key: cord-0706445-tvfjrksc
authors: Kalyanaraman, Meena; Anderson, Michael R.
title: COVID-19 in Children
date: 2022-02-02
journal: Pediatr Clin North Am
DOI: 10.1016/j.pcl.2022.01.013
sha: 418805005d1b6a62b41d85fc71eb838ccdd4cf92
doc_id: 706445
cord_uid: tvfjrksc

Coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by the SARS-CoV-2 virus. While less susceptible to SARS-CoV-2 than adults, over five million children have been infected in the United States. Several important risk factors for more severe disease progression include obesity, pulmonary disease, gastrointestinal disorders, and neurological co-morbidities. Children with COVID-19 are admitted to the PICU because of severe acute COVID-19 illness or COVID-19 associated MIS-C. The primary reasons for admission for severe acute COVID-19 are respiratory problems such as pneumonia and acute respiratory distress syndrome (ARDS). Patients with MIS-C require PICU admission because of cardiac, cardiorespiratory, and gastrointestinal complications. MIS-C can be especially difficult to differentiate from Kawasaki disease. Hyperinflammation seen in SARS-CoV-2 infections plays a major role in pathogenesis and complications seen in severe acute COVID-19. Precautions to be taken during aerosol generating procedures, management strategies of COVID-19 acute respiratory failure, recognition and management of hypercoagulable states, and diagnosis and treatment of MIS-C have demanded unprecedented, rapid and unique adaptations in the PICU. The delta surge of 2021 was responsible for an increased disease burden in children and points to the key role of vaccinating children against this sometimes-deadly disease. Other long term public health impacts of the pandemic (mental health crisis, strain on the medical home and school disruption) will be felt for a long time.

hospitalized. 10 Severe COVID-19 disease was associated with males younger than 1 year, and the presence of co-morbidity. There was no association between race/ethnicity and severe COVID-19.

The American Academy of Pediatrics (AAP) and the Children's Hospital Association (CHA) began publishing pediatric data weekly starting in the Fall of 2020, indicating increasing numbers of children (<17 y) with COVID-19 and hospitalization rates, especially during the Delta surge of 2021. 11 As of October 2021, 5,899,148 children were reported to have COVID-19, representing 16 .2% of US cases with an overall rate of 7,838 cases per 100,000 children. 

Transmission of SARS-CoV-2 is primarily through airborne droplets and to a lesser extent from contaminated surfaces and rarely through body fluids. The virus can transmit over long distances especially when indoors. Incubation period is 3-6 days. The entry into host cells is mediated by its spike glycoprotein (S-glycoprotein) binding to ACE2 cellular receptor in the upper respiratory tract to begin primary replication. 13 Patients can be asymptomatic carriers or have mild symptoms at this stage. Viral load is elevated in the first week followed by a progressive decline in seven to ten days with increase in IgM and IgG antibodies against viral antigens. The persistence of high viral load leads to migration of virus in the airway with entry into alveolar epithelial cells where it replicates, causing localized inflammation and pneumonia.

Cell apoptosis occurs, with increased capillary permeability and release of proinflammatory proteins. Cytokine storm can ensue with release of inflammatory markers such as interleukins (IL) -IL-2/6/7/10, granulocyte colony stimulating factor (GCSF), interferon gamma-induced protein 10 (IP-10), macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 (MIP-1), and tumor necrosis factor-α (TNF-α) which can cause acute respiratory distress syndrome (ARDS), septic shock and multi-organ dysfunction. 14 Tags for SEO: COVID-19, CDC, Delta variant J o u r n a l P r e -p r o o f Children with COVID-19 are admitted to the PICU because of severe acute COVID-19 illness   which is SARS-CoV-2 infection with one or more organ system involvement or COVID-19 associated MIS-C.

