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Systemic inflammation
Systemic inflammation
Systemic inflammation
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Chronic systemic inflammation is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease, autoimmune and neurodegenerative disorders,[1] and coronary heart disease.[2]

Mechanisms

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Release of pro-inflammatory cytokines and activation of the innate immune system may be the result of either external (biological or chemical agents) or internal (genetic mutations/variations) factors. The cytokine Interleukin 6 and C-reactive protein are common inflammatory markers used to diagnose systemic inflammation risk.[3] Baseline C-reactive protein levels deviate due to natural genetic variation, but significant increases can result from risk factors such as smoking, obesity, lifestyle, and high blood pressure.[3] Excess advanced glycation end-products attach to RAGE receptors to produce chronic inflammation.[4]

Systemic chronic inflammation increases with age (also known as inflammaging) due to unresolved acute inflammation and an individual's exposome. Age-related systemic chronic inflammation is associated with several cytokines including CXCL9, TRAIL, interferon gamma, CCL11, and CXCL1, and a proposed measurement of chronic systemic inflammation based on these cytokines (iAge) correlates with immunosenescence and predicts risk for cardiovascular disease, frailty syndrome, and multimorbidity.[5] Damaged proteins and other cellular debris can provoke chronic inflammation in the innate immune system.[6]

Comorbidities

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It is firmly established that systemic markers for inflammation predict coronary heart disease complications with or without existing heart disease.[2] Inflammation also plays a role in diabetes risk and new research continues to support this conclusion.[7] Cancer is often caused by chronic inflammation.[8]

Research suggests chronic inflammation plays a major role in COVID-19 morbidity.[9][10] In severe cases, COVID-19 causes a cytokine storm which contributes to excessive and uncontrolled inflammation of organs, particularly respiratory tissues.[11][12] If untreated, this increased inflammation can result in reduced immune response, pneumonia, lymphoid tissue damage, and death.[11] Individuals with abnormal cytokine production, such as those with obesity or systemic chronic inflammation, have poorer health outcomes from COVID-19.[9][10] Elevated cytokine production alters the innate immune response which leads to abnormal T-cell and B-Cell function that decreases control of viral replication and host defense.[9] Anti-viral therapeutic drugs which also reduce inflammation seem to be the most effective treatment, but research is still ongoing.[12] Reactive oxygen species are upregulated during inflammation as part of the immune response to defend against pathogens.[13] However, excessive inflammation causes dangerous levels of reactive oxygen species which cause oxidative stress to tissues.[13] The immune system naturally produces antioxidant compounds to regulate and detoxify reactive oxygen species.[13] Anti-oxidative therapy with supplements such as vitamin C, vitamin E, curcumin, or baicalin is speculated to reduce infection severity in COVID-19,[14][12] but previous research has not found antioxidants supplementation to be effective in the prevention of other diseases.[15] Shifting from the typical western diet to a Mediterranean diet or plant-based diet may improve COVID-19 health outcomes by reducing prevalence of comorbidities (i.e. obesity or hypertension), decreasing intake of pro-inflammatory foods, and increasing consumption of anti-inflammatory and antioxidant nutrients.[12][16][17]

Research

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While systemic inflammation may be induced by multiple external factors, research suggests that a lack of control by tolerogenic dendritic cells and T-regulatory cells (Treg) is possibly the primary risk factor. In functioning immune responses, T-helper and T-cytotoxic cells are activated by presentation of antigens by antigen-presenting cells (APCs). Chief among these are dendritic cells (DCs). When a DC presents an antigen to a Treg cell, a signal is then sent to the nucleus of the DC, resulting in the production of indoleamine 2,3-dioxygenase (IDO). IDO inhibits T cell responses by depleting tryptophan and producing kynurenine, which is toxic to the cell.[citation needed]

Individuals susceptible to developing chronic systemic inflammation appear to lack proper functioning of Treg cells and TDCs. In these individuals, a lack of control of inflammatory processes results in multiple chemical and food intolerances, and autoimmune diseases.[citation needed]

