Sepsis in children: Definitions, clinical manifestations, and diagnosis

INTRODUCTION — 

The definition, clinical manifestations, and diagnosis of sepsis and infection-related shock in children are discussed here.

The rapid recognition, resuscitation, and initial management of pediatric sepsis and septic shock and the evaluation and management of undifferentiated shock in children are discussed separately:

●(See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

●(See "Sepsis and septic shock in children in resource-abundant settings: Ongoing management after resuscitation".)

●(See "Initial evaluation of shock in children".)

●(See "Shock in children in resource-abundant settings: Initial management".)

●(See "Shock in children in resource-limited settings: Recognition" and "Shock in children in resource-limited settings: Initial management".)

DEFINITIONS

Infection — Infection is defined as a pathologic process caused by a microorganism. Infection puts children at risk for sepsis, a life-threatening condition in which a dysregulated host response to infection leads to organ dysfunction [1]. Infection is suspected based upon a combination of clinical findings that often include fever, hypothermia, or temperature instability, tachycardia, tachypnea, and laboratory abnormalities (e.g. abnormal white blood count or absolute neutrophil count, or elevated inflammatory markers such as C-reactive protein or procalcitonin), but may also include signs of poor perfusion (delayed capillary refill), rashes or other findings.

Suspected infection is a necessary condition to define sepsis. Infection may be microbiologically confirmed by positive culture, tissue stain, polymerase chain reaction test, or other diagnostic tests that identify an infecting pathogen. The definition also includes clinical syndromes associated with a high probability of infection, such as petechiae and purpura in a child with hemodynamic instability, or fever, cough, and hypoxemia in a patient with leukocytosis and pulmonary infiltrates on chest radiograph (table 1). However, definitive identification of an infecting organism is not required to make the diagnosis of sepsis.

The pediatric systemic inflammatory response syndrome (pSIRS) criteria provide age-specific parameters for heart rate, respiratory rate and white blood cell count that are associated with possible infection. pSIRS was previously a component of the diagnostic criteria for sepsis and septic shock in children [2]. The presence of two or more of the following criteria (one of which must be abnormal temperature or abnormal leukocyte count) defines pSIRS (table 2) [3]:

●Abnormal core temperature (measured by rectal, bladder, oral, or central probe) typically fever with temperature >38.5°C (101.3°F or, in young infants, >38.0°C [100.4°F]) (see "The febrile infant (younger than 90 days of age): Definition of fever") but also including hypothermia with temperature <36°C (96.8°F) (see "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Infection')

●Tachycardia, defined as a mean heart rate more than two standard deviations above normal for age, or for children younger than one year of age, bradycardia defined as a mean heart rate <10^th percentile for age

●Mean respiratory rate more than two standard deviations above normal for age or mechanical ventilation for an acute pulmonary process

●Leukocyte count elevated or depressed for age, or >10 percent immature neutrophils

Studies have demonstrated the value and reproducibility of pSIRS criteria for the recognition of children with suspected infection who are at risk for progression to sepsis [4-6]. pSIRS criteria have also been successfully integrated into institutional tools and protocols designed to trigger rapid clinical assessment, closer monitoring, and early intervention for children at risk for sepsis; they remain a key component of institutional bundles that identify these patients and guide the administration of goal-directed therapy. Other vital sign ranges (such as those used in the Pediatric Advanced Life Support [PALS] septic shock guidelines) may be more practical to implement for diagnostic and therapeutic decisions in specific settings [7,8]. (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Institutional guidelines and protocols'.)

Although pSIRS was part of the 2005 International Pediatric Consensus Conference definition for sepsis, the definition was based on expert consensus aiming to have a low likelihood of missing patients at risk [3]. However, subsequent studies have shown that the majority of children meeting pSIRS criteria are not at risk for a potentially life-threatening infection. For example, pSIRS has low sensitivity for critical care interventions after presentation to the emergency department [9]. A population-based epidemiologic study in Switzerland of children with bacteremia also reported that over 99 percent of patients who were pSIRS-positive without organ failure survived [10]. In addition, during derivation and validation of the 2024 International Consensus Criteria for Pediatric Sepsis and Septic Shock, pSIRS did not accurately distinguish between those patients with suspected or confirmed infection who survived hospitalization versus those who died. The newly derived Phoenix Sepsis Score performed much better [1,11]. Therefore, the 2024 International Consensus Criteria for Pediatric Sepsis and Septic Shock do not use pSIRS criteria to diagnose sepsis in children and instead use the Phoenix score criteria [11].

Evolving sepsis — Clinicians often evaluate children with suspected infection and clinical findings of altered perfusion that are not severe enough to meet the 2024 International Consensus Criteria for sepsis or septic shock [11]. For the purposes of this topic, we identify these children as having "evolving sepsis."

Many children with evolving sepsis may have either compensated or hypotensive shock:

●Compensated shock – These children have suspected infection with normal blood pressure and signs of inadequate tissue perfusion (two or more of the following):

•Prolonged capillary refill

•Oliguria (urine output <0.5 mL/kg/hr)

•Unexplained metabolic acidosis

•Elevated blood lactate (2 to 4.9 mmol/L)

These children also have fever and typically meet pSIRS criteria (table 2).

●Hypotensive shock – These children have suspected infection with hypotension (a systolic pressure that is <5th percentile for age) but do not meet the age-based mean arterial pressure values or lactate threshold value (≥5 mmol/L) used in the Phoenix Sepsis Score (table 3). They also will have signs of inadequate tissue perfusion and typically meet pSIRS criteria as well.

Some children may have organ dysfunction without shock (eg, fever, respiratory compromise, and altered mental status in a child with pneumonia) that is not severe enough to meet the Phoenix criteria.

