COVID-19 associated pediatric complications

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Harmeet Kharoud M.D.[2]; Abdelrahman Ibrahim Abushouk, MD[3]; Asra Firdous, M.B.B.S.[4] Neepa Shah, M.B.B.S.[5]

Overview

• Cases of COVID-19 have been reported in children. It ranges from asymptomatic, mild cases to Multisystem Inflammatory Syndrome in Children MIS-C. There are less cases of SARS-CoV 2 in children compared to adults.

Epidemiology and Demographics

• Less than 2% of the confirmed positive cases of COVID-19 comprise of children less than 19 years of age.

Incidence

• Among the 1,761,503 aggregate cases reported to CDC from January 22–May 30, the incidence of confirmed cases was 403.6 cases per 100,000 population .
• Lowest cumulative incidence being in the group of children less than 9 years. (51.1) per 100,000 population.
• To accurately calculate the incidence of COVID-19 in children a study called Human Epidemiology and Response to SARS-CoV-2 HEROS led by Dr. Hartet is under process and has started enrolling 6000 healthy children as well as children with asthma, allergies from 2000 U.S families across 11 states.

Prevalence

Prevalence of coronavirus in children is less compared to adults as the number of cases are less and most of the cases are with the mild presentation.

• The following data is from CDC Surveillance from January 22 to May 30.

Comorbidities

• • The 3 most common comorbidity in children <9 years among a total of 20,458 children.
    • Chronic Lung disease (CLD) 12.5%
    • Cardiovascular disorder 2.7%
    • Immunocompromised children 2.1%
  • The 3 most common comorbidity in children 10-19 yearsamong a total of 49,245 children.
    • Chronic Lung disease (CLD) 18%
    • Cardiovascular disorder 2.3%
    • Immunocompromised children 2.0%

ICU and total hospitalization in children

• • <9 years of age among 20,458 children
    • Total number of all hospitalization is 4.1%
    • Total number of ICU admissions is 0.7%
  • 10-19 years of age among 49,245 children
    • Total number of all hospitalization is 2.5%
    • Total number of ICU admissions is 0.4%

Data of children with different comorbidities as reported by the CDC for a period of January 22 to May 30

	Age
Different comorbidities	<9	10-19
Underlying medical condition	2896(14.2%)	7123(14.5%)
Cardiovascular disorders	78(2.7%)	164(2.3%)
Chronic lung disease	363(12.5%)	1285(18%)
Renal disease	21(0.7%)	34(0.5%)
Diabetes	12(0.4%)	34(0.5%)
Liver disease	5(0.2%)	19(0.3%)
Immunicompromised	61(2.1%)	146(2.0%)
Neurological disease	41(1.4%)	113(1.6%)
Total cases in the population 1,320,488	20458	49245

Data of children with hospitalized children and ICU admissions as reported by CDC for a period of January 22 to May 30

Age	All admissions in the hospital and ICU divided according to associated comorbidity
<9 years (20458 cases)	All patients (20458)			Among all patients with reported underlying disease (619)			Among all patients with no reported underlying disease (2277)
	All admissions in the hospital including ICU		ICU admissions	All admissions in the hospital including ICU		ICU admissions	All admissions in the hospital including ICU	ICU admissions
	848/20458 (4.1%)		141/20458 (0.7%)	138/619 (22.3%)		31/619 (5%)	84/2277(3.7%)	116/2277 (0.7%)
10-19 years (49245 cases)	All patients (49245)		Among all patients with reported underlying disease (2076)			Among all patients with no reported underlying disease (5047)
	All admissions in the hospital including ICU	ICU admissions	All admissions in the hospital including ICU (2076)		ICU admissions	All admissions in the hospital including ICU (5047)			ICU admissions
	1234/49245 (2.5%)	216/49245 (0.4%)	309/2076 (14.9%)		72/2076 (3.5%)	115/5047 (2.3%)		17/5047 (0.3%)

Age

• According to the data published by CDC for a period of January 22 to May 30
  • The cumulative incidence of COVID-19 cases in children age 0-9 is 51.1 from 20,458 cases.
  • The cumulative incidence of COVID-19 cases in children age 10-19 is 117.3 from 49,245 cases.

