Coronavirus Disease 2019 (COVID-19) in Children

Coronavirus disease 2019 (COVID-19) is an illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the United States and throughout the world, fewer cases of COVID-19 have been reported in children than in adults. Whereas children comprise slightly over 22% of the US population, 17.2% of all cases of COVID-19 reported to the Centers for Disease Control and Prevention (CDC) were among children (as of January 11, 2023). ^[1]  Most cases in children are mild, and treatment consists of supportive care.  

The American Academy of Pediatrics (AAP) reports children represent 18.1% of all cases in the 49 states reporting by age; nearly 15.2 million children have tested positive in the United States since the onset of the pandemic as of January 5, 2023. This represents an overall rate of 20,247 cases per 100,000 children. During the 2-week period of December 22, 2022, to January 5, 2023, there was less than a 1% increase in the cumulated number of children who tested positive, representing 66,323 new cases. In the week from December 29, 2022, to January 5, 2023, cases in children numbered 31,153 and represented 9.8% of the new weekly cases. ^[2]  As of June 16, 2022, owing to only a portion of states reporting hospitalizations and deaths, the AAP are no longer providing updates on cumulative hospitalizations and mortality data. Hospital admissions can be found at the CDC COVID Data Tracker. 

Signs and symptoms of COVID-19 in children

Common symptoms of COVID-19 in children are cough and fever. It is important to note, however, that these symptoms may not always be present and may not be the classic symptoms seen in adult patients; thus, a high index of suspicion for SARS-CoV-2 infection is required in children. ^{[3, 4, 5]}  Other symptoms include the following:

• Shortness of breath
• Pharyngeal erythema/sore throat
• Diarrhea
• Myalgia
• Fatigue
• Rhinorrhea
• Vomiting
• Nasal congestion
• Abdominal pain
• Conjunctivitis
• Rash
• Loss of sense of taste (ageusia) and/or smell (anosmia)

Diagnosis

Laboratory studies

Although a consistent pattern of characteristic laboratory findings has not yet been identified in children with confirmed COVID-19, the following abnormalities have been observed:

• Lymphopenia
• Increased levels of liver and muscle enzymes and lactate dehydrogenase
• Increased myoglobin and creatine kinase isoenzyme levels
• Elevated C-reactive protein (CRP) level
• Elevated erythrocyte sedimentation rate
• Increased procalcitonin level
• Elevated D-dimer
• Elevated ferritin
• Elevated fibrinogen
• Abnormalities in prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin time (PTT)

If antivirals or immunomodulators are being used, it is important to follow the above laboratory values both to monitor for drug-induced toxicity and to measure the clinical and laboratory response to treatment. In patients who are clinically deteriorating, these laboratory findings should be used to monitor the development of hyperinflammation that may warrant the use of more aggressive immunomodulatory agents.

Imaging studies

Common chest radiograph findings in children with COVID-19 pneumonia include bilaterally distributed peripheral and subpleural ground-glass opacities and consolidation. ^[6]

Findings observed on computed tomography (CT) of the chest in children with COVID-19 include the following:

• Ground-glass opacities/nodules
• Consolidation with a surrounding halo sign
• Bilateral or local patchy shadowing
• Interstitial abnormalities

Management

Treatment consists mainly of supportive care, including oxygen therapy in children with hypoxia. 

The antiviral agent remdesivir, an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, is indicated for treatment of COVID-19 in adults and pediatric patients aged 28 days and older who weigh at least 3 kg. Dosage regimens are available for those requiring hospitalization, or are not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19. 

Two mRNA vaccines – BNT-162b2 (Pfizer) and mRNA-1273 (Moderna) – have gained full FDA approval for individuals aged 12 years and older and 18 years and older, respectively. Two other vaccines are available via EUAs for adults in the United States, including a viral vector vaccine – Ad26.COV2.S (Johnson & Johnson) – and an adjuvanted protein subunit vaccine – NVX-CoV2372 (Novavax).

On June 17, 2022, the FDA granted emergency use authorization for the Moderna and Pfizer vaccines for children aged 6 months and older.  

EUAs have been issued for other vaccines, monoclonal-directed antibodies, convalescent plasma, baricitinib (a Janus kinase inhibitor), and tocilizumab (an interleukin-6 inhibitor) in the United States. A full list of EUAs and access to the Fact Sheets for Healthcare Providers is available from the FDA.

Use of corticosteroids improves survival in hospitalized patients with severe COVID-19 disease requiring supplemental oxygen, with the greatest benefit shown in those requiring mechanical ventilation. Dexamethasone was the first drug to reduce mortality from COVID-19, shown in the RECOVERY trial in March 2020 to reduce the 28-day mortality rate by 17%, reducing deaths by one-third in ventilated patients and by one-fifth in patients receiving oxygen only. There was no benefit seen in patients who did not require respiratory support. ^[7]

Please see Coronavirus Disease 2019 (COVID-19) for continually updated clinical guidance concerning COVID-19, Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies for updated drug information, and COVID-19 Vaccines for current information about the vaccines. Health care personnel are also referred to Medscape’s Novel Coronavirus Resource Center for the latest news, perspective, and resources.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease was first reported in December 2019 from Wuhan, Hubei province, China and has since spread throughout the world. The World Health Organization declared a global pandemic on March 11, 2020. As of January 1, 2022, there are over 288 million confirmed cases of COVID-19 and over 5.4 million deaths reported globally. In the United States, confirmed cases as of January 1, 2022, are nearly 55 million with over 825,000 deaths. ^[8] As these numbers are constantly changing, the reader is referred to the Johns Hopkins Coronavirus Resource Center, CDC, and WHO websites for the most recent official numbers.

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infection is characterized by an initial cytokine storm that can result in acute respiratory distress syndrome and macrophage activation syndrome. This initial phase is then followed by a period of immune dysregulation, which is the major cause of sepsis-related fatalities. ^[9]

While we are learning more about SARS-CoV-2 infection almost daily, differences between adult and pediatric disease are likely the result of changes within both immune function and the angiotensin-converting enzyme (ACE) 2 receptor, used by the virus to enter type II pneumocytes in the lung. Decreases in ACE2 seen in animal models of aging result in changes in neutrophil influx and resultant lung injury. Not only has it been hypothesized that the maturity and function of ACE2 may be lower in children than adults, but the distribution of the receptor may also be different. ^[10]  Thus, immunosenescence and changes in inflammatory responses with age likely account for the different spectrum and severity of disease in children versus adults and, furthermore, in neonates versus older children. The profound lymphopenia seen in patients with COVID-19 is likely the result of T lymphocyte infection and death that occurs as SARS CoV-2 infects these cells. ^[11]  

As the infection progresses, with acceleration in viral replication and epithelial-endothelial injury, the inflammatory response is accentuated. Interstitial mononuclear inflammatory infiltrates and edema followed by hyaline membrane formation occurs leading to acute respiratory distress syndrome (ARDS). These changes may be visible as ground glass opacities on a CT scan. Further injury to the endothelial tissues results in microthrombi formation and can lead to thrombotic complications such as pulmonary embolism, venous thrombosis, and thrombotic arterial complications as seen in severely ill patients. These complications have been seen more in adult than in pediatric patients, although they have been reported in the latter as well. Secondary sepsis in these individuals further contributes to the severity of the illness. ^{[12, 13, 14]}

Transmission

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) is a highly infectious virus, ^[15]  and the main routes of transmission are respiratory droplets, contact with respiratory secretions and saliva, and aerosol particles. ^[16] SARS CoV-2 can remain viable on various surfaces for hours to days, although transmission is much more common through respiratory droplets and aerosol particles than through fomites. ^[17]  Fecal shedding has been detected for several weeks after diagnosis, which has led to concerns about fecal-oral transmission of the virus. ^[18]

