Continuing Education Activity

Systemic inflammatory response syndrome (SIRS) represents an exaggerated immune response to a range of stressors, including infections, trauma, surgery, or malignancy. This response aims to isolate and eliminate the insult but often results in a widespread inflammatory cascade, potentially causing reversible or irreversible organ dysfunction. SIRS is diagnosed when ≥2 specific criteria—alterations in temperature, heart rate, respiratory rate, or white blood cell count—are present. While SIRS may arise from noninfectious causes, when accompanied by a suspected infection, it is defined as sepsis. The most severe form, septic shock, involves persistent circulatory and metabolic dysfunction despite resuscitation.

This course offers an in-depth review of the definition, diagnostic criteria, pathophysiology, epidemiology, and management of SIRS. Defined initially to standardize early recognition and treatment, SIRS criteria proved highly sensitive but lacked specificity, prompting revised definitions that prioritize identifying life-threatening organ dysfunction caused by dysregulated host responses. Additionally, this course discussed the differentiation of SIRS from related syndromes, such as sepsis and multiple organ dysfunction syndrome, the interpretation of relevant biomarkers, and the application of evidence-based guidelines to guide evaluation and therapy. The activity covers the progression of SIRS, risk factors associated with poorer outcomes, and complications involving multiple organ systems. This activity for healthcare professionals is designed to enhance the learner's competence in the timely recognition of SIRS, targeted therapy of the underlying cause, prevention of progression to sepsis or multiple organ dysfunction syndrome, and implementing an appropriate interprofessional approach when managing this condition.

Objectives:

• Identify patients who meet clinical criteria for systemic inflammatory response syndrome.
• Implement evidence-based diagnostic strategies, including the utilization of biomarkers, to enhance the early recognition and management of systemic inflammatory response syndrome.
• Differentiate between infectious and noninfectious etiologies of systemic inflammatory response syndrome.
• Collaborate with members of the interprofessional care team to coordinate timely interventions and ensure appropriate escalation of care for patients exhibiting signs of systemic inflammatory response.

Introduction

Systemic Inflammatory Response Syndrome

Systemic inflammatory response syndrome (SIRS) is an exaggerated defense response of the body to a noxious stressor, which can include infection, trauma, surgery, acute inflammation, ischemia or reperfusion, or malignancy, aimed at localizing and then eliminating the endogenous or exogenous source of the insult. This response involves the release of acute-phase reactants, which are direct mediators of widespread autonomic, endocrine, hematological, and immunological alterations in the subject. Even though the purpose is defensive, the dysregulated cytokine storm can cause a massive inflammatory cascade leading to reversible or irreversible end-organ dysfunction and even death.

 Objectively, SIRS is defined by the presence of any 2 of the following criteria:

• Body temperature >100.4 °F (38 °C) or <96.8 °F (36 °C)
• Heart rate >90 bpm
• Respiratory rate >20 breaths/minute or PaCO₂ <32 mm Hg (4.3 kPa)
• Leukocyte count >12,000/μL, <4,000/μL, or >10% immature forms (bands)

Sepsis, Septic Shock, and Multiple Organ Dysfunction Syndrome 

SIRS with a suspected infectious source is termed sepsis. Culture confirmation is not required early in diagnosis. Historically, "severe sepsis" described sepsis with organ dysfunction; however, the Sepsis-3 task force removed this category in 2016, consolidating it under the revised definition of sepsis as "life-threatening organ dysfunction caused by a dysregulated host response to infection. This distinction is no longer used clinically but may appear in older literature. Septic shock represents the most severe form, marked by circulatory, cellular, and metabolic abnormalities that persist despite adequate fluid resuscitation. Together, sepsis and septic shock are considered a continuum of worsening host response to infection.[1]

The American College of Chest Physicians/Society of Critical Care Medicine-sponsored sepsis definitions consensus conference also identified the entity of multiple organ dysfunction syndrome (MODS) as the presence of altered organ function in acutely ill septic patients such that homeostasis is not maintainable without intervention.[2]

In the pediatric population, the definition is modified to a mandatory requirement of abnormal leukocyte count or temperature to establish the diagnosis, as abnormal heart rate and respiratory rates are more common in children. Recent survey data show that most pediatric clinicians define sepsis as infection with life-threatening organ dysfunction, moving away from older pediatric criteria that relied on SIRS and the redundant term "severe sepsis." The SCCM task force now recommends using the Phoenix Sepsis Score, where a score ≥2 in a child with suspected infection indicates sepsis due to dysfunction in respiratory, cardiovascular, coagulation, or neurologic systems. Septic shock is defined by cardiovascular dysfunction, marked by hypotension for age, lactate >5 mmol/L, or need for vasoactive support.[3]

In summary, almost all septic patients exhibit SIRS, but not all patients with SIRS are septic. Kaukonen et al explained exceptions to this theory by suggesting that there are subgroups of hospitalized patients, particularly at extremes of age, who do not meet the criteria for SIRS on presentation but progress to severe infection, multiple organ dysfunction, and death. Establishing laboratory indices to identify such subgroups of patients and the clinical criteria that we currently rely upon has been gaining prominence over recent years.[4]

Several scores exist to assess the severity of damage to individual organ systems. The Acute Physiology and Chronic Health Evaluation (APACHE) score version II and III, multiple organ dysfunction (MOD) score, sequential organ failure assessment (SOFA), and logistic organ dysfunction (LOD) score are to name a few.