Racial predilection to COVID-19

Non-Hispanic American Indian or Alaska Native persons have an age-adjusted hospitalization rate approximately 5 times that of non-Hispanic White persons, while non-Hispanic Black persons and Hispanic or Latino persons each have a rate approximately 4.5 times that of non-Hispanic White persons

Gender

• According to the data published by CDC for a period of January 22 to May 30
  • The cumulative incidence of COVID-19 cases:
    • Boys age 0-9 years is 52.5 (1.7%) out of 10,743
    • Boys age 10-19 years is 113.4 (3.8%) out of 24,302
    • Girls age 0-9 years is 49.7 (1.4%) out of 9,715
    • Girls age 10-19 years is 121 (3.7%)out of 24,943

Region

• COVID-19 has become a pandemic with current cases around 188 countries.
• The following data is up to 29th June 2020
  • The total number of Coronavirus cases worldwide is 10,055,037.
  • The total number of deaths worldwide is 499,990.
  • The top 5 countries worldwide with the highest number of COVID-19 cases are the U.S, Brazil, Russia, India, and the U.K.
• The total number of COVID-19 cases in the U.S is 2,534,981.

Mode of transmission

• SARS-CoV 2 spreads by respiratory droplets within 6 feet from the infected person.
• Pregnant women with COVID- 19 are at more risk of developing adverse obstetric and perinatal outcomes.
• Most children who were COVID-19 positive were found to have acquired infection from parents and other household contacts.
• For newborn babies testing positive for the COVID-19 could be infected via vertical transmission, breastfeeding, or contact with virus-contaminated surfaces

Breastfeeding

• According to the CDC, there is no transmission of the SARS CoV-2 virus from an infected mother to the newborn while breastfeeding. However limited studies are available to yet decide if there is a true transmission risk while breastfeeding.
• CDC advises all mothers who are positive or suspected to be COVID-19 positive to practice precaution like covering the mouth with a face mask, washing hands with soap and water before and after washing hands.
• Bulk RNA-seq profiles from two public databases including The Cancer Genome Atlas TCGA and Functional Annotation of The Mammalian Genome Cap Analysis of Gene Expression FANTOM5 CAGE dataset were collected. Ace- 2 receptors are used by the coronavirus to gain entry into the cells. The RNA Sequence database found ACE-2 expression in the breast tissue similar to the expression in the lung tissue.
• However, the current data suggest there is one isolated case reported where the breast milk sample was found to be positive for COVID-19 sample on Day 1 and subsequently negative in the day 3 sample. More research needs to be done to conclude if there is any transmission vis breastfeeding.

Vertical transmission

• A study by Marzieh Zamaniyan et all discusses about a pregnant women who developed severe pneumonia with 32 weeks of gestation delivered a healthy pre-term baby without COVID-19 symptoms.
  • The first neonatal nasal swab, vaginal secretion and umbilical cord RT-PCR was negative.
  • However, the second neonate and amniotic sample for RT-PCR tested positive for COVID-19. This study shows more research needs to be done to identify more cases with possible intrauterine infection.
• Another study documented a possible vertical transmission as increased levels of neonatal Ig M antibodies were found in 3 cases.
  • Seropositivity with IgM antibodies found in neonates needs reflex testing for example - virus neutralization, IgG avidity index, molecular and immunoblotting. A study by Dong E et all discussed decreasing levels of neonatal IgM antibodies in the serum 2 weeks later. So far RT-PCR is the preferred test to docuement for possible vertical transmission.
• Pregnant women with severe COVID-19 pneumonia were found to have placental inflammation which increases the risk for transplacental infection and pre-term births.
• Detection of IgM and IL-6 in neonates serum is used as one of the markers for possible transplacental transmission.
• Some studies which detected the virus hours to days after birth in the nasopharyngeal samples and hence those newborns could have been exposed to the virus after birth via the nosocomial infection.