Mother-to-child transmission

Based on limited data, no confirmed cases of vertical mother-to-fetus intrauterine transmission of the virus have been reported thus far. ^{[19, 20]}  It may also be valuable to note that vertical transmission of the SARS-CoV-2 from 2005 infected mothers to newborns was not observed.  ^[21] A multicenter study involving 16 Spanish hospitals reported outcomes of 242 pregnant women diagnosed with COVID-19 during their third trimester from March 13 to May 31, 2020. The women and their 248 newborns were monitored until the infant was 1 month old. COVID-19–positive mothers who were hospitalized had a higher risk of ending their pregnancy via cesarean section (P = .027). Newborns whose mothers had been admitted owing to their COVID-19 infection had a higher risk of premature delivery (P = .006). No infants died, and no vertical or horizontal transmission was detected. The percentage of infants exclusively breastfed at discharge was 41.7% and was 40.4% at 1 month. ^[22]

To date, SARS CoV-2 has not been detected in breast milk. A study by Chambers et al found human milk is unlikely to transmit SARS CoV-2 from infected mothers to infants. ^[23] The study included 64 milk samples provided by 18 mothers infected with COVID-19. Samples were collected before and after COVID-19 diagnosis. No replication-competent virus was detectable in any of their milk samples compared with samples of human milk that were experimentally infected with SARS CoV-2.

Family clustering

Family clustering appears to play a major role in disease transmission. In one report, transmission through familial exposure in pediatric COVID-19 infection is estimated to be between 45% and 91%. ^[24]  Most of the children in the US data also had exposure to a patient with COVID-19 in the household or community. ^[3]

Conversely, transmission of SARS-CoV-2 from 12 young children who acquired COVID-19 at childcare facilities to family members has been reported. Findings showed 25% of their close contacts became infected—most often mothers or siblings. Three of the children were asymptomatic, two of whom likely infected their contacts, including a mother who required hospitalization. One mildly symptomatic child too young for face masks (age 8 months) likely infected both parents. ^[25]

Posfay-Barbe et al reported on the transmission of SARS-CoV-2 within the families of 39 children (aged < 16 years) with confirmed infection in Geneva, Switzerland. ^[26]  In 31 of 39 households (79%), at least one adult family member had a suspected or confirmed SARS-CoV-2 infection before symptoms occurred in the child. In only 3 of 39 households (8%), the child was the first family member to develop symptoms. These findings suggest that children most often acquire COVID-19 from adult family members rather than transmitting the virus to them.

A study from South Korea found that older children and adolescents are more likely to transmit SARS-CoV-2 to family members than are younger children. The researchers reported that the highest infection rate (18.6%) was in household contacts of patients with COVID-19 aged 10-19 years and the lowest rate (5.3%) was in household contacts of those aged 0-9 years. ^[27]

In contrast, Canadian researchers found that infants and toddlers (up to age 3) were about 43% more likely than adolescents (aged 14-17 years) to transmit SARS-CoV-2 to household contacts. Data were analyzed from 6280 households with a pediatric COVID-19 case and a subset of 1717 households in which a household member younger than age 17 was the source of transmission. ^{[28, 29]}

Community transmission

Cruz and Zeichner suggested that children have a role in community-based viral transmission. ^[30]  They noted that children are more likely than adults to have upper respiratory tract involvement, including nasopharyngeal carriage. They may also have prolonged respiratory and fecal shedding. ^[31]  We continue to learn more as data emerge and more cases in children are described.

More data are emerging on the role of children in the spread of the disease. Simulation results from mathematical models of the effect of delayed school opening in South Korea showed that the number of cases could be reduced by at least 200 over a 3-week period. The models were based on different school opening dates and assumed a 10-fold increase in the transmission rate after schools opened. ^[32]

Ertem et al concluded that schools do not substantially increase community case rates. In most regions of the United States, the incidence of SARS-CoV-2 infection was not statistically different in counties with in-person school attendance compared with those with remote learning. ^[33]

Child care facilities can play a role in the transmission of SARS CoV-2. A CDC study found that 12 children who acquired COVID-19 at facilities in Utah spread the virus to at least 12 (26%) of 46 household contacts (confirmed or probable cases). ^[25]

The results of a South Korean study lend more data to unapparent infections in children that may be associated with silent COVID-19 community transmission. A case series of 91 children who tested positive for COVID-19 in South Korea showed 22% were asymptomatic during the entire observation period. Among 71 symptomatic cases, 47 children (66%) had unrecognized symptoms before diagnosis, 18 (25%) developed symptoms after diagnosis, and 6 (9%) were diagnosed at the time of symptom onset. Twenty-two children (24%) had lower respiratory tract infections. The mean (SD) duration of the presence of SARS-CoV-2 RNA in upper respiratory samples was 17.6 (6.7) days. ^[34]

However, researchers in Milan, Italy, suggest that the role of asymptomatic children in the transmission of SARS-CoV-2 infection may need to be reconsidered, based on the results of their case-control study. Among patients hospitalized for noninfectious conditions, who had no signs or symptoms of COVID-19, only 1 in 83 children (1.2%) tested positive for SARS-CoV-2, compared with 12 in 131 adults (9.2%). ^[35]

A US study failed to identify any instance of child to adult transmission, but less than half of participants had a household contact with COVID-19. This finding contrasts with data from other studies that implicated household sick contacts as the main driver of childhood infection. ^[36]  Teenagers have been shown to be the source of clusters of cases, which illustrates the role of older children. ^[37]

Fewer cases of coronavirus disease 2019 (COVID-19) have been diagnosed in children than in adults, and the majority of the pediatric cases have been mild. Whereas children comprise slightly over 22% of the US population, 17.2% of all cases of COVID-19 reported to the Centers for Disease Control and Prevention (CDC) were among children (as of January 11, 2023). This initial paucity and decreased severity of cases in children as compared to adults was thought to be because children generally have less exposure, especially those who are cared for at home, and they typically experience more winter respiratory tract infections and may have higher antibody to virus than adults. ^[10]  The number and rate of cases in children in the US have been steadily increasing. ^[1]

The true incidence of SARS-CoV-2 infection in children is not known, owing to the lack of widespread testing and the prioritization of testing for adults and those with severe illness. Hospitalization rates in children are significantly lower than hospitalization rates in adults with COVID-19, which suggests that children may have less severe illness from COVID-19 compared with adults. ^[1]

The American Academy of Pediatrics (AAP) reports children represent 18.1% of all cases in the 49 states reporting by age; nearly 15.2 million children have tested positive in the United States since the onset of the pandemic as of January 5, 2023. This represents an overall rate of 20,247 cases per 100,000 children. During the 2-week period of December 22, 2022, to January 5, 2023, there was less than a 1% increase in the cumulated number of children who tested positive, representing 66,323 new cases. In the week from December 29, 2022, to January 5, 2023, cases in children numbered 31,153 and represented 9.8% of the new weekly cases. ^[2] As of June 16, 2022, owing to only a portion of states reporting hospitalizations and deaths, the AAP are no longer providing updates on cumulative hospitalizations and mortality data. Hospital admissions can be found at the CDC COVID Data Tracker. ^[2]

