COVID-19

Introduction

• Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents a diverse clinical spectrum in the pediatric population.
• While initial epidemiological data suggested children were relatively spared from severe disease compared to adults, the evolution of the pandemic, emergence of variants (Delta, Omicron), and identification of post-infectious hyperinflammatory syndromes have reshaped the understanding of pediatric COVID-19.
• The clinical landscape encompasses acute infection, which ranges from asymptomatic to critical respiratory failure, and post-infectious sequelae such as Multisystem Inflammatory Syndrome in Children (MIS-C) and Neonates (MIS-N).

Epidemiology and Prevalence

• Global and Regional Trends
  • Historically, children accounted for a small proportion of total COVID-19 cases early in the pandemic.
  • However, surveillance data from the United States indicates that children made up approximately 18% of all reported COVID-19 cases between 2020 and 2023.
  • Data from the United Kingdom showed seropositivity rates in adolescents aged 16–17 years reaching 99% by September 2022, indicating widespread exposure.
• Age-Specific Susceptibility
  • There is a distinct age-stratified risk profile.
  • While adolescents generally experience mild disease, infants under 1 year of age are disproportionately vulnerable.
  • Surveillance data from 2024–2025 reveals that children under 2 years accounted for the largest share (54%) of pediatric COVID-19 deaths and 57% of hospitalizations.
  • This "healthy infant paradox" highlights that unlike older children, where comorbidities drive severity, otherwise healthy infants are at significant risk for hospitalization and intensive care admission due to anatomical airway differences and immunological immaturity.
• Variant Impact
  • The clinical presentation and prevalence have shifted with viral evolution.
  • The Delta variant was associated with increased hospitalization rates, while the Omicron variant, though highly transmissible, generally resulted in less severe individual disease but higher overall pediatric hospitalization numbers due to the sheer volume of infections.

Pathophysiology of COVID-19

• The pathophysiology of Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), involves a complex interplay between viral replication, host immune responses, and subsequent systemic inflammation.
• The disease spectrum ranges from asymptomatic or mild respiratory symptoms to severe pneumonia, acute respiratory distress syndrome (ARDS), and multiorgan failure.
• In pediatric populations, specific post-infectious hyperinflammatory syndromes (MIS-C and MIS-N) represent unique pathophysiological entities.

1. Viral Entry and Replication mechanisms

The initial step in the pathogenesis of COVID-19 is the entry of SARS-CoV-2 into host cells.

• Receptor Binding: The virus utilizes its spike (S) protein to bind to the Angiotensin-Converting Enzyme 2 (ACE2) receptor on the surface of host cells.
• Cellular Tropism: ACE2 receptors are widely expressed throughout the body, which explains the multisystem nature of the disease. High expression is found in the nasal epithelium, alveolar epithelial cells (type 1 and 2), and lung endothelium. Crucially, ACE2 is also abundant in the enterocytes of the ileum and colon, the heart, pancreas, kidneys, and the endothelium and smooth muscle cells of arterial and venous vessels.
• Viral Entry: Following receptor binding, viral entry is facilitated by host proteases, particularly TMPRSS2, which primes the spike protein for fusion. The virus can enter cells through direct membrane fusion or endocytosis.
• Variant Differences: The evolution of the virus has altered its pathogenicity. The Omicron variant, for example, has accumulated mutations in the spike protein that shift its preference toward the endosomal route of entry rather than TMPRSS2-mediated fusion. This results in a preference for infecting the upper respiratory tract over the lung tissue, contributing to a generally milder clinical course compared to the Delta variant.
• Alternative Receptors: Research has identified potential alternative receptors for SARS-CoV-2, including ASGR1, KREMEN1, histamine receptor 1, and neuropilin 1, which may facilitate cell entry.

2. Immune Response and Inflammation

Once inside the cell, the virus replicates and causes direct cellular damage, triggering local inflammation. The host's immune response is the primary driver of disease severity.

• Innate Immune Response: Upon infection, the body mounts an innate immune response involving the release of interferons and inflammatory cytokines. In the majority of pediatric patients, a robust innate immune response helps contain the virus early, leading to milder disease.
• Cytokine Storm: In severe cases, particularly in adults or vulnerable populations, a dysregulated and excessive immune response occurs, often referred to as a "cytokine storm." This is characterized by the rapid and massive release of pro-inflammatory cytokines, including Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), Interferon-gamma (IFN-γ), IL-1β, IL-8, IL-10, IL-17, and IL-18.
• Consequences of Hyperinflammation: This uncontrolled inflammation leads to diffuse alveolar damage, endothelial injury, and multiorgan dysfunction. The cytokine storm is a central mechanism in the progression to ARDS and septic shock in critical COVID-19.