Presentations

• Presentation of COVID-19 is less severe in children as compared to adults.
• According to CDC, as of April 2, 2020, 1.7% confirmed cases of COVID-19 were reported in children aged <18 years age among the total number of confirmed cases of COVID-19.
• Illness severity of COVID-19 in children ranges from asymptomatic to critical.

Symptoms

• Fever and Cough are one of the most common symptoms reported in children. One study showed fever is prevalent in 47.5% of children and cough in 41.5% among the 1124 children with COVID-19.According to the CDC, fever, and cough was reported in 56% and 54% of children with COVID 19
• Dyspnea, nasal congestion, pharyngeal erythema, and sore throat are also common presentations in children.
• Gastrointestinal symptoms-The gastrointestinal manifestation in COVID-19 positive children are diarrhea, vomiting, abdominal pain, nausea, and anorexia. Children can present with gastrointestinal symptoms in the absence of respiratory symptoms.
• Cutaneous Findings

Clinical Course of COVID-19 in children.

• Asymptomatic presentation-
  • Children present with no clinical signs or symptoms with normal chest imaging.
  • Among 2143 children with COVID-19 infection 4% of children were asymptomatic.
  • According to one study 14.2% of children were asymptomatic. Another study showed 18% of asymptomatic children with COVID-19.
• Mild Disease
  • Children present with mild symptoms including fever, fatigue, myalgia, cough.
  • Among 2143 children with COVID-19 infection 51% of children had a mild disease of COVID-19.
  • A study showed 36.3% of children present with a mild form of the disease.
• Severe
  • Children present with dyspnea, central cyanosis, hypoxia.
  • Among 2143 children with COVID-19 infection 5% of children had a severe presentation.
  • 2.1% of children present with a severe form of COVID-19 disease.
  • Children with underlying comorbidities are more susceptible to getting severe COVID-19 disease.
• Critical
  • Children present with acute respiratory distress syndrome(ARDS), respiratory failure, shock, or multi-organ dysfunction.
  • Among 2143 children with COVID-19 infection, 0.6%% of children had a critical presentation.

Complications

Some of the complications associated with COVID-19 pediatric population are

• Multisystem Inflammatory Syndrome in Children (MISC-C)
• Exacerbation of the underlying conditions
• Sepsis
• Septic shock
• Secondary Bacterial infections.
• Acute Heart Failure
• Negative effects of lockdown in children

Multisystem Inflammatory Syndrome in Children (MIS-C)

• It is a condition that causes inflammation of some parts of the body like heart, blood vessels, kidneys, digestive system, brain, skin, or eyes.
• According to recent evidence, it is suggested that children with MISC had antibodies against COVID-19 suggesting children had COVID-19 infection in the past.

Pathophysiology

• Exact cause of MIS-C is unclear. It is suspected that it is caused by a delayed immune response to the SARS-CoV-2, causing inflammation of organs."Multisystem Inflammatory Syndrome in Children (MIS-C) | Boston Children's Hospital".
• It is also suspected that it is occurring due to antibody-mediated reaction."Multisystem Inflammatory Syndrome in Children (MIS-C) | Boston Children's Hospital".

Symptoms

• Fever lasting 24 hours or longer.
• Vomiting
• Diarrhea
• Abdominal pain
• Skin rash
• Red eyes
• Redness or swelling of the lips and tongue
• Lethargy
• Redness or swelling of the hands or feet

Emergency Warning Signs

• Difficulty Breathing
• Chest pain
• New onset confusion
• Lethargy
• Cyanosis
• Abdominal pain

Diagnosis

Preliminary WHO case definition: Children and adolescents

• 0–19 years of age with fever >3 days

AND

• Two of the following:

1. Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet)
2. Hypotension or shock
3. Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP)
4. Evidence of coagulopathy (by PT, PTT, elevated D-Dimers)
5. Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain)

AND

• Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin

AND

• No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes

AND

• Evidence of COVID-19 (RT-PCR, antigen test or serology-positive), or likely contact with patients with COVID-19

Prevention of MIS-C

• MIS-C can be prevented by reducing the risk of child exposure to COVID-19 infection.

Acute Heart Failure

• Acute Cardiac decompensation have been reported in children due to severe inflammatory state following COVID-19 infection. A case series describe 35 children in 14 centers admitted to PICU for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state.
• Treatent with immunoglobulin is associated with recovery of left ventricular systolic function.