In the United States, a modeling study found one child loses a parent or caregiver for every four COVID-19 associated deaths. From April 1, 2020 through June 30, 2021, more than 140,000 children younger than 18 years in the United States lost a parent, custodial grandparent, or grandparent caregiver who provided the child’s home and basic needs. Overall, the study showed that about one of 500 children in the United States has experienced COVID-19-associated orphanhood or the death of a grandparent caregiver. The study also revealed racial, ethnic, and geographic disparities in COVID-19-associated death of caregivers: children of racial and ethnic minorities accounted for 65% of those who lost a primary caregiver due to the pandemic. ^{[38, 39]}

An estimated 10.5 million children throughout the world have experienced the loss of a parent or caregiver because of COVID-19–associated deaths, according to a modeling study from the CDC and WHO. The highest numbers of children who have been affected by orphanhood are in Africa and Southeast Asia. ^[40]

Race-, sex-, and age-related demographics

No racial predilection has been observed in children, although US data in adults suggest that minority communities are affected disproportionately. ^[41]  A CDC study found that a disproportionate percentage of the deaths related to COVID-19 among persons aged < 21 years occurred in Black and Hispanic youths. Of the 121 deaths reported to CDC by July 31, 2020, 94 (78%) were among Hispanic, non-Hispanic Black, and non-Hispanic American Indian/Alaskan Native persons. ^[42]  Emerging data suggest that children aged < 10 years may be less susceptible to SARS CoV-2 infection compared with adults. ^{[43, 44]}

In a retrospective Chinese study of 2143 children younger than 18 years with confirmed or suspected COVID-19, slightly more of the cases occurred in boys (56.6%) than in girls (43.4%), but the difference was not statistically significant. The ages of the children in the study ranged from 1 day to 18 years; the median age was 7 years. ^[45]  Slight male predominance was also seen in the US data, similar to what was observed in China. ^[3]

While the numbers are much smaller than in adults, emerging data do suggest that children of color are disproportionately affected, similar to what has been reported in adults. ^[46]  It has been reported that the cumulative hospitalization rate is eight times higher in children of Hispanic ethnicity and five times higher in African American as compared to White children. ^[47] A study from Detroit, Michigan, reported an 82% hospitalization rate among African American and Hispanic children, up to ten times the national rate for pediatric hospitalizations, with a 37% ICU admission rate, compared to the 1.7-16% previously reported. ^[48]

Morbidity/mortality

Morbidity

Overall, current data continue to support the fact that whereas children are infected with SARS-CoV-2 similar to adults, they are more likely to be asymptomatic or to have less severe disease. ^[49]

Although most children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have either asymptomatic infection or mild illness, severe illness has been reported in 2.5% of pediatric cases in China, according to the World Health Organization (WHO). ^[50]  In a study of more than 2000 children in China, Dong et al found that approximately 4% of children with coronavirus disease 2019 (COVID-19) were asymptomatic, 51% had mild illness, and 39% had moderate illness. About 6% of pediatric patients had severe or critical illness, and one patient (a 14-year-old boy) died. ^[45]

The Chinese investigators also found that severe or critical illness was more common in infants and toddlers than in older children. More than 10% of infants had severe or critical illness compared with 7% of children aged 1-5 years, 4% of those aged 6-10 years, 4% of those aged 11-15 years, and 3% of those aged 16 years or older. ^[45]

The data from China showed that most children with COVID-19 recovered within 1-2 weeks after the onset of symptoms. ^[50]

Data on hospitalizations from 25 states and New York City showed that children were 0.7-3.6% of total reported hospitalizations, and between 0.2-7.9% of all child COVID-19 cases resulted in hospitalization. ^[51]  

CDC researchers used data from the Premier Healthcare Database Special COVID-19 Release to identify patients aged 18 years or younger with an inpatient or emergency department encounter with a primary or secondary COVID-19 discharge diagnosis (March 1 to October 31, 2020). ^[52] Among 20,714 pediatric patients with COVID-19 (52.9% girls; 53.8% aged 12-18 years), nearly 1 in 3 patients had 1 or more chronic conditions (29.2%). Overall, 11.7% were hospitalized, and one-third of those hospitalized (31.1%) experienced severe COVID-19.

An association was observed between severe COVID-19 and having 1 or more chronic conditions versus having none (adjusted odds ratio, 3.27). Additionally, severe COVID-19 was more likely in hospitalized children aged 2-5 years or 6-11 years compared with those aged 12-18 years (adjusted odds ratios, 1.53 and 1.53, respectively); this finding was also true for male versus female patients (adjusted odds ratio, 1.52). ^[52]

In a retrospective cohort study, Martin et al found that rates of SARS-CoV-2-positive upper airway infection rose among children during the period that Omicron (B.1.1.529) became the dominant strain of the virus. Among children hospitalized with COVID, the percentage of those with upper airway disease increased from 1.5% (206 of 14,473) in the pre-Omicron period to 4.1% (178 of 4376) in the Omicron period (P <  .001). During the Omicron period, SARS-CoV-2-positive upper airway infections were more common in younger and Hispanic or Latino children. ^[53]  For more information about the Omicron variant, see COVID-19 Variants.

Mortality

The CDC reports that 121 deaths related to SARS-CoV-2 infection occurred among persons younger than 21 years of age in the United States from February to July 2020. Of the persons who died, 63% were male, 10% were aged < 1 year, 20% were aged 1-9 years, and 70% were aged 10-20 years. Ninety-one (75%) had an underlying medical condition. ^[42]

Complications

Although cardiovascular complications of COVID-19 are rare in children and adolescents, SARS-CoV-2 infection can cause arrhythmias, myocarditis, pericarditis, and multisystem inflammatory syndrome (MIS-C). (See the Multisystem Inflammatory Syndrome in Children section for more detail.) The arrhythmias seen in children with COVID-19 have included ventricular tachycardia and atrial tachycardia, in addition to first-degree atrioventricular block. In patients with myocardial involvement, elevated troponin levels, electrocardiographic abnormalities, including ST-segment changes, and delayed gadolinium enhancement on cardiac magnetic resonance imaging have been observed. ^{[54, 55]}

A study by Edlow et al found that neurodevelopmental disorders in the first year of life were more common among infants born to mothers with SARS-CoV-2 infection during pregnancy. The risk was greatest among infants who were exposed during the third trimester. ^{[56, 57]}

A meta-analysis by D’Souza et al found that the incidence of type 1 diabetes mellitus rose among children and adolescents during the COVID-19 pandemic. The review demonstrated a higher incidence of type 1 diabetes in the first year (incidence rate ratio [IRR], 1.14) and second year (IRR, 1.27) of the pandemic. The investigators also reported an increase in the incidence of diabetic ketoacidosis (IRR, 1.26). ^{[58, 59]}

History

The typical incubation period of coronavirus disease 2019 (COVID-19) ranges from 1 to 14 days, with an average of 3-7 days ^{[60, 61]}  (mean, 6.4 days ^[62] ). However, longer incubation periods (up to 24 days) have been reported. ^[63]  In most of the early pediatric cases reported from China, the patient had a close contact with COVID-19 or was part of a family cluster of cases. ^[64]  

Physical examination

Lu et al evaluated 171 children with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who were treated at the Wuhan Children’s Hospital in China. ^[4]  They reported that the most common signs and symptoms were cough (48.5% of patients), pharyngeal erythema (46.2%), and fever (41.5%). Other signs and symptoms included the following:

• Diarrhea (8.8% of patients)
• Fatigue (7.6%)
• Rhinorrhea (7.6%)
• Vomiting (6.4%)
• Nasal congestion (5.3%)

About 29% of patients had tachypnea on admission, and about 42% had tachycardia. Slightly more than 2% of children had an oxygen saturation of < 92% during their hospitalization. ^[4]

Wu et al reported on the clinical characteristics of 68 pediatric patients with COVID-19 in China. ^[65] They found that the most common initial symptoms among the 44 symptomatic patients were cough (32.43%) and fever (27.03%). This finding also highlights the significant number of children with SARS-CoV-2 infection who are asymptomatic.