All children with evolving sepsis require rapid recognition and emergency treatment consisting of fluid resuscitation and empiric antibiotics because they remain at significant risk of developing new or worsening end-organ dysfunction and progressing to life-threatening sepsis and septic shock. (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Resuscitation'.)

Sepsis and septic shock (Phoenix Sepsis Score) — The International Society of Critical Care Medicine Pediatric Sepsis Definition Task Force developed the International Consensus Criteria for Pediatric Sepsis and Septic Shock in 2024 for children (<18 years old) [11]. It defines sepsis as a clinical syndrome that complicates severe infection and causes end-organ dysfunction.

The 2024 International Consensus Criteria definition of pediatric sepsis consists of two components [11]:

●Suspected infection and

●Phoenix Sepsis Score ≥2 (table 3)

Because the 2024 International Consensus Criteria for Pediatric Sepsis definition relies on the presence and severity of organ dysfunction, it now includes patients previously described as having severe sepsis by the 2005 criteria [3].

Septic shock is defined as sepsis and ≥1 cardiovascular points on the Phoenix Sepsis Score (any one of the following):

●Severe hypotension for age

●Blood lactate >5 mmol/L

●Need for vasoactive medication

Unresponsiveness to fluids (eg, persisting shock despite the administration of ≥40 mL/kg of isotonic fluid in one hour) is no longer considered a criterion for septic shock [3,11]. However, lack of responsiveness to rapid fluid administration still identifies the need for vasoactive medication and represents a risk for developing septic shock.

These definitions for sepsis and septic shock are derived from over three million pediatric encounters worldwide [1,11]. They do identify children at risk for death but are not designed to help with screening of children for evolving sepsis who may progress to sepsis and septic shock and require emergency resuscitation.

Reliably identifying and quantifying organ dysfunction is essential to diagnose sepsis and septic shock. Thresholds for four systems are included in the Phoenix Sepsis Score (table 3):

●Respiratory – Oxygen requirement (either PaO₂:FiO₂ or Spo₂:FIO₂ ratio)

●Cardiovascular – Blood lactate, requirement for vasoactive medications, and age-based mean arterial pressure

●Coagulation – Platelet count, international normalized ratio (INR), D-dimer, and fibrinogen

●Neurologic system – Glasgow Coma Scale score (table 4) and pupillary response

During derivation and validation of the Phoenix Sepsis Score, this four-organ system model had similar predictive capability for mortality in children with sepsis across 13 study sites, including three resource-limited settings, when compared with an eight-organ system model consisting of the four systems and the following [1]:

●Endocrine – Blood glucose

●Immunologic – Absolute neutrophil count (ANC) and absolute lymphocyte count (ALC)

●Renal – Serum creatinine

●Hepatic – Total serum bilirubin and alanine aminotransferase (ALT)

However, monitoring organ dysfunction in all eight of these systems to track the response to therapy and prognosis is part of routine intensive care for sepsis and septic shock.

Clinical application — The 2024 International Consensus Criteria for Pediatric Sepsis and Septic Shock and the Phoenix Sepsis Score provide updated criteria for the definition of sepsis and septic shock (table 3). (See 'Sepsis and septic shock (Phoenix Sepsis Score)' above.)

These definitions are important for the standardization of evidence from observational studies and in the evaluation of therapeutic interventions in clinical trials. They may also be useful in helping clinicians determine the severity of illness, identify patients at highest risk of mortality, and monitor clinical progression and response to therapy for patients with sepsis and septic shock in the ICU. (See "Sepsis and septic shock in children in resource-abundant settings: Ongoing management after resuscitation", section on 'Prognosis'.)

However, provider concern for sepsis usually precedes development of the degree of organ dysfunction reflected by the 2024 International Consensus Criteria [12]. Early recognition is essential for prompt initiation of treatment to prevent progression along the spectrum from evolving sepsis to sepsis and septic shock as well as to decrease mortality. For this reason, the many clinical criteria used to define sepsis, severe sepsis, and septic shock from the 2005 International Pediatric Consensus Conference maintain relevance [3]. Specifically, the pediatric systemic inflammatory response syndrome (table 2) and signs of inadequate tissue perfusion remain important findings as part of bedside clinical assessment and trigger tools to guide emergency assessment and treatment [2]. (See 'Infection' above and 'Evolving sepsis' above and "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

Fluid-refractory and catecholamine-resistant shock — Patients with evolving sepsis or who meet Phoenix criteria for sepsis or septic shock may be further categorized by their response to resuscitation:

●Fluid-refractory shock – Patients with fluid-refractory shock have persistent abnormal perfusion or hypotension after at least 40 to 60 mL/kg of fluid resuscitation or development of signs of fluid-overload prior to resolution of shock.

●Catecholamine-resistant shock – Patients with catecholamine-resistant, infection-related shock have persistent abnormal perfusion or hypotension despite fluid resuscitation and therapy with vasoactive medications (eg, epinephrine or norepinephrine).

PATHOPHYSIOLOGY — 

Sepsis is a clinical syndrome that complicates severe infection and is caused by a dysregulated response to the infection leading to end-organ dysfunction [13]. In this syndrome, tissues remote from the source of infection display the cardinal signs of inflammation with microcirculatory vasoconstriction followed by vasodilation, increased microvascular permeability, and leukocyte accumulation.

Although inflammation is an essential host response to injury, the onset and progression of sepsis result from a "dysregulation" in the normal response to infection, accompanied by an increase in both proinflammatory and anti-inflammatory mediators, initiating a chain of events that leads to widespread tissue injury. Evidence supports a state of acquired immune suppression or immunoparalysis in some patients, which may occur simultaneously with or following the initial proinflammatory response. It is this dysregulated host response rather than the primary infectious microorganism that is typically responsible for multiple organ failure and adverse outcomes in sepsis. (See "Pathophysiology of sepsis".)