Historical Evolution of Systemic Inflammatory Response Syndrome

The emergence of new insights into the pathophysiology and treatment of sepsis in the early 1990s highlighted the growing need to identify a uniform group of potential subjects for clinical trials exploring novel therapeutic strategies. In response to the surge of ongoing research, a consensus has emerged emphasizing the importance of a time-sensitive approach to diagnosis and intervention, aiming to improve patient survival and reduce morbidity. The ability to recognize individuals affected by various conditions across different care settings using standardized, easy-to-apply clinical parameters became essential. To address this, the American College of Chest Physicians and the Society of Critical Care Medicine convened a consensus conference on sepsis definitions in Chicago, Illinois, in August 1991, with the intention of establishing a standard set of clinical criteria for broad application. This effort led to the introduction of the SIRS definition.[2]

A second consensus meeting, held in Washington, DC, in 2001, expanded on this foundation by introducing a conceptual framework for staging sepsis using the PIRO model—predisposition, insult or infection, response, and organ dysfunction.[5] This model aimed to enhance the understanding and clinical categorization of sepsis, offering a more structured approach to guide research and therapeutic decisions.

The goal of the initial definition was to be highly sensitive using easily available parameters across all healthcare settings. An unavoidable corollary of such a definition was, therefore, the lack of specificity. Additional limitations of the SIRS definition include the following:

1. The universal prevalence of the parameters in an ICU setting
2. Lack of ability to distinguish between beneficial host response from pathologic host response that contributes to organ dysfunction
3. Distinguishing between infectious and noninfectious etiology purely based on the definition
4. Lack of weight to each criterion, eg, fever and elevated respiratory rate, has precisely the same significance as leukocytosis or tachycardia by the SIRS definition.
5. Inability to predict organ dysfunction [6]

Kaukonen et al, in their study of over 130,000 septic patients, established that 1 out of 8 patients in their observational study of sepsis did not meet ≥2 SIRS criteria.[4] They also established that each criterion in the SIRS definition does not translate to an equivalent risk of organ dysfunction or death.

Sequential organ failure assessment

In 2016, following this debate, the European Society of Intensive Care Medicine and the Society of Critical Care Medicine (SCCM) established a task force that proposed Sepsis-3, a revised definition for sepsis. The new definition excluded the establishment of SIRS criteria to define sepsis and made it more nonspecific, as any life-threatening organ dysfunction caused by the dysregulated host response to infection.[7] The task force claimed that the sequential organ failure assessment (SOFA) has better predictive validity for sepsis than the SIRS criteria. It has better prognostic accuracy and the ability to predict in-hospital mortality. To reduce the complexity of calculating the SOFA, a simplified version of the SOFA, known as qSOFA, was introduced.

The qSOFA score is a modified version of the SOFA. A score ≥2 is associated with the following poor outcomes due to sepsis:

• A systolic blood pressure of ≤100 mm Hg indicates a potential problem with the cardiovascular system 
• A respiratory rate of ≥22 breaths/min suggests possible respiratory distress
• A Glasgow Coma Scale score of <15 indicates a change in the patient's level of consciousness

Although the validity of qSOFA is limited in an ICU setting, it has consistently outperformed SIRS criteria in predicting organ dysfunction in a non-ICU and ER setting. The use of vasopressors, mechanical ventilation, and aggressive therapeutic interventions in the ICU limits the efficacy of qSOFA.[8] Interestingly, Hague et al, in their study of the utility of SIRS criteria in gastrointestinal surgery, also found it a useful criterion for identifying postoperative complications.[9]

A 2023 systematic review comparing qSOFA and SIRS in emergency and critical care settings found that while qSOFA excels in predicting mortality with greater specificity and AUROC values, SIRS criteria are met significantly faster, which may offer practical advantages for early triage. These findings underscore the trade-off between early detection and prognostic accuracy, guiding clinicians in tailoring their approach according to the specific setting and resource availability.[10]

Etiology

At the molecular level, the etiopathogenesis of SIRS is broadly categorized into the following 2 primary pathways:

1. Damage-associated molecular patterns (DAMPs)
2. Pathogen-associated molecular patterns (PAMPs)

These patterns activate innate immune receptors, eg, toll-like receptors (TLRs) and inflammasomes, triggering the release of cytokines, HMGB1, and other pro-inflammatory mediators. While SIRS is often associated with infection, it can also arise in noninfectious settings, making it a critical diagnostic and prognostic entity in both infectious and sterile inflammation.