See also

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References

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Systemic inflammation

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Systemic inflammation refers to a widespread, body-wide inflammatory response orchestrated by the , 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., ), in reaction to systemic stressors including infections, trauma, tissue damage, or chronic conditions. Unlike localized confined to a specific tissue or organ, systemic inflammation involves diffuse microcirculatory disturbances and can lead to multi-organ involvement if unresolved. This process can occur in acute or chronic forms, with acute systemic inflammation typically arising rapidly from severe insults like or major injury, manifesting as a , fever, elevated heart rate, and potential progression to (MODS), which carries high mortality rates (e.g., up to 71% in cases). In contrast, chronic systemic inflammation is a low-grade, persistent state lasting months to years, often driven by ongoing factors such as , autoimmune disorders, or environmental irritants, and is marked by sustained elevation of biomarkers like high-sensitivity (hsCRP) and fibrinogen. 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), , and metabolic dysregulation, which activate signaling pathways like and MAPK to amplify the response. Common markers for detection include (IL-1β, IL-6, IL-8), tumor necrosis factor-α (TNF-α), , and , with clinical scales such as the Systemic Inflammation (SI) scale or used to assess severity, particularly in acute settings. 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. In chronic forms, it underlies "inflammaging," the age-related increase in inflammatory markers that exacerbates frailty and disease susceptibility. 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.

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. This process represents an escalated defense mechanism where immune cells and signaling molecules disseminate via the bloodstream, potentially leading to diffuse physiological alterations. The concept of systemic inflammation gained formal recognition in the early 1990s in relation to , with the 1992 American College of Chest Physicians/Society of Critical Care Medicine consensus conference introducing the (SIRS) criteria to describe the host's systemic reaction to or other insults. Over time, the understanding has broadened to include chronic low-grade systemic inflammation, which contributes to the of contemporary diseases such as cardiovascular disorders and . Key characteristics of systemic inflammation include the elevated circulation of pro-inflammatory mediators, notably cytokines like interleukin-6 (IL-6) and tumor factor-alpha (TNF-α), which orchestrate immune cell recruitment and amplify the response across distant tissues. 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. It manifests in both acute and chronic forms, with the latter involving persistent, low-level activation.

Types

Systemic inflammation is primarily classified into two types: acute and chronic, distinguished by their duration, intensity, and underlying physiological processes. Acute systemic inflammation features a rapid onset, typically developing within hours to days in response to acute stressors such as or . This high-intensity response aims to eliminate the threat and restore , often resolving spontaneously if the trigger is addressed, though it can escalate to life-threatening conditions like (SIRS) or multiple organ dysfunction. 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. For instance, exemplifies acute systemic inflammation, involving a and widespread changes. 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. This form promotes ongoing tissue remodeling and rather than acute resolution, with and activation playing central roles in sustaining the inflammatory milieu through prolonged production and immune cell recruitment. Unlike its acute counterpart, it rarely induces fever but contributes to insidious progression in age-related pathologies. An example is the low-grade observed in , where adipose tissue-derived signals perpetuate a smoldering response. Key differences between the two types lie in their timelines, cellular orchestration, and outcomes: acute is neutrophil-led with intense, short-lived effects often marked by fever and potential for self-limitation or rapid deterioration, whereas chronic involves macrophage-driven persistence, emphasizing low-intensity remodeling over acute defense.

Causes and Triggers

Infectious Causes

Systemic inflammation often arises from infectious agents that breach local barriers and trigger a widespread , particularly in the context of acute . Bacterial infections are primary initiators, with such as releasing (LPS), also known as endotoxin, a potent immunostimulant that binds to (TLR4) on immune cells, leading to massive production and systemic effects like . Similarly, like species expose peptidoglycan and lipoteichoic acid (LTA) components of their cell walls, which activate TLR2 and other receptors, provoking proinflammatory storms that amplify beyond the infection site. 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. 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. Fungal and parasitic pathogens also elicit systemic inflammation, predominantly in immunocompromised individuals where host defenses are impaired. Candida species, particularly , can disseminate from mucosal sites into the bloodstream, releasing β-glucan and mannoproteins that stimulate inflammatory pathways via dectin-1 and TLRs, culminating in with high mortality rates. Parasitic infections like , caused by species, provoke systemic responses through hemozoin and glycosylphosphatidylinositols, which induce TNF-α and IL-1 production, contributing to fever, , and in endemic regions. The spread of these pathogens often involves invasion of the bloodstream, transforming localized infections into , a life-threatening condition characterized by dysregulated host responses. This dissemination can activate the (SIRS), defined by the 1992 American College of Chest Physicians/Society of Critical Care Medicine consensus criteria, which include abnormalities in temperature, , , and count (from any cause, including ).