EPIDEMIOLOGY — 

The overall burden of illness from pediatric sepsis worldwide is high and occurs in an estimated 28 million children and adolescents ≤19 years old [14]. In-hospital mortality from pediatric sepsis varies; it is highest in resource-limited settings where, based on a global retrospective cohort study from 2010 to 2019, deaths occurred in approximately 33 percent of children with sepsis compared with just over 10 percent in resource-abundant settings [1].

The occurrence of sepsis (previously called pediatric severe sepsis based on the 2005 International Pediatric Consensus Conference definition [3]) has been steadily rising since the mid-1990s and now accounts for 4.4 percent of admissions to children's hospitals, with 7 percent of patients treated in pediatric intensive care units (PICUs) in the United States, and up to 25 percent of patients treated in PICUs in South America [15-18].

Diarrheal disease, respiratory infection, and neonatal disorders account for over two-thirds of cases of sepsis worldwide [14]. Many of these illnesses are caused by vaccine-preventable pathogens [19]. Since 1960, mortality from pediatric sepsis among patients managed in resource-abundant settings has decreased from 97 percent to approximately 4 to 10 percent in patients treated with sepsis [15-17,20-22] and 10 to 34 percent in patients with septic shock [4,11,15-17,19-28]. (See "Pneumonia in children: Epidemiology, pathogenesis, and etiology", section on 'Epidemiology' and "Sepsis and septic shock in children in resource-abundant settings: Ongoing management after resuscitation", section on 'Ongoing management'.)

Risk factors — The following factors have been associated with an increased risk for sepsis [20,29,30]:

●Age younger than one month

●Serious injury (eg, major trauma, burns, or penetrating wounds)

●Chronic debilitating medical condition (eg, static encephalopathy with quadriplegia and frequent aspiration pneumonia, uncorrected congenital heart disease, short bowel syndrome)

●Host immunosuppression (malignancy, human immunodeficiency virus infection, severe malnutrition, congenital immunodeficiency, sickle cell disease and other diseases with splenic dysfunction, or immunomodulating medications [eg, chemotherapy, Janus Kinase inhibitors, monoclonal antibody therapy]) (see "Approach to the child with recurrent infections")

●Large surgical incisions

●In-dwelling vascular catheters or other invasive devices (eg, endotracheal tube, Foley catheter, chest tube)

●Urinary tract abnormalities with frequent infection

By contrast, routine immunization of infants and children against Haemophilus influenzae type b, Neisseria meningitidis, and Streptococcus pneumoniae has been associated with a dramatic decrease in the incidence of invasive disease in young children caused by these organisms. (See "Prevention of Haemophilus influenzae type b infection", section on 'Efficacy/effectiveness'.)

PATHOGENS — 

Sepsis can be caused by bacterial, viral, fungal, parasitic, and rickettsial infections. Bacteria and viruses are the most frequently identified pathogens.

Bacteria — Although the frequency of specific pathogenic organisms varies from institution to institution, the most common bacterial pathogens isolated from children with severe sepsis include [15,21,31-37]:

●Staphylococcus aureus including methicillin-resistant strains (MRSA)

●Coagulase-negative Staphylococcus especially in neonates or young infants with in-dwelling vascular catheters

●Streptococcus pneumoniae

●Streptococcus pyogenes

●Neisseria meningitidis (especially in sub-Saharan Africa)

●Group B streptococcus in the neonate

●Pseudomonas aeruginosa including carbapenem-resistant strains

●Escherichia coli, including those with extended spectrum beta-lactamase activity (ESBL)

●Enterococcus species, including vancomycin-resistant species

●Klebsiella species, including those with ESBL activity

●Alpha streptococcus in children with acute myelogenous leukemia with mucositis and neutropenia

●Haemophilus influenzae type b in unimmunized children

Although less common, the toxic shock syndrome caused by toxin-producing strains of Staphylococcus aureus and Streptococcus pyogenes remain important additional causes of sepsis in children. (See "Clinical manifestations of meningococcal infection" and "Staphylococcal toxic shock syndrome" and "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

Factors that alter the prevalence of causative pathogens include age, immunocompromise, and the presence of an in-dwelling vascular catheter:

●In young infants three months of age or younger, gram-negative organisms, particularly Escherichia coli, and Group B streptococcus are most frequently isolated. Staphylococcus aureus is also a frequent pathogen. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Pathogens and type of infections'.)

●In patients with sepsis and febrile neutropenia, both gram-positive (eg, coagulase-negative Staphylococcus, Staphylococcus aureus, Streptococcus pneumoniae, alpha Streptococci) and gram-negative organisms (eg, Pseudomonas aeruginosa, Escherichia coli, Klebsiella species) are common. Other gram-negative organisms, including Enterobacter, Citrobacter, and Acinetobacter species and Stenotrophomonas maltophilia, also occur though less frequently. MRSA and multidrug-resistant gram-negative bacteria, such as certain strains of Pseudomonas aeruginosa and ESBL-producing organisms, are frequently isolated. (See "Fever in children with chemotherapy-induced neutropenia", section on 'Infectious causes of fever'.)

●In hospital-acquired bacterial infections, such as catheter-associated bloodstream infections, coagulase-negative Staphylococcus is the most commonly isolated organism, followed by gram-negative organisms.

