Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis

INTRODUCTION — Sepsis is a clinical syndrome that complicates severe infection and is characterized by the systemic inflammatory response syndrome (SIRS), immune dysregulation, microcirculatory derangements, and end-organ dysfunction. In this syndrome, tissues remote from the original insult display the cardinal signs of inflammation, including vasodilation, increased microvascular permeability, and leukocyte accumulation.

Although inflammation is an essential host response, the onset and progression of sepsis center upon a "dysregulation" of the normal response, usually with an increase in both proinflammatory and antiinflammatory 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".)

Early recognition of sepsis is crucial to ensuring the best outcomes in children and is aided by a working knowledge of the children at particular risk, the common pathogens, and the clinical manifestations. The definition, epidemiology, clinical manifestations, and diagnosis of the systematic inflammatory response syndrome and sepsis in children are discussed here.

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

●(See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

●(See "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".)

INTERNATIONAL CONSENSUS CRITERIA FOR PEDIATRIC SEPSIS AND SEPTIC SHOCK — New international criteria are published for pediatric sepsis and septic shock and are available using this reference [1]. This topic is undergoing revision to update definitions and terminology.

DEFINITIONS — Definitions for sepsis and organ dysfunction for children have been developed by the International Consensus Conference on Pediatric Sepsis [2]. These definitions are important for the standardization of observational studies and in the evaluation of therapeutic interventions in clinical trials. They may also be useful in helping clinicians determine the severity of a child's illness and in monitoring clinical progression and response to therapy. However, it should be noted that clinical concern for sepsis should not be limited to pre-defined cut-points for physiologic or laboratory abnormalities [3]. As an example, in an observational study of 1729 children younger than 18 years of age who were admitted to an intensive care unit (ICU), only two-thirds of children treated for severe sepsis or septic shock also met consensus criteria at the time of clinical diagnosis [4]. Thus, clinical suspicion for sepsis often occurs even though all components of the consensus criteria are not present.

Infection — Infection is defined as a suspected or proven infection caused by any pathogen. Infections can be proven by positive culture, tissue stain, polymerase chain reaction test, or other diagnostic test. 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.

Systemic inflammatory response syndrome — Per more recent international consensus criteria for pediatric sepsis and septic shock, the clinician should not use the systemic inflammatory response syndrome (SIRS) to diagnose sepsis in children [1]. This topic is undergoing revision to update the definitions and terminology.

The systemic inflammatory response syndrome (SIRS) is a widespread inflammatory response that may or may not be associated with infection. The presence of two or more of the following criteria (one of which must be abnormal temperature or leukocyte count) defines SIRS [2]:

●Core temperature (measured by rectal, bladder, oral, or central probe) of >38.5°C or <36°C

●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 (table 1)

●Mean respiratory rate more than two standard deviations above normal for age or mechanical ventilation for an acute pulmonary process (table 1)

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

These original cutpoints that define age-specific SIRS criteria were chosen to be sensitive to physiological parameters indicative of a systemic inflammatory state, allowing for the maximum number of potential patients with sepsis to be identified for observational and clinical trials.

While several studies have demonstrated value and reproducibility of these SIRS criteria in the clinical trial setting [4-6], other vital sign ranges (such as those used in the Pediatric Advanced Life Support [PALS] septic shock guidelines [7]) may be more informative to guide diagnostic and therapeutic decisions outside of the research setting and other cutoff values have been proposed for respiratory rates [8].

The consensus panel used age-related physiologic and laboratory values to modify definitions that had been developed for adult patients [9]. Six age groups for age-specific vital signs (heart rate, respiratory rate, and blood pressure) and laboratory variables (leukocyte count) are identified (table 1):

●Newborn: 0 days to 1 week

●Neonate: 1 week to 1 month

●Infant: 1 month to 1 year

●Toddler and preschool: >1 to 5 years

●School age child: >5 to 12 years

●Adolescent and young adult: >12 to <18 years

In children, SIRS-positivity has demonstrated low sensitivity for critical care interventions after presentation to the emergency department [10]. SIRS criteria also have exhibited lower discrimination between those who survived ICU admission due to infection than the presence of organ dysfunction quantified using other scoring systems [11]. Moreover, even among children with bacteremia, a population-based epidemiologic study in Switzerland found that the 61 percent of patients that were SIRS-positive but without organ failure had <1 percent mortality [12]. Thus, SIRS criteria, should not be used in isolation to make decisions about critical interventions.