Damage-Associated Molecular Pattern-Related (Noninfectious) Etiologies

Common DAMP triggers, eg, cellular injury or necrosis, releasing intracellular content into the extracellular space, including:

• Burns
• Trauma (including polytrauma and soft tissue injury)
• Surgical procedure-related tissue damage
• Acute aspiration
• Acute pancreatitis
• Substance abuse and intoxication
• Acute end-organ ischemia (eg, myocardial, hepatic, and intestinal)
• Exacerbation of autoimmune vasculitis
• Medication-induced hypersensitivity or toxicity
• Intestinal ischemia and perforation
• Hematologic malignancy (especially with tumor lysis or cytokine release)
• Dermatologic emergencies (eg, erythema multiforme, Stevens-Johnson syndrome)
• Extracorporeal circulation (eg, ECMO) and acute liver failure (newer evidence suggests high SIRS prevalence even without infection)

Pathogen-Associated Molecular Pattern-Related (Infectious) Etiologies

PAMPs are microbial-derived molecules that trigger immune responses via pathogen-recognition receptors, including:

• Bacterial infections (eg, pneumonia, pyelonephritis, and cellulitis)
• Viral infections (eg, influenza and SARS-CoV-2)
• Disseminated fungal infections, particularly in immunocompromised hosts
• Toxic shock syndrome (due to staphylococcal or streptococcal exotoxins and endotoxins)

PAMP-induced SIRS can range from localized infections to disseminated infections and bacteremia, ultimately progressing to sepsis or septic shock if organ dysfunction ensues.

Risk Factors

Several clinical and demographic factors can increase the risk of developing SIRS in response to a noxious insult, including:

• Intensive care unit (ICU) admission
• Advanced age (65 years or older)
• Immunosuppression (eg, from medications, HIV)
• Diabetes mellitus
• Obesity
• Active malignancy
• Recent hospitalization
• Genetic predisposition (eg, polymorphisms in cytokine or immune response genes)

Epidemiology

A highly sensitive but less specific definition of SIRS may lead to an inaccurate capture of its true incidence. Many individuals with SIRS, especially those with self-limiting viral syndromes, may never reach a hospital and are instead managed in urgent care or outpatient settings. Therefore, current estimates may skew toward more severe cases requiring hospitalization, which biases mortality and morbidity data upward.

The incidence of SIRS varies significantly across clinical settings and patient populations, with rates ranging from as low as 17.8% in adult emergency departments to as high as 95% in febrile inpatients and 92.4% in trauma ICUs.[11] In one pediatric ICU study, the SIRS incidence was 82%,[12] while a retrospective study of 8995 CICU admissions at Mayo Clinic between 2007 and 2015 found that 33.9% of patients had SIRS on admission, and rates were higher among patients with advanced SCAI (Society for Cardiovascular Angiography and Interventions) shock stages.[13]

A nationwide study of 103,701 emergency department encounters, representing over 372 million visits, found that SIRS was present in approximately 17.8% of all adult ED visits, or roughly 16.6 million cases per year. Importantly, only one-quarter of these cases were associated with confirmed infections, emphasizing the heterogeneity and potential overdiagnosis of SIRS using current criteria.[14] Churpek et al, in a large-scale study of 269,951 hospitalized ward patients, found that 15% met at least 2 SIRS criteria on admission, while 47% met the criteria at some point during their hospital stay. Mortality among SIRS-positive patients was significantly higher (4.3%) compared to SIRS-negative patients (1.2%).[15] Pittet et al revealed an overall in-hospital incidence of 542 episodes per 1000 hospital days.[16] 

A prospective study of tertiary care admissions reported that 68% met SIRS criteria during hospitalization. Of these, 26% progressed to sepsis, 18% to severe sepsis, and 4% to septic shock within 28 days of admission.[17] Comstedt et al demonstrated that among emergency department patients who met SIRS criteria, 62% had a confirmed infection; however, 38% of infected patients did not initially meet SIRS criteria, suggesting a substantial limitation in SIRS sensitivity.[18] Temporal trends in ICUs show that SIRS prevalence declines over time, from 91% in trauma ICU patients during the first week to 50% by the third week, and in surgical ICU patients, from 49.4% on day 1 to 34.5% on day 2.[19]

In terms of demographic variation, studies suggest that women and African Americans may have a lower incidence of SIRS, possibly due to protective hormonal or genetic factors. Choudhry et al showed estrogen had a protective effect in trauma and sepsis animal models, and NeSmith et al found a lower SIRS incidence in these demographic groups.[20][21] 

Pathophysiology

Inflammation triggered by an infectious or noninfectious stimulus sets forth a complex interplay of the humoral and cellular immune response, cytokines, and the complement pathway. Eventually, systemic inflammatory response syndrome results when the balance between proinflammatory and anti-inflammatory cascades tips over towards the former.

Roger Bone outlined a 5-stage overlapping sepsis cascade that begins with SIRS and progresses to MODS, unless appropriately countered by a compensatory anti-inflammatory response or alleviation of the primary inciting etiology.[22] 

Stage 1

Stage 1 involves a localized response at the site of injury, designed to contain the insult and prevent its spread. Immune effector cells present in the area release cytokines that activate the reticuloendothelial system, initiating wound repair through localized inflammation. Nitric oxide and prostacyclin induce vasodilation (rubor), while disruption of endothelial tight junctions facilitates the margination and migration of leukocytes into surrounding tissue. Leakage of immune cells and protein-rich fluid into the extravascular space results in swelling (tumor) and elevated temperature (calor). Inflammatory mediators stimulate somatosensory nerves, producing pain (dolor) and functional impairment (functio laesa), which in turn promotes rest and recovery of the affected area.