3. Endothelial Dysfunction and Coagulopathy

A hallmark of severe COVID-19 is endotheliitis (inflammation of the blood vessels) and a prothrombotic state.

• Endothelial Injury: Direct viral infection of endothelial cells via ACE2, combined with cytokine-mediated injury, leads to widespread endothelial dysfunction.
• Immunothrombosis: The damaged endothelium releases tissue factor and von Willebrand factor, promoting coagulation. Neutrophil extracellular traps (NETs) further propagate this process. This results in a hypercoagulable state termed "pulmonary intravascular coagulopathy," characterized by microvascular thrombosis.
• Clinical Markers: This state is clinically evidenced by elevated D-dimer and fibrinogen levels, which are strongly associated with poor outcomes and the development of arterial and venous thromboembolism.

4. Pediatric Pathophysiology: Mechanisms of Milder Disease

Children generally experience milder acute COVID-19 than adults. Several physiological factors contribute to this "pediatric protection":

• ACE2 Expression: Children are observed to have lower expression of ACE2 receptors in the nasal epithelium compared to adults, potentially limiting initial viral load.
• Binding Affinity: There may be a lower binding affinity between the pediatric ACE2 receptor and the viral spike protein.
• Immune System Differences: Children possess a stronger innate immune response and higher levels of early interferon, which helps clear the virus before the adaptive immune system triggers a cytokine storm. Furthermore, higher lymphocyte counts and fewer comorbidities compared to adults provide a protective buffer.
• Cross-Immunity: Frequent exposure to seasonal coronaviruses in children may provide significant cross-immunity against SARS-CoV-2.

5. Pathophysiology of Multisystem Inflammatory Syndrome in Children (MIS-C)

MIS-C is a severe hyperinflammatory condition that typically occurs 2–6 weeks after acute SARS-CoV-2 infection. It is distinct from acute COVID-19 and is believed to be driven by post-infectious immune dysregulation rather than direct viral replication.

• Adaptive Immune Dysregulation: At the time of MIS-C onset, most patients are PCR-negative but antibody-positive, indicating the condition is driven by the adaptive immune response.
• Superantigen Hypothesis: The SARS-CoV-2 spike protein may act as a superantigen, containing a motif similar to Staphylococcal enterotoxin B. This can bypass normal antigen processing and directly activate large numbers of T-cells, leading to the massive release of inflammatory cytokines.
• Autoimmunity: Molecular profiling has identified autoantibodies in MIS-C patients that target endothelial cells, gastrointestinal cells, and immune cells. This suggests a transient autoimmune etiology where the immune system attacks host tissues.
• Specific Cytokine Signatures: MIS-C is characterized by a specific inflammatory signature, including elevated IFN-γ and CXCL9, suggesting a distinct cytokine amplification loop compared to acute COVID-19. Activation of CX3CR1+ CD8+ T-cells has been linked to vascular complications.

6. Pathophysiology of Multisystem Inflammatory Syndrome in Neonates (MIS-N)

MIS-N is a rare condition observed in neonates born to mothers with COVID-19 during pregnancy. Its pathophysiology differs from MIS-C in the source of the immune trigger.

• Transplacental Antibody Transfer: The primary mechanism is believed to be the passive transfer of maternal SARS-CoV-2 IgG antibodies across the placenta. These antibodies, or maternal inflammatory cytokines, may trigger an exaggerated immune response in the fetal or neonatal immune system.
• Antibody-Mediated Injury: Transferred antibodies may bind to receptors on neonatal neutrophils and macrophages, activating them and causing a cytokine storm and tissue damage in the neonate, distinct from direct viral infection.
• Vertical Transmission: In rare cases, MIS-N may result from in-utero viral transmission, where the fetus mounts its own endogenous antibody response, leading to inflammation. However, vertical transmission is considered infrequent due to low placental expression of viral entry receptors.

Clinical Classifications and Management Protocols

According to the Ministry of Health and Family Welfare (MoHFW) and Indian Academy of Pediatrics (IAP) guidelines, pediatric COVID-19 is categorized based on respiratory status and saturation.

1. Asymptomatic Infection

A significant proportion of infected children remain asymptomatic. Estimates suggest 25–73% of PCR-positive children show no symptoms. These children are usually identified through contact tracing and require no treatment other than isolation and monitoring for developing symptoms.