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. Trauma and , including surgical procedures, burns, and accidents, are major non-infectious inducers of systemic inflammation. In these scenarios, cellular releases DAMPs such as high-mobility group box 1 (), a potent proinflammatory mediator that binds to receptors like (TLR4), triggering production and immune cell recruitment. For instance, or burns leads to a (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. Autoimmune and autoinflammatory disorders drive persistent systemic inflammation through aberrant recognition of self-antigens or innate immune dysregulation. In (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 (FMF) caused by gene mutations, involve hyperactivation leading to excessive IL-1β production and recurrent sterile inflammatory episodes, affecting multiple organs. Environmental and lifestyle factors, including , , and poor diet, promote chronic low-grade systemic inflammation. In , visceral produces proinflammatory cytokines like IL-6 and TNF-α due to , hypoxia, and immune cell infiltration, elevating circulating inflammatory markers and increasing risks for metabolic diseases. induces and xenobiotic exposure, activating pathways and elevating levels. High-sugar diets exacerbate this by increasing gut permeability via mechanisms like zonulin upregulation, allowing bacterial endotoxins to translocate and trigger TLR-mediated . Ischemia-reperfusion injury, as seen in , represents another key non-infectious cause, where restoration of blood flow paradoxically amplifies inflammation. During reperfusion, cardiomyocytes release DAMPs that activate TLRs and , leading to infiltration, production, and 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.

Pathophysiology

Molecular Mechanisms

Systemic inflammation involves a 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 () pathway. These cytokines bind to their respective receptors on target cells, triggering a cascade that leads to the and degradation of the inhibitory protein IκB, thereby allowing dimers to translocate to the nucleus and induce transcription of genes encoding additional inflammatory mediators. This amplification sustains and propagates the systemic response, particularly in response to triggers like infections. The 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 surfaces, bypasses early components and directly amplifies activity to produce C3a. Both C3a and C5a act as potent chemoattractants, binding to G-protein-coupled receptors on immune cells to induce , release, and further production, thereby enhancing and leukocyte recruitment. Arachidonic acid metabolites, including prostaglandins and leukotrienes, are synthesized via (COX-2) and (LOX) enzymes, respectively, and mediate key inflammatory effects such as fever and increased . COX-2, inducible by pro-inflammatory stimuli, converts to (PGH2), which is further metabolized to (PGE2); PGE2 acts on hypothalamic neurons to elevate body temperature and on endothelial cells to promote and . Similarly, 5-LOX catalyzes production, with (LTB4) serving as a chemoattractant that exacerbates tissue damage and permeability. Feedback mechanisms regulate the network to prevent excessive , with cytokines like interleukin-10 (IL-10) providing negative control by suppressing activity and pro-inflammatory . 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 , characterized by uncontrolled amplification of pro-inflammatory mediators. A key step in activation is the of the inhibitor IκB by the (IKK) complex, followed by its ubiquitination and proteasomal degradation, enabling nuclear translocation: IκB phosphorylation→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.

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. 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. These cells interact with molecular signals like cytokines to propagate responses across the body. 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 activity and recruitment to perpetuate inflammation. In chronic systemic inflammation, B cells contribute by differentiating into plasma cells that produce autoantibodies, such as anti-nuclear antibodies in conditions like systemic , which form immune complexes that trigger ongoing immune activation. Non-immune cells, including endothelial and epithelial cells, actively participate by undergoing barrier dysfunction during systemic inflammation, releasing alarmins like and IL-33 that alert immune cells and promote leukocyte and through upregulated expression of selectins and on endothelial surfaces. Dysregulation of these cellular components can prolong systemic inflammation; for instance, excessive M1 macrophage activation in chronic states leads to persistent storms, while elevated circulating monocytes indicate heightened monocytic infiltration and contribute to sustained pro-inflammatory signaling.