Stage 2

Stage 2 marks the onset of an early Compensatory Anti-inflammatory Response Syndrome (CARS), aimed at preserving immunological balance. Growth factors become activated, while macrophages and platelets undergo recruitment as proinflammatory mediator levels decline to support the restoration of homeostasis.

Stage 3

Stage 3 reflects a transition toward a dominant proinflammatory SIRS response, marked by worsening endothelial dysfunction and dysregulation of coagulation. Activation of the coagulation cascade contributes to end-organ microthrombosis and a sustained rise in capillary permeability, culminating in the breakdown of circulatory integrity.

Stage 4

Stage 4 is characterized by CARS taking over SIRS, resulting in a state of relative immunosuppression. The individual, therefore, becomes susceptible to secondary or nosocomial infections, thus perpetuating the sepsis cascade.

Stage 5

Stage 5 manifests in MODS with persistent dysregulation of both SIRS and CARS response. At a cellular level, noninfectious noxious stimuli, an infectious agent, or an endotoxin or exotoxin produced by an infection activate a multitude of cells, including neutrophils, macrophages, mast cells, platelets, and endothelial cells.

The early response mediated by these inflammatory cells involves the following 3 major pathways:

• Activation of IL-1 and TNF alpha
• Activation of the prostaglandin and leukotriene pathway
• Activation of the C3a to C5a complement pathway

Interleukin 1 (IL1) and tumor necrosis factor alpha (TNF-alpha) are the early mediators within the first hour. Their role is of paramount importance in tilting the scale towards a proinflammatory overdrive.

Their actions can broadly be divided into the following 3 categories

1. Propagation of the cytokine pathway
2. Alteration of coagulation, causing microcirculatory abnormalities
3. Release of stress hormones

Propagation of Cytokine Pathway

The release of IL-1 and TNF-alpha leads to the dissociation of nuclear factor-kB (NF-kB) from its inhibitor, allowing NF-kB to initiate the widespread release of additional proinflammatory cytokines, including IL-6, IL-8, and interferon-gamma. IL-6 promotes the production of acute-phase reactants such as procalcitonin and C-reactive protein. Infectious triggers typically generate a more pronounced surge in TNF-alpha, which amplifies the release of IL-6 and IL-8. High-Mobility Group Box 1 (HMGB1) protein, another potent proinflammatory mediator, contributes to the delayed cytotoxic effects observed in SIRS and sepsis. In patients with traumatic brain injury, HMGB1 has been identified as an independent predictor of 1-year mortality.[23]

Alteration of Coagulation Causing Microcirculatory Abnormalities

Like many early responses in SIRS, changes in the coagulation pathway begin with stimulation by IL-1 and TNF-alpha. Activation of plasminogen activator inhibitor-1 disrupts fibrinolysis, while direct injury to the endothelium promotes the release of tissue factor, which initiates the coagulation cascade. Simultaneously, key anti-inflammatory and anticoagulant mediators, eg, activated protein C and antithrombin, become suppressed. This combination leads to widespread microvascular thrombosis, heightened capillary permeability, increased vascular fragility, and compromised tissue perfusion, all of which contribute to the progression of organ dysfunction.

Release of Stress Hormones

Primarily, the catecholamine, vasopressin, and activation of the renin-angiotensin-aldosterone axis result in an increased surge of endogenous steroids. Catecholamines are responsible for the tachycardia and tachypnea component of sepsis, while glucocorticoids contribute to leukocyte count increase as well as their margination in the peripheral circulation.

Compensatory Anti-inflammatory Response Syndrome 

Interleukins IL-4 and IL-10 mediate the compensatory anti-inflammatory response by suppressing the production of TNF-alpha, IL-1, IL-6, and IL-8. The interplay between SIRS and CARS determines the point of resolution or progression along the continuum from systemic inflammation to MODS. Although CARS serves to restore immune balance, its unchecked continuation can lead to prolonged immunosuppression in survivors. This immunosuppressed state increases vulnerability to nosocomial infections, which may, in turn, reactivate the septic cascade and worsen clinical outcomes.

Additional mechanisms contributing to the inflammatory milieu in SIRS include:

• IL-33 and thymic stromal lymphopoietin have been identified as key amplifiers of early proinflammatory signaling, particularly in trauma and burn-induced SIRS models. IL-33 acts through the ST2 receptor, enhancing neutrophil recruitment and systemic inflammation.[24]
• Autonomic dysregulation, particularly vagal nerve activity, modulates the severity of inflammation, indicating a potential neuroimmune axis in the pathogenesis of SIRS.[25]
• Mitochondrial dysfunction, fueled by excessive nitric oxide and reactive oxygen species, plays a central role in oxidative stress and cellular energy failure, further aggravating organ injury.