We know now that gastrointestinal manifestations often accompany the initial presentation with fever. These commonly include abdominal pain, diarrhea, and/or vomiting. Neurologic manifestations have also been described. ^{[66, 67, 68]}

Rash has been reported in patients with COVID-19. ^[69]  An 8-year-old Italian girl with confirmed SARS-CoV-2 infection presented with an asymptomatic papulovesicular exanthem and mild cough. Her symptoms resolved without therapy within a week. ^[70]

Hoang et al published a systematic review of 7780 pediatric COVID-19 cases, comprising 131 studies spanning 26 countries. The mean age was 8.9 years (SD, 0.5), and 75% were exposed to family with COVID-19. The most common symptoms included fever in 59% and cough in 56%; 19% were asymptomatic. The overall mortality rate was 0.09%. ^[71]  In general, symptoms are less pronounced in children when compared with adults. ^[3]

According to Shen et al, children with SARS-CoV-2 infection who are at risk for severe disease include those with underlying conditions (eg, congenital heart disease, bronchial pulmonary hypoplasia, respiratory tract anomaly, abnormal hemoglobin level, or severe malnutrition) and those with immune deficiency or immunocompromised status (eg, as a result of long-term immunosuppressant use). ^[61]  The following conditions indicate a greater likelihood of severe disease:

• Dyspnea: Respiration rate of >50 breaths/min in children aged 2-12 months; >40 breaths/min in children aged 1-5 years; >30 breaths/min in patients older than 5 years old (after excluding the effects of fever and crying).
• Persistent high fever for 3-5 days.
• Poor mental response, lethargy, disturbance of consciousness, and other changes of consciousness.
• Abnormally increased levels of enzymes, such as myocardial and liver enzymes and lactate dehydrogenase.
• Unexplained metabolic acidosis.
• Chest imaging findings indicating bilateral or multi-lobe infiltration, pleural effusion, or rapid progression of conditions during a very brief period.
• Age younger than 3 months.
• Extrapulmonary complications.
• Coinfection with other viruses or bacteria.

Xia et al found that 8 of 20 pediatric inpatients with COVID‐19 infection were co-infected with other pathogens, including influenza viruses A and B, mycoplasma, respiratory syncytial virus, and cytomegalovirus. ^[72]

Chao et al retrospectively reviewed medical charts for all children aged 1 month to 21 years between March 15 and April 13, 2020 who were seen at Children’s Hospital Emergency Department at Montefiore in New York City. Sixty-seven patients (34.5%) tested positive for SARS-CoV-2 infection. Of these, 46 patients were admitted to the hospital, with 13 requiring PICU care. The most common symptoms at admission were cough (63%) and fever (50.9%). The clinical symptom found to be significantly associated with PICU admission was shortness of breath (92.3% vs 30.3%; P< .001). ^[73]  

The following conditions are included in the differential diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection:

• Adenovirus infection
• Bacterial pneumonia
• Chlamydia pneumoniae
• Human metapneumovirus infection
• Influenza
• Mycoplasma pneumoniae
• Parainfluenza virus infection
• Respiratory syncytial virus infection
• Rhinovirus infection
• Severe acute respiratory syndrome (SARS)

Laboratory studies

A consistent pattern of laboratory abnormalities has not yet been identified in children with confirmed coronavirus disease 2019 (COVID-19), although some patterns are emerging. ^[74]  Early in the course of the disease, the white blood cell count is normal or decreased, and the lymphocyte count is decreased. The majority of patients have normal neutrophil counts.

In a study by Wu et al of 68 pediatric patients with COVID-19 in China, 23 children (31.08%) had abnormal white blood cell counts, and 10 (13.51%) had an abnormal lymphocyte count. ^[65] Slightly more than half of the children who underwent nucleic acid testing for common respiratory pathogens showed co-infection with pathogens other than SARS-CoV-2. This finding illustrates the need to test for COVID-19 even in the setting of other confirmed viral infections. Finally, 10 (13.51%) children in the study had reverse transcription–polymerase chain reaction (RT-PCR) analysis of fecal specimens, and 8 demonstrated the prolonged existence of SARS-CoV-2 RNA. This finding may suggest the risk of further transmission.

Levels of liver and muscle enzymes and myoglobin are increased in some children. Many patients have elevated C-reactive protein (CRP) levels and erythrocyte sedimentation rates. In severe cases, patients have high D-dimer levels and progressively decreasing lymphocyte counts. ^[61]

In a literature review of case reports involving 66 children and adolescents with confirmed COVID-19, Henry et al found that CRP and procalcitonin (PCT) levels were elevated in 13.6% and 10.6% of cases, respectively. ^[75]  In a study that included 20 pediatric inpatients in Wuhan, China, 80% of the children had elevated PCT levels. ^[4]  Because PCT values can increase significantly in systemic bacterial infections and sepsis, higher levels are strongly suggestive of bacterial co-infection in patients with COVID-19. ^[76]

For more information on testing, please see Laboratory Studies in Coronavirus Disease 2019 (COVID-19).

Imaging studies

Common chest radiograph findings in children with COVID-19 pneumonia include bilaterally distributed peripheral and subpleural ground-glass opacities and consolidation. Nonspecific findings include the following ^[6] :

• Unilateral ground-glass opacities and consolidation
• Bilateral peribronchial thickening and peribronchial opacities
• Multifocal or diffuse ground-glass opacities and consolidation without specific distribution

A common abnormality seen on computed tomography (CT) of the chest in children with COVID-19 is ground-glass opacity and nodules, which are usually bilateral. ^[4]  Other CT findings include the following:

• Local patchy shadowing
• Bilateral patchy shadowing
• Interstitial abnormalities

Chest CT findings in children with COVID-19 are similar to those seen in adults. Xia et al reported that consolidation with a surrounding halo sign was observed in up to 50% of cases, and they suggested that this finding could be considered a typical sign in pediatric patients. ^[72]  Pleural effusion is rare. Radiographic changes may be seen in children without severe disease.

Imaging recommendations

Chest imaging is not generally recommended for initial screening of mildly symptomatic or asymptomatic children with suspected COVID-19 unless they are at risk for disease progression or have worsening symptoms, according to an international expert consensus statement. ^[6]  It is worth noting that some institutions may include radiographic evidence of pneumonia as a criterion for initiation of remdesivir or other immunomodulatory agents.

An initial chest radiograph may be appropriate for children with moderate to severe symptoms, and a chest CT scan may be warranted if the results could affect clinical management. A series of chest radiographs may be useful to assess therapeutic response, evaluate clinical worsening, or determine positioning of life support devices.

Post-recovery imaging may be appropriate for asymptomatic children who initially had moderate to severe illness and who may be at risk for long-term lung injury. In addition, follow-up imaging may be warranted for children with persistent or worsening symptoms regardless of the severity of the initial illness.

Supportive care

Recommendations for supportive care for children with coronavirus disease 2019 (COVID-19) are similar to those for adults. Among the recommendations are bed rest and ensuring sufficient calorie and water intake. Oxygen therapy is recommended for patients with hypoxia. Antibiotics should generally be reserved for children with bacterial co-infection. ^[61]

Prevention

Vaccines

The American Academy of Pediatrics recommends that children and adolescents aged 6 months and older receive the COVID-19 vaccine.

