Pediatrics

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Epidemiology in ChildrenCopy Link!

Literature Review (Pediatrics): Gallery View, Grid View
Updated Date: February 1, 2021

There are many challenges associated with quantifying the true number of children infected with SARS-CoV-2 and other relevant epidemiologic factors:

1. The lack of population-level testing, low levels of access to testing for children in particular, and the focus on testing only patients presenting with symptoms.
2. The heterogeneity across data sources with regard to the chronological definition of a “child” and surveillance methods used (PCR vs. rapid antigen tests vs. clinical suspicion).
3. The lack of disaggregation by age in pediatric data sources. This makes it challenging to tease out epidemiologically significant differences that may exist between neonates, infants, young school-aged children, and adolescents (Cruz et al).

Susceptibility: Data from a systematic review of contact tracing and population-based studies suggests that children are less susceptible to infection than adults.

• One analysis of 32 studies comprising 41,640 children and adolescents and 268,945 adults showed that the pooled odds ratio of being an infected contact (PCR or serology confirmed) in children (relative to adults) was 0.56 (Viner et al).

• However, there is a significant amount of variability between studies. One seroprevalence study of household secondary infections reported that children and adults appear equally likely to become infected while quarantined in a household with another infected individual (Brotons et al).

• Lower susceptibility may be less true for adolescents: The above analysis found lower seroprevalence in children compared with adults, although seroprevalence in adolescents appeared similar to adults (Viner et al).

Viral variants change susceptibility. Delta variant appears to affect children more than prior variants have, with fully 18% of new cases reported in children in the USA (AAP, a higher fraction than before), which could represent increased susceptibility or social factors (e.g. fewer precautions). The delta variant also could increase severity, with 1.9% of pediatric patients ending in hospitalization as of August, 2021 (CDC Data Tracker).

Prevalence: The prevalence of SARS-CoV-2 is lower in children compared to adults (MMWR, 2021). In addition, children account for a smaller percent of total cases than their population prevalence would suggest, which appears to be due to lower susceptibility rather than asymptomatic carriage. A large cohort study from Italy reported that children accounted for 1.8% of total SARS-CoV-2 infections (Bellino et al). As mentioned above, this may change with new variants.

Clinical CourseCopy Link!

SymptomsCopy Link!

Updated Date: February 5, 2021

Common SymptomsCopy Link!

Many children present with minimal or no symptoms (see asymptomatic). Children who are infected tend to exhibit milder symptoms compared to adults (Wald et al).

Those who do exhibit symptoms tend to report:

• Fever, dry cough, fatigue and mild respiratory symptoms (Castagnoli et al).Other studies conducted in Morocco and Turkey report similar findings (Fakiri et al; Korkmaz et al).
• Gastrointestinal symptoms, such as vomiting and diarrhea (more common in children) (Gonzalez-Dambrauskas et al; Fernandes et al).

In infants <3 months old a wide range of fever, respiratory, gastrointestinal, cardiac and neurologic findings have been reported. A high index of suspicion for SARS-CoV-2 is needed in young infants presenting with generalized symptoms such as fever, decreased feeding or lethargy even in the absence of respiratory symptoms (Mithal et al).

Uncommon ManifestationsCopy Link!

Since SARS-CoV-2 symptoms vary widely in children, when community infection rates are high, it is important to maintain a high level of suspicion for children with unusual presentations. Case reports have described previously healthy children presenting with:

• Cholestasis and hepatitis (Perez et al)
• Generalized Seizures and Ischemic Stroke due to focal cerebral arteriopathy (Mirzaee et al)
• Rhabdomyolysis (Gilpin et al)
• Intussusception (Athamnah et al)
• Guillain-Barre Syndrome (Curtis et al)
• New onset Diabetes Mellitus with Diabetic Ketoacidosis
• Atypical Hemolytic Uremic Syndrome (Alizadeh et al)
• Croup (Pitstick et al)
• Immune Thrombocytopenia (Tsao et al)
• Giant Desquamating Urticaria (Rotulo et al)
• Thrombotic complications including venous gangrene, massive PE, extensive lower extremity VTE and cardiac arrest (Visveswaran et al)
• Fulminant myocarditis with complete heart block and depressed systolic function (Lara et al)

Asymptomatic InfectionCopy Link!

Many children infected with SARS-CoV-2 are asymptomatic. While a study from Milan concluded that the asymptomatic carrier rate is not higher in children compared to adults (Milani et al), studies differ widely on estimated asymptomatic carrier rates in children. For example:

• Studies from China and Korea reported that approximately one in four PCR+ children were asymptomatic (Qiu et al, Han et al).
• A small study from France found that 45% of PCR+ children were asymptomatic (Poline et al).
• A study from India reported that 73% of PCR+ children were asymptomatic (Fakiri et al).
• A study from Barcelona found that almost all (99.9%) PCR+ children living in a household with an infected adult were asymptomatic or very mildly symptomatic (Brotons et al).

Another large study from 28 children’s hospitals in the US that conducted PCR testing on asymptomatic children presenting for medical or surgical care found that positivity rates among asymptomatic children across 25 regions varied from 0% to 2.2% with a pooled prevalence of 0.65%; positive rates among asymptomatic children were significantly associated with the incidence in the general population during the period when testing occurred (Sola et al).

Asymptomatic children can still transmit to others, including to vulnerable older adults:

• Viral loads and duration of viral shedding may be similar in asymptomatic and symptomatic children. In a study from France, asymptomatic, PCR+ children exhibited similar viral loads to those with symptoms suggesting a comparable potential to spread infection (Poline et al).
• The duration of viral RNA detection is only slightly shorter in asymptomatic children (mean of 14.1 days after initial positive test result) compared to symptomatic children, though the importance of duration of PCR positivity in infectiousness remains unknown (see infectiousness timeline), (Han et al).

SeverityCopy Link!

Severe manifestations: For those with a more severe course, manifestations may include (Derespina et al, Nepal et al):

• Acute Respiratory Distress Syndrome (ARDS)
• Sepsis
• Acute Kidney Injury (AKI)
• Myocarditis and Cardiac Arrest (Derespina et al)
• Neurologic Manifestations
• Multisystem Inflammatory Syndrome in Children (MIS-C) (Nepal et al)

Lab indicators of severity: Similar to adults, children with severe disease had significantly higher levels of CRP and procalcitonin at admission and significantly higher peak IL-6, ferritin and D-dimer levels during hospitalization (Zachariah et al). Other variables associated with increased disease severity include: lymphopenia, elevated WBC count, elevated platelet count, elevated creatine kinase MB, and elevated proBNP (Qiu et al; Kainth et al; Chao et al).

Age:

• Adolescents: Adolescents and those with comorbidities are at higher risk for developing severe disease (Derespina et al; Shekerdemian et al). A study comparing characteristics of infected children requiring hospitalization and intensive care found that adolescents >15 years old were overrepresented in the hospitalized cohort. Adolescents >15 years old were also overrepresented in the critically ill cohort (DeBiasi et al).
• Infants and Neonates: Some studies show that neonates are also more likely to be hospitalized (DeBiasi et al) and have severe infection (Bellino et al). In a systematic review of 52 studies on outcomes of pregnant women with SARS-CoV-2 infection and their newborns showed only one study was deemed to be “at low risk of bias.” Results were also highly variable across studies, with neonatal death rates ranging from 0-11.7%, suggesting that the evidence base on infant and neonatal severity remains poor (Vergara-Merino et al). However, most cases are still mild to moderate and improve with supportive care (Mark et al; Leibowitz et al; Nathan et al; Paret et al; McLaren et al; Zhang et al). Rarely, neonatal infection can be associated with life-threatening pulmonary disease (Coronado et al). Cases of silent hypoxemia requiring respiratory support have also been reported, highlighting the importance of training parents to recognize signs of possible hypoxemia, such as poor breastfeeding or changes in skin color (Sinelli et al).

Literature Review (Neonatal Care): Gallery View, Grid View

Hospitalization, ICU rates, and death: Rates of hospitalization, ICU level-of-care, and mortality tend to be lower in children than adults, but are highly variable depending on testing patterns, case definitions and resources.

• According to data from the US Department of Health, as of September 2020, children represented 1.7% of total SARS-CoV-2 hospitalizations and 0.07% of total deaths (Sisk et al).
• These rates may vary by age and geographic location:

• One large retrospective cohort study that included people <25 years of age in the US found that 7% of SARS-CoV-2-infected children required hospitalization, and of those hospitalized, 28% required ICU-level care and 9% required mechanical ventilation. Case fatality rate was 0.2% (Bailey et al).
• Another that included 51 children <13 years of age who were hospitalized with SARS-CoV-2 symptoms in South Africa reported that 21.6% required ICU-level care and 2% died (Van der Zalm et al).