Viruses — Viral pathogens can cause sepsis and be difficult to differentiate from bacterial pathogens. Etiologies include:

●Influenza (see "Seasonal influenza in children: Clinical features and diagnosis")

●Parainfluenza (see "Parainfluenza viruses in children")

●Adenovirus (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infections")

●Respiratory syncytial virus (RSV) (see "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children")

●Human metapneumovirus (see "Human metapneumovirus infections")

●Crimean-Congo hemorrhagic fever, a tick-borne virus (see "Crimean-Congo hemorrhagic fever")

●Dengue virus, a mosquito-borne pathogen that can cause dengue shock syndrome (see "Dengue virus infection: Clinical manifestations and diagnosis")

●Ebola virus (see "Clinical manifestations and diagnosis of Ebola disease")

●Marburg virus (see "Marburg virus")

●Lassa fever (see "Lassa fever")

While these viruses, especially pandemic H1N1 influenza strain and SARS-CoV-2, may cause the sepsis syndrome in isolation, the presence of bacterial coinfections, particularly Staphylococcus aureus and Streptococcus pneumoniae, should be suspected in patients with sepsis or septic shock.

In immunocompromised patients, Epstein-Barr virus, cytomegalovirus, and adenovirus may also cause sepsis. (See "Dengue virus infection: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

In neonates and young infants, Herpes simplex virus (HSV), enterovirus, and adenovirus infection can be indistinguishable from bacterial sepsis. Characteristic vesicular lesions (skin, eye, or mucus membrane) suggesting the diagnosis of herpes simplex may be absent in 30 to 40 percent of infected infants. Most neonates become symptomatic with the first three weeks of life. Nonspecific clinical manifestations include (see "Neonatal herpes simplex virus (HSV) infection: Clinical features and diagnosis", section on 'Clinical manifestations'):

●Disseminated disease – Respiratory collapse, liver failure, and disseminated intravascular coagulation

●Central nervous system disease – Seizures, lethargy, irritability, and bulging fontanelle

Coronavirus disease 2019 (COVID-19) can cause severe infection and sepsis in children, particularly those with underlying medical conditions, although most children have asymptomatic or mild disease. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Severe disease in children'.)

Fungi — Fungal infections, especially Candida species, have been reported in 10 percent of pediatric patients with sepsis and septic shock [15,16,21]. Fungal sepsis is more common in hospitalized children and those with certain risk factors including [38]:

●Malignancy or other immunocompromising medical conditions

●Indwelling vascular catheters

●Prolonged neutropenia (>4 to 7 days)

●Recent broad-spectrum antibiotic use

Other pathogens — Parasitic (eg, malaria) and Rickettsial infections (eg, Rocky Mountain spotted fever) may present with sepsis and should be suspected based upon the local prevalence of disease and travel history. (See "Epidemiology, clinical manifestations, and diagnosis of Rocky Mountain spotted fever", section on 'Clinical manifestations' and "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children".)

Culture-negative sepsis — Approximately 30 to 75 percent of children with sepsis have no infectious etiology identified [4,30,31]. This "culture-negative" sepsis may indicate host response to bacterial components, such as endotoxin, in the circulatory system or result from antibiotic treatment prior to obtaining bacterial cultures.

Alternatively, current diagnostic tests may not be sufficiently sensitive to detect the inciting pathogen in all cases. Newer molecular diagnostic techniques, such as multiplex polymerase chain reaction (PCR), have the potential to improve the rate of organism identification. As an example, in a study comparing multiplex PCR to routine blood culture in 1673 samples obtained from 803 children with suspected sepsis, the rate of positive results was significantly higher with PCR than blood culture (15 versus 10 percent, respectively) with significantly fewer contaminants (2 versus 6 percent, respectively) [39]. However, this testing is not widely available, and it is undergoing further investigation.

CLINICAL MANIFESTATIONS

Infection — Infection is typically suggested by physical findings (table 1) including fever with tachycardia, tachypnea, cough, hypoxemia, petechiae and purpura, cellulitis, skin abscess, and/or leukocytosis on complete blood count. Infections can also be proven by positive culture, tissue stain, or polymerase chain reaction (PCR) test. However, these results are frequently not available during the initial phase of treatment. Furthermore, in many patients with sepsis, no pathogen is identified. (See 'Pathogens' above and 'Laboratory studies' below.)

The pediatric systemic inflammatory response syndrome (pSIRS) criteria provide age-specific parameters for white blood cell count, heart rate and respiratory rate associated with possible infection, and identify children who may have evolving sepsis (table 2) [2]. (See 'Infection' above.)

Abnormal vital signs and tissue perfusion — Children with evolving sepsis have significant alterations in vital signs and often in white blood cell measurements indicating a systemic inflammatory response (table 2). They also have clinical signs of shock with abnormal perfusion (one or more of the following) (see 'Infection' above and 'Evolving sepsis' above):

●Altered mental status

●Warm or cold extremities

●Decreased urine output

●Bounding or thready/absent peripheral pulses

●Abnormal capillary refill (either "flash" or >2 seconds)

Manifestations of organ dysfunction, including hypoxia, cardiovascular dysfunction, metabolic acidosis with elevated blood lactate, and coagulopathy, may be emerging in these patients but may not meet the 2024 criteria for diagnosing sepsis (table 3).

Shock — In children with evolving sepsis, evidence of inadequate tissue perfusion and oxygen delivery with or without hypotension indicates significant risk for the development of sepsis by the Phoenix criteria (table 3); these patients require emergency intervention. (See 'Evolving sepsis' above and "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

Tachycardia is a sensitive, though nonspecific, indicator often seen in the early stages of shock. Hypotension is a late sign of shock in infants and children who are better able to maintain blood pressure than adults through an increase in heart rate, systemic vascular resistance, and venous tone. (See "Pathophysiology and classification of shock in children", section on 'Common features'.)