Negative effects of lockdown in children

• Children less than 10 years in the school develop very important language, social and developmental traits with the mitigation in place these kids are at risk to develop anxiety, anger, and post-traumatic stress disorder.
• Children whose parents have either suffered economically or have mental health issues are more prone to physical and mental abuse.
• With the schools using digital media to continue classes during mitigation, those kids who are not able to get these devices are suffering from little to no education in this period of lockdown.
• Children of healthcare workers are facing a great deal with change in the environment with a new baby sitter and not being able to interact and hug the parents working in the frontline.

Diagnosis

Most of the children with SARS-CoV-2 infection are either asymptomatic or produce mild symptoms. As asymptomatic patients do not get tested for COVID-19 and are potential carriers for viral transmission, high clinical suspicion is required to prevent such transmissions to a population at risk of developing severe disease. A pediatrician should be cautious to eliminate other causes of respiratory illnesses like seasonal influenza before any diagnostic tests. No diagnostic test is required for a kid with mild illness and no history of exposure to SARS-CoV-2.

Reverse-Transcriptase Polymerase Chain Reaction

U.S. Food and Drug Administration (FDA) has approved real-time Reverse-Transcription Polymerase Chain Reaction (RT-PCR) as the preferred test for diagnosing COVID-19 in children

• RT-PCR has high specificity and sensitivity of 66-80% in diagnosing SARS-CoV-2 infection
• The test is negative during the first 7-10 days of the infection and remains positive for several weeks after the infection subsides
• Swab contamination may produce false-positive results
• High levels of SARS-CoV-2 RNA were obtained in the samples from the upper respiratory tract in both symptomatic and asymptomatic patients
• Nasopharyngeal swabs and oropharyngeal swabs or throat swab are the preferred samples for the diagnostic test
• Nasopharyngeal swab is collected in children less than 2 years of age
• A throat swab is preferred for children above 2 years
• Due to the difficulty in obtaining samples and poor cooperation of children, it is advised to use saliva samples to diagnose SARS-CoV-2 infection
• Saliva samples reportedly showed higher positive rates than Nasopharyngeal swabs in adults. It is quick and non-invasive that decreases the risk of exposure and contamination
• In patients with a high risk of exposure, one negative test result does not exclude the infection. The test should be repeated or lower respiratory tract samples like Bronchoscopic Alveolar Lavage (BAL) should be used as a specimen in such patients
• Due to the increased risk of exposure for both patient and health care worker, bronchoscopy is not recommended to diagnose SARS-CoV-2 infection
• In patients on mechanical ventilation, bronchoscopic alveolar lavage fluid or endotracheal aspirates can be used
• The virus RNA was also detected in blood and stools specimen
• Real-time Fluorescent RT-PCR is used in children with atypical symptoms
• Alternatively, some researchers suggest using metagenomic next-generation sequencing (mNGS) of viral RNA for the diagnosis

Lab abnormalities

Studies reportedly showed following lab abnormalities in pediatric patients with COVID-19

• Leucocytosis(7.5%) or Leucopenia(16.6%)
• Increased (27.4%) or decreased (24%) neutrophils
• Lymphopenia (12.9%) or Lymphocytosis (11.7%)
• Increased (9.5%) or decreased (3.2%) platelets
• Increased CRP levels (19.3%)
• Increased procalcitonin levels (49.8%)
• Increased liver enzymes (19.2%)
• Increased Serum Creatinine (4%)
• Increased blood urea nitrogen (5%)
• Increased lactate dehydrogenase (LDH) levels (29%)
• Increased Creatine kinase levels (21%)
• Increased D-dimer levels (12%)

Co-infections

Co-infection with other pathogens were reported in 27% of cases. Some common microorganisms associated with SARS-CoV-2 infection in children are:

• Mycoplasma pneumoniae
• Influenza B virus
• Influenza A virus
• Respiratory syncytial virus (RSV)
• Cytomegalovirus (CMV)
• Enterobacter aerogenes