History and Physical

Clinical History

The early clinical presentation of SIRS, regardless of etiology, reflects the classic inflammatory signs of rubor (redness), calor (heat), dolor (pain), tumor (swelling), and functio laesa (loss of function). A detailed history focusing on the location, character, radiation, and exacerbating or relieving factors of pain, as well as the timing and progression of symptoms, is essential. However, pinpointing the exact etiology or primary source of inflammation may be challenging at onset.

Clinicians should carefully evaluate for subtle changes in baseline activities or exposures, including new medications, food intake, travel, environmental or occupational exposures, and recreational drug use. Identifying underlying predisposing factors such as immunosuppression, diabetes mellitus, malignancy (solid tumors or hematologic), dysproteinemias, cirrhosis, and extremes of age is critical for prioritizing management intensity and anticipating complications.

Physical Examination

A complete physical examination is not only helpful in localizing the source but also in assessing the true extent of involvement and complications related to end-organ involvement. Physical examination findings also help in guiding the appropriate investigations and imaging studies.

The definition of systemic inflammatory response syndrome is based on vital signs, rather than evaluating leukocyte count. However, vital signs can be falsely altered by the stress of arrival to a healthcare facility in extremes of age or by concomitant use of medications (beta-blockers and calcium channel blockers). Hence, periodic evaluation of vital signs and evidence of persistent instability becomes important to establish the diagnosis. In addition to baseline vital signs, trending parameters over time, eg, rising lactate, increasing respiratory effort, or evolving neurologic changes, may offer early clues to progression toward sepsis. 

In pediatric populations, frequent reassessment is particularly important due to the developmental variability in baseline vital signs and the subtle presentations of organ dysfunction.

Evaluation

Over time, the approach to sepsis has shifted from relying solely on clinical judgment to incorporating more objective parameters. Although sepsis remains fundamentally a clinical diagnosis that cannot be defined solely by diagnostic assays, consistent recognition of standardized clinical criteria has gained critical importance for timely intervention.

Advancements in understanding the complex pathophysiology, etiology, and pharmacologic targets by the late twentieth century highlighted the urgent need for early diagnosis and treatment to reduce mortality and morbidity. Recognizing the continuum from initial inflammation to multiorgan dysfunction further emphasized this urgency. As a result, the concept of SIRS emerged, capturing both infectious and noninfectious triggers that leave the body vulnerable to subsequent infections.

When the underlying cause of SIRS becomes apparent, diagnostic efforts are tailored to the affected organ system. In cases where no clear source is evident, a time-sensitive search for infection takes precedence. Current guidelines recommend obtaining blood cultures and samples from likely infection sites, eg, sputum, urine, or wounds, within the first hour of clinical suspicion and before the initiation of antibiotic therapy.

Vital sign measurements—particularly temperature, heart rate, respiratory rate, and white blood cell count—remain cornerstone diagnostic elements, satisfying ≥2 criteria to define SIRS. Depending on the severity of the presentation, routine investigations involve periodic evaluation of a basic metabolic panel and lactic acid level to assess the extent of end-organ injury and perfusion impairment.

Over time, a growing discussion has emerged in the community about the importance of distinguishing sepsis earlier in SIRS, using biomarkers, even before microbial cultures become positive. Biomarkers also become important in identifying SIRS due to secondary infection in patients who were initially admitted with a noninfectious etiology, eg, trauma or burns, or for a planned surgical intervention. Mere clinical criteria are not enough to capture the change in etiopathogenesis midway through hospitalization.[26][27]

Procalcitonin

A glycoprotein precursor of calcitonin, procalcitonin (PCT), is produced by C cells of the thymus and also from leukocytes, liver, kidney, adipose, and muscle tissue.[28] In healthy individuals, serum levels are typically below 0.1 mg/dL but can become significantly abnormal in bacterial, fungal, or parasitic infections. Levels can mildly elevate in viral infection or noninfectious acute inflammation, and can also rise in individuals with neuroendocrine tumors or postsurgical stress.[29] Serum concentrations rise within 2 to 4 hours of the inflammatory surge and fall rapidly after halting the primary insult. Half-life is about 25 to 30 hours. The peak serum concentration, therefore, seems to parallel the timeline of disease severity and outcome.[28][30][31][32] 

Research has primarily focused on the utility of procalcitonin in differentiating between infectious and noninfectious causes of SIRS, as well as its value in serial assessment to determine the duration of antimicrobial therapy. Kibe et al showed a favorable association between procalcitonin and CRP in the diagnosis and prognosis of sepsis, but only in conjunction with clinical parameters.[33] Karzai et al also confirmed its value in predicting a systemic infectious process, although the cutoff value seemed to differ based on the disease process.[28] Ciriello et al, in their comparison of a wide assembly of biomarkers in trauma patients, found procalcitonin to be the only biomarker of benefit in predicting sepsis. Persistently high levels correlated well with increased mortality and severity scores.[34] Agarwal and Schwartz demonstrated that serial PCT measurements in the ICU contributed to a significant reduction of ICU days and the duration of antimicrobial therapy.[35]

Selberg et al demonstrated in their study that plasma concentrations of PCT, C3a, and IL-6, obtained up to 8 hours after the clinical onset of sepsis or SIRS, were significantly higher in patients with infectious etiologies. PCT, IL-6, and C3a were more reliable in distinguishing SIRS from sepsis.[36]