TimecourseCopy Link!

Updated Date: February 1, 2021

Incubation and window period: (see Adult Incubation and Window Period)

• In one study, children were found to be pre-symptomatic for a median of 2.5 days (i.e. symptoms developed approximately 2.5 days after viral levels were detected) (Han et al). This pre-symptomatic period is slightly shorter than is estimated for adults (5 days, see Incubation).
• Testing during this phase may be unreliable (see Window Period).

Duration of symptoms

• In one large cohort study, symptoms lasted for a median of 11 days (Han et al). This period also appears to be slightly shorter than is estimated for adults (see Timecourse)

PCR positivity timeline: As with adults, testing positive via PCR does not necessarily correlate with infectivity, as the test may detect non-infectious viral particles (see Infectiousness Timeline).

• A large cohort study of children who underwent PCR and antibody testing for SARS-CoV-2 between March and June 2020 found that the median duration of PCR positivity was 19.5 days (Bahar et al). A study from Korea reported a mean duration of 17.6 days(Han et al).
• This period of positivity may be slightly shorter in infants: In one cohort of infants <1 year of age, time between symptom onset to negative detection of SARS-CoV-2 RNA was 13 days (Liu et al).

ComorbiditiesCopy Link!

Updated Date: February 1, 2021

AsthmaCopy Link!

While asthma is the most frequent underlying diagnosis in SARS-CoV-2 infected children, patients with asthma do not seem to be overrepresented among those requiring hospitalization (DeBiasi et al). It is unclear whether there is an increased risk of SARS-CoV-2 susceptibility among children with asthma or whether infection increases risk of asthma exacerbation, but (similar to adults) mild asthma does not appear to be linked with higher morbidity (see Asthma). Treatment of concurrent asthma and SARS-CoV-2 is the same as treatment of each individually, including oral corticosteroids if required. Meter-dosed inhalers are preferred to nebulizers in health facilities where possible due to increased risk of viral transmission (Abrams et al). See Nebulizers, Bronchodilators, Inhaled Corticosteroids.

Congenital Heart DiseaseCopy Link!

Congenital heart disease may be a risk factor for severe disease, though data remains limited. A case series of 7 children with congenital heart disease who contracted SARS-CoV-2 reported that all 7 developed acute decompensation (Simpson et al).

DiabetesCopy Link!

As with adults, children with diabetes are at risk for severe complications of SARS-CoV-2 infection. The main strategy for decreasing risk is to optimize glycemic control. Patients with T1D and SARS-CoV-2 should adhere to standard sick-day guidelines with increased frequency of monitoring of blood glucose and ketones. Frequent changes in dosage and correction in insulin boluses may be required to maintain normoglycemia. In patients with T2D and SARS-CoV-2, dosage of drugs such as Metformin should be adjusted or held to decrease the risk of lactic acidosis (Ho et al).

Sickle Cell Disease or ThalassemiaCopy Link!

Differentiating between standard SARS-CoV-2 infection and Acute Chest Syndrome (ACS) is important for patients with Sickle Cell Disease (SCD). Testing and radiographic appearance (diffuse vs. subpleural changes) may help with differentiation. A close watch for pulmonary hypertension is necessary. Aggressive blood transfusion or exchange transfusion is recommended in those who develop or are at high risk for developing ACS. This commentary describes topics specific to patients with SCD and Thalassemia including hydroxyurea, medication concerns, thrombosis prophylaxis, and recommended blood tests (Taher et al).

Trisomy 21Copy Link!

Children with Trisomy 21 and associated comorbidities such as congenital heart disease, pulmonary hypertension, or obstructive sleep apnea who become infected with SARS-CoV-2 should be considered high risk and monitored closely (Newman et al; Krishnan et al).

Immune DeficienciesCopy Link!

The clinical course of immunocompromised children (including HIV, malnutrition and cancer) is generally not more severe than other children (Kainth et al; Marais; Wald et al). In a cohort of 50 children and adolescents hospitalized with SARS-CoV-2 infection, infants and immunocompromised patients were not at increased risk for severe disease requiring mechanical ventilation. However, obesity and hypoxia on admission were associated with severe disease (Zachariah et al; Fernandes et al).

Vertical TransmissionCopy Link!

Updated Date: February 1, 2021
Literature Review (Vertical Transmission): Gallery View, Grid View

This section addresses transmission to neonates and breastfeeding infants. While studies differ on how transmission rates compare between children, between children and adults, and between adults (Zhu et al; Brotons et al, Viner et al; Szablewski et al; D’Agostino et al) the mode of transmission in these scenarios is likely the same. Please also see Transmission Prevention.

Placental TransmissionCopy Link!

Definitive evidence that SARS-CoV-2 crosses the placenta and infects the fetus is lacking, though the possibility is not ruled out (Lamouroux et al). Expression of the main receptor (ACE2) used for entry of SARS-CoV-2 is rare on the surface of the placenta and could explain the low rates of placental infection.

A few cases where placental tissues have been positive for SARS-CoV-2 have been described, as have a few cases of possible in utero transmission during the third trimester, some in premature infants (Gupta et al). Many neonatal transmissions are likely due to respiratory transmission from mother to neonate after birth. While it can be hard to definitively prove that transmission occurred intrauterine or intrapartum, testing the umbilical cord, blood and amniotic fluid in the first hour after birth may provide more definitive answers to the source of infection (Lo Vecchio).

• In a systematic review of studies including 936 pregnant women with SARS-CoV-2 infection, viral RNA was found in 3.2% of neonatal nasopharyngeal swabs, 2.9% of cord blood samples, 7.7% of placenta samples, and 0% of amniotic fluid and infant urine samples (Kotlyar et al). Another review of approximately 800 patients reported similar findings (Kyle et al).
• Other cohort studies of neonates born to mothers infected with SARS-CoV-2 reported no evidence of vertical transmission (Dumitriu et al; Verma et al).

However, neonates of infected mothers may have an inflammatory response without direct infection. Another case report described a systemic inflammatory response in an infant born to a mother with SARS-CoV-2; though the infant tested negative for SARS-CoV-2, the systemic inflammation likely occurred in response to the virus in the absence of vertical transmission (McCarty et al).

BreastfeedingCopy Link!

Updated Date: February 1, 2021
Literature Review: Gallery View, Grid View

Virus in BreastmilkCopy Link!

Breast milk isolated from SARS-CoV-2 positive mothers has only rarely been found to contain SARS-CoV-2 viral RNA, and it is unclear if the viral RNA detected is capable of infecting an infant (Groß R et al). If there is any transmission through breast milk, it is likely very uncommon (Centeno-Tablante et al). In situations where there is concern, pasteurization can eliminate the infectivity (Conzelmann). Many preliminary laboratory and clinical reports support the safety of breastfeeding regardless of mother’s infection status as breast milk is unlikely to be a source of infection for infants (Furman et al; Chan et al; Lugli et al). However, transmission by respiratory droplets from mother to infant during the process of breastfeeding is possible due to the necessary proximity.

Breastfeeding RecommendationsCopy Link!

While breast milk itself is unlikely to transmit the virus, there is still uncertainty around neonatal risk from breastfeeding that has led to wide variations in care practices for newborns. Breast milk helps protect newborns against many illnesses and has been shown to contain neutralizing antibodies to SARS CoV-2 in mothers who are immune (Demers-Matheiu et al; Fox et al; Pace et al); it is also known to be the best source of nutrition for most infants. Despite the inherent proximity in direct breastfeeding, healthy neonates do not often become infected: In a study of 62 neonates (95% breastfed) who roomed in with mothers with SARS-CoV-2 infection, only one infant was diagnosed with the virus, and that infant developed only transient mild dyspnea (Ronchi et al). In a cohort of 188 infants delivered at a large county medical center, neonatal infection occurred in 3% of infants, predominantly among infants born to asymptomatic or mildly symptomatic women (Adhikari et al).

For healthy neonates, recommendations on breastfeeding differ:

• The American Academy of Pediatrics prefers separation of healthy newborns from infected mothers and feeding initially with expressed breast milk (AAP).
• The World Health Organization prefers rooming together and breastfeeding (WHO).
• The Center for Disease Control and Prevention (CDC) recommends shared decision-making (Gupta et al).