The FDA has granted full approval for 2 mRNA vaccines – BNT-162b2 (Pfizer) in adolescents and adults, and mRNA-1273 (Moderna) in adults. 

On June 17, 2022, the FDA granted emergency use authorization for the Moderna and Pfizer vaccines for children aged 6 months and older.  

The FDA authorized Moderna and Pfizer bivalent COVID-19 vaccines for booster doses in August 2022 for adolescents and adults, and for children as young as 5 years in October 2022, and for children aged 6 months and older in December 2022. The bivalent vaccines contain original (wild-type spike protein) plus an omicron BA.4/BA.5 subvariants spike protein. These vaccines replace the use of the original monovalent vaccines for booster doses. The bivalent boosters may be administered at least 2 months after either completion of primary vaccination with any monovalent COVID-19 vaccine or receipt of the most recent booster dose.

FDA approval of BNT-162b2 (Pfizer) in adolescents aged 12-17 years was based on extrapolation of safety and effectiveness from adults aged 18 years and older. The phase 3 trial data lists the vaccine as 100% effective in preventing SARS-CoV-2 infection in this age group. The study for younger adolescents was conducted between October 15, 2020 and January 12, 2021.  There were no cases of COVID-19 disease in adolescents aged 12-15 years who received the vaccine (n = 1,131), compared with 18 cases in those who received placebo (n = 1,129). ^[77]

On October 29, 2021, the FDA authorized the BNT-162b2 vaccine to include children aged 5-11 years. The dose for this age group is smaller than the dose for adults and adolescents. The vaccine is packaged in a smaller vial size and strength specific for younger children. A booster dose for children aged 5-11 years was authorized on May 17, 2022, for administration at least 5 months after completing a primary series with BNT-162b2.

As the vaccination regimen evolves to include boosters and timing of primary series doses, the CDC has an interim COVID-19 immunization schedule. The schedule includes the 3 vaccines described above, dosage regimens, and boosters, including those for moderately or severely immunocompromised individuals. For the mRNA vaccines, an 8-week interval may be optimal for some people, including males aged 12-39 years owing to the small risk of myocarditis associated with mRNA COVID-19 vaccines. Vaccine effectiveness may also be increased with an interval longer than 3 or 4 weeks (depending on the product). 

Treatment

Antiviral Agents

Remdesivir

Remdesivir, an antiviral agent, is the only drug fully approved for treatment of COVID-19. It gained FDA approval for young children in April 2022. Numerous antiviral agents and immunotherapies are being investigated as potential therapies. ^{[78, 79, 80]}

Remdesivir is indicated for treatment of COVID-19 in adults and pediatric patients aged 28 days and older who weigh at least 3 kg. Dosage regimens are available for those requiring hospitalization, or are not hospitalized and have mild-to-moderate COVID-19 and are at high risk for progression to severe COVID-19.

Note that treatment does not preclude isolation and masking for those who test positive for SARS-CoV-2.

Inpatient remdesivir

The initial EUA for remdesivir was based on preliminary data analysis of the Adaptive COVID-19 Treatment Trial (ACTT) and was announced on April 29, 2020. The final analysis included 1,062 hospitalized patients with advanced COVID-19 and lung involvement, showing that patients treated with 10 days of remdesivir recovered faster than similar patients who received placebo. Results showed that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (P< 0.001). Specifically, the median time to recovery was 10 days in patients treated with remdesivir compared with 15 days in those who received placebo. Patients with severe disease (n = 957) had a median time to recovery of 11 days compared with 18 days for placebo. A statistically significant difference was not reached for mortality by day 15 (remdesivir 6.7% vs placebo 11.9%) or by day 29 (remdesivir 11.4% vs placebo 15.2%). ^[81]  

Remdesivir has been available through compassionate use to children with severe COVID-19 disease since February 2020. The CARAVAN phase 2/3 trial was initiated in June 2020 to assess safety, tolerability, pharmacokinetics, and efficacy of remdesivir in children with moderate-to-severe COVID-19. CARAVAN is an open-label, single-arm study of remdesivir in children from birth to age 18 years. Interim results were reported in February 2022 in children aged 28 days to younger than 18 years from 53 participants. More than half (57%) were on high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) at baseline.  Overall, 60% of patients were discharged by Day 10, and 83% by Day 30. Three patients (6%) died during the study; all had complex medical histories, including multisystem organ failure and cardiorespiratory arrest, which were not considered treatment related. The study is ongoing and includes term and preterm neonates. ^[82]

Early in the pandemic, data were presented on compassionate use of remdesivir in children at the virtual COVID-19 Conference held July 10-11, 2020. Results showed most of the 77 children with severe COVID-19 improved with remdesivir. Clinical recovery was observed in 80% of children on ventilators or extracorporeal membrane oxygenation and in 87% of those not on invasive oxygen support. ^[83]

A study funded by the National Institutes of Health will assess the pharmacokinetics of drugs currently given to children and adolescents with COVID-19, including antiviral and anti-inflammatory agents. The goal of this study is to provide specific dosing recommendations and safety data for these drugs in pediatric patients. Data will be collected at more than 40 sites throughout the United States. ^[84]  

Outpatient remdesivir

Remdesivir gained approval from the FDA for outpatient use in nonhospitalized adults and pediatric patients aged 12 years and older who weigh at least 40 kg with mild-to-moderate COVID-19 who are at high risk for progression to severe disease, including hospitalization or death. In April 2022, the FDA approved remdesivir for children aged 28 days and older (who weigh at least 3 kg). 

Approval for adults and adolescents was based on results from the PINETREE study that evaluated three consecutive daily infusions of remdesivir administered on an outpatient basis. Among 562 patients who were at high risk for COVID-19 progression, remdesivir or placebo was administered within 7 days of symptom onset. The researchers found that a 3-day course of remdesivir resulted in an 87% lower risk of hospitalization or death compared to placebo (P = .008). Overall, 2 of 279 patients who received remdesivir (0.7%) required COVID-19 related hospitalization compared with 15 of 283 patients who received a placebo (5.3%). The study included patients who tested positive for SARS-CoV-2 with symptom onset within the previous 7 days and at least 1 risk factor for disease progression. Patients received either 3 consecutive days of IV remdesivir (200 mg IV on Day 1, then 100 mg on Days 2 and 3) or placebo. ^[85] Data are currently limited at this time, but remdesivir is expected to be effective against the Omicron variant. 

The outpatient remdesivir dose for children weighing less than 40 kg is 5 mg/kg IV on Day 1, then 2.5 mg/kg on Days 2 and 3. 

Investigational Antivirals

Nirmatrelvir/ritonavir

Nirmatrelvir/ritonavir (Paxlovid) was granted an EUA on December 22, 2021, for treatment of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years and older who weigh at least 40 kg who test positive for SARS-CoV-2 virus, and are at high risk for progression to severe COVID-19, including hospitalization or death. Nirmatrelvir inhibits SARS-CoV2-3CL protease, and thereby inhibits viral replication at the proteolysis stage (ie, before viral RNA replication). Nirmatrelvir is combined with low-dose ritonavir to slow its metabolism and provide higher systemic exposure.  