Lactate

Lactic acid elevation can be a type A lactic acidosis with excessive production from tissue hypoperfusion-related anaerobic metabolism or type B lactic acidosis from inadequate clearance due to liver dysfunction. The use of epinephrine as a vasopressor agent can also lead to excessive lactate production due to the alteration of the pyruvate cycle.[37]

Interleukin 6

An IL-6 level of >300 pg/mL correlates with an increased incidence of MODS and death. Similarly, a reduction in level by the second day of antimicrobial therapy has been shown to be a positive prognostic sign.[38][39] 

Leptin

Serum leptin concentrations exceeding 38 µg/L correlate strongly with IL-6 and TNF-alpha levels, demonstrating a sensitivity of 91.2% and a specificity of 85% in differentiating infectious from noninfectious causes of SIRS.[40][41] Leptin, a hormone produced by adipocytes, acts centrally on the hypothalamus and serves as a potential biomarker in systemic inflammatory conditions.

Endothelial Markers

Angiopoietin-1 and Angiopoietin-2 function as ligands for the Tie-2 receptor on endothelial cells. During acute inflammation, increased binding of Angiopoietin-2 to the Tie-2 receptor promotes capillary permeability and microvascular thrombosis. Circulating levels of Ang-2 correlate with 28-day mortality in SIRS, as well as with APACHE and SOFA severity scores.[42][43] Similar diagnostic and prognostic potential has been noted with soluble E-selectin and P-selectin, which help differentiate between septic and nonseptic SIRS. In a study involving 92 SIRS patients, soluble E-selectin emerged as the most effective marker for early identification and severity prediction. Soluble intracellular adhesion molecule-1 (sICAM-1) also proved useful in distinguishing between septic and nonseptic cases.[30] However, analytic standardization and validated cutoff thresholds remain necessary before these markers can be widely implemented in clinical practice.

Emerging Biomarkers

Other emerging biomarkers in research to distinguish septic and nonseptic etiology of SIRS include triggering receptor expressed on myeloid cells 1 (TREM-1), Decoy receptor 3 (DcR3) (belongs to the tumor necrosis factor family), and suPAR (soluble urokinase-type plasminogen activator receptor).[44][45][46] Among them, suPAR correlated particularly well with disease severity scores and the identification of nonsurvivors in the sepsis group.

Transcriptome Analysis

A growing body of research in recent years has shifted the understanding of SIRS pathophysiology toward immune dysregulation as a central mechanism, rather than viewing it solely as an excessive inflammatory response. High-throughput sequencing of cDNAs from mononuclear cells has led to the identification of a genetic profile known as the endotoxin tolerance signature (ETS). This signature appears more frequently in septic patients and shows strong associations with organ failure and greater disease severity. By recognizing this pattern early, clinicians may be able to identify a high-risk subpopulation of septic patients who would benefit from prompt ICU admission and intensive therapy, ultimately influencing both mortality and morbidity outcomes.[47] 

Treatment / Management

SIRS is a conglomeration of clinical manifestations of a triggering cause. Management focuses on treating the underlying etiology while providing supportive care to prevent end-organ dysfunction and progression to sepsis or MODS. Management is designed around the following parallel approach:

• Time-sensitive supportive interventions to maintain perfusion and prevent MODS.
• Targeted interventions directed at treating the primary insult (infectious or noninfectious).

Early identification and risk stratification are essential. Clinical scoring systems, including APACHE II/III, SOFA, qSOFA, and MODS score, are used to assess severity, predict organ dysfunction, and estimate in-hospital mortality.

Hemodynamic Stabilization Therapies

Hemodynamic stabilization is a cornerstone of SIRS management. In cases with suspected or confirmed septic shock, the following are recommended:

• A bolus of 30 mL/kg isotonic crystalloid is recommended as initial fluid resuscitation, per the Surviving Sepsis Campaign guidelines.[48]
• Further fluid administration should be guided by the following dynamic markers of volume responsiveness: 

  • Passive leg raising test
  • Stroke volume variation
  • Inferior vena cava (IVC) diameter variation on ultrasonography

Vasopressors (eg, norepinephrine) and inotropes are used when hypotension persists despite fluid repletion.[48] If infection is suspected, particularly in high-risk patients (eg, immunosuppressed, neutropenic, or asplenic individuals), the following should be initiated:

• Empiric broad-spectrum antibiotics within 1 hour after cultures are obtained [49]
• Tailor antibiotics based on community versus hospital-acquired exposure, individual microbiologic history, and facility antibiogram
• Deescalation of therapy promptly once culture results and clinical response are reviewed [50]

Source control may require the following:

• Surgical or interventional drainage
• Debridement of infected tissue
• Removal of infected indwelling devices

Antiviral and Antifungal Therapy

Antivirals (eg, oseltamivir) are considered in influenza-related SIRS. Empiric antifungals are reserved for high-risk populations, eg, neutropenic patients, individuals on total parenteral nutrition, or those with persistent fevers despite antibiotic therapy.[51]

Steroid Use

Low-dose corticosteroids (eg, hydrocortisone 200 to 300 mg/day) may benefit patients with vasopressor-refractory septic shock.[52] These are not recommended based on cortisol levels or ACTH stimulation testing, as relative adrenal insufficiency is often due to tissue resistance rather than a serum hormone deficiency.