For neonates requiring intensive care, isolation from SARS-CoV-2 positive individuals is recommended. However, feeding with expressed breast milk may still be permitted.

Instructions for mothers with SARS-CoV-2 infection who wish to breastfeed or express breast milk include:

1. Wash hands (and, if possible, breasts) with soap and water before and after touching the infant or any pumps or bottle parts
2. Avoid using a pump shared by others
3. Wear a mask or cloth face covering during breastfeeding or pumping
4. Follow manufacturer instructions for proper pump cleaning after each use, cleaning all parts that come into contact with skin or breast milk
5. If the child is not being breastfed directly, pumped breast milk should be fed to the infant by a healthy caregiver to minimize exposure (Sullivan et al)

Distancing for Infected CaregiversCopy Link!

The decision about whether an infected caretaker should be physically distanced from an infant to minimize respiratory transmission is personal and recommendations vary widely. Providers and families should engage in shared decision-making, balancing the risks to the neonate, the availability of non-infected caretakers, the desire to breastfeed, Higher rates of breastfeeding are noted in unseparated dyads both in the hospital and at home (Popofsky et al) and the psychological harms to parents and neonate that can result from early separation. Provided that mothers adhere to proper respiratory and skin hygiene measures including hand washing and masking, many studies suggest that the benefits of rooming together after birth may outweigh the risks if mothers are able to care for their newborns (Ronchi et al; Kaufman et al; Williams et al; Boscia). However, given the lack of definitive answers surrounding neonatal risk, some studies and institutions still recommend that infants be separated from infected mothers (use barriers, distance 1-2 meters) and fed initially with either formula or expressed breast milk if there is a well caregiver who can attend to the infant until the mother meets criteria to discontinue isolation (Zeng et al; ACOG).

Clinical AssessmentCopy Link!

Initial EvaluationCopy Link!

Updated Date: January 24, 2021

Infection Control: Children presenting in person with possible signs and symptoms of SARS-CoV-2 infection should be evaluated in separate clinical spaces by providers wearing appropriate PPE per IPC guidance.

Acuity TriageCopy Link!

Any child with confirmed or suspected SARS-CoV-2 infection should be triaged based on Disease Severity using definitions of mild, moderate, severe, and critical to determine appropriate treatment location and disposition. Healthy children and adolescents with mild symptoms may be candidates for phone-based triage and monitoring (see mild disease). The following patients should be evaluated at a healthcare facility:

• Any child with altered mental status, respiratory distress, or signs of organ dysfunction such as decreased urine output should be immediately triaged to an emergency unit.
• Any febrile infants <3 months should be evaluated in person due to their increased risk of severe disease and bacterial infection.
• Infants and young children with >3 days of fever and any other symptoms should be seen in person so a trained clinical can rule-out bacterial supra-infection and assess hydration and respiratory status.

Tool: Risk Categorization Algorithm for Children with Suspected COVID Infection
This algorithm helps classify children with suspected infection into severity categories and suggests an appropriate location of care and management approach. Note that we do not recommend routine use of Azithromycin except with suspected secondary bacterial infection (Feketea et al).

School EvaluationCopy Link!

Recommendations about school closures, epidemiology in schools, and minimizing transmission in schools are available here.

Tool: Algorithms for Parents and Schools for Symptomatic or COVID-Exposed Children These tools can help parents, students, administrators, and school nurses approach students with suspected SARS-CoV-2 symptoms or exposure (Orscheln et al).

Differential Diagnosis: It is important to consider a broad differential including bacterial co-infection (Mithal et al) when working up symptomatic infants and children. The Differential Diagnosis for children with suspected SARS-CoV-2 infection is similar to adults. Other respiratory viruses to consider include: influenza, adenovirus, RSV, parainfluenza, and metapneumovirus; atypical pneumonias such as mycoplasma or chlamydia pneumoniae can also present similarly. Severe disease, especially MIS-C may be confused with Toxic Shock Syndrome (TSS), Kawasaki Disease (KD), or severe sepsis.

SARS-CoV-2 TestingCopy Link!

Updated Date: February 1, 2021

Nucleic Acid Amplification and Rapid Testing: Indications for testing children for SARS-CoV-2 vary by local epidemiology and practice. The timing and type of testing for children is similar to adults (CDC), but the sample collection technique may be different as children may not tolerate nasopharyngeal swabs. Many places use mid-turbinate swabs (or back-of-throat swabs) instead. These less invasive swabbing techniques are likely 5-10% less sensitive (Boston Children’s Hospital).

Serology: The timeframe to antibody response (seropositivity) is likely similar to adults as well. In one study, the median time from PCR positivity to seropositivity was 18 days, but median time to reach adequate levels of neutralizing antibodies was 36 days (Bahar et al).

Laboratory TestingCopy Link!

Common laboratory findings in children infected with SARS-CoV-2 are similar to those of adults and include: leukocytosis, lymphopenia, and elevated inflammatory markers, D-dimer and troponin (Gonzalez-Dambrauskas). We recommend the same laboratory monitoring schedule recommended for adults.

ImagingCopy Link!

Common radiologic findings for children infected with SARS-CoV-2 are similar to those of adults and include bronchial thickening and ground-glass opacities in a basilar and peripheral distribution. Peribronchial patterns and bronchial wall thickening appear to be more common in pediatrics (Chen et al). These findings were noted in both symptomatic and asymptomatic children (Castagnoli et al).

Ultrasound: A preliminary report from Italy noted a high concordance between radiologic and lung ultrasound findings in children infected with SARS-CoV-2, suggesting that lung ultrasound may be a reasonable method to detect lung abnormalities in children (Denina et al).

CT Scan: Routine use of CT scanning is not recommended. In pediatric patients with SARS-CoV-2 infection but minor or no upper airway symptoms, a chest CT may be normal in up to 50% of cases, creating a false sense of security while exposing children to ionizing radiation. Thus, CT scanning of the chest is not a suitable screening tool to rule out infection in children (Merkus).

Management by SeverityCopy Link!

Updated Date: Jan 22, 2021
Tool: ID COVID-19 Treatment Guidelines
Tool: NIH COVID-19 Treatment Guidelines

Routine supportive care is the mainstay of therapy for children with SARS-CoV-2 and should be provided to all pediatric patients, even those with severe or critical disease (Chiotos et al; Larson et al).

Severity Classification and Vitals MonitoringCopy Link!

To classify disease by severity, see severity and disposition (which includes pediatric vitals).

For suggested monitoring frequency by severity, see vitals and monitoring.

Mild DiseaseCopy Link!

Most patients with mild disease and no significant risk factors can be managed at home.

Medications: Most cases can be managed in an outpatient setting with symptomatic treatment.

1. In otherwise healthy patients without comorbidities, currently we do not recommend disease-targeted therapies

1. Certain patients with comorbidities may be candidates for outpatient monoclonal antibodies on a case-by-case basis

2. We do not recommend VTE prophylaxis apart from ambulation
3. Existing medications generally should be continued:

1. Immunosuppressants: case-by-case
2. Nonsteroidal Anti-Inflammatory Drugs: can continue in most patients
3. Inhalers: can continue; avoid nebulizers if possible due to increased risk of transmission

4. Comorbidities may need extra attention and monitoring (e.g. T1D or adrenal insufficiency)

Household and Caregivers: Children should have a designated caregiver (ideally someone who has already been exposed), and should isolate within the household as much as possible (see household assessment and preparation).

Followup: As with adults, disease may progress in severity in the second week, so patients with new symptoms should be re-evaluated to exclude evolution to ARDS, severe neutropenia and possible secondary infection (Venturini et al). We recommend a followup schedule similar to the one recommended for adults.

When to seek care: Patients should seek care if they have worsening symptoms or danger signs. Infants and young children with >3 days of fever should be seen in person so a trained clinician can rule-out bacterial supra-infection and assess hydration and respiratory status. In some patients, home pulse oximetry may be helpful.

Moderate or Severe DiseaseCopy Link!

MedicationsCopy Link!

1. Corticosteroids should be considered in patients with oxygen requirements or severe disease
2. Convalescent Plasma may be beneficial in some hospitalized patients
3. Remdesivir is generally not recommended, but further data in pediatric patients is forthcoming
4. VTE Prophylaxis is indicated in some, but not all patients
5. Symptomatic Treatments are discussed below
6. As with adults, most existing medications (“home” medications, or medications taken regularly prior to hospitalization) can be continued unless cessation is otherwise indicated (e.g. for renal failure). Immunosuppressants should be discussed on a case-by-case basis.

Fluid ManagementCopy Link!