Radiological findings

CT chest is an important diagnostic modality in pediatric patients with COVID-19. Chest CT scans has reportedly shown higher positive rates in suspected patients than RT-PCR. It has better sensitivity. CT chest and a series of chest X-rays can be used to monitor the progression of the disease. Imaging findings reported in the studies are

• Local patchy shadows (18.7%)
• Bilateral patchy shadows (12.3%)
• Consolidation (33%)
• Ground glass opacities (28%)
• Interstitial abnormalities (1.2%)
• Pleural effusion was reported in a 2-month old child who had a co-infection with RSV along with SARS-CoV-2

Children are at increased risk of radiation and its effects, so CT scans and X-rays should be judiciously used in them. It is advised to perform Pulmonary Ultrasonography (USG) in newborns. It has better sensitivity and is safer than CT scans and Chest X-rays.

Management

Management of COVID-19 in pediatric patients depends on the severity of symptoms.

• Hospital admission and level of care depend on the clinical presentation, supportive care requirement, underlying comorbidities, and availability of health care facilities at home
• Suspected patients must be isolated at a hospital or home until the diagnosis is excluded
• After confirming the diagnosis, they should be hospitalized and isolated in the wards maintained for pediatric patients with COVID-19
• Critical and severe cases require Intensive Care Unit (ICU) admission and management

As no effective treatment has been approved by the FDA yet, the main goal of managing patients with COVID-19 is to treat the symptoms, provide supportive care, prevent and treat complications, treat underlying diseases and secondary infections, and provide organ function support. Following measures are reported to be crucial in the management of COVID-19

• Bed rest
• Adequate calorie and water intake
• Maintain electrolyte balance and homeostasis
• Maintain airways patency
• Monitor vital signs and SpO2
• Symptomatic treatment and Supportive care
• Routine blood tests to monitor organ functions
• Repeat chest imaging to monitor the progression of the disease

Symptomatic treatment and Supportive Care

Fever should be treated with physical cooling and antipyretics. If the body temperature exceeds 38.5C, antipyretic drugs should be started. Drugs that can be used in children are acetaminophen 10-15 mg/kg and ibuprofen 5-10 mg/kg orally.

Respiratory support

• When the oxygen saturations are low, oxygen therapy should be started using a nasal catheter or mask oxygen
• Alternatively, heated humidified high flow nasal cannula (HHHFNC) can be used to improve oxygenation
• If symptoms of respiratory difficulty persist, continuous positive airway pressure (CPAP) or non-invasive high-frequency ventilation should be considered
• Patients should be started on mechanical ventilation immediately when no improvement occurs or respiratory health is rapidly deteriorating.

Mechanical Ventilation

Low tidal volume mechanical ventilation is preferred to prevent ventilation related lung injury. Criteria for starting mechanical ventilation

• No improvement observed with non-invasive ventilation

OR

• Intolerant to non-invasive ventilation

OR

• Increased airway secretions, severe cough, and hemodynamic instability

Antibiotics

Antibiotics and antifungals help in reducing symptoms and preventing complications of secondary infections

Corticosteroids

Steroids are used in severe cases and to prevent complications. Any of the following criteria must be met before starting corticosteroid therapy in patients with COVID-19. Intravenous methylprednisolone 1-2mg/kg/day used for 3-5 days. Long-term usage is highly discouraged.

• Rapid progression of the disease as documented from chest imaging and development of ARDS

OR

• Patients who develop encephalitis or encephalopathy, hemophagocytic syndrome, and other serious complications

OR

• Patient develops septic shock

OR

• Patient presents with wheezing

Anticoagulation therapy

• Patients with raised D-dimer levels are at increased risk of thrombus formation
• Anticoagulant or antiplatelet therapy can be given to prevent this complication
• Low molecular weight Heparin was reportedly used during the early stages.

Convalescent plasma therapy

Evidence suggests the use of plasma therapy in children with exacerbations and severe and critical disease.