Other clinical findings of shock vary depending upon whether the patient has distributive ("warm") shock or "cold" shock (see "Pathophysiology and classification of shock in children", section on 'Common features'):

●Distributive ("warm") shock – Distributive shock is characterized by hyperdynamic (or high output) physiology with decreased systemic vascular resistance and elevated cardiac output. In some patients, signs of warm shock may include (see "Pathophysiology and classification of shock in children", section on 'Distributive shock'):

•Flash capillary refill (<1 second)

•Bounding pulses

•Warm, dry extremities

•Wide pulse pressure (typically greater than 40 mmHg in older children and adults; lower pulse pressures may reflect widening in infants and neonates)

●Cold shock – "Cold" shock reflects increased systemic vascular resistance and decreased cardiac output. In some patients, signs of cold shock may include (see "Pathophysiology and classification of shock in children", section on 'Hypovolemic shock'):

•Delayed capillary refill (>2 seconds)

•Diminished pulses

•Mottled or cool extremities

•Narrow pulse pressure (typically <40 mmHg in older children and adults)

The 2020 Surviving Sepsis Campaign suggests against using bedside clinical signs in isolation to categorize septic shock in children as "warm" or "cold." However, this categorical distinction may be helpful if advanced hemodynamic monitoring is available to assess patient physiology more accurately. Examples of advanced monitoring often used in the intensive care unit include (see "Sepsis and septic shock in children in resource-abundant settings: Ongoing management after resuscitation", section on 'Vasoactive drug therapy'):

●Invasive arterial blood pressure monitoring with pulse contour analysis

●Ultrasound Doppler of the ascending or descending thoracic aorta (suprasternal or esophageal Doppler)

●Cardiac ultrasound/echocardiography, or measurement of ScvO₂

Sepsis and septic shock — Some children may fully meet the 2024 criteria for sepsis and septic shock at presentation. In addition to the clinical findings of shock described above, they will also manifest findings of significant organ dysfunction per the Phoenix Sepsis Score (table 3). They may also have abnormalities in other organ systems. (See 'Sepsis and septic shock (Phoenix Sepsis Score)' above.)

Other physical findings — Additional clinical findings in infants and children with evolving or existing sepsis may indicate a primary site of infection or arise from organ dysfunction caused by inadequate perfusion [40]:

●Toxic or ill appearance

●Signs of dehydration (eg, dry mucus membranes, sunken eyes, decreased urine output, prolonged capillary refill time, decreased skin turgor, and, in infants, a sunken fontanelle) (table 5)

●Rigors

●Altered mental status (eg, irritability, anxiety, confusion, lethargy, somnolence)

●Decreased tone in neonates and infants

●Seizures

●Meningismus

●Respiratory depression or failure

●Pulmonary rales or decreased breath sounds caused by bronchopneumonia

●Distended, tender abdomen (eg, perforated viscus or intraabdominal abscess)

●Costovertebral angle tenderness (eg, pyelonephritis)

●Macular erythema (toxic shock syndrome) (picture 1 and picture 2)

●Skin cellulitis or abscess (picture 3)

●Peripheral edema caused by capillary leak

●Petechiae or purpura suggesting either a specific infectious source (eg, meningococcemia, rickettsial infection) or disseminated intravascular coagulopathy (picture 4 and picture 5)

●Multiple nodules which can be seen with disseminated S. aureus or fungal infections (picture 6)

●Ecthyma gangrenosum

Laboratory studies — Children with sepsis or findings that suggest evolving sepsis should undergo the following laboratory studies:

●Rapid blood glucose – Hypoglycemia may accompany the metabolic demands and decreased oral intake associated with sepsis in children, especially in neonates and infants. Stress hyperglycemia may be noted initially and has been most carefully studied in meningococcemia in children [41].

●Arterial blood gas or venous blood gas and pulse oximetry – Patients with sepsis frequently have inadequate tissue perfusion with lactic acidosis. Hypoxemia from bronchopneumonia or pulmonary edema may also occur.

●Complete blood count with differential (including platelet count) – Age-specific leukocytosis or leukopenia are common in children presenting with acute infection but are nonspecific. In addition, neutrophilia, neutropenia, or thrombocytopenia may indicate acute infection. (See "Approach to the patient with neutrophilia", section on 'Infection'.)

●Blood lactate – Elevation of blood lactate >2.0 mmol/L (18 mg/dL) suggests tissue hypoperfusion. Higher levels above 2.0 mmol/L have also been associated with progression to organ dysfunction and mortality [42-44]. A blood lactate ≥5 mmol/L is the minimum threshold for assigning a point for cardiovascular dysfunction in the Phoenix Sepsis Score (table 3).

Rapid determination of blood lactate may be obtained at the bedside. Although venous lactate may at times yield slightly higher values than simultaneous arterial samples (in part due to increased use of tourniquets for venous samples), there is a strong correlation between venous and arterial lactate levels in most patients [45]. (See "Shock in children in resource-abundant settings: Initial management", section on 'Clinical and physiologic targets'.)

●Serum electrolytes – Electrolyte disturbances (eg, hyponatremia, hyperkalemia, hypokalemia, and hypophosphatemia) may accompany disease processes associated with risk for sepsis and septic shock, such as syndrome of inappropriate antidiuretic hormone secretion, gastroenteritis, and capillary leak.

●Blood urea nitrogen and serum creatinine – Elevation in blood urea nitrogen may indicate dehydration. Elevation in creatinine may reflect prerenal azotemia. Serum creatinine should be serially measured to identify and monitor acute kidney injury. Some patients progress to renal failure requiring renal replacement therapy. (See 'Sepsis and septic shock (Phoenix Sepsis Score)' above.)

●Serum calcium – Hypocalcemia (ionized calcium <1.1 mmol/L) may affect myocardial function and vascular tone and should be corrected if present. If serum calcium is abnormal, serum phosphorus and magnesium should also be measured.

●Serum total bilirubin and alanine aminotransferase – Elevation of total bilirubin or alanine aminotransferase (ALT) indicates liver dysfunction and is also routinely monitored in children with sepsis and septic shock. (See 'Sepsis and septic shock (Phoenix Sepsis Score)' above.)