1. A conservative approach to intravenous fluid administration should be used in children with SARS-CoV-2 infection in the absence of shock and dehydration. This is especially true in settings where mechanical ventilation is limited, as aggressive fluid resuscitation may worsen oxygenation and pulmonary compliance (Schultz; WHO). If the patient does need resuscitation, initial fluid management should be conservative (around 10mg/kg boluses while monitoring hemodynamics and urine output). Avoid large boluses (20mg/kg or more) which may compromise gas exchange and exacerbate hypoxemia (Maitland et al).
2. Maintenance fluids are only indicated if the patient is dehydrated and unable to take oral fluids.

Oxygen TherapyCopy Link!

Oxygen delivery and escalation is covered in Oxygen Therapy.

Critical CareCopy Link!

Respiratory Failure and ARDSCopy Link!

Updated Date: January 29, 2021

While most children with acute SARS-CoV-2 infection have mild symptoms, children, especially with comorbidities, can develop severe pneumonia, respiratory failure, and ARDS (Liguoro et al). Severe pneumonia is defined by the WHO clinical signs of pneumonia (cough or difficulty breathing) and at least one of the following:

• Central cyanosis or SpO2 < 90%; severe respiratory distress (i.e. fast breathing, grunting, severe chest indrawing); general danger signs (i.e. inability to breastfeed or drink, lethargy or unconsciousness, or convulsions)
• Fast breathing (in breaths/min): < 2 months: ≥ 60; 2–11 months: ≥ 50; 1–5 years: ≥ 40 (WHO)

Oxygen TherapyCopy Link!

1. Goals of Therapy: SpO2 >90% and manageable work of breathing (i.e. age-appropriate respiratory rate and no subjective or objective signs of labored breathing such as retractions and nasal flaring)
2. Begin supplemental oxygen therapy by nasal cannulaNasal cannula or prongs tend to be well tolerated in young children. when SpO2 < 90%

1. If emergency signs such as obstructed or absent breathing, severe respiratory distress, central cyanosis, shock, coma, or convulsions are present, use a higher initiation target of < 94% and consider proceeding directly to intubation and mechanical ventilation

3. Titrate oxygen to target saturation SpO2 > 90% (> 94% if emergency signs are present) and manageable work of breathing. If goals of therapy are not met:

1. Escalate support by delivering oxygen via face mask with a reservoir bag. If this is insufficient, evaluate the patient’s risk for developing ARDS including age, timing, origin, and imaging criteria as ARDS and oxygenation (Pediatric Acute Lung Injury Consensus Conference Group):

1. If the patient is not at risk for developing ARDS:

1. Escalate to high flow nasal cannula (HFNC) if available. If goals of therapy are still not met or HFNC is not available:

1. Escalate to noninvasive positive pressure ventilation (NIPPV), bubble continuous positive airway pressure (bCPAP) or bilevel positive airway pressure (BiPAP) if available.

2. If the patient is at risk for ARDS:

1. NIPPV should be considered in early disease to improve gas exchange and work of breathing (The Pediatric Acute Lung Injury Consensus Conference Group). Some locations will also use HFNC for this indication.

3. If the patient is at risk for ARDS and has severe hypoxia or work of breathing: proceed to intubation with low tidal volume ventilation unless unavailable or otherwise contraindicated.

4. A child with respiratory distress and hypoxia should be closely monitored for signs of clinical deterioration as children can rapidly progress to respiratory failure and shock. If the child worsens to moderate or severe ARDS, the child should be intubated and mechanically ventilated by a trained healthcare worker using an appropriately sized cuffed endotracheal tube (WHO; Kache et al).

Acute Respiratory Distress SyndromeCopy Link!

Children with SARS-CoV-2 infection can progress to ARDS. Pediatric ARDS has similarities to adult ARDS, but both the definition and management take into account pediatric-specific conditions (e.g., cyanotic heart disease) and physiology. Pediatric ARDS is defined by the Pediatric Acute Lung Injury Consensus Conference Group as (Kemani et al):

1. Age: Exclude patients with perinatal related lung disease
2. Timing: Within 7 days of a known clinical insult
3. Origin: Not fully explained by cardiac failure or fluid overload. For special populations (cyanotic heart disease, chronic lung disease, and left ventricular dysfunction), the acute deterioration in oxygenation should not be explained by the underlying disease.
4. Imaging: New infiltrate(s) consistent with acute pulmonary parenchymal disease
5. Oxygenation:

OI: oxygenation index; OSI: oxygen saturation index. Use PaO2-based metrics when available. If PaO2 is not available, wean FIO2 to maintain SpO2 ≤ 97% to calculate oxygen saturation index (OSI; [FIO2 × mean airway pressure × 100]/SpO2) or SpO2:FIO2 (SF) ratio.

Mechanical VentilationCopy Link!

For children with SARS-CoV-2--associated ARDS requiring mechanical ventilation, target:

• Initial tidal volumes of 6 ml/kg per ideal body weight (PBW). Tidal volume should then be adapted to disease severity: 3–6 mL/kg PBW if poor respiratory compliance, and 5–8 mL/kg PBW with preserved compliance.
• Plateau pressures <28 cmH2O
• pH 7.15–7.30
• Optimized positive end expiratory pressure (PEEP): PEEP titration should be individualized to the patient and the ARDS phase
• Note: These targets are different from those used in adult patients! More detailed instructions on mechanical ventilation parameters and adjustment, synchrony, and weaning is available in the adult mechanical ventilation section.

Proning: Consider Prone Positioning in children with ARDS and severe hypoxemia. Methodology is similar to proning in adults.

Sedation and Neuromuscular Blockade: Consider intermittent or continuous neuromuscular blockade in cases of significant ventilator dyssynchrony despite adequate sedation, refractory hypoxemia, or refractory hypercapnia (WHO). Information on adult sedation and neuromuscular blockade is available for reference, though pediatric practice is different.

Extracorporeal Membrane Oxygenation (ECMO): If resources are available, ECMO should be considered in pediatric patients to manage ARDS and/or cardiac failure (myocarditis, arrhythmias, PE) (Kache et al). Information on adult ECMO is available here. Criteria for children are often different depending on the institution.

ShockCopy Link!

Updated Date: March 5, 2021

Septic ShockCopy Link!

While sepsis and septic shock are rare manifestations of SARS-CoV-2 infection in children (Liguoro et al), they can occur, and should be promptly recognized and treated. Sepsis is a dysregulated immune and inflammatory response to an infection that can cause life-threatening organ dysfunction (Singer et al). In children, it is defined as a suspected or proven infection with ≥ 2 age-based systemic inflammatory response syndrome (SIRS) criteria, one of which must be abnormal temperature or WBC count:

• Abnormal temperature (>38.5°C or <36°C)
• Tachycardia for age or bradycardia for age if <1 year
• Tachypnea for age or need for mechanical ventilation
• Abnormal WBC count for age or > 10% bands (Goldstein et al)

Signs of septic shock in children may include any combination of the following:

• Altered mental status
• Bradycardia or tachycardia (HR < 90 bpm or > 160 bpm in infants and heart rate < 70 bpm or > 150 bpm in children)
• Peripheral vasodilation and bounding pulses (warm shock), or prolonged capillary refill (> 2 sec) and weak pulses (cold shock)
• Fast breathing
• Mottled or cool skin, or petechial or purpuric rash
• Elevated blood lactate
• Reduced urine output
• Hyperthermia or hypothermia
• Hypotension (SBP < 5th percentile or > 2 SD below normal for age) as a late sign (Davis et al; WHO).

The immediate goals when managing pediatric septic shock are to maintain perfusion to the organs and treat the underlying infection. Below is a brief overview of pediatric septic shock management (Weiss et al; WHO; Kache et al):

1. Antimicrobial therapy: Within 1 hour of recognition, initiate empiric, broad-spectrum antimicrobial therapy.
2. Monitoring and Targets: Perfusion targets include age-appropriate MAP, urine output (1 mL/kg/hr), and improvement of skin mottling and extremity perfusion, capillary refill, heart rate, level of consciousness, and lactate. Monitor frequently to guide fluid resuscitation and vasoactive medications.

1. In settings where accurate MAPs cannot be easily obtained, systolic blood pressure is an acceptable alternative.
2. Given the concurrence of cardiogenic and septic shock in some patients (particularly those with MIS-C), we recommend performing a thorough cardiac evaluation including ECG, echocardiography and cardiac biomarkers (troponin, CK and CK MB, mixed venous oxygen saturation if central line is present) on all patients who present in shock to rule out cardiac involvement and mixed shock, even if presenting with a distributive picture.