Sepsis — The systemic inflammatory response syndrome in the presence of suspected or proven infection constitutes sepsis. Several definitions further describe sepsis in terms of severity and response to therapy:

●Severe sepsis – Sepsis is considered severe when it is associated with cardiovascular dysfunction, acute respiratory distress syndrome (ARDS), or dysfunction in two or more other organ systems as defined in the section on multiple organ failure below. The diagnostic criteria for ARDS are discussed elsewhere. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults", section on 'Diagnosis'.)

●Septic shock – Septic shock refers to sepsis with cardiovascular dysfunction (as described in the section on multiple organ failure below) that persists despite the administration of ≥40 mL/kg of isotonic fluid in one hour [2].

●Refractory septic shock – There are two types of refractory septic shock: fluid-refractory septic shock exists when cardiovascular dysfunction persists despite at least 40 to 60 mL/kg of fluid resuscitation, and catecholamine-resistant septic shock exists when shock persists despite therapy with dopamine ≥10 mcg/kg per minute and/or direct-acting catecholamines (epinephrine, norepinephrine) [2].

●Multiple organ failure – Reliably identifying and quantifying organ dysfunction is useful for tracking clinical changes and the response to therapy in children with septic shock. The International Consensus on Pediatric Sepsis [2] developed criteria for organ dysfunction based upon several scoring systems [13-15], taking into account a balance of specificity, sensitivity, and widespread availability of laboratory tests.

•Cardiovascular – Hypotension, or reliance on a vasoactive drug to maintain blood pressure, or two of the following: metabolic acidosis, elevated arterial lactate, oliguria, or prolonged capillary refill.

•Respiratory – Arterial oxygen tension/fraction of inspired oxygen (PaO₂/FiO₂) <300, arterial carbon dioxide tension (PaCO₂) >65 torr or 20 mmHg over baseline PaCO₂, need for >50 percent FiO₂ to maintain oxygen saturation ≥92 percent, or need for nonelective mechanical ventilation.

•Neurologic – Glasgow coma score ≤11 (table 2), or acute change in mental status.

•Hematologic – Platelet count <80,000/microL or a decline of 50 percent from highest value recorded over the past three days or disseminated intravascular coagulation (DIC), a consumptive coagulopathy diagnosed by clinical findings of hemorrhage and microthrombi and laboratory abnormalities including thrombocytopenia, prolongation of clotting times (PT and aPTT), and evidence of fibrinolysis (low fibrinogen with elevated fibrin degradation products), which is a common hematologic manifestation in sepsis. (See "Disseminated intravascular coagulation in infants and children", section on 'Diagnosis'.)

•Renal – Serum creatinine ≥2 times upper limit of normal for age or twofold increase in baseline creatinine.

•Hepatic – Total bilirubin ≥4 mg/dL (not applicable to newborn) or alanine aminotransferase (ALT) >2 times upper limit of normal for age.

Pediatric versus adult definitions — The pediatric sepsis definitions differ from the 2016 adult definitions in several important ways (see "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis", section on 'Definitions'):

●Adult sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, which corresponds to the pediatric definition of severe sepsis.

●Organ dysfunction in adults is based upon an increase of 2 or more points on the Sequential (Sepsis-related) Organ Failure Assessment (SOFA) score, which uses a graded scale of increasing severity of dysfunction within six organ systems. SIRS criteria are no longer included in the definition of adult sepsis because it is not always caused by infection and is less sensitive than the SOFA score for predicting sepsis in adults.