●Prothrombin time (PT), partial thromboplastin time (aPTT), international normalized ratio (INR) – Elevation in PT and aPTT or INR suggests disseminated intravascular coagulopathy (DIC) and is a key criteria in the Phoenix Sepsis Score along with fibrinogen and D-dimer (table 3).

●Fibrinogen and D-dimer – Decreased fibrinogen and increased D-dimer support the presence of a consumptive coagulopathy and DIC. Hypofibrinogenemia <150 mg/dL may also be an early marker of secondary hemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) in children with sepsis [46].

●Blood culture – Given the high prevalence of bacterial bloodstream infections in children with sepsis, blood cultures should be obtained in all patients, preferably before antibiotics are administered.

●Urinalysis – The presence of bacteria, nitrites, or pyuria suggests a urinary tract infection.

●Urine culture – Urinary tract infection is a common source of infection in children with sepsis and urine cultures (either via "clean-catch" or catheterization depending on age and development) should be obtained in all patients, preferably before antibiotic administration.

●Other cultures – Other cultures (eg, cerebrospinal fluid [CSF], wound culture, aspirated fluid from an abscess collection, and/or viral or fungal cultures) should be obtained as indicated by clinical findings. Children with shock should undergo appropriate resuscitation before lumbar puncture (LP). As an example, a hemodynamically unstable patient with septic shock who may have bacterial meningitis should undergo emergency fluid resuscitation, have a blood culture obtained, and receive empiric antibiotics as soon as possible; LP should be deferred until the child's condition stabilizes. (See "Lumbar puncture in children", section on 'Contraindications'.)

●Diagnostic testing – For some infections (eg, herpes simplex virus, enterovirus, influenza), other diagnostic testing (eg, viral culture, polymerase chain reaction, rapid immunoassay antigen test, or direct and immunofluorescent antibody staining) may be helpful in establishing the source of infection. See UpToDate topics on clinical manifestations and diagnosis of the specific infection suspected for guidance on diagnostic testing.

In addition to the above parameters, patients with clinical features of multisystem inflammatory syndrome in children (MIS-C) (table 6) warrant testing as determined by the specific clinical presentation (algorithm 1). (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

Inflammatory biomarkers, such as C-reactive protein and procalcitonin, may be useful in select cases, and these biomarkers are increasingly used to assess risk for infection and sepsis [47]. For example, elevations in procalcitonin and C-reactive protein may be useful in identifying the presence of serious bacterial infection in infants and young children who present to an emergency department with fever and no apparent source of infection (see "The febrile infant (29 to 90 days of age): Outpatient evaluation", section on 'Inflammatory markers'). They may also be useful in predicting bacterial infection in patients with fever and neutropenia [48,49]. In addition, C-reactive protein may guide safe de-escalation of antibiotics for patients who clinically improve in the absence of an identifiable source of infection [50].

However, white blood cell count, procalcitonin, and C-reactive protein may be elevated in the absence of serious bacterial infection or sepsis [51]; thus, they require clinical correlation for proper interpretation. A relatively high negative predictive value for procalcitonin, particularly when trended serially over 24 to 48 hours, can be helpful to exclude an invasive bacterial infection or sepsis as a diagnosis, especially if patients are clinically improving and microbiological evaluation has been unrevealing [52].

Molecular methods to identify bacterial and viral infections include polymerase chain reaction (PCR) and detection of bacterial 16S ribosomal ribonucleic acid (RNA) genes or host RNA signatures. Preliminary evidence suggests that these methods have the potential to discriminate bacterial from viral infection in children but remain investigational for use in determining bacterial versus viral infection in patients with sepsis and septic shock [53-58]. (See "Fever without a source in children 3 to 36 months of age: Evaluation and management", section on 'Molecular assays'.)

Imaging — Children with tachypnea, rales, wheezing, hypoxemia, or white blood cell count greater than 20,000/mm³ warrant a chest radiograph to assess for bronchopneumonia, pulmonary edema, and heart size. Cardiomegaly suggests fluid overload or congenital heart disease.

Other imaging may be appropriate depending upon clinical findings. For example, computed tomography (CT) of the head may be necessary in the patient with evidence of coagulopathy and altered mental status to evaluate for intracranial hemorrhage; ultrasound or CT of the abdomen may be indicated to evaluate for intra-abdominal abscess.

DIAGNOSIS — 

The diagnosis of sepsis and septic shock in children requires a suspicion for infection and findings of severe organ dysfunction based upon clinical parameters and ancillary testing (table 3).

Recognition of children with evolving sepsis is based upon suspected infection including those with physical findings of an infectious source (table 1), the presence of pediatric systemic inflammatory response syndrome (pSIRS) (table 2) and inadequate tissue perfusion or organ dysfunction not severe enough to meet the Phoenix sepsis criteria (see 'Evolving sepsis' above and 'Clinical manifestations' above):

●Compensated shock – These children have suspected infection with normal blood pressure and signs of inadequate tissue perfusion (two or more of the following):

•Prolonged capillary refill

•Oliguria (urine output <0.5 mL/kg/hr)

•Unexplained metabolic acidosis

•Elevated blood lactate (2 to 4.9 mmol/L)

These children also have fever and typically meet pSIRS criteria.

●Hypotensive shock – In addition to findings of tissue hypoperfusion, these children have suspected infection with hypotension (a systolic pressure that is <5^th percentile for age) but do not meet the age-based mean arterial pressure values or blood lactate thresholds used in the Phoenix Sepsis Score (table 3).

DIFFERENTIAL DIAGNOSIS — 

All children with suspected sepsis require fluid therapy and antibiotic administration pending documentation of an infectious etiology. However, several conditions may have similar clinical manifestations and, once clinical stabilization has occurred, an alternative etiology to sepsis may be evident based on careful review of clinical findings.