Clinical Manifestations

Symptoms and Signs

Systemic inflammation manifests through a range of subjective symptoms and objective signs that reflect the body's widespread immune . Common symptoms include fever, often induced by interleukin-1 (IL-1) binding to receptors on endothelial cells in the preoptic , leading to synthesis and elevated body temperature. Hypothalamic inflammation triggered by IL-1 and tumor necrosis factor-alpha (TNF-α) also contributes to , , and anorexia, as these cytokines disrupt energy balance and in the . Observable signs of systemic inflammation include , with heart rate exceeding 90 beats per minute, and , defined as a white blood cell count greater than 12,000/μL. In severe cases, may develop as part of the inflammatory cascade, particularly when progressing to conditions like . Additionally, elevated levels of acute-phase proteins, such as , occur as the liver responds to proinflammatory cytokines like IL-6, marking the systemic acute-phase response. 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. In contrast, chronic systemic inflammation typically presents more subtly, with low-grade fever and gradual due to persistent anorexia and metabolic alterations. 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 greater than 90 beats per minute, among others.

Organ System Effects

Systemic inflammation exerts profound effects on the cardiovascular system primarily through endothelial damage, which accelerates and heightens the risk of . Proinflammatory cytokines such as TNF-α and (CRP) activate endothelial cells, reducing nitric oxide bioavailability by downregulating endothelial expression, thereby impairing and promoting leukocyte adhesion. This endothelial dysfunction facilitates the recruitment of inflammatory cells into the arterial wall, initiating and exacerbating atherosclerotic plaque formation. Furthermore, systemic inflammation enhances prothrombotic states by increasing the expression of and , which weaken plaque stability and promote formation upon rupture, significantly elevating the risk of acute coronary events. Cytokines like IL-6 also elevate fibrinogen levels, contributing to a hypercoagulable environment that links chronic low-grade inflammation to progression. In the , systemic inflammation can precipitate (ARDS) via widespread capillary leak and resultant ventilation-perfusion (V/Q) mismatch. Inflammatory mediators, including cytokines and released from activated alveolar macrophages and recruited neutrophils, disrupt the alveolar-capillary barrier, increasing permeability and leading to protein-rich fluid accumulation in the alveoli. This exudative phase impairs by flooding airspaces, while concurrent endothelial injury causes microvascular and heterogeneous , particularly in dependent regions. The resulting V/Q mismatch manifests as intrapulmonary shunting and increased physiologic dead space, contributing to refractory that is often resistant to supplemental oxygen. Vascular changes from inflammation further exacerbate this by elevating pressure and right ventricular strain, amplifying the mismatch and overall . Systemic inflammation impacts the renal and hepatic systems by inducing through hypoperfusion and driving hepatic production of acute-phase reactants such as CRP. In the kidneys, proinflammatory cytokines and from systemic sources reduce renal blood flow via and , leading to ischemic hypoperfusion and tubular injury. 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. 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. 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. Neurological effects of systemic inflammation include arising from cytokines breaching the blood-brain barrier (BBB), which contributes to 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 and triggering within brain regions like the hippocampus. This leads to endothelial activation, reduced expression of junctional proteins like and claudin-5, and increased permeability, allowing further influx of inflammatory mediators that cause neuronal and metabolic stress. The resulting manifests clinically as , affecting up to 70% of septic patients, with associated EEG changes and long-term cognitive deficits due to sustained neuroinflammatory damage.

