruits, vegetables, whole grains, and omega-3 fatty acids from sources like fish and nuts. This dietary pattern has been shown to lower biomarkers of inflammation, including C-reactive protein (CRP) and interleukin-6 (IL-6), by modulating gut microbiota and reducing oxidative damage. Studies indicate that long-term adherence can decrease systemic inflammation by up to 20-30% in at-risk populations.^[94]^[93] Regular physical activity is another essential intervention, with guidelines recommending at least 150 minutes of moderate-intensity aerobic exercise per week. This level of activity has been associated with a reduction in circulating IL-6 levels by approximately 20-30%, alongside improvements in endothelial function and decreased adipokine production, particularly beneficial in cases linked to obesity or diabetes.^[95]^[96] Smoking cessation is critical, as tobacco use exacerbates systemic inflammation through increased production of reactive oxygen species and cytokines. Quitting smoking leads to measurable reductions in inflammatory markers, such as CRP and fibrinogen, within weeks to months, with sustained benefits including up to a 90% decrease in smoking-related inflammatory risks over time.^[97]^[98] Pharmacological options target specific pathways in chronic inflammation, often tailored to associated conditions. Statins, beyond their lipid-lowering effects, exert pleiotropic anti-inflammatory actions by inhibiting NF-κB signaling and reducing monocyte adhesion to endothelium, thereby lowering CRP levels by 15-25% in patients with cardiovascular risks.^[99]^[100] In metabolic cases, such as those involving insulin resistance or type 2 diabetes, metformin is commonly used for its direct anti-inflammatory properties, including suppression of NLRP3 inflammasome activation and reduction of IL-1β and TNF-α. Clinical evidence supports its role in decreasing systemic inflammation independently of glycemic control, with reductions in CRP observed in treated individuals.^[101]^[102] For autoimmune-linked inflammation, biologics like anti-TNF agents, exemplified by infliximab, block tumor necrosis factor-alpha to interrupt cytokine cascades. Infliximab has demonstrated efficacy in reducing systemic inflammatory burden in conditions such as rheumatoid arthritis, with rapid decreases in CRP and erythrocyte sedimentation rate in responsive patients.^[103] Ongoing monitoring is vital to assess treatment efficacy and adjust interventions. Serial measurements of CRP are recommended every 3-6 months to guide therapy, with a target level below 3 mg/L indicating remission or low-grade inflammation control. This threshold correlates with reduced cardiovascular and metabolic risks in chronic settings.^[83] Pharmacogenomics is an emerging approach for personalized management in inflammatory disorders, analyzing genetic variants to optimize therapies like biologics and analyze response rates.^[104] Emerging therapies include IL-6 inhibitors such as tocilizumab for conditions like rheumatoid arthritis and cytokine release syndrome, which target specific inflammatory pathways.^[105]

Research Directions

Current Findings

Recent research has elucidated the critical role of gut microbiome dysbiosis in perpetuating chronic systemic inflammation. Dysbiosis, characterized by an imbalance in microbial composition, compromises the intestinal epithelial barrier, facilitating the translocation of lipopolysaccharides (LPS) from gram-negative bacteria into the bloodstream. This process, known as metabolic endotoxemia, triggers low-grade systemic inflammation by activating Toll-like receptor 4 (TLR4) on immune cells, leading to the release of pro-inflammatory cytokines such as IL-6 and TNF-α. A 2023 narrative review highlights how this mechanism underlies the inflammatory basis of metabolic disorders like obesity and type 2 diabetes, emphasizing the gut barrier's function in modulating systemic immune responses.^[106] In the context of aging, the phenomenon of inflammaging—chronic, low-grade systemic inflammation—has been linked to cellular senescence, where senescent cells accumulate and secrete senescence-associated secretory phenotype (SASP) factors. These factors, including pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α, propagate a vicious cycle of inflammation that contributes to age-related frailty and multimorbidity. Studies indicate that IL-6 levels in the elderly often double compared to younger adults, correlating with increased frailty scores and functional decline. A comprehensive 2023 review in Signal Transduction and Targeted Therapy underscores how SASP-driven inflammaging impairs tissue homeostasis and accelerates the onset of conditions such as cardiovascular disease and neurodegeneration.^[107] The legacy of COVID-19 has spotlighted post-acute systemic inflammation in long COVID, affecting a significant subset of survivors. Long COVID manifests as persistent symptoms driven by ongoing immune dysregulation and low-grade inflammation, including elevated markers like C-reactive protein and cytokines, even months after acute infection. Prevalence estimates suggest 10-20% of COVID-19 patients experience these protracted effects, with fatigue, cognitive impairment, and cardiopulmonary issues predominating. A 2024 review in Cell details how viral persistence and immune exhaustion contribute to this inflammatory state, providing mechanistic insights into symptom chronicity.^[108] Epidemiological data underscore the profound global burden of systemic inflammation, primarily through its role in non-communicable diseases (NCDs). NCDs, encompassing cardiovascular diseases, cancers, diabetes, and chronic respiratory conditions, accounted for 43 million deaths in 2021, representing 75% of non-pandemic-related global mortality as of September 2025. Chronic inflammation is a key driver in many of these deaths, fueling disease progression across the life span via sustained immune activation. The World Health Organization's 2025 fact sheet on NCDs highlights this escalating burden, particularly in low- and middle-income countries, where inflammatory processes exacerbate socioeconomic disparities in health outcomes.^[109]^[8]

Emerging Therapies

Targeted biologics represent a promising frontier in modulating systemic inflammation by precisely inhibiting key cytokine pathways. Janus kinase (JAK) inhibitors, such as tofacitinib, block cytokine signaling downstream of receptors involved in pro-inflammatory cascades, with phase I and II trials demonstrating safety and efficacy in reducing disease activity in conditions like systemic lupus erythematosus and COVID-19-associated hyperinflammation.^[110] Similarly, interleukin-1 (IL-1) antagonists like anakinra have shown potential in managing cytokine release syndrome (CRS), a severe manifestation of systemic inflammation; ongoing phase II trials, including prophylactic administration post-CAR T-cell therapy, have been evaluated with mixed results on CRS incidence and severity, while studies in refractory cases report disease overall response rates up to 77%.^[111]^[112] Cell-based therapies, particularly mesenchymal stem cells (MSCs), offer immunomodulatory effects by secreting anti-inflammatory factors and regulating immune cell activity. In phase II trials for acute respiratory distress syndrome (ARDS) and severe COVID-19, intravenous MSC infusions have demonstrated safety and feasibility, with significant reductions in inflammatory markers such as C-reactive protein (CRP) and IL-6 in treated patients.^[113]^[114] Nanomedicine approaches enhance precision in drug delivery to inflamed sites, minimizing systemic side effects. For instance, endothelium-targeted nanogels delivering small interfering RNA (siRNA) against NF-κB have shown preclinical efficacy in suppressing endothelial inflammation and reducing plaque progression in atherosclerosis models, with in vivo studies reporting decreased expression of adhesion molecules and inflammatory cytokines.^[115]^[116] Preventive strategies, including anti-inflammaging vaccines, aim to target chronic low-grade inflammation underlying age-related conditions. Preclinical studies on vaccines targeting senescent cells and inflammaging pathways, such as nanovaccines against senescence-associated antigens in adipose tissue, have demonstrated reduced metabolic dysfunction in models of metabolic syndrome, with early clinical evaluations initiating in 2025.^[117]^[118]^[119]

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