●The adult definition for septic shock includes lactate >2 mmol/L (>18 mg/dL) and is defined as sepsis that has circulatory, cellular, and metabolic abnormalities that are associated with a greater risk of mortality than sepsis alone.

The concept of sepsis as life-threatening organ dysfunction caused by a dysregulated response to infection has face validity for children, but the most appropriate criteria for operationalizing organ dysfunction and the utility of lactate in pediatric sepsis have not yet been established. Nevertheless, studies support using a stratified scoring system for organ dysfunction over SIRS criteria in children [11], and efforts to update the definition and clinical criteria for pediatric sepsis are currently underway. Until revised data-driven clinical criteria are determined to better describe pediatric sepsis and septic shock, existing consensus criteria should continue to be used to define pediatric sepsis [2].

EPIDEMIOLOGY — The overall burden of illness from pediatric sepsis is high globally with important regional differences. As an example, in a prospective cross-sectional study at 128 sites in 26 countries, the prevalence of severe sepsis in children admitted to pediatric intensive care units was as follows [16]:

●Approximately 6 to 8 percent of patients were treated in pediatric intensive care units (PICUs) in North America, Europe, Australia, and New Zealand with PICU mortality ranging from 21 to 32 percent

●An estimated 15 to 16 percent of patients were treated in 10 PICUs across Asia and 10 PICUs across South America with mortalities of 40 and 11 percent, respectively

●Almost 25 percent of patients were treated in the three South African PICUs with a mortality rate of 40 percent mortality

The incidence of sepsis also varies by region. For example, in the United States approximately 75,000 children are hospitalized for severe sepsis each year with an annual incidence of about 1 case per 1000 population [17]. The occurrence of pediatric severe sepsis has been steadily rising since the mid-1990s and now accounts for 4.4 percent of admissions to children's hospitals and 7 percent of patients treated in PICUs in the United States [17-20], and up to 25 percent of patients treated in PICUs in South America. In China, the incidence of sepsis is estimated at 1.8 cases per 1000 population or more than 360,000 cases annually [21].

Respiratory infection and bloodstream infections are found in almost two-thirds of cases of severe sepsis worldwide [16-18]. Many of these illnesses are caused by vaccine-preventable pathogens [22]. Since 1960, mortality from pediatric severe sepsis among patients managed in resource-rich regions has decreased from 97 percent to approximately 4 to 10 percent in patients treated with severe sepsis [17-19,23,24] and 13 to 34 percent in patients with septic shock [4,17-19,21-29]. (See "Pneumonia in children: Epidemiology, pathogenesis, and etiology", section on 'Epidemiology' and "Septic shock in children in resource-abundant settings: Ongoing management after resuscitation", section on 'Ongoing management'.)

Risk factors — Among infected children, septic shock, including refractory septic shock or multiple system organ failure, is the most severe form. (See 'Sepsis' above.)

The following factors have been associated with an increased risk for septic shock [30,31]:

●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 gut syndrome)

●Host immunosuppression (malignancy, human immunodeficiency virus infection, severe malnutrition, congenital immunodeficiency, sickle cell disease and other disease with splenic dysfunction, or immunomodulating medications [eg, chemotherapy]) (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

In contrast, routine immunization of infants and children against Haemophilus influenzae type b, Neisseria meningitidis, and Streptococcus pneumoniae has resulted in a dramatic decrease in the incidence of invasive disease in young children due to 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 [23,32-37]:

●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

●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

Although less common, meningococcal infections, especially in unimmunized populations, and 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, Streptococcus viridans) 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 ESB-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 respiratory viruses (eg, influenza, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], parainfluenza, adenovirus, respiratory syncytial virus [RSV], and human metapneumovirus) and Dengue virus, a mosquito-borne pathogen that can cause Dengue shock syndrome. While these viruses, especially pandemic H1N1 influenza strain and SARS-CoV-2, may cause the sepsis syndrome in isolation, the presence of bacterial co-infections, particularly methicillin-resistant Staphylococcus aureus, should be suspected in patients with severe 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'.)