Final analysis of the phase 2/3 trial Evaluation of Protease Inhibition for COVID-19 in Nonhospitalized High-Risk Adults (EPIC-HR) (n = 2246) has been completed. Results showed nirmatrelvir/ritonavir reduced the risk of hospitalization or death by 89% when initiated within 3 days of symptom onset and by 88% when initiated within 5 days of symptom onset compared with placebo. Hospitalization through day 28 among patients who received nirmatrelvir/ritonavir within 3 days was 0.7% (5/697 hospitalized with no deaths), compared with 6.5% of patients who received placebo and were hospitalized or died (44/682 hospitalized with 9 subsequent deaths) (P< .0001). Similarly, patients who received nirmatrelvir/ritonavir within 5 days had a reduced risk of hospitalization or death for any cause by 88% compared with placebo (P< .0001). ^[86]  

Molnupiravir 

An EUA for molnupiravir was granted on December 23, 2021, for treatment of mild-to-moderate COVID-19 in adults aged 18 years and older who test positive for SARS-CoV-2 virus, and are at high risk for progression to severe COVID-19, including hospitalization or death. Molnupiravir is not recommended for treatment of COVID-19 in children aged 18 years or younger. Also, it is not recommended in pregnant females. 

The phase 3 MOVe-OUT study (n = 1433) found molnupiravir reduced risk of hospitalization or death from 9.7% (68 of 699) in the placebo group to 6.8% (48 of 709) in the molnupiravir group for an absolute risk reduction of 3% (p = 0.02) and a relative risk reduction of 30%. ^[87]  

Antibody-Directed Therapy

Monoclonal antibody effectiveness

Monoclonal antibodies that have gained emergency use authorization are continually tested to evaluate activity against VOCs. 

Data analyzed by the FDA and NIH in mid-December 2021 found tixagevimab plus cilgavimab (Evusheld) and sotrovimab retain their neutralizing activity against the Omicron B.1.1.529 variant. However, casirivimab plus imdevimab (REGN-COV) and bamlanivimab plus etesevimab lost most of their effectiveness when exposed in laboratory tests to Omicron B.1.1.529. Bebtelovimab has also shown to be effective against the Omicron VOC, including the BA.2 variant. 

Sotrovimab showed decreased efficacy against the Omicron BA.2 subvariant that increased in March 2022 in the United States, prompting distribution to be paused in regions with high BA.2 prevalence and within weeks across all US regions. 

Bebtelovimab

An EUA was granted by the FDA on February 11, 2022, for bebtelovimab (LY-CoV1404; Eli Lilly). Bebtelovimab is a neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2 that maintains binding and neutralizing activity across currently known and reported variants of concern, including Omicron and BA.2. 

Data supporting the EUA are primarily based on analyses from the phase 2 BLAZE-4 trial conducted before the emergence of the Omicron VOC. The majority of participants were infected with the delta (49.8%) or alpha (28.6%) VOCs. Efficacy of bebtelovimab, alone and together with bamlanivimab and etesevimab, was evaluated in low-risk adults. High-risk adults and adolescents received open-label active treatments.

Preexposure Prophylaxis in High-risk and Immunocompromised Individuals

Tixagevimab plus cilgavimab

An EUA was granted by the FDA in December 2021 for the long-acting antibodies (LAAB) tixagevimab plus cilgavimab (Evusheld; AstraZeneca) for preexposure prophylaxis of individuals aged 12 years or older (weighing at least 40 kg) who are moderately-to-severely immunocompromised owing to a medical condition or medications/treatment and may not mount an adequate immune response to COVID-19 vaccination, or have a history of severe adverse reactions to a COVID-19 vaccine and/or component(s), who are not currently infected with SARS-CoV-2, and have a known recent exposure. These antibodies prevent viral attachment and entry and confer at least six months of protection.

The EUA was based on results from the phase 3, multicenter PROVENT trial that enrolled 5197 unvaccinated participants, of which 75% had comorbidities that placed them at increased risk for severe COVID-19. Participants were randomized 2:1 to receive a one-time dose of tixagevimab IM and cilgavimab IM (n = 3460 or saline placebo (n = 1737). In the primary efficacy analysis, risk of developing symptomatic COVID-19 was reduced by 77% with tixagevimab plus cilgavimab compared with placebo (P < .001). No cases of severe COVID-19 or COVID-19–related deaths were reported in the study drug arm; in the placebo group, 1 case of severe/critical COVID-19 and 2 COVID-19–related deaths were reported. ^[88]   

Postexposure prophylaxis: Tixagevimab and cilgavimab are not authorized for postexposure prophylaxis of COVID-19 in individuals who have been exposed to someone infected with SARS-CoV-2. The STORM CHASER phase 3 trial did not demonstrate benefit in preventing symptomatic COVID-19 in the first 30 days. However, there was a higher proportion of symptomatic COVID-19 cases among placebo recipients after Day 29. The primary efficacy analysis compared the incidence of a participant’s first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post-dose and before Day 183, did not demonstrate a statistically significant effect for tixagevimab and cilgavimab compared with placebo with 23 cases of symptomatic COVID-19 in the treatment arm (3.1%) and 17 cases in the placebo arm (4.6%). ^[89]    

Treatment: Tixagevimab and cilgavimab are not authorized for treatment of patients with COVID-19 disease. In the TACKLE phase 3 trial (primary analysis n = 822), outpatients with confirmed COVID-19 who had been symptomatic for 7 days or less received either tixagevimab plus cilgavimab 600 mg IM or placebo.  Tixagevimab plus cilgavimab reduced the risk of developing severe COVID-19 or death by 50% compared with placebo (18/407 vs 37/415, respectively). In those administered tixagevimab plus cilgavimab within 5 days of symptom onset, the risk was reduced by 67% compared with placebo (9/253 vs 27/251, respectively). ^[90]    

Immunomodulators 

Besides corticosteroids, tocilizumab and baricitinib are drugs that blunt the hyperinflammation caused by cytokine release and have obtained EUAs for hospitalized patients with severe COVID-19 disease. 

The interleukin-6 (IL-6) inhibitor, tocilizumab, was issued an EUA in June 2021 for hospitalized adults and pediatric patients (aged 2 years and older) with COVID-19 who are receiving systemic corticosteroids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or ECMO. 

Baricitinib is a Janus kinase inhibitor that was granted an EUA in November 2020 for treatment of suspected or laboratory confirmed coronavirus disease 2019 (COVID-19) in hospitalized patients aged 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or ECMO. 

Either of these drugs may be used with or without remdesivir, depending on the stage of COVID-19 disease. 

For more information on investigational drugs and biologics being evaluated for COVID-19, see Treatment of Coronavirus Disease 2019 (COVID-19): Investigational Drugs and Other Therapies.

The American Academy of Pediatrics (AAP) issued interim guidance on follow-up care for infants, children, and adolescents who have had COVID-19. ^[91] All patients who test positive for SARS-CoV-2 should have at least one follow-up visit with their primary care provider. Follow-up visits should occur after the recommended quarantine period and before the patient returns to physical activity.