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 and , becomes a major source of pro-inflammatory cytokines, linking low-grade systemic inflammation to . Obese individuals exhibit elevated levels of interleukin-6 (IL-6) derived from , which impairs insulin signaling by inhibiting tyrosine phosphorylation of substrates in adipocytes and hepatocytes, thereby promoting and development. This adipose-derived IL-6 activates the JAK/STAT pathway, fostering a chronic inflammatory state that extends to and liver, worsening systemic . Cardiovascular diseases, including and , are significantly worsened by systemic inflammation, which drives and plaque vulnerability. In , inflammatory cells such as macrophages release matrix metalloproteinases that degrade the fibrous cap of plaques, increasing the risk of rupture and , while T lymphocytes inhibit synthesis by smooth muscle cells, further destabilizing lesions. Chronic inflammatory conditions, like , elevate the risk of cardiovascular morbidity and mortality by approximately 50%, highlighting the role of sustained inflammation in accelerating plaque instability and progression. Neurodegenerative disorders, such as and , involve systemic inflammation that activates , amplifying and neuronal damage. In , peripheral inflammatory signals trigger microglial responses to amyloid-β plaques, leading to the formation of disease-associated that release pro-inflammatory cytokines like IL-1β and TNF-α, which impair amyloid clearance and promote pathology. Similarly, in , systemic inflammation enhances microglial activation in response to α-synuclein aggregates, resulting in loss through inflammasome-mediated cytokine release and peripheral infiltration via the CCL2-CCR2 axis. In cancer, systemic inflammation creates a pro-tumorigenic microenvironment that supports tumor growth, , and . Elevated (CRP) levels, a marker of systemic inflammation, correlate with poor , as demonstrated in a 2019 study of patients receiving PD-1 inhibitors, where CRP >10 mg/L was associated with significantly shorter (3.0 months vs. 17.0 months) and overall survival (12.0 months vs. not reached). This inflammatory state fosters immune evasion and tumor progression across various cancers, including and non-small cell . 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 . 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); exceeding 90 beats per minute; greater than 20 breaths per minute or partial pressure of arterial carbon dioxide (PaCO₂) less than 32 mmHg; and count greater than 12,000/mm³, less than 4,000/mm³, or more than 10% immature (band) forms. SIRS frequently precedes , particularly in infectious contexts, where it reflects the body's attempt to combat pathogens but can escalate to if unchecked. Cytokine Release Syndrome (CRS) represents an acute and severe manifestation of systemic inflammation, driven by excessive 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 , leading to symptoms like fever, , and organ hypoperfusion. Severity is graded using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus criteria, where grade 3 involves requiring vasopressor support despite fluid resuscitation, alongside fever and potential hypoxia. Management focuses on supportive care and targeted blockade, such as with , to mitigate life-threatening complications. Hemophagocytic Lymphohistiocytosis (HLH) is a hyperinflammatory triggered by uncontrolled and activation, resulting in overproduction and tissue damage, often secondary to infections, malignancies, or autoimmune disorders. The HLH-2024 diagnostic criteria (updated as of 2024) require either a molecular confirmation of HLH-associated mutations or fulfillment of five out of seven clinical and laboratory features: fever for at least seven days; ; cytopenias affecting at least two of three lineages ( <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. This core set of features, including fever, , cytopenias, hypertriglyceridemia or hypofibrinogenemia, and hemophagocytosis, underscores the syndrome's multisystem involvement. HLH demands prompt immunosuppression and etiological treatment to prevent fatal outcomes. 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.

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. 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. 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. 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. 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.

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. 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. 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. Cytokine profiling provides deeper insights into the inflammatory cascade but is not routinely employed in due to high costs and technical complexity associated with assays like enzyme-linked immunosorbent assays () or multiplex platforms. Plasma levels of IL-6, a key pro-inflammatory , can exceed 100 pg/mL in severe systemic inflammation, such as in or cytokine release syndromes, reflecting intense immune activation; however, routine measurement is limited to research or specialized settings where it aids in prognostic assessment. Imaging techniques complement laboratory tests by visualizing organ-specific inflammatory involvement. Computed tomography (CT) and (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 or interstitial lung diseases. (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 or large-vessel inflammation. Emerging diagnostic approaches integrate multi-omics data for more personalized assessment of systemic inflammation. Recent studies have developed multi-omics approaches integrating , , and transcriptomics to identify metabolite signatures, such as altered lipid profiles or imbalances, that enhance diagnostic accuracy in conditions like , enabling tailored interventions beyond traditional markers. These approaches hold promise for early detection but require validation in larger clinical cohorts before widespread adoption.