Herpes simplex virus (HSV), enterovirus and adenovirus infection in neonates and young infants 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 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

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

Multisystem inflammatory syndrome in children (MIS-C), which can meet SIRS criteria and mimic sepsis, is a post-COVID-19 infectious syndrome. It refers to Kawasaki disease-like or toxic shock syndrome-like features in children with evidence of past COVID-19 infection or exposure (table 3 and table 4). Although the clinical features of acute severe COVID-19 and MIS-C overlap, acute severe COVID-19 and MIS-C have differing patterns of clinical presentation and organ involvement. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

Fungi — Fungal infections, especially candida species, have been reported in 10 percent of pediatric patients with severe sepsis and septic shock [17,18,23]. Fungal sepsis is more common in children 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 "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 — Between approximately 30 and 75 percent of children with sepsis have no infectious etiology identified [4,31,32]. 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].

CLINICAL MANIFESTATIONS — Children with sepsis have significant alterations in vital signs and white blood cell count indicating a systemic inflammatory response syndrome (SIRS) in the presence of clinical or laboratory findings of infection. Clinical signs of abnormal perfusion indicate septic shock and include one or more of the following:

●Altered mental status

●Warm or cold extremities

●Decreased urine output

●Bounding or thready/absent peripheral pulses

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

Other manifestations of organ dysfunction, including hypoxia and laboratory abnormalities, also often accompany clinical signs of sepsis.

Physical findings

Infection — Infection is typically suggested by physical findings such as petechiae and purpura in a child with shock, or fever, cough, and hypoxemia in a patient with leukocytosis and pulmonary infiltrates on chest radiograph (table 5). Infections can also be proven by positive culture, tissue stain, or polymerase chain reaction test. However, these results are frequently not available during the initial phase of treatment. Furthermore, in up to 60 percent of patients with sepsis, no pathogen is identified. (See 'Pathogens' above and 'Laboratory studies' below.)

Systemic inflammatory response syndrome — As defined above, the systemic inflammatory response syndrome (SIRS) is present when a child has an abnormality of temperature (fever or hypothermia) or age-specific abnormality of the white blood cell count and one of the following: tachycardia, bradycardia, respiratory distress, or pulmonary condition requiring mechanical ventilation (table 1). (See 'Systemic inflammatory response syndrome' above.)

Among these criteria for SIRS, the presence of fever and tachypnea or fever and abnormal white blood cell count are most common. In an observational study of 92 hospitalized children with SIRS, these two presentations were found in approximately 75 and 50 percent of patients, respectively [5]. However, the sensitivity and specificity of SIRS to identify sepsis in children has been increasingly called into question, as most children with SIRS will not have other features of sepsis (eg, organ failure) and respond well to treatment of the primary infection, while approximately 10 to 20 percent of children with infection, organ failure, and critical illness may not manifest SIRS criteria. (See 'Systemic inflammatory response syndrome' above.)

Shock — Evidence of inadequate tissue perfusion and oxygen delivery with or without hypotension often accompanies sepsis in children. In infants and children, tachycardia is a sensitive, though non-specific, indicator often seen in 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 include 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. (See "Septic shock in children in resource-abundant settings: Ongoing management after resuscitation", section on 'Vasoactive drug therapy'.)

Other physical findings — Additional clinical findings in infants and children with sepsis may indicate a primary site of infection or arise from organ dysfunction caused by inadequate perfusion and include [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 6)

●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)

Laboratory studies — Children with suspected 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 a criteria for pediatric SIRS (table 1). 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 hypoperfusion. Initial blood lactate>3.5 mmol/L (31.5 mg/dL) in pediatric patients with septic shock is associated with an increased risk of mortality, especially if persistent [42]. Preliminary results in an observational study of blood lactate levels in 239 children with SIRS also suggest that venous blood lactate >4 mmol/L (36 mg/dL) at initial presentation is associated with progression to organ dysfunction at 24 hours [43]. In children with suspected infection, elevated lactate >4 mmol/L is also associated with a more than threefold higher odds of mortality at 30 days for children presenting to an emergency department or requiring ICU admission [44]. 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 sepsis and septic shock, such as syndrome of inappropriate anti-diuretic 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 ≥2 times upper limit of normal for age or twofold increase in baseline creatinine defines renal dysfunction in the setting of sepsis. (See 'Sepsis' 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 – Total bilirubin ≥4 mg/dL (not applicable to newborn) or alanine aminotransferase (ALT) >2 times upper limit of normal for age indicates liver dysfunction in the setting of sepsis. (See 'Sepsis' above.)