In general, during the first 4-12 weeks after the illness, the AAP recommends a conservative approach that involves minimal diagnostic assessment. If concerns persist beyond 12 weeks, the AAP advises further testing or referral to a multidisciplinary post-COVID-19 clinic. According to the AAP, the following are some of the ongoing or residual symptoms that can occur after a SARS-CoV-2 infection in children and adolescents:

• Respiratory symptoms, such as cough, chest pain, and exercise-induced dyspnea
• Cardiac involvement, including myocarditis
• Anosmia and/or ageusia, which typically resolve in several weeks in children
• Neurodevelopmental impairment, such as delays or changes in cognitive, language, academic, motor, or mood/behavior domains
• Cognitive “fogginess” or fatigue, which may manifest as inattentiveness or slower reading or processing
• Physical fatigue and/or poor endurance
• Headache, which is common both during and after SARS-CoV-2 infection
• Mental and behavioral health problems

Similarly, as has been reported in adults, there are cases of children with long COVID, with many of the same symptoms as adults and as mentioned above. A 2021 Dutch study identified 89 children, aged 2-18 years, with 36% experiencing severe limitations in daily function. The most common complaints identified were fatigue, dyspnea, and concentration difficulties. As with many of the manifestations of COVID-19 in the pediatric population, this entity also will require further study and data collection. ^[92]

In mid-April 2020, over a period of 10 days, an unprecedented cluster of cases was reported from the South Thames Retrieval Service in London. They noted eight children who presented with signs of hyperinflammation and shock with features similar to Kawasaki disease (KD) or toxic shock syndrome. Four of these children had known family exposure to COVID-19. All tested negative for SARS-CoV-2 on bronchoalveolar lavage or nasopharyngeal aspirates. Seven of these children were noted to have abnormalities in cardiac function on echocardiograms, including coronary dilatations with giant coronary aneurysm noted in one child a week after discharge from the intensive care unit. ^[93]  This was the first case cluster highlighting what has since been termed multisystem inflammatory syndrome in children (MIS-C) by the CDC. Since the initial reporting, multiple case clusters have been reported from different countries and, as of October 1, 2020, there were 1,027 cases reported in the United States with a total of 20 deaths. ^[94]  The CDC case definition for MIS-C is as follows:

• An individual aged < 21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND
• No alternative plausible diagnoses; AND
• Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.

Since initial reporting, the American Academy of Pediatrics has also published interim guidelines on MIS-C. ^[95]   

Children reported seem to be predominantly Hispanic and Black (non-Hispanic). This is different from KD, which seems to affect children of Asian descent more often. Also unlike KD, affected children have been predominantly in the 5-9 and 9-14 age groups. The pathophysiology of MIS-C in children has been described in its initial stages, with COVID-19 infection triggering macrophage activation followed by helper T-cell activation. This in turn leads to massive cytokine release with B-cell and plasma cell activation and the production of antibodies, which leads to immune dysregulation and a hyperimmune response. ^[96]   

Children with severe MIS-C present with a cytokine storm believed to be related to delayed interferon gamma responses and slow viral clearance, further leading to more pronounced inflammation. ^[97]  They present with systemic signs of inflammation, often with significant cardiac, neurologic, and/or hematologic abnormalities. They require a multidisciplinary team of individuals who should be involved in their management, including intensivists and pediatric infectious disease, rheumatology, cardiology, and hematology specialists. Guidelines for management have been proposed by several of these specialty groups. ^{[98, 99, 100, 101]}  

Gaining evidence to support therapeutic decisions for pediatric patients is challenging. ^[102]  Studying MIS-C is challenging, as it is a rare syndrome and patients present at differing times from the time of diagnosis with COVID-19. Outcomes of patients with MIS-C may be difficult to interpret, owing to whether observations were early in the pandemic when little was known regarding treatment, changing therapeutic strategies over time, and geographical differences for available therapies. 

An international observational cohort study collected data regarding clinical outcomes. Data regarding the course of treatment for 614 children from 32 countries from June 2020 through February 2021 were analyzed, of which 490 cases met the World Health Organization criteria for MIS-C. Among 614 children with suspected MIS-C, 246 received primary treatment with intravenous immunoglobulin (IVIG) alone, 208 with IVIG plus glucocorticoids, and 99 with glucocorticoids alone. Twenty-two children received other treatment combinations, including biologic agents, while 39 received no immunomodulatory therapy. In this study, recovery from MIS-C did not differ between regimens of IVIG alone, IVIG plus glucocorticoids, or glucocorticoids alone. The dosing of glucocorticoids was not described in this study; there has been significant debate about initiating low-moderate dose versus high dose glucocorticoids, balancing out timely reduction of severe inflammation with the adverse effects of high dose glucocorticoids. The optimal dosing and escalation strategies for patients refractory to other treatments remain to be fully studied.The observational study occurred during the first, second, and third waves, and SARS-CoV-2 variants had emerged. ^[102]   

In contrast, surveillance data on inpatients younger than 21 years (n = 518; median age, 8.7 years) with MIS-C admitted to 1 of 58 US hospitals showed a lower risk of new or persistent cardiovascular dysfunction when treated with IVIG plus glucocorticoids than IVIG alone. The timing of this study was earlier in the pandemic, during the first wave in the United States and before SARS-CoV-2 variants emerged. ^[103]   

A randomized controlled trial is recruiting patients presenting with MIS-C who have received IVIG but warrant further anti-inflammatory therapy to 1 of 3 treatment arms (ie, infliximab, steroids, or anakinra). However, recruitment will likely be slow for this rare condition, and results are not expected until the end of 2023. ^[104]   

Ahmed et al published a review of 39 MIS-C reports from 1/1/20-7/25/20 comprising 662 patients. The mean age was 9.3 years, and mortality was 1.7%. The most common symptoms were fever (100%), abdominal pain or diarrhea (74%), and vomiting (68%). Levels of inflammatory markers, troponin, and D-dimer were highly abnormal in most cases. In cases in which an echocardiogram was performed, over half were abnormal. ^[105]

A case series compared 539 patients who had MIS-C with 577 children and adolescents who had severe COVID-19. The patients with MIS-C were typically younger (predominantly aged 6-12 years) and more likely to be non-Hispanic Black. They were less likely to have an underlying chronic medical condition, such as obesity. Severe cardiovascular or mucocutaneous involvement was more common in those with MIS-C. Patients with MIS-C also had higher neutrophil to lymphocyte ratios, higher CRP levels, and lower platelet counts than those with severe COVID-19. ^[106]

In a cross-sectional study that included 1733 patients, CDC researchers identified two peaks in the incidence of MIS-C that each occurred about 2-5 weeks after peaks in COVID-19. This finding suggests that delayed immunologic responses to SARS-CoV-2 infection lead to the development of MIS-C. The researchers also found that young children (aged 0 to 4 years) had fewer cardiovascular complications than older children and adolescents. Patients with MIS-C who were aged 18-20 years were the most likely to have myocarditis, pneumonia, and acute respiratory distress syndrome. ^[107]

Farooqi et al reported on longitudinal outcomes in a cohort of 45 children who were hospitalized with MIS-C. Most of the children (84%) had no underlying medical conditions. All of the patients received steroids and immunoglobulins (2 g/kg), as well as enoxaparin prophylaxis or low-dose aspirin and GI prophylaxis. After a follow-up period of 9 months, only one child had persistent mild cardiac dysfunction. ^[108]

A study by Encinosa et al found that the rate of hospitalization for MIS-C is 17 for every 100 hospitalizations for COVID-19. Severe cases that affect a greater number of organs are more common among Black patients than among Whites. For patients with the most severe cases of MIS-C (affecting 6 to 8 organs), mortality is 5.8%. ^[109]

According to the American Heart Association, up to 50% of children with MIS-C have myocardial involvement, including decreased left ventricular function, coronary artery dilation or aneurysms, myocarditis, elevated troponin and BNP or NT-proBNP, or pericardial effusion. The first-line treatment for MIS-C is usually intravenous immunoglobulin (IVIG); patients with poor ventricular function may require IVIG in divided doses. Supportive treatment for heart failure and vasoplegic shock often involves the administration of inotropes and vasoactive medications in an ICU. Inflammation and cardiovascular abnormalities typically resolve within 1-4 weeks of diagnosis; however, progression of coronary artery aneurysms after discharge has been reported. Mortality associated with MIS-C ranges from 1.4-1.9%. ^{[54, 55]}

For more information on testing for patients with MIS-C, please see Laboratory Studies in Coronavirus Disease 2019 (COVID-19).