Blood Glucose Control

Maintaining blood glucose levels below 180 mg/dL remains the recommended target based on the findings of the NICE-SUGAR trial, which demonstrated improved outcomes with moderate glucose control. Tight glycemic control in the range of 80 to 110 mg/dL is no longer advised due to the significantly increased risk of hypoglycemia and associated adverse events.

Supportive Care

The following supportive therapies are also recommended:

• Mechanical ventilation: In patients with ARDS, apply lung-protective strategies (low tidal volumes, plateau pressure limitation).
• Early enteral nutrition: Recommended within 72 hours if feasible.
• Venous thromboembolism (VTE) prophylaxis: Pharmacologic VTE prevention is consistently recommended.
• Stress ulcer prophylaxis: Indicated for patients at risk of gastrointestinal bleeding.
• Renal replacement therapy: Intermittent and continuous modalities are considered equivalent in the treatment of acute kidney injury associated with sepsis.
• Goals of care discussion: Recent guidelines emphasize early, patient-centered discussions on prognosis and preferences

Differential Diagnosis

SIRS, by design, is a highly sensitive but nonspecific clinical construct. Its definition requires only 2 of 4 physiologic criteria, making it prone to overlap with a wide array of acute medical conditions that do not reflect true systemic inflammation or immune activation. Differentiating the following mimics is crucial to avoid diagnostic error and inappropriate management:

• Tachypnea and tachycardia without inflammation

  • Acute status asthmaticus (tachypnea and tachycardia due to hypoxia and frequent beta-agonist use)
  • Salicylate toxicity (stimulates the respiratory center, leading to respiratory alkalosis)
  • Alcohol withdrawal or acute intoxication
  • Diabetic or starvation ketoacidosis
  • Hyperventilation syndrome and panic attack
  • Anemia or hypovolemia (compensatory tachycardia without an inflammatory source)
  • Pulmonary embolism (may also progress to a true inflammatory state if infarction or sepsis ensues)

• Tachycardia with hyperthermia (SIRS mimics with thermoregulatory dysfunction)

  • Thyrotoxic crisis (thyroid hormone excess raises metabolic rate and sympathetic drive)
  • Neuroleptic malignant syndrome (dopamine blockade-related thermodysregulation)
  • Serotonin syndrome (especially with serotonergic drug combinations)
  • Malignant hyperthermia (anesthetic-induced metabolic crisis)
  • Drug intoxication (eg, amphetamines, PCP, and cocaine)

• Hyperthermia with leukocytosis (noninfectious hematologic and neurologic mimics)

  • Acute hemorrhagic stroke, particularly pontine or hypothalamic hemorrhage
  • Postoperative leukocytosis (surgical stress response rather than infection)
  • Blood transfusion reaction (especially delayed hemolytic reactions)

• Metabolic and endocrine conditions resembling SIRS

  • Adrenal insufficiency or crisis
  • Hypoglycemia with adrenergic surge
  • Pheochromocytoma crisis

• Toxin- and drug-induced syndromes

  • Cytokine release syndrome (eg, after CAR-T therapy or monoclonal antibodies)
  • DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome
  • Heat stroke (environmental hyperthermia causing systemic vasodilation and multi-organ stress)

• Hematologic or autoimmune inflammatory mimics

  • Macrophage activation syndrome or hemophagocytic lymphohistiocytosis 
  • Flare of systemic lupus erythematosus (SLE)
  • Paraneoplastic fevers and leukemoid reactions

Prognosis

SIRS carries a wide spectrum of outcomes depending on the severity of the response, underlying etiology, and associated organ dysfunction. A SIRS score of ≥2 on day 1 of hospitalization has been associated with increased risk of progression to MODS, longer ICU stays, and a higher need for vasopressor support and mechanical ventilation. The median time from SIRS to sepsis is inversely proportional to the number of SIRS criteria met at admission, indicating more rapid deterioration in severe cases.[53]

Rangel-Fausto et al reported a stepwise increase in mortality: SIRS (7%), sepsis (16%), severe sepsis (20%), and septic shock (46%).[54] In contrast, Shapiro et al reported lower mortality rates—1.3% for sepsis, 9.2% for severe sepsis, and 28% for septic shock [55]—reflecting improved clinical outcomes over time due to advances like early goal-directed therapy, DVT prophylaxis, glucose control, lung-protective ventilation strategies, and early mobilization.