In neonates and young infants, alternative diagnoses include (see "Approach to the ill-appearing infant (younger than 90 days of age)"):

●Child abuse with significant trauma (eg, abusive head or abdominal trauma)

●Hypoglycemia

●Environmental hyperthermia

●Environmental hypothermia (in young infants)

●Seizures

●Congenital heart disease, particularly left-sided obstructive lesions (eg, aortic coarctation, hypoplastic left heart syndrome) presenting in patients less than two weeks of age

●Cardiac arrhythmias (primarily supraventricular tachycardia)

●Myocarditis or primary cardiomyopathy

●Inborn errors of metabolism

●Congenital adrenal hyperplasia

●Malrotation with volvulus

●Intussusception

●Pyloric stenosis

●Necrotizing enterocolitis, seen occasionally in newborns who have been discharged from the well-baby nursery

●Gastroenteritis with dehydration

●Water intoxication

●Toxic exposures (eg, methemoglobinemia or carbon monoxide poisoning)

●Acute bilirubin encephalopathy

Detailed history, physical examination, and selected diagnostic studies frequently can differentiate these conditions from sepsis. Among older children and adolescents, the following conditions can cause elevated temperature with tachycardia or hemodynamic instability:

●Heat stroke – The diagnostic criteria for patients with heatstroke are elevated core temperature (≥40°C [104°F]) and central nervous system (CNS) abnormalities following environmental heat exposure. Other typical clinical manifestations include tachycardia, tachypnea, flushed and warm skin, diaphoresis, and coagulopathy (table 7). Exposure to excessive ambient heat is present on history. The height of the fever may exceed 41°C (105.8°C), and an infectious prodrome or source of infection is absent. (See "Heat stroke in children".)

●Serotonin syndrome – Hyperthermia commonly occurs in patients with serotonin syndrome, a potentially life-threatening condition associated with increased serotonergic activity in the CNS. Serotonin syndrome encompasses a spectrum of disease where the intensity of clinical findings is thought to reflect the degree of serotonergic activity. Mental status changes can include anxiety, agitated delirium, restlessness, and disorientation. Patients may startle easily. Autonomic manifestations can include diaphoresis, tachycardia, hyperthermia, hypertension, vomiting, and diarrhea. Neuromuscular hyperactivity can manifest as tremor, muscle rigidity, myoclonus, hyperreflexia, and bilateral Babinski sign. Hyperreflexia and clonus are particularly common; these findings, as well as rigidity, are more often pronounced in the lower extremities.

The recognition that the patient has been exposed to a serotonergic drug is essential to the diagnosis (algorithm 2). (See "Serotonin syndrome (serotonin toxicity)".)

●Neuroleptic malignant syndrome – Neuroleptic malignant syndrome (NMS) is an idiosyncratic reaction to antipsychotic agents. In addition to hyperthermia, NMS is also characterized by "lead pipe" muscle rigidity, altered mental status, choreoathetosis, tremors, and evidence of autonomic dysfunction, such as diaphoresis, labile blood pressure, and arrhythmias. The history of antipsychotic drug exposure is an essential component of the diagnosis. (See "Neuroleptic malignant syndrome".)

●Malignant hyperthermia – Malignant hyperthermia is a rare genetic disorder that manifests following exposure to certain agents, most commonly succinylcholine and halothane. Other potent inhalational anesthetics (eg, sevoflurane, desflurane, isoflurane) can also cause malignant hyperthermia. The onset of malignant hyperthermia is usually within one hour of the administration of general anesthesia but rarely may be delayed up to 10 hours after induction. In children, clinical manifestations include tachycardia, hypercapnia, and hyperthermia; muscle rigidity (generalized or persistent masseter rigidity) and/or metabolic acidosis further support the diagnosis. (See "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'Pediatric presentation'.)

●Toxic overdose – Drug-related causes of hyperthermia, tachycardia, shock, and multiple organ dysfunctions include the following:

•Cocaine (see "Cocaine: Acute intoxication")

•Methamphetamine or related compounds (eg, bath salts) (see "Methamphetamine: Acute intoxication")

•Amphetamine, or related compounds (synthetic cathinones [“bath salts”]) (see "Acute amphetamine and synthetic cathinone ("bath salt") intoxication")

•MDMA (ecstasy) (see "MDMA (ecstasy) intoxication")

•Salicylates (see "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation")

•Anticholinergic agents (see "Anticholinergic poisoning")

A history of drug exposure, an elevated salicylate level, or a positive toxicology screen for drugs of abuse may be present. (See "Cocaine: Acute intoxication" and "MDMA (ecstasy) intoxication" and "Methamphetamine: Acute intoxication" and "Anticholinergic poisoning" and "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation".)

Although less common in children opioid or benzodiazepine withdrawal are also considerations in patients with chronic exposure. (See "Opioid withdrawal in adolescents" and "Benzodiazepine withdrawal".)

●Kawasaki disease – Kawasaki disease is a clinical syndrome consisting of fever for ≥5 days and four of five physical findings (bilateral bulbar conjunctival injection, oral mucous membrane changes [eg, injected lips or strawberry tongue], peripheral extremity changes [eg, erythema of palms or soles, edema of hands or feet, and eventual periungual desquamation], rash, or cervical lymphadenopathy). Tachycardia is frequently present and poor peripheral perfusion may occur, especially in infants. However, shock is unusual in patients with Kawasaki disease. Shock may be present in up to 7 percent of children with Kawasaki disease [59]. (See "Kawasaki disease: Clinical features and diagnosis", section on 'Clinical manifestations'.)