3. Fluid resuscitation: Within 1 hour of recognition, initiate fluid resuscitation:

1. Use balanced/buffered crystalloids for fluid resuscitation rather than albumin or normal saline. Do not use hypotonic fluids, starches or gelatin.
2. Fluid resuscitation may lead to volume overload and capillary leak, exacerbating respiratory failure. It is important to discontinue fluid administration if the patient is not responding or benefiting, or if risks of precipitating respiratory failure outweigh marginal benefits of ongoing fluids. In these cases, vasoactive medications may be preferable.

1. In healthcare systems with intensive care capacity including ventilatory support, administer bolus fluids, 10–20 mL/kg per bolus, up to 40–60 mL/kg, over the first hour, titrated to clinical markers of perfusion Improved tachycardia, improved blood pressure, capillary refill time, level of consciousness, and urine output.

1. Discontinue if signs of fluid overload develop or respiratory consequences outweigh benefits.Jugular venous distension, pulmonary edema, or new or worsening hepatomegaly

2. In healthcare systems without intensive care capacity:

1. If the child has a normal blood pressure for age, initiate maintenance fluids and do not administer fluid boluses
2. If the child has hypotension, administer bolus fluids, 10–20 mL/kg per bolus, up to 40 mL/kg over the first hour with titration as above

4. Vasoactive medications: Administer vasoactive medications if signs of fluid overload are apparent, or signs of shock (listed above) persist after two fluid boluses. Monitor blood pressure frequently and titrate the vasoactive medication to the minimum dose necessary to maintain perfusion and prevent side-effects.

1. Initiate either epinephrine or norepinephrine, ideally through a central venous catheter. Diluted vasoactive solutions can be initiated through a peripheral intravenous catheter if central access is not available.

1. Dopamine can be used in places where epinephrine and norepinephrine are not available.
2. For children requiring high doses of catecholamines (definitions vary between institutions), consider adding vasopressin if available
3. Inodilators (milrinone, dobutamine or levosimendan) should not be used routinely, and are typically not used for septic shock in the absence of evidence for cardiac dysfunction. They can worsen peripheral blood pressure and thus should only be considered in cases of refractory hypoperfusion and evidence of cardiac dysfunction by practitioners familiar with their use.

5. Corticosteroids: There is insufficient evidence to recommend for or against glucocorticoids to treat refractory shock in children with SARS-CoV-2. However, corticosteroids may be indicated for the treatment of SARS-CoV-2 infection.

Tool: See Surviving Sepsis Campaign International Guidelines for more detailed recommendations. Surviving Sepsis Campaign: Initial Resuscitation Algorithm for Children (Bundle)

Cardiogenic ShockCopy Link!

Cardiogenic shock can occur with SARS-CoV-2 infection in the setting of sepsis or MIS-C. Cardiogenic shock is characterized by circulatory failure due to impaired of cardiac contractility.

Signs and symptoms of cardiogenic shock in children may include any combination of the following:

• Shortness of breath
• Jugular venous distention
• Hepatomegaly
• Peripheral edema
• Pulmonary crackles
• Altered mental status (e.g., lethargy, confusion)
• Decreased perfusion
• Tachycardia
• Decreased urine output
• Cardiac murmur
• Gallop
• Decreased peripheral pulses
• Arrhythmia
• Hypotension
• Cardiomegaly and/or pulmonary edema on chest x-ray

The immediate goal when managing any type of pediatric shock, including cardiogenic shock, is to maintain perfusion and restore oxygen delivery to the organs. The recommendations below pertain to pure cardiogenic shock in the absence of congenital heart disease. Additionally, undifferentiated shock can occur (e.g., septic shock with myocardial dysfunction) and clinical judgement and frequent reassessment should be used to determine appropriate therapy.

1. Optimize cardiac output

1. Fluid resuscitation with balanced/buffered crystalloids is indicated in patients with cardiogenic shock only after clinical assessment demonstrating preload insufficiency, ideally by echocardiogram. If indicated, use small volume boluses (5-10ml/kg) over 30-60 min and assess frequently for clinical response and signs of fluid overload and respiratory compromise.
2. In children with fluid overload, ventricular dysfunction and adequate blood pressure (with or without the use of vasoactives), consider the use of diuretics (e.g., furosemide infusion) to achieve euvolemia.
3. In patients without hypotension, dobutamine or milrinone can be administered to decrease afterload and improve cardiac output.
4. In patients with hypotension, epinephrine can be administered to improve inotropy. Be aware that epinephrine doses > 0.05 µg/kg/min can increase afterload.

2. Treat reversible causes such as electrolyte abnormalities, arrhythmias, pulmonary embolism, pneumothorax, tamponade, sepsis.

1. If sepsis is suspected, initiate empiric, broad-spectrum antimicrobial therapy.

3. Optimize ventilation/gas exchange:

1. Provide oxygen therapy as above with a goal SpO2 >94%
2. If either noninvasive or invasive ventilation are clinically indicated, be aware of the cardio-pulmonary interactions and prepare for the possibility of cardiac arrest on intubation.

4. Monitoring and Targets: Early goal-directed therapy should be based on clinical (volume status, urine output, blood pressure, mental status) and laboratory (end organ function [blood urea, creatinine, transaminases], blood pH, lactate levels, BNP/NT-proBNP, troponin) measurements as well as echocardiogram.

Other ICU ManagementCopy Link!

1. Renal Replacement Therapy: For children with fluid overload or renal dysfunction who are unresponsive to diuretic therapy, consider renal replacement therapy.
2. Nutrition: After adequate resuscitation (e.g., no longer requiring escalating doses or in the process of weaning vasoactive medications), initiate enteral nutrition for children with no contraindications. Parenteral nutrition need not be initiated in the first 7 days of admission.
3. Transfusions: Do not routinely transfuse hemodynamically stable children with a blood hemoglobin concentration ≥ 7 g/dL.

Cardiac ArrestCopy Link!

Updated Date: February 1, 2021

The American Heart Association (AHA), in collaboration with the American Academy of Pediatrics (AAP) among other groups, compiled interim guidance to help rescuers treat pediatric and neonatal victims of cardiac arrest with suspected or confirmed SARS-CoV-2 infection (Topjian et al). Some guidance specifically related to children and neonates include:

• For out-of-hospital cardiac arrest: lay rescuers should perform chest compressions and consider mouth-to-mouth ventilation, if willing and able, given the higher incidence of respiratory arrest in children. A face mask or cloth covering the mouth and nose of the rescuer and/or patient may reduce the risk of transmission if the rescuer is unwilling to perform direct mouth-to-mouth ventilation.
• For an in-hospital cardiac arrest in a patient who is intubated: consider adjusting respiratory rate to 10 breaths/min for pediatric patients and 30 breaths/min for neonates.

Neonatal ResuscitationCopy Link!

For neonates born to mothers with confirmed or suspected SARS-CoV-2 infection, suction of the airway after delivery should not be performed for clear or meconium-stained amniotic fluid since suctioning is an aerosol-generating procedure (AGP). Since endotracheal installation of medications such as epinephrine is also aerosol-generating, intravenous delivery via a low-lying umbilical venous catheter is the preferred route of administration during neonatal resuscitation.

Multisystem Inflammatory Syndrome in ChildrenCopy Link!

Updated Date: January 24, 2021
Literature Review: Gallery View, Grid View

Multisystem Inflammatory Syndrome in Children (MIS-C), also known as Pediatric Inflammatory Multi-System Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS or PIMS), is a rare manifestation of SARS-CoV-2 that has been described in children and young adults in multiple case series (Panupattanapong et al, Riphagen et al, Verdoni et al, Toubiana et al, Pouletty et al, Jones et al).

PathophysiologyCopy Link!

The pathophysiology of MIS-C is not yet well understood, but is likely related to immune dysregulation.

Innate immune mechanisms:

1. One possible contributor is an innate immune response called neutrophil extracellular traps (NETs), which are webs of cell-free DNA, histones, and neutrophil granule content (Jiang et al). An overabundance of NETs, or NETosis, can cause an exaggerated systemic inflammatory response (Mozzini et al) and promote thrombosis (Martinod et al). NETs have been shown to be elevated in the plasma of patients infected with SARS-CoV-2, and higher concentrations are seen in patients with respiratory failure (Zuo et al).
2. A dysregulated innate immune response and a subsequent cytokine storm (Cytokine Storm Syndrome) with endothelial damage may also contribute to clinical manifestations of severe SARS-CoV-2 infection (Jiang et al; Liu et al; Varga et al) and development of MIS-C (Consiglio et al, Gruber et al).