2. Mild Illness

• Definition: Patients with upper respiratory tract symptoms (sore throat, rhinorrhea, cough) without fast breathing or hypoxia ( $Sp{O}_2\ge 94\mathrm{\%}$ on room air).
• Clinical Features: Fever, cough, fatigue, myalgia, and sore throat. Gastrointestinal symptoms (nausea, vomiting, diarrhea) are more common in children than adults.
• Management: Home isolation and symptomatic management (Paracetamol 10-15 mg/kg/dose for fever; hydration).

3. Moderate Illness

• Definition: Presence of pneumonia with rapid respiration for age or $Sp{O}_2$ between 90–93% on room air.

• Fast Breathing Criteria:

  • < 2 months: > 60/min
  • 2–12 months: > 50/min
  • 1–5 years: > 40/min

  • 5 years: > 30/min.

• Management: Hospital admission is recommended for monitoring. Supportive care includes oxygen therapy to maintain $Sp{O}_2>94\mathrm{\%}$, fluid/electrolyte balance, and antibiotics only if bacterial superinfection is suspected.

4. Severe Illness

• Definition: Severe pneumonia, Acute Respiratory Distress Syndrome (ARDS), Septic Shock, or $Sp{O}_2<90\mathrm{\%}$ on room air.
• Clinical Signs: Grunting, severe chest indrawing, cyanosis, lethargy, somnolence, or seizures.
• Management: Immediate hospitalization in HDU/ICU. Management involves respiratory support (HFNC, NIV, or mechanical ventilation), corticosteroids (Dexamethasone 0.15 mg/kg), and anticoagulation if risk factors for thrombosis exist. Remdesivir is generally restricted and not routinely recommended for children under 18 years unless specific high-risk criteria are met.

Multisystem Inflammatory Syndrome in Children (MIS-C)

MIS-C is a severe, post-infectious hyperinflammatory condition occurring 2–6 weeks after SARS-CoV-2 infection. It shares features with Kawasaki Disease (KD) and Toxic Shock Syndrome (TSS) but has distinct epidemiology and pathophysiology.

Case Definition (Revised CDC 2023/CSTE): An illness in a person aged <21 years characterized by:

1. Fever: Subjective or documented ($\ge {38.0}^{\circ }C$).
2. Severity: Requires hospitalization or results in death.
3. Inflammation: CRP $\ge 3.0$ mg/dL (30 mg/L).
4. Organ Involvement: New onset manifestations in at least two of the following categories:
   • Cardiac: LVEF <55%, coronary aneurysm, elevated troponin.
   • Shock: Clinician documentation or vasopressor use.
   • Mucocutaneous: Rash, inflammation of oral mucosa, conjunctivitis, extremity edema.
   • Gastrointestinal: Abdominal pain, vomiting, diarrhea.
   • Hematologic: Platelet count <150,000 cells/$\mu$L or Lymphopenia (ALC <1,000 cells/$\mu$L).
5. Viral Link: Evidence of SARS-CoV-2 infection (PCR, antigen, or serology) within 60 days prior.

Clinical Presentation of MIS-C:

• Gastrointestinal: The most common non-fever symptom, affecting 80-90% of patients. Abdominal pain may mimic appendicitis.
• Cardiovascular: Occurs in 60-80% of cases. Manifestations include myocarditis, pericarditis, ventricular dysfunction, and coronary artery dilation/aneurysms. Shock is a distinguishing feature from classic Kawasaki Disease.
• Mucocutaneous: Polymorphic rash, conjunctival injection, "strawberry tongue," and red/swollen hands and feet are common.
• Neurologic: Headache, altered mental status, and occasionally encephalopathy or seizures.

Pathophysiology of MIS-C: It is hypothesized to be a dysregulated adaptive immune response. SARS-CoV-2 may act as a superantigen, activating T-cells and leading to a cytokine storm (elevated IL-6, IL-10, IFN-$\gamma$). Autoantibodies targeting endothelial and immune cells may also contribute to vascular damage.

Multisystem Inflammatory Syndrome in Neonates (MIS-N)

A newly recognized entity, MIS-N occurs in neonates born to mothers with SARS-CoV-2 infection during pregnancy. It is distinct from vertical transmission of the virus.

Pathogenesis: MIS-N is believed to result from the transplacental transfer of maternal SARS-CoV-2 IgG antibodies or inflammatory cytokines, triggering immune activation in the fetus/neonate. Alternatively, it may result from endogenous antibody production if the fetus was infected in utero .