●MIS-C – Multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 refers to Kawasaki disease-like or toxic shock syndrome-like features in children with evidence of COVID-19 infection or exposure (table 8 and table 6). Cardiovascular and gastrointestinal system involvement are very common, with many children showing myocardial dysfunction and requiring cardiovascular support. MIS-C emerged early in the COVID-19 pandemic but is now rarely diagnosed. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

●Baclofen withdrawal syndrome – Baclofen is chemically derived from the natural inhibitory neurotransmitter gamma aminobutyric acid (GABA) and binds to GABA_b receptors that inhibit neuronal excitation in the spinal cord. Intrathecal baclofen has become an established therapy for spasticity in children with cerebral palsy. The medication is delivered by a programmable pump that is implanted in the subcutaneous layer of the abdomen. Baclofen withdrawal may occur if the pump fails, the delivery catheter becomes occluded, the medication runs out, or the amount of baclofen in the pump reservoir falls below 2 mL. One to three days after abrupt withdrawal of baclofen, the patient can develop (see "GABA-B agonist (baclofen, phenibut) poisoning and withdrawal", section on 'Baclofen'):

•Marked spasticity

•Muscle rigidity

•Hyperthermia

•Seizures

•Hypertension

•Pruritus

In advanced cases, rhabdomyolysis with multiple system organ failure and disseminated intravascular coagulopathy may occur. These manifestations may be confused with other diseases including sepsis, serotonin syndrome, or neuroleptic malignant syndrome. Treatment of baclofen withdrawal is discussed separately. (See "GABA-B agonist (baclofen, phenibut) poisoning and withdrawal", section on 'Baclofen'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sepsis in children and adults" and "Society guideline links: Shock in children".)

SUMMARY AND RECOMMENDATIONS

●Definitions – We use the following definitions to identify children with sepsis:

•Infection – Infection is a pathologic process caused by a microorganism. It is suspected based on physical findings, including symptoms or signs of infection on examination (table 1) and the presence of pediatric systemic inflammatory response syndrome (pSIRS) (table 2). Confirmation of infection is not required to diagnose sepsis. (See 'Infection' above.)

•Evolving sepsis – Clinicians often evaluate children with suspected infection and clinical findings of altered perfusion that are not severe enough to meet the 2024 International Consensus Criteria for sepsis or septic shock. We define these children as having "evolving sepsis." (See 'Evolving sepsis' above.)

•Sepsis and septic shock – The 2024 International Consensus definitions for sepsis and septic shock rely on suspected infection and the presence and severity of organ dysfunction; thresholds for four organ systems are included in the Phoenix Sepsis Score (see 'Sepsis and septic shock (Phoenix Sepsis Score)' above):

The definition of sepsis consists of two components:

-Suspected infection and

-Phoenix Sepsis Score ≥2 (table 3)

Septic shock is defined as sepsis and ≥1 cardiovascular points on the Phoenix Sepsis Score (any one of the following):

-Severe hypotension for age

-Blood lactate >5 mmol/L

-Need for vasoactive medication

These definitions should not be used as screening criteria for trigger tools designed to identify children with evolving sepsis who require rapid clinical assessment and treatment. (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

●Pathogens – Bacterial, viral, fungal, parasitic, and rickettsial infections can all cause sepsis. Common bacteria that cause severe sepsis include Staphylococcus aureus, Streptococcus pneumoniae, and gram-negative organisms. Viral pathogens can mimic bacterial sepsis, especially herpes simplex virus infection and enterovirus in neonates (≤28 days of age). However, the presence of bacterial coinfections, particularly Staphylococcus aureus, should be suspected in patients with severe sepsis or septic shock. (See 'Pathogens' above.)

●Clinical manifestations – Children with evolving sepsis have significant alterations in vital signs and white blood cell count indicating a systemic inflammatory response (table 2). They also have clinical signs of shock with abnormal perfusion (one or more of the following) (see 'Abnormal vital signs and tissue perfusion' above and 'Shock' above):

•Altered mental status

•Warm or cold extremities

•Decreased urine output

•Bounding or thready/absent peripheral pulses

•Abnormal capillary refill (either "flash" or >2 seconds)

Manifestations of organ dysfunction, including hypoxia, cardiovascular dysfunction, metabolic acidosis with elevated blood lactate, and coagulopathy may be emerging in these patients but may not meet the Phoenix criteria for the diagnosis of sepsis (table 3). Such patients require emergency intervention (algorithm 3). (See "Children with sepsis in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

Additional clinical findings in infants and children with sepsis may indicate a primary site of infection (table 1) or arise from organ dysfunction caused by inadequate perfusion. (See 'Other physical findings' above.)

●Ancillary studies – Children with evolving or existing sepsis should undergo the following studies (see 'Laboratory studies' above and 'Imaging' above):

•Rapid blood glucose

•Arterial blood gas or venous blood gas and pulse oximetry

•Complete blood count with differential (including platelet count)

•Blood lactate

•Serum electrolytes

•Blood urea nitrogen and serum creatinine

•Serum calcium

•Serum total bilirubin and alanine aminotransferase

•Prothrombin time (PT), partial thromboplastin time (aPTT), international normalized ratio (INR)

•Fibrinogen and D-dimer

•Urinalysis

•Cultures of blood, urine, other potential infectious sources and, as indicated, specific diagnostic testing for potential pathogens

•Chest radiograph in patients with respiratory distress; other imaging may be appropriate depending upon clinical findings

●Diagnosis – The diagnosis of sepsis in children requires a suspicion for infection and a Phoenix Sepsis Score of ≥2 (table 3). Recognition of children with evolving sepsis is based on suspected infection, including those with physical findings of an infectious source (table 1), the presence of pSIRS (table 2), and evidence of tissue hypoperfusion. (See 'Diagnosis' above.)

●Differential diagnosis – All children with findings consistent with sepsis warrant timely antibiotic administration and prompt initiation of goal-directed therapy pending documentation of an infectious etiology. However, several conditions may have similar clinical manifestations and, once clinical stabilization has occurred, an alternative etiology to sepsis may become evident. (See 'Differential diagnosis' above.)