Acquired immune mechanisms:

1. Antibody or T-cell recognition of self-antigens (viral mimicry of the host) resulting in autoantibodies (Gruber et al)
2. Antibody or T-cell recognition of viral antigens expressed on infected cells (Waggoner et al)
3. Formation of immune complexes which activate inflammation (Hoepel et al)
4. Viral superantigen sequences which activate host immune cells (Cheng et al)

Clinical PresentationCopy Link!

SymptomsCopy Link!

Presenting Symptoms: Many children with MIS-C do not exhibit respiratory symptoms at any point in their course. Common symptoms include:

• Fever
• Gastrointestinal (GI) symptoms including abdominal pain, nausea, vomiting, and non-blood diarrhea (87%, Abrams et al). In some cases, GI symptoms occurred 1-2 weeks prior to presentation, and may represent the period of acute infection.
• Dermatologic manifestations such as rash and malar erythema (73%, Abrams et al) that develops a mean of 2.7 days after onset of fever and lasts for a median of 5 days. Mucocutaneous features can be an important clue in recognizing MIS-C, but does not correlate with disease severity (Young et al).
• Conjunctival Injection
• Periorbital Edema and/or Distal Extremity Edema
• Strawberry Tongue

Timing: MIS-C appears to be a late (i.e. post-viral) manifestation SARS-CoV-2 infection, as many patients presented 2-3 weeks after the peak of infection in their geographic area (Panupattanapong et al and Jamal et al).

Differential DiagnosisCopy Link!

MIS-C has manifestations that overlap with Kawasaki Disease (KD), Toxic Shock Syndrome, and Macrophage Activation Syndromes like Cytokine Storm. All of these can occur in a post-acute illness setting and involve fever, rash, erythema, edema, conjunctivitis, and oral mucosal changes (e.g. “strawberry tongue”). Severe disease can also cause multi-organ failure. However, there are key differences:

• Age: KD tends to occur in very young children with a mean age of 2 years but almost always < 5 years old, whereas the average age of MIS-C patients is 7-9 years old (Whittaker et al; Feldstein et al; Jiang et al)
• Race: MIS-C is seen in a higher proportion of children of Hispanic, African and Afro-Caribbean descent and a lower proportion in those of East Asian descent compared with KD (Whittaker et al; Feldstein et al).
• Triggering event: MIS-C is associated with SARS-CoV-2 infection. TSS is associated with Staphylococcus and Group A Strep infection (risk factors include recent tampon use, surgery or infection, especially skin or soft tissue). KD is triggered by many different infections (Whittaker et al; Jiang et al).
• Laboratory findings: MIS-C patients generally have a greater elevation of inflammatory markers such as CRP, IL-6 and fibrinogen than patients with KD or TSS (Whittaker et al; Jiang et al).
• Organ involvement: MIS-C has more diffuse cardiovascular involvement than KD, which has a predilection for the coronary arteries (Whittaker et al; Panupattanapong et al).

ComplicationsCopy Link!

• Cardiac: In one study, 71% had cardiovascular complications including coronary artery aneurysms, myocardial dysfunction, pericarditis, valvulitis, or coronary dysfunction (Abrams et al). Other common cardiac complications include: arrhythmias, pericardial effusion, coronary artery dilatation, and reduced LVEF potentially leading to cardiogenic shock (Valverde et al). Another study that analyzed echocardiographic findings in 28 children with MIS-C found that unlike in KD, coronary arteries may be spared in early MIS-C; however, myocardial injury is common. After approximately 5 days, children demonstrated good recovery of systolic function, but diastolic dysfunction persisted (Matsubara et al). Medium- and long-term sequelae, particularly cardiovascular complications, are not yet known (Alsaeid et al).
• Renal: In one study, 41% had AKI (27.6% severe) (Deep et al).
• Hematologic: In another study, 4% had coagulopathy and thrombus (Davies et al).

Workup and MonitoringCopy Link!

Case Definition: The case definition for MIS-C from the CDC and WHO requires:

1. FeverCopy Link!

2. Clinical signs of multi-system involvementCopy Link!

3. Laboratory signs of inflammationCopy Link!

4. No other plausible diagnosis such as bacterial sepsis or staphylococcal/streptococcal TSSCopy Link!

5. Evidence of SARS-CoV-2 infection by PCR, antigen test or serology, or exposure to a SARS-CoV-2 infected personCopy Link!

Diagnosis may be particularly difficult in places that do not have easy access to testing, so clinicians should maintain a high level of suspicion for MIS-C and potentially treat patients for multiple potential etiologies.Copy Link!

SARS-CoV-2 Testing: Because of the late timing, not all patients are positive via PCR, and some may not yet be positive on serology. Pooled data shows that 60-80% of patients have positive SARS-CoV-2 serology with a smaller number positive via PCR. Up to 5-10% are negative on both tests (Feldstein et al; Jiang et al).

• Children with MIS-C have significantly higher SARS-CoV-2 receptor binding domain (RBD) IgG antibody titers than children with KD or SARS-CoV-2 without MIS-C. RBD IgG titers also correlate with ESR and with hospital and ICU lengths of stay, suggesting that quantitative SARS-CoV-2 serology may help to distinguish MIS-C from similar clinical entities, and help to stratify risk for adverse outcomes (Rostad et al).

Laboratory evaluation: Laboratories should be followed as outlined for Cytokine Storm.

Imaging and Procedures:

Cardiac evaluation: Suspected cardiac involvement should be evaluated via ECG and echocardiogram (Kache et al; ACR).

1. ECGs should be performed at a minimum every 48 hours in MIS-C patients who are hospitalized, and during follow-up visits

1. In a single-center cohort study of 32 patients with MIS-C, 6 developed atrioventricular block a median of 8 days after initial symptom onset suggesting that patients admitted with MIS-C require close ECG monitoring during the acute phase (Choi et al).

2. Echocardiogram should be conducted at diagnosis and at a minimum of 7-14 days and 4-6 weeks after presentation.
3. Patients should be followed on telemetry per consultation with a cardiology specialist.

Other evaluation: A child under investigation for MIS-C should be evaluated for other infectious etiologies (i.e. Septic Shock, meningitis) and non-infectious etiologies (i.e. oncological, rheumatological, Cardiogenic Shock) that may have similar presentations.

ManagementCopy Link!

Tool: Management Guidelines for MIS-C (American College of Rheumatology Multidisciplinary Task Force)

General ManagementCopy Link!

• Stabilize hemodynamics and Shock; judicious fluid resuscitation is recommended given the high incidence of cardiac involvement and the cardiogenic etiology of shock (see Undifferentiated Shock (describes how to tell them apart) and Septic and Cardiogenic Shock).
• Consider transferring the patient to a care facility where subspecialty care and IVIG are available if these are not available at your institution.
• Involve the pediatric ICU team, and infectious disease, cardiology, rheumatology, and hematology services, if available.

ImmunomodulatorsCopy Link!

Most of the treatment of MIS-C with immunomodulators is taken from evidence in treating Kawasaki Disease (KD). There is a paucity of evidence supporting the use of immunomodulators for patients with mild cases of MIS-C, and there is no evidence that use of immunomodulators can prevent coronary artery aneurysms or cardiac involvement. However, the American College of Rheumatology (ACR) Multidisciplinary Task Force strongly recommends use of immunomodulators in patients hospitalized with MIS-C. While there is no set treatment protocol, the following is recommended by the ACR and several pediatric institutions:

Mild to Moderate Disease

Patients with suspected MIS-C should be evaluated much as a patient with KD would be. For MIS-C patients meeting criteria for complete or incomplete KD without shock, myocardial dysfunction or coronary artery changes:

1. Initiate high dose IVIG at 2 gm/kg based on ideal body weight up to 100gm for 1 dose, preferably in the first 7-10 days of illness (McCrindle). See MIS-C Medication Dosing.

1. Consider monitoring patients with any myocardial dysfunction in an ICU setting during IVIG infusion

2. Methylprednisolone 2 mg/kg/day for 2 weeks followed by a taper over 2-3 weeks (this is generally higher than doses used to treat hypoxemia from SARS-CoV-2 infection). See MIS-C Medication Dosing.