Persistence of SIRS is also a negative prognostic marker. Bochicchio et al found that patients with unresolved SIRS by day 7 had a 4.7-fold higher mortality risk.[56] Talmor et al observed that mortality increased based on SIRS score trends: patients whose SIRS score decreased had an 11% mortality rate, those with unchanged scores had an 18% mortality rate, and those with increasing scores had a 22% mortality rate.[19] Similarly, Kaukonen et al demonstrated a dose-response relationship, with each additional SIRS criterion increasing mortality odds by 13% (OR 1.13 per criterion).[4]

Brun-Buisson et al noted a 50% reduction in 5-year life expectancy among patients who had SIRS during hospitalization.[57]ICU studies by Jentzer et al showed 16.8% mortality in SIRS-positive patients compared to 3.8% in SIRS-negative counterparts.[13] In postoperative settings, Chao et al observed 12.7% mortality in emergency surgery patients with SIRS versus 0.4% in those without.[58] Notably, Henriksen et al found no significant difference in mortality between SIRS and non-SIRS ICU patients (18.4% versus 16.6%), suggesting other factors (eg, organ dysfunction) may play a larger role in predicting outcomes.[59]

Collectively, these findings highlight that while SIRS remains an important early clinical marker, progression to sepsis, organ dysfunction, and shock, along with biomarkers and newer scoring systems, eg, SOFA and qSOFA, provides better prognostic clarity.

Complications

SIRS may progress along a clinical continuum, especially in infectious cases, evolving from sepsis to severe sepsis, septic shock, and ultimately MODS. Complications may also arise independently due to isolated end-organ involvement. The following are common and clinically significant complications associated with SIRS:

• Central nervous system: Acute encephalopathy, often presenting as delirium or altered mental status, can result from cytokine-mediated neuroinflammation or secondary to metabolic derangements.

• Respiratory system: Acute respiratory distress syndrome (ARDS) due to inflammatory alveolar damage; aspiration pneumonitis may occur secondary to impaired mental status or encephalopathy.

• Cardiovascular system: Tachyarrhythmias and troponin elevation from demand ischemia; hemodynamic instability due to systemic vasodilation or myocardial depression.

• Gastrointestinal system: Stress-related mucosal disease leading to ulcers and gastrointestinal bleeding; acute transaminitis due to hypoperfusion or inflammatory injury.

• Renal system: Acute kidney injury, typically due to acute tubular necrosis, may result in metabolic acidosis and electrolyte disturbances.

• Hematologic system: Thrombocytopenia or thrombocytosis, disseminated intravascular coagulation (DIC), hemolysis, and increased risk of venous thromboembolism (eg, deep vein thrombosis).

• Endocrine system: Hyperglycemia due to stress-related insulin resistance and catecholamine surge; adrenal insufficiency, particularly in patients with sepsis or prolonged critical illness.

Deterrence and Patient Education

Given the critical importance of time in the management of SIRS and sepsis, early recognition remains paramount for improving outcomes. Patient and caregiver education should focus on recognizing early warning signs, including fever, rapid breathing, confusion, or low blood pressure, especially in high-risk groups.

Particular attention should be paid to individuals with primary or acquired immunosuppression, including those with malignancy, transplant recipients, or patients on long-term corticosteroids or immunomodulators. These patients and their families should be counseled on the need for early medical evaluation at the onset of even mild symptoms.

During hospitalization, engaging patients and family members in understanding the nature and severity of the illness, prognostic indicators, treatment goals, potential complications, and risk-benefit profiles is equally important. Such communication helps alleviate anxiety and can reduce the sympathetic stress response, which may otherwise worsen clinical status.

Assessing the patient's and family's emotional readiness, health literacy, and coping mechanisms is crucial. When appropriate, palliative care or pastoral care services should be involved early to provide additional emotional and spiritual support—resources that are often underutilized but can significantly enhance holistic care and shared decision-making.

Enhancing Healthcare Team Outcomes

Effective management of SIRS requires a highly coordinated interprofessional approach to ensure timely recognition, risk stratification, and appropriate intervention. Physicians, including internists, intensivists, and infectious disease specialists, lead diagnostic efforts by applying clinical scoring systems and biomarkers to identify SIRS and differentiate between infectious and noninfectious triggers. Advanced practitioners, often serving in triage and acute care settings, provide critical support in patient stabilization and ongoing evaluation. Nurses, through continuous monitoring, medication administration, and early identification of deterioration, serve as the frontline of care while also educating patients and families. Pharmacists contribute to expert medication management, ensuring the appropriate use of antibiotics and minimizing drug interactions. Radiology and laboratory professionals support timely diagnostics, which are essential to initiating early therapy and anticipating organ dysfunction.

Strong interprofessional communication and coordinated workflows are central to improving outcomes in patients with SIRS. Structured interprofessional rounds, standardized sepsis bundles, and early warning systems promote rapid response to clinical changes. Clear protocols for documentation and escalation foster shared accountability and reduce errors. Beyond hospital walls, community health education enhances early symptom recognition by patients and caregivers, potentially expediting care. Social workers and care coordinators extend this continuum by ensuring safe discharge planning and follow-up, particularly in high-risk populations. A systems-based model that empowers each healthcare professional to act decisively and collaboratively remains essential for enhancing patient-centered care, improving safety, and achieving optimal team performance in managing SIRS.

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Disclosure: Sujatha Baddam declares no relevant financial relationships with ineligible companies.

Disclosure: Bracken Burns declares no relevant financial relationships with ineligible companies.