Clinical Features of MIS-N: Unlike MIS-C in older children, fever is present in only ~20% of MIS-N cases. The presentation is dominated by:

• Cardiovascular: Cardiac dysfunction, hypotension, arrhythmias (e.g., AV block), and coronary artery dilatation are seen in >80% of cases.
• Respiratory: Respiratory distress and Persistent Pulmonary Hypertension of the Newborn (PPHN) are common.
• Differentiation: Diagnosis requires high suspicion in neonates with multisystem involvement (cardiac + respiratory/GI) and positive SARS-CoV-2 antibodies (IgG), in the absence of active viral infection (negative PCR/Antigen) and exclusion of sepsis or asphyxia.

Outcomes: Most neonates require intensive care but respond well to immunomodulatory therapy (steroids and IVIG). Mortality is reported between 5-10%.

Long COVID (Post-Acute Sequelae)

Children can experience Long COVID, defined as new, returning, or ongoing symptoms 4 or more weeks after infection.

• Prevalence: Lower in children (0.4% to 1.4%) compared to adults.
• Symptoms: Fatigue, headache, sleep disturbance, concentration difficulties ("brain fog"), and muscle pain.
• Risk Factors: Increasing age (adolescents > young children) and severity of the initial acute infection. Vaccination has been shown to reduce the risk of developing Long COVID.

Laboratory Diagnosis and Monitoring

• Viral Detection: NAAT (RT-PCR) is the gold standard for acute infection. Antigen tests have lower sensitivity but are useful for rapid screening.
• Serology: Useful for diagnosing MIS-C/MIS-N (IgG antibodies indicating past infection/maternal transfer).
• Biomarkers:
  • Inflammatory: CRP, ESR, Procalcitonin, Ferritin (markedly elevated in MIS-C).
  • Cardiac: Troponin-I and BNP/NT-proBNP are critical for assessing myocardial injury in MIS-C/MIS-N.
  • Coagulation: D-dimer and Fibrinogen are often elevated, indicating a hypercoagulable state.
  • Hematology: Lymphopenia and thrombocytopenia are markers of severity.

Management of COVID-19 Infections in Children

Management of Acute COVID-19

1. Asymptomatic and Mild Cases (Home Isolation)

Children with mild symptoms and no risk factors are managed in home isolation.

• Supportive Care:
  • Fever: Paracetamol 10–15 mg/kg/dose every 4–6 hours for temperature >38°C (100.4°F).
  • Hydration: Ensure adequate oral fluid intake and a nutritious diet.
  • Cough: Warm saline gargles or throat soothing agents for older children.
• Monitoring: Parents should monitor respiratory rate, chest indrawing, activity level, urine output, and fluid intake.
• Contraindications: Systemic corticosteroids and anticoagulants are not indicated and may be harmful in mild disease. Antibiotics are not recommended unless there is suspicion of bacterial coinfection.
• High-Risk Children: Children with comorbidities (congenital heart disease, chronic lung disease, immunocompromised state, obesity) with mild symptoms may require close monitoring or admission if home monitoring is not feasible.

2. Moderate Disease (Ward/HDU Admission)

• Oxygen Therapy: Initiate oxygen if $Sp{O}_2<94\mathrm{\%}$ to maintain target saturation between 94–96%.
• Fluid Management: Maintain fluid and electrolyte balance. Encourage oral feeds; initiate IV fluids if oral intake is poor.
• Corticosteroids: Not routinely required for all moderate cases. They may be administered in rapidly progressive disease.
  • Drug: Dexamethasone 0.15 mg/kg/dose (max 6 mg) once daily or Methylprednisolone 0.75 mg/kg/dose.
• Anticoagulation: Prophylactic doses of Low Molecular Weight Heparin (LMWH) or unfractionated heparin may be indicated in hospitalized adolescents with risk factors for thrombosis.
• Antibiotics: Administer amoxicillin or alternative only if there is clinical evidence of bacterial superinfection.

3. Severe Disease (PICU/HDU Admission)

• Respiratory Support:
  • Oxygen: Immediate supplementation to maintain $Sp{O}_2>94\mathrm{\%}$.
  • Non-Invasive: High Flow Nasal Cannula (HFNC) or Non-Invasive Ventilation (NIV) for mild-moderate ARDS.
  • Invasive: Mechanical ventilation with lung-protective strategies (low tidal volume 6 mL/kg, high PEEP) for severe ARDS. Prone positioning (awake or ventilated) may be beneficial.
• Corticosteroids: Strongly recommended for severe illness.
  • Dose: Intravenous Dexamethasone 0.15 mg/kg/dose (max 6 mg) twice daily or Methylprednisolone 1–2 mg/kg/day for 5–14 days. Taper over 10–14 days depending on clinical improvement.
• Antivirals: According to MoHFW (Jan 2022) guidelines, antivirals (Remdesivir) and monoclonal antibodies are NOT recommended for children <18 years, irrespective of severity, due to lack of safety/efficacy data. (Note: Some international guidelines and earlier interim protocols permitted restricted Remdesivir use in select high-risk cases within 3 days of onset, but exam answers should reflect the strict national contraindication unless specified otherwise).
• Management of Shock:
  • Fluid resuscitation with crystalloids (10–20 mL/kg) in aliquots, with careful monitoring for fluid overload.
  • Early initiation of vasoactive agents (Epinephrine/Nor-epinephrine) if shock persists.
• Anticoagulation: Therapeutic anticoagulation may be needed if thrombosis is confirmed or risk is high (e.g., elevated D-dimer).