●Prothrombin time (PT), partial thromboplastin time (aPTT), international normalized ratio (INR) – Elevation in PT and aPTT or INR suggests disseminated intravascular coagulopathy (DIC).

●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 to establish 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 4) 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, both procalcitonin and C-reactive protein may be elevated in the absence of serious bacterial infection or sepsis [51]; thus, we recommend that such biomarkers should be interpreted along with other clinical features rather than in isolation. 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 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 with sepsis with high accuracy [53-57]. Although these results are promising, further investigation using larger sample sizes and more diverse clinical settings is needed to determine the clinical utility of these tests in routine practice.

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 computed tomography of the abdomen may be indicated to evaluate for intra-abdominal abscess.

DIAGNOSIS — The diagnosis of sepsis is made in children with suspected or proven infection who meet two or more criteria for SIRS (table 1) and/or have associated organ dysfunction. Pneumonia, bloodstream, skin, or urinary tract infections, and, less commonly, meningitis comprise the most common infections. (See 'Systemic inflammatory response syndrome' above and 'Clinical manifestations' above.)

Sepsis is primarily a clinical diagnosis. Clinical manifestations typically progress along a continuum of severity from sepsis to severe sepsis (sepsis plus cardiac, respiratory, or dysfunction in two or more other organ systems), septic shock (persistent hemodynamic instability despite initial fluid therapy), and multiple organ failure. (See 'Sepsis' above.)

When suspected, the clinician must rapidly respond to signs of hemodynamic instability, organ dysfunction, and administer antibiotics to ensure optimal outcomes. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Resuscitation'.)

DIFFERENTIAL DIAGNOSIS — All children with findings consistent with sepsis warrant goal-directed 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 upon careful review of clinical findings.

In neonates and young infants, alternative diagnoses include:

●Child abuse (eg, abusive head trauma)

●Hypoglycemia

●Environmental hyperthermia

●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

●Posterior urethral valves

●Necrotizing enterocolitis

●Gastroenteritis with dehydration

●Water intoxication

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

●Acute bilirubin encephalopathy

●Viral hemorrhagic fever (eg, Hantavirus)

Detailed history, physical examination, and selected diagnostic studies frequently can differentiate these conditions from sepsis. The approach to the septic-appearing infant is discussed separately. (See "Approach to the ill-appearing infant (younger than 90 days of age)".)

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. 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", section on 'Clinical features' and "Heat stroke in children", section on 'Differential diagnosis'.)

●Serotonin syndrome – Hyperthermia commonly occurs in patients with serotonin syndrome, a potentially life-threatening condition associated with increased serotonergic activity in the central nervous system (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. (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 a key 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. Clinical manifestations include hypercapnia, hyperthermia, tachycardia, masseter muscle rigidity, and rhabdomyolysis. (See "Malignant hyperthermia: Diagnosis and management of acute crisis".)

●Toxic overdose – Drug-related causes of hyperthermia, tachycardia, shock, and multiple organ dysfunctions include overdose of cocaine, methamphetamine or related compounds (eg, bath salts), amphetamine, MDMA [ecstasy], salicylates, anticholinergic agents and withdrawal from opioid or benzodiazepine medications. 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".)

●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 [58]. (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 3 and table 4). Cardiovascular and gastrointestinal system involvement are very common with many children showing myocardial dysfunction and requiring cardiovascular support. (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 [59]. 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 [59,60].