1. Most evidence supporting use of corticosteroids in MIS-C is limited to case series in which ~50-60% of patients were treated with corticosteroids at varying doses with most patients responding rapidly (Feldstein et al; Dufort et al; Godfred-Cato et al; Kaushik et al).
2. A retrospective cohort study of 111 patients showed treatment with IVIG and methylprednisolone vs. IVIG alone was associated with lower risk of treatment failure, lower risk of escalation to second-line therapy, lower risk of requiring hemodynamic support, lower risk of acute left ventricular dysfunction after initial therapy, and lower duration of stay in a pediatric ICU (Ouldali et al).
3. Currently, corticosteroids are suggested when patients meet criteria for complete or incomplete KD with a risk factor for IVIG resistance (i.e. coronary artery enlargement, age <12 months) (McCrindle et al) or persistent fevers or rising inflammatory markers despite treatment with IVIG, which may suggest MAS or Cytokine Release Syndrome.
4. If no IVIG is available, use methylprednisolone (or equivalent, see MIS-C Medication Dosing) alone.
5. Consider adding a Proton Pump Inhibitor (PPI) for GI prophylaxis.
6. Start low dose Aspirin. See MIS-C Medication Dosing.

3. If refractory (i.e. continued fever >36 hours after IVIG, worsening clinical condition, new cardiac dysfunction or shock), consider biologics in consultation with a rheumatology and infectious disease specialist.

Severe Disease

For patients with signs of shock, coronary artery dilation, arrhythmia, or cardiac dysfunction even in the absence of Kawasaki-like features:

1. Initiate high dose IVIG at 2 gm/kg based on ideal body weight up to 100gm for 1 dose
2. Concomitant high dose methylprednisolone 30 mg/kg (up to 1000mg) daily for 1-3 days followed by 2mg/kg divided q8-q12. Continue high dose for 2 weeks (can consolidate to daily) then taper over 2-3 weeks.

1. If no IVIG is available, use corticosteroids alone.
2. Consider adding a PPI for GI prophylaxis.

3. Discuss use of biological medications (e.g. Anakinra, Infliximab, Tocilzumab - see dosing table below) in consultation with a rheumatology specialist.
4. Start low dose Aspirin; discuss high dose Aspirin with a cardiology specialist if there are coronary changes. See MIS-C Medication Dosing.

Antiplatelet and anticoagulation therapyCopy Link!

1. Give low dose Aspirin (3-5 mg/kg/day; max 81 mg/day) until normalization of platelet count and confirmed normal coronary arteries by echocardiogram at >4 weeks after diagnosis in consultation with a cardiology specialist. If coronary artery aneurysm is identified, low dose Aspirin should be continued with possible therapeutic anticoagulation in consultation with a cardiology specialist.
2. Additional anticoagulation or antiplatelet therapy may be recommended for patients with large coronary aneurysms, documented thrombosis, or reduced ejection fraction in consultation with a cardiology specialist.
3. Anticoagulant thromboprophylaxis is recommended for hospitalized children with MIS-C per the clinical recommendations outlined in the VTE prophylaxis section below (Goldenberg et al).

MIS-C Medication Dosing TableCopy Link!

Post MIS-C CourseCopy Link!

Updated Date: June 1, 2021

In the acute phase of MIS-C, there is a comparable incidence of coronary artery aneurysm and dilation in MIS-C and Kawasaki disease (20 and 25%, respectively) (Henderson et al). that resolve in most patients in mid- and long-term follow up. Neurological complications such as headache, muscle weakness, reduced reflexes, altered mental status, encephalopathy, cranial nerve palsies, stroke, and seizure appear more frequent than in Kawasaki disease (Schupper et al, Jin et al) with persistence following the acute phase.

In a pooled meta-analysis of follow up MIS-C studies, recovery was reported in 91.1% and death in 3.5% of patients (Jiang et al). In a 6 month follow up study (N=45), systemic inflammation was resolved in all but one patient with 96% of patients with normal echocardiograms, gastrointestinal symptoms decreased by 75% and all renal, hematological and otolaryngological findings largely resolved. Minor neurological abnormalities persisted in 39% of patients compared to 52% in cohort at diagnosis with ~20% with severe emotional difficulties and 50% with persisting poor exercise tolerance. Ongoing studies will help define the extended natural history of MIS-C.(Penner et al)

TherapeuticsCopy Link!

Tool: COVID Drug Interaction Tracker

Symptomatic TreatmentsCopy Link!

Updated Date: Jan 22, 2021

CoughCopy Link!

Non-Pharmacologic Therapy

1. Drink fluids (preferably warm)
2. Honey (2.5-5mL [0.5-1 teaspoon]) given straight or diluted in liquid may help ease coughing symptoms and improve sleep for children >12 months old (Cohen et al). Using honey for infants aged <12 months is not advised due to risk of botulism.
3. Cough drops may be used for school-aged children and adolescents; however, there is a risk of aspiration with use in younger children.

Pharmacologic Therapy

1. The WHO recommends against the use of codeine preparations for cough in children. However, dextromethorphan-containing cough medications may be warranted in the unusual circumstance where severe prolonged cough interferes with feeding or sleeping (WHO).

Nasal Secretions / SuctioningCopy Link!

1. There is currently no specific guidance on nasal suctioning in SARS-CoV-2.
2. Extrapolating from literature on children hospitalized with bronchiolitis, saline nasal drops and mechanical aspiration of the nares can relieve nasal obstruction and decrease length of hospital stay (Mussman et al).
3. There is insufficient evidence to support frequent “deep” suctioning of the oropharynx or larynx with a nasopharyngeal catheter (Ralston et al).

DyspneaCopy Link!

1. Appropriate Oxygen therapy in conjunction with creating a calm and comforting environment is the mainstay of management of dyspnea in most pediatric patients (Mussman et al). See Non-opioid Management.

1. Opioid Management (adult doses presented here) should only be used when survival is unlikely and treatment is focused solely on comfort and control of symptoms, or in cases of significant refractory dyspnea despite treatment.

2. Respiratory Secretions can be managed in a manner similar to adults.

CorticosteroidsCopy Link!

Updated Date: Jan 22, 2021

1. For respiratory indications: Corticosteroids have been shown to decrease mortality in adult patients with oxygen requirements (Review of Evidence in Adults) and are currently being studied through clinical trials in the pediatric population (WHO REACT Working Group). For MIS-C dosing, see MIS-C Medication Dosing.

1. Low dose corticosteroids may be beneficial for select pediatric patients with severe or critical SARS-CoV-2 infection (i.e. requiring supplemental oxygen or mechanical ventilation) (Dulek et al).

1. Dosing is per the chart below. Duration of therapy is up to 10 days or until discharge; shorter durations are preferable.

2. Recommendations about the use of corticosteroids for children with oxygen requirements are uncertain due to underrepresentation of children in the clinical trials (WHO).

2. Monitoring:

1. Monitor glucose, WBC count, mental status, and blood pressure in adolescents.
2. If the patient has other risk factors requiring initiation of stress ulcer prophylaxis, add famotidine or a PPI.

Pediatric Glucocorticoid DosingCopy Link!

Antibody TherapiesCopy Link!

Updated Date: January 24, 2021

Convalescent PlasmaCopy Link!

1. In adults: The FDA has issued an Emergency Use Authorization (EUA) for use of convalescent plasma to treat patients hospitalized with SARS-CoV-2 infection. However, convalescent plasma is not routinely recommended due to insufficient data on safety and effectiveness. See Convalescent Plasma for further information.
2. In children: There are no high quality studies investigating use of convalescent plasma in children and adolescents. A systematic review that included 8 case studies suggested a potential benefit. Currently there are ongoing clinical trials in pediatric patients that may help clarify whether convalescent plasma should be used for treatment in children (Zaffanello et al).

1. The National Institute of Health (NIH) and Infectious Diseases Society of America Guidelines recommend use in hospitalized pediatric and adult patients in the setting of a clinical trial.

Monoclonal AntibodiesCopy Link!

1. Outpatient: Outpatient treatment of SARS-CoV-2 in children with monoclonal antibodies is recommended only on a case-by-case basis, and ideally in the context of a clinical trial (Dulek et al). The FDA has issued an EUA for two investigational monoclonal antibody therapies - Bamlanivimab-Etesevimab (EUA) and Casirivimab-Imdevimab (EUA) - for treatment of non-hospitalized pediatric patients >12 years and >40 kg with mild to moderate SARS-CoV-2 who have certain risk factors for severe disease and/or hospitalization.