Immunoglobulin therapy

• Intravenous immunoglobulins (IVIG) can be used in severe cases
• Dose of 1g/kg/day for 2days or 400mg/kg/day for 8 days is recommended for children
• More studies are required to support its efficacy and safety in children with COVID-19

Antiviral therapy

Following are the experimental drugs that are being considered to treat children with COVID-19. Various clinical trials are being conducted on the efficacy and safety of these drugs in children with COVID-19.

Interferon-alpha

Inhaled interferon-alpha was the most commonly used antiviral in patients with COVID-19. Reports suggest that it helps in decreasing the viral load, alleviating symptoms and shortening the disease course.

Remdesivir

• It is a nucleotide analogue that inhibits viral RNA polymerase
• It was effectively used during Ebola, SARS, and MERS outbreaks
• It was effective in-vitro against SARS-CoV-2
• No adverse effects were reported in a newborn treated for Ebola
• Phase III clinical trial is being conducted on the effectiveness of Remdesivir in treating COVID-19 in adults and children above 12 years of age
• FDA has approved the emergency use of Remdesivir in treating hospitalized children with severe disease"Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment | FDA".

Favipiravir

• Favipiravir is an RNA dependent RNA polymerase inhibitor
• In patients above 16 years, reports showed faster viral clearance and higher recovery rate with Favipiravir
• It was effective during Ebola and Influenza outbreak
• The safety and efficacy of Favipiravir are still being debated
• Due to its efficiency in treating SARS, MERS, Ebola, and Influenza, it is being considered as a potential treatment for severely ill children who did not respond to other treatment options

Prevention

Re-opening of schools

• The pandemic which started in China in January 2020 and now is all over the world has had a tremendous effect on the everyday life of many however children are the most affected.
• With the peak of the coronavirus cases being over in many countries like the USA and Europe, there is a dilemma for the school officials about when to reopen schools for children.
• According to the data collected by the CDC and other articles children are affected less compared to adults with asymptomatic to mild COVID-19 symptoms.
• The challenge faced by the school committees around the world is to decide between the pros and cons of whether to reopen the school with children facing the emotional toll of the lockdown and quarantine.

The CDC guidelines for re-opening schools are as follows

• These guidelines are to be followed by schools by coordinating with the local health department to know the level of mitigation in your community as the coronavirus cases are increasing.
• Educate the teachers and the parents on signs of coronavirus like dry cough, cold, high fever, and other flu-like symptoms.
• If the child has the above-mentioned symptoms or is in contact with an adult at home having these symptoms or the adult at home has tested positive the child should stay home.
• Teachers, children, and other staff members with the immunocompromised state should be given the option to work from home virtually as they are in the high-risk group.
• Hand hygiene- Soap and water should be provided by the school for students to wash hands frequently for 20 seconds
• If soap and water are not available provide hand sanitizer with at least 60% alcohol.
• Use a tissue to cover cough/sneeze and wash hands after discarding the tissue safely.
• Cloth face mask is advised for all the school staff and the children except kids younger than 2 years of age or kids with a breathing problem who needs assistance in removing the face mask.
• Signs about COVID 19 should be placed in places frequently visited like the school entrance, cafeteria, and the bathroom.
• Avoid sharing objects and if possible give kids individual supplies.
• Ensure proper ventilation systems are in place, open windows when it's safe and possible.
• Identify small groups of children and try to keep them together with the same teacher.
• Food brought from home is advisable. If not then food should be distributed in the classroom, not the cafeteria.
• Advise students and teachers to limit their exposure to the news stories. It can be overwhelming for the students.
• Encourage the students to talk to anyone they trust or to reach out to teachers to talk when overwhelmed.
• If a child tests positive or is suspected to have COVID-19 the school should arrange special transport for the student separately.
• Inform the local health care department and close contacts if the student tests positive.
• Proper contact tracing, isolation, disinfecting the common places frequently used by the students should be made a priority.

Domestic violence in children

• In this lockdown even though children are affected less compared to adults with COVID -19 that however is not the case when it comes to mental health and safety.
• A study by Silvia Bressan et all reported a sharp increase in pediatric emergency visit due to domestic violence with majority of limb fractures, facial fracture, subdural hematoma and ingestion of caustic cleaning product.
• Increased measures for children's safety and frequent disinfection should be encouraged.