Management and Treatment

Acute Management

Acute management of systemic inflammation prioritizes rapid stabilization to prevent and mortality, particularly in conditions like 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 (ARDS). 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. 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. Source control is essential to eliminate the inflammatory trigger, involving prompt administration of empiric broad-spectrum antibiotics (e.g., combined with piperacillin-tazobactam for coverage against and gram-negative organisms) within 1 hour of recognition in infectious cases, followed by based on cultures. In trauma-related systemic inflammation, surgical of necrotic or infected tissue and drainage of abscesses are performed as soon as feasible, ideally within 6 hours, to halt ongoing release and bacterial dissemination. Anti-inflammatory agents like corticosteroids are reserved for refractory , with intravenous 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.

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. interventions form the cornerstone of these approaches, emphasizing modifiable behaviors that reduce pro-inflammatory cytokines and . A key recommendation is adherence to an diet, such as the , 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 (CRP) and interleukin-6 (IL-6), by modulating and reducing oxidative damage. Studies indicate that long-term adherence can decrease systemic inflammation by up to 20-30% in at-risk populations. Regular is another essential intervention, with guidelines recommending at least 150 minutes of moderate-intensity 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 production, particularly beneficial in cases linked to or . 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. 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. In metabolic cases, such as those involving or , metformin is commonly used for its direct properties, including suppression of 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. For autoimmune-linked inflammation, biologics like anti-TNF agents, exemplified by , block tumor necrosis factor-alpha to interrupt cascades. has demonstrated efficacy in reducing systemic inflammatory burden in conditions such as , with rapid decreases in CRP and in responsive patients. 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 control. This threshold correlates with reduced cardiovascular and metabolic risks in chronic settings. Pharmacogenomics is an emerging approach for personalized management in inflammatory disorders, analyzing genetic variants to optimize therapies like biologics and analyze response rates. for conditions like and , which target specific inflammatory pathways.

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 into the bloodstream. This process, known as metabolic endotoxemia, triggers low-grade systemic inflammation by activating (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 and , emphasizing the gut barrier's function in modulating systemic immune responses. In the context of aging, the phenomenon of inflammaging—chronic, low-grade systemic inflammation—has been linked to , where senescent cells accumulate and secrete (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 . 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 and accelerates the onset of conditions such as and neurodegeneration. The legacy of has spotlighted post-acute systemic in , affecting a significant subset of survivors. manifests as persistent symptoms driven by ongoing immune dysregulation and low-grade , including elevated markers like and cytokines, even months after acute infection. Prevalence estimates suggest 10-20% of patients experience these protracted effects, with , , and cardiopulmonary issues predominating. A review in Cell details how viral persistence and immune exhaustion contribute to this inflammatory state, providing mechanistic insights into symptom chronicity. Epidemiological data underscore the profound global burden of systemic inflammation, primarily through its role in non-communicable diseases (NCDs). NCDs, encompassing cardiovascular diseases, cancers, , 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.

Emerging Therapies

Targeted biologics represent a promising frontier in modulating systemic inflammation by precisely inhibiting key pathways. (JAK) inhibitors, such as , block 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. Similarly, interleukin-1 (IL-1) antagonists like have shown potential in managing (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%. 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 (ARDS) and severe , intravenous MSC infusions have demonstrated safety and feasibility, with significant reductions in inflammatory markers such as (CRP) and IL-6 in treated patients. Nanomedicine approaches enhance precision in drug delivery to inflamed sites, minimizing systemic side effects. For instance, endothelium-targeted delivering (siRNA) against have shown preclinical efficacy in suppressing endothelial and reducing plaque progression in models, with in vivo studies reporting decreased expression of adhesion molecules and inflammatory cytokines. Preventive strategies, including anti-inflammaging , aim to target chronic low-grade inflammation underlying age-related conditions. Preclinical studies on targeting senescent cells and inflammaging pathways, such as nanovaccines against senescence-associated antigens in , have demonstrated reduced metabolic dysfunction in models of , with early clinical evaluations initiating in 2025.

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