The American Academy of Pediatrics Committee on Fetus and Newborn, Section on Neonatal Perinatal Medicine, and Committee on Infectious Diseases initially issued guidance on the management of infants born to mothers with coronavirus disease 2019 (COVID-19) on April 2, 2020. ^[20]  These guidelines have since been revised as more data have emerged. ^[110]  

Early evidence has shown low rates of peripartum severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and uncertainty concerning in utero viral transmission. To date there does not seem to be any conclusive evidence indicating vertical transmission of COVID-19 from infected pregnant mothers to their neonates, ^[19]  though some cases have been suspected.

A series of 66 British infants (aged < 28 days) with COVID-19 was described, and an incidence of 5.6 [95% CI, 4.3-7.1] per 10,000 live births was estimated. The most common symptoms were fever and poor feeding reported in approximately one-third of the patients. Forty-two percent had severe neonatal SARS-CoV-2 infection, 24% of those were born preterm. Only 5% required mechanical ventilation. Twenty-six percent of infants with confirmed infection were born to mothers with known perinatal SARS-CoV-2 infection; 3% were considered to have possible vertically acquired infection (SARS-CoV-2–positive sample within 12 hours of birth when the mother was also positive). Twelve percent of the infants had suspected nosocomially acquired infection. At the time of publication, 88% of the babies had been discharged home, 11% were still admitted, and 2% had died of a cause unrelated to SARS-CoV-2 infection. ^[111]

Neonates can be infected by SARS-CoV-2 after birth. Because of their immature immune systems, they are vulnerable to serious respiratory viral infections. SARS-CoV-2 may be able to cause severe disease in neonates. Infants less than one year of age have had the greatest proportion of severe illness, 10.6% of the severe and critical cases of the 2135 children described in a 2020 Chinese study. ^[10]  A recent review of neonates born to mothers with perinatal confirmed COVID-19 infection showed that severe maternal disease can lead to fetal distress, premature delivery, and other adverse outcomes. These small case series are predominantly out of China. ^[112]

Another case series of 33 infants born to mothers with COVID-19 from China also described a varying course of the disease with an overall favorable outcome, including a 31-weeks' gestation infant who developed Enterobacter sepsis; however, the baby recovered. ^[113]

In an international cohort study, Villar et al found that 12.1% of neonates who were born to SARS-CoV-2–positive mothers also tested positive. Neonatal test positivity was associated with cesarean delivery (relative risk [RR] 2.15; 95% CI, 1.18-3.91) but not with breastfeeding (RR, 1.10; 95% CI, 0.66-1.85). The infants who tested positive for SARS-CoV-2 were at substantially higher risk for requiring neonatal intensive care (RR, 6; 95% CI, 3.3-10.9). Overall, the risk of severe neonatal complications was significantly greater among infants born to mothers with COVID-19, compared with those born to women without COVID-19. ^{[114, 115]}

The results of a Swedish prospective cohort study, which included 88,159 infants, demonstrated that SARS-CoV-2 infection during pregnancy is associated with adverse outcomes in neonates. Norman et al found higher rates of respiratory disorders, hyperbilirubinemia, and admission for neonatal care in infants born to mothers who tested positive for SARS-CoV-2. ^{[116, 117]}

Data from the early months of the pandemic (February-April 2020) demonstrated that 15% of all pediatric COVID-19 cases occurred in infants less than one year of age but that infants as a group accounted for the highest percentage of hospitalizations, between 15% and 62%. ^[3]

Infection-control measures for birth attendants 

Staff attending deliveries involving women with COVID-19 should observe airborne, droplet, and contact precautions owing to the increased risk of aerosolized virus and the potential requirement for administering resuscitation to newborns with SARS-CoV-2 infection.

Separation of mother and newborn

A pilot study suggests that rooming in for term or near term neonates may be considered for mothers with asymptomatic COVID-19 infection. Infection control measures still need to be followed strictly. ^[118]

A more recent study looking at 49 infants (36 weeks' gestational age) who were allowed to room in with their mothers with asymptomatic COVID-19 infection did not demonstrate any symptoms up to two weeks after discharge. One infant did have a positive reverse transcriptase polymerase chain reaction (RT_PCR), but repeat RT-PCR at 48 hours was negative. ^[119]  

Breastfeeding

As of April 2, 2020, SARS-CoV-2 has not been detected in breast milk. Mothers with COVID-19 may express breast milk after appropriate hand and breast hygiene to be fed to the newborn by caregivers without COVID-19.

Breastfeeding guidelines from AAP are available for post hospital discharge for mothers or infants with suspected or confirmed SARS-CoV-2 infection. ^[120]  

Neonatal testing for COVID-19

Following birth, newborns born to mothers with COVID-19 should be bathed to remove virus from the skin. Newborns should undergo testing for SARS-CoV-2 at 24 hours and 48 hours (if still at the birth facility) after birth. Centers with limited testing resources can make testing decisions on a case-by-case basis. ^[110]

Follow-up

Newborns who have documented SARS-CoV-2 infection or who are at risk for postnatal transmission because of testing inability require frequent outpatient follow-up (via telephone or telemedicine) or in-person assessments for 14 days after discharge.

Precautions following discharge

After discharge from the hospital, mothers with symptomatic COVID-19 should stay at least 6 feet away from their newborns. If a closer proximity is required, the mother should wear a mask and observe hand hygiene for newborn care until (1) her temperature has normalized for 72 hours without antipyretic therapy and (2) at least 1 week (7 days) has passed since the onset of symptoms.

Ongoing in-hospital neonatal care

Mothers with COVID-19 whose newborns require ongoing hospital care should maintain separation until (1) her temperature has normalized for 72 hours without antipyretic therapy, (2) her respiratory symptoms have improved, and (3) a minimum of 2 consecutive nasopharyngeal swab tests collected at least 24 hours apart are negative for SARS-CoV-2.

COVID-19 vaccines in pregnant and lactating women

A cohort study (n = 131) by Gray et al found mRNA SARS-CoV-2 vaccines generated humoral immunity in pregnant and lactating women, similarly to that observed in nonpregnant women. All serum titers from vaccination were significantly higher compared with titers induced by SARS-CoV-2 infection during pregnancy (P< .0001). Importantly, vaccine-generated antibodies were present in all umbilical cord blood and breast milk samples, showing immune transfer to neonates via placenta and breast milk. ^[121]

A nationwide, register-based cohort study included all live-born infants born in Norway between September 1, 2021, and February 28, 2022. Of 21,643 live-born infants, 9739 (45%) were born to women who received a second or third dose of a COVID-19 vaccine during pregnancy. The first 4 months of life incidence rate of a positive test for SARS-CoV-2 was 5.8 per 10,000 follow-up days. The study found infants of mothers vaccinated during pregnancy had a lower risk of a positive test compared with infants of unvaccinated mothers (0.5% vs 1.5% during the Delta phase; 4.0% vs 5.2% during the Omicron phase). Evidence showed a lower risk during the Delta variant-dominated period (incidence rate, 1.2 vs 3 per 10,000 follow-up days) compared with the Omicron period (7 vs 10.9 per 10,000 follow-up days). ^[122]

The American Academy of Pediatrics (AAP) has created a website for Critical Updates on COVID-19 to provide clinicians with resources. 

In addition to guidance on the management of infants born to mothers with coronavirus disease 2019 (COVID-19), which is summarized below, the AAP has provided guidance on the following topics:

• Caring for Children and Youth With Special Health Care Needs During the COVID-19 Pandemic
• Multisystem Inflammatory Syndrome in Children (MIS-C)