One to three days after abrupt withdrawal of baclofen, the patient can develop marked spasticity, muscle rigidity, seizures, hyperthermia, hypertension, pruritus, and, in advanced cases, rhabdomyolysis with multiple system organ failure and disseminated intravascular coagulopathy [59,61,62]. These manifestations may be confused with other diseases including sepsis, serotonin syndrome, or neuroleptic malignant syndrome [59,62,63].

The diagnosis of baclofen withdrawal is made when evaluation of the pump identifies an empty or low drug reservoir or an unexpectedly full reservoir indicating tubing failure [59,62]. Resumption of intrathecal baclofen delivery is the definitive treatment. Benzodiazepine administration (eg, lorazepam) may temporarily control spasticity and seizures until intrathecal baclofen can be reestablished. High-dose oral baclofen may also be attempted but is frequently not effective.

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 – New international criteria are published for pediatric sepsis and septic shock This topic is undergoing revision to update definitions and terminology. (See 'International consensus criteria for pediatric sepsis and septic shock' above.)

The International Consensus Conference on Pediatric Sepsis has developed the following definitions for children with sepsis and organ dysfunction:

•Systemic inflammatory response syndrome – The systemic inflammatory response syndrome (SIRS) is present when a child has an abnormality of temperature (fever or hypothermia) or age-specific abnormality of the white blood cell count and one of the following: tachycardia, bradycardia, respiratory distress, or pulmonary condition requiring mechanical ventilation (table 1). (See 'Systemic inflammatory response syndrome' above.)

•Sepsis – SIRS in the presence of suspected or proven infection constitutes sepsis. Clinical manifestations typically progress along a continuum of severity from sepsis to severe sepsis, septic shock, and multiple organ failure. Definitions for sepsis and septic shock and clinical criteria to guide interventions differ between pediatric and adults. (See 'Sepsis' above and 'Pediatric versus adult definitions' above.)

Infection is typically suggested by physical findings, such as petechiae and purpura in a child with shock, or fever, cough, and hypoxemia in a patient with leukocytosis and pulmonary infiltrates on chest radiograph (table 5). Infections can also be proven by positive culture, tissue stain, polymerase chain reaction test, or other diagnostic test. However, these results are frequently not available during the initial phase of treatment. Furthermore, in up to 60 percent of patients with sepsis, no pathogen is identified. (See 'Pathogens' above and 'Laboratory studies' above.)

●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 co-infections, particularly Staphylococcus aureus, should be suspected in patients with severe sepsis or septic shock. (See 'Pathogens' above.)

●Clinical manifestations – Clinical findings of septic shock may include fever, a toxic or ill appearance, edema (as the result of capillary leak), respiratory distress, altered mental status, and inadequate tissue perfusion. Patients may have high (or preserved) cardiac output with decreased systemic vascular resistance (SVR) or poor peripheral perfusion due to myocardial dysfunction with increased SVR. Although often categorized as "warm" or "cold" shock, respectively, clinicians should be aware that clinical findings may not accurately reflect the patient’s underlying pathophysiology such that more advanced monitoring (arterial catheter, echocardiography) may be necessary for children who do not immediately respond to initial therapy. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of sepsis is made in children with suspected or proven infection who meet two or more criteria for SIRS (table 1) and/or have evidence of organ dysfunction. Pneumonia, bloodstream, skin, or urinary tract infections, and, less commonly, meningitis comprise the most common infections. Sepsis is primarily a clinical diagnosis. Clinical manifestations typically progress along a continuum of severity from sepsis to severe sepsis (sepsis plus cardiac, respiratory, or dysfunction in two or more other organ systems), septic shock (persistent hemodynamic instability despite initial fluid therapy), and multiple organ failure. (See 'Diagnosis' above.)

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 be evident based upon careful review of clinical findings. (See 'Differential diagnosis' above.)

●Management – The management of septic shock is provided in the algorithm (algorithm 2) and discussed in detail separately. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)" and "Septic shock in children in resource-abundant settings: Ongoing management after resuscitation".)