1. Risk factors for children age 12-17 years include any of the following:

1. BMI >85 percentile
2. Sickle Cell Disease
3. Congenital or acquired heart disease
4. Neurodevelopmental disorders (e.g., Cerebral Palsy)
5. Medical-related technological dependance (e.g., tracheostomy, gastrostomy)
6. Chronic respiratory disease that requires daily medication for control (e.g. asthma)

2. See Monoclonal Antibodies for further information on pharmacology, evidence for use in adults, dosing and monitoring and toxicity

2. Inpatient: There is insufficient data to support the use of monoclonal antibodies in the inpatient setting. (In adults, use of monoclonal antibodies late in the disease course does not appear to be effective).

VTE prophylaxisCopy Link!

Updated Date: February 23, 2021

Thromboembolic Disease is a major complication of SARS-CoV-2 infection in adults. In general, children are at lower risk of thromboembolic disease, but the incidence of VTE in children with SARS-CoV-2 infection is uncertain. Pediatric intensivists, hematologists, and rheumatologist have published guidance on VTE prophylaxis (Goldenberg et al; Loi et al):

Outpatients:

1. VTE prophylaxis is not recommended in the absence of indwelling central venous catheters and significant clinical risk factors for VTE (listed below), except for some post-discharge cases (see below).

Hospitalized patients:

1. Lab monitoring: Obtain a CBC with platelet count, fibrinogen, prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and D-dimer on admission and serially (schedule for suggested lab frequencies).

1. Consider calculating a DIC score (ISTH scoring system) and evaluating for VTE when there is a rising D-Dimer and DIC score.
2. Common findings include: Elevated D‐dimer, elevated fibrinogen, mildly decreased platelet count, evidence of DIC

2. Indications: Anticoagulant thromboprophylaxis should not be routinely prescribed in hospitalized children who have asymptomatic SARS‐CoV‐2 infection in the absence of risk factors for hospital‐associated VTE (listed below). Hospitalized patients with SARS-CoV-2 infection in addition to the following risk factors for thrombosis and the absence of contraindications should be started on anticoagulant thromboprophylaxis (see dosing below) in combination with mechanical thromboprophylaxis with sequential compression devices:

1. Personal or family history of VTE
2. Presence of a central venous line
3. Post-pubertal
4. Decreased mobility from baseline
5. Burns
6. Active malignancy
7. Evidence of venous stasis or cardiac low-flow state
8. Estrogen therapy
9. Systemic infection or flare of inflammatory disease
10. Obesity (BMI>95th percentile)
11. Severe dehydration
12. Recent surgery or trauma
13. Inherited thrombophilia (e.g., protein S, protein C, or antithrombin deficiency; factor V Leiden; factor II G20210A; persistent antiphospholipid antibodies)
14. Sickle Cell Disease vaso-occlusive crisis
15. Previous splenectomy for hemoglobinopathy
16. Autoimmune disorder
17. Nephrotic syndrome

3. Contraindications: Thromboprophylaxis should be held in patients with active bleeding or with platelets < 20,000/uL or per provider discretion for procedures or risk of bleeding.

1. Note: In the absence of other bleeding risk factors, low‐dose anticoagulant thromboprophylaxis is not believed to increase the risk of clinically significant bleeding in MIS‐C patients receiving Aspirin at doses ≤5 mg/kg/d.

4. Duration: Prophylaxis is typically continued for the duration of hospitalization. Ongoing thromboprophylaxis following discharge may be considered for patients with additional risk factors for VTE such as persistently decreased mobility, active cancer, autoimmune disorders, recent surgery, or D-dimer > 2x upper limit of normal.

1. If post-discharge prophylaxis is indicated, LMWH subcutaneously twice a day (as below) is recommended in children < age 18.

1. DOACs (e.g, Rivaroxaban 10 mg po qd), can be used in young adults > age 18 as an alternative.
2. Duration of post-discharge prophylaxis (whichever occurs first): clinical risk factor resolution or 30 days post-discharge

Summary of anticoagulant thromboprophylaxis recommendations in children hospitalized with asymptomatic SARS‐CoV‐2 infection and children hospitalized for SARS-CoV-2–related illness (Goldenberg et al):

Prophylaxis dosing:

1. Low-molecular weight heparin (LMWH; e.g., Enoxaparin) is used in patients who are clinically stable (e.g., without hemodynamic compromise, renal failure or significant risk of bleeding). LMWH Prophylactic Doses:

1. Age < 2 months: 0.75 mg/kg bid SC
2. Age > 2 months: 0.5 mg/kg bid SC
3. Adjust dose to achieve a 4‐hour post‐dose anti‐Xa activity level of 0.2 to <0.5 units/mL

2. Unfractionated heparin (UFH) is used in patients who are unstable (e.g., with hemodynamic compromise, renal failure, or high risk for bleeding). Patients who become unstable while on LMWH should be transitioned to UFH prophylactic dose:

1. 10-15 units/kg/hour, with no loading dose. Heparin level should be 0.1-0.3 units/mL (equivalent to aPTT of 40-70 seconds).

1. Note: aPTT at baseline may be elevated or low and may not correlate with heparin levels. In these cases, anti-Xa levels may be used.

3. Direct oral anticoagulants (DOACs) (e.g., Rivaroxaban and Apixaban) are not recommended for inpatient VTE prophylaxis because of possible drug interactions with some medications used to treat SARS-CoV-2 infection (including Dexamethasone) and limited data in children with SARS-CoV-2. This COVID drug interaction tracker can help determine if there are relevant interactions.
4. Antiplatelet agents are not recommended for VTE prophylaxis in patients with SARS-CoV-2 infection. However, antiplatelet agents may be indicated for patients with atypical KD or MIS-C per cardiology and/or rheumatology specialists.

Therapeutic dosing:

1. Consider advancing dose to therapeutic-intensity anticoagulation (e.g., LMWH 1 mg/kg/dose q 12 hours for patients with normal renal function) in patients considered very high risk for VTE/microvascular thrombosis

1. Very high-risk patients include: those receiving anticoagulation therapy prior to admission; those with a highly suspected or diagnosed VTE; those with high levels of D-dimer; those with abnormal coagulation parameters including prolonged PT, prolonged aPTT, or decreased fibrinogen; those with markedly elevated inflammatory markers; and/or those with multi-organ failure (Loi et al).

RemdesivirCopy Link!

Updated Date: February 23, 2021

Remdesivir has been FDA-approved for children ≥12 years old and ≥40 kg with confirmed SARS-CoV-2 infection requiring hospitalization. Remdesivir may also be available via Emergency Use Authorization (EUA) for pediatric patients <12 years old (≥3.5 kg) or <40 kg. Use of non-FDA approved Remdesivir under the EUA requires additional documentation and procedures. The recommended dosing for children <40 kg is 5 mg/kg IV loading dose on day 1 followed by 2.5 mg/kg IV q24h for 4 additional days (Garcia-Prats et al). Pharmacokinetic modeling and simulation has been used to extrapolate pediatric-specific dosing regimens for use of Remdesivir to treat SARS-CoV-2 infection; the dosing scheme provides weight-normalized dosages for patients weighing <60 kg (Maharaj et al).

TocilizumabCopy Link!

Updated Date: February 23, 2021

Tocilizumab is FDA-approved to treat cytokine storm in children 2 years of age and older, but its use in SARS-CoV-2 is highly debated (see Tocilizumab for a review of the literature in adults). As of December, 2020 it is not recommended by the American College of Rheumatology for SARS-CoV-2 infection in pediatric patients (Henderson et al.), though it is used in some cases of MIS-C.

1. Though not specifically studied in pediatric patients with SARS-CoV-2 infection, studies of cytokine storm in other clinical settings showed that doses of 6.9 to 12 mg/kg were pharmacologically active and resulted in appropriate concentrations.
2. There is an increased risk of developing TB while taking Tocilizumab, which may be a concern in areas where prevalence of TB is high (Garcia-Prats et al).

AntibioticsCopy Link!

Updated Date: February 23, 2021

A discussion on the risks and benefits of empiric antibiotics with recommendations of initial antibiotics is covered here: Bacterial Infections. Antibiotics in SARS-CoV-2 infection are indicated for suspected or confirmed bacterial co-infection or secondary infection, which appears to be infrequent (Rawson et al; Vaughn et al). However, empiric antimicrobials may still be indicated at least temporarily during workup for indications such as shock or in situations where there is a high risk of not treating empirically. The recommended initial regimen for community acquired pneumonia is Ampicillin if the patient is unable to take oral medications, or high-dose Amoxicillin if able to take oral medications with the addition of Azithromycin in school-aged and adolescent patients (Bradley et al) (IDSA Guidelines).