Management of Multisystem Inflammatory Syndrome in Children (MIS-C)

MIS-C is a life-threatening hyperinflammatory state managed ideally in a tiered manner.

Diagnostic Criteria (WHO/CDC): Fever >3 days in a child 0–19 years AND two of: (a) Rash/conjunctivitis/mucocutaneous signs, (b) Hypotension/shock, (c) Cardiac dysfunction/coronary abnormalities, (d) Coagulopathy, (e) Acute GI symptoms; AND elevated inflammatory markers (CRP, ESR, Procalcitonin); AND evidence of COVID-19 (PCR, antigen, or serology) with exclusion of other causes (sepsis, tropical fevers).

Therapeutic Protocol:

1. First-Line Immunomodulation:
   • Intravenous Immunoglobulin (IVIG): 2 g/kg as a single infusion over 12–24 hours. In patients with cardiac failure or fluid overload, divide the dose over 48 hours.
   • Corticosteroids: Methylprednisolone 1–2 mg/kg/day IV in divided doses.
   • Note: Recent evidence supports combining IVIG and steroids upfront for moderate-severe cases (shock, cardiac involvement) to reduce treatment failure and ICU stay.
2. Refractory Disease:
   • If fever or symptoms persist after 48–72 hours of initial treatment, consider Pulse Steroids (Methylprednisolone 10–30 mg/kg/day for 3 days, max 1g/day).
   • Biologics: In cases refractory to steroids and IVIG, cytokine blockers may be considered after expert consultation.
     • Anakinra (IL-1 receptor antagonist): Often the first-choice biologic (2–10 mg/kg/day).
     • Tocilizumab (IL-6 inhibitor): Alternative for specific phenotypes.
     • Infliximab (TNF-alpha inhibitor).
3. Supportive Therapies for MIS-C:
   • Antiplatelet: Low-dose Aspirin (3–5 mg/kg/day, max 81 mg) is recommended for all MIS-C patients to prevent coronary thrombosis, continued until inflammatory markers and cardiac status normalize (usually 4–6 weeks).
   • Anticoagulation: Enoxaparin (1 mg/kg twice daily) indicated for patients with significantly elevated D-dimer (>5x upper limit), coronary aneurysms (Z-score >10), or LVEF <30%.
   • Antibiotics: Broad-spectrum antibiotics (e.g., Ceftriaxone/Meropenem) should be started empirically to cover toxic shock syndrome/sepsis and stopped once cultures are negative and MIS-C diagnosis is confirmed.

Management of MIS-N (Neonates)

• Suspicion: Neonates with respiratory distress, shock, or cardiac dysfunction born to mothers with COVID-19 history and positive IgG antibodies.
• Treatment: Primarily supportive (respiratory support, fluids, inotropes).
• Immunomodulation: In severe cases with cardiac dysfunction or shock, IVIG (2 g/kg) and/or Corticosteroids (Methylprednisolone) may be beneficial. Routine use in mild cases is discouraged.

Infection Prevention and Control (IPC)

• Isolation: Suspected or confirmed cases should be isolated.
• PPE: Healthcare workers must use appropriate PPE (N95 masks, gowns, gloves, eye protection) during patient care, especially for aerosol-generating procedures (intubation, nebulization, CPR).
• Masking in Children:
  • <5 years: Not recommended.
  • 6–11 years: Depending on ability to use safely.

  • 12 years: Same as adults.

Post-COVID Care

Children with moderate-severe COVID-19 or MIS-C require follow-up.

• Cardiac: Repeat Echocardiography at 2 weeks, 6 weeks, and 1 year for MIS-C patients (especially with coronary involvement).
• Functional: Respiratory rehabilitation and nutritional counseling.
• Vaccination: Vaccination is recommended for eligible age groups. In children with history of MIS-C, vaccination should be deferred until clinical recovery and at least 90 days after diagnosis.

Summary of Drug Doses