Children with severe acute COVID-19 are admitted to the PICU for respiratory problems such as pneumonia and ARDS. Cardiovascular, gastrointestinal, neurologic, hematologic, and acute kidney injury (AKI) complications can result from severe acute COVID-19. Risk factors for severe acute COVID-19 are the presence of one or more underlying conditions such as obesity, chronic pulmonary disease, neurological disease, cardiovascular disease, medical complexity and technology dependence, sickle cell disease, or immunosuppresion. [15] [16] [17] [18] [19] Underlying chronic respiratory diseases such as asthma and cystic fibrosis were not significantly exacerbated by SARS-CoV-2. 19 Younger age, obesity, hypoxia on admission, elevated white blood cell count, and bilateral infiltrates on chest radiograph, are predictors of severe respiratory disease. 20

Detection of SARS-CoV-2 nucleic acid using real-time reverse transcriptase-polymerase chain reaction (RT-PCR) is considered the gold-standard for the diagnosis of COVID-19. 21 The virus can be detected in the upper airway (nasopharynx swab) or lower airway secretions (tracheal aspirates, bronchoalveolar lavage), blood, urine, and stool. Leukocytosis or leukopenia, lymphocytosis or lymphopenia, and elevations of C-reactive protein (CRP), serum ferritin, lactate dehydrogenase (LDH), D-dimers, procalcitonin, erythrocyte sedimentation rate (ESR), J o u r n a l P r e -p r o o f serum aminotransferases, and creatine kinase-myocardial bands (CK-MB) have been observed. 22, 23 Elevations of CRP, procalcitonin, pro-B type natriuretic peptide (BNP) and platelet count are more common in children requiring PICU admission compared to other hospitalized patients. 24 Organ dysfunction was associated with elevated CRP, elevated white blood cell (WBC) count, and thrombocytopenia. 25 Hyperinflammation associated with elevated LDH, D-dimer, IL-6, CRP, ferritin and decreased lymphocyte count, platelet count, and albumin level were associated with worse outcomes in adult patients with Imaging studies:

Chest radiography is routinely performed in most children hospitalized for acute respiratory failure from COVID-19. While chest radiographs do not have high sensitivity and specificity for the diagnosis of COVID-19, it is useful to monitor disease progression. Bilateral distribution with presence of peripheral or subpleural ground glass opacifications and consolidation are common findings in COVID-19 pneumonia or ARDS (Fig.4) . Typical features of viral respiratory infections in children such as increased perihilar markings and hyperinflation were not reported in children with COVID-19. 27, 28 Computerized tomography (CT) scans are considered the 'gold-standard' for imaging with COVID-19 respiratory disease. 29 CT scans are highly sensitive and specific and can detect infection before the appearance of clinical signs. 29, 30 Three phases of evolution have been observed in children with COVID-19 disease. These include the "halo" sign defined as nodules or masses surrounded by ground glass opacifications seen in the early phase of the disease, widespread ground-glass opacifications in the progressive phase and consolidative opacities in the developed phase. Peribronchial thickening and inflammation along the bronchovascular J o u r n a l P r e -p r o o f bundle are observed more frequently in children than adults. 31 Fine mesh reticulations and "crazy paving" sign have been reported. Pleural effusion and lymphadenopathy are rare. 31 When compared to adults, children were found to have less positive CT findings, lower number of pulmonary lobes involved, and lower overall semiquantitative lung score which measures the extent of lung involvement. 31 Because of these findings and concerns for radiation exposure, transport of unstable patients to CT suites, and infection control issues, chest CT is not recommended as the initial diagnostic test in children suspected of having COVID-19. However, it may be considered to answer specific clinical questions such as presence of pulmonary embolism, assessment of those not responding to treatment and to track evolution of fibrotic disease. Lung ultrasound is a useful imaging modality as semiquantitative scores in lung ultrasound have been shown to be consistent with those in lung CT scans in adults who are critically ill with COVID-19, and should be considered in children. 30, 32 Recommendations for diagnostic tests in Severe Acute COVID-19: Imaging studies: chest radiograph in all patients, CT scan if pulmonary embolism is suspected.

 Severe acute COVID-19 which is SARS-CoV-2 infection with one or more organ system involvement requires PICU admission. Pathologic changes in these patients are like PARDS from other causes with initial diffuse alveolar damage and fibrosis with disease progression. Differences have been noted in adults between ARDS from COVID-19 as compared to ARDS from other causes including phenotypic subtypes such as 'Type L', characterized by low elastance with preserved compliance and 'Type J o u r n a l P r e -p r o o f H', characterized by high elastance with low compliance, and increased association with thrombosis. 34 Studies in children have not shown significant differences in compliance between PARDS from COVID-19 and other causes.

I: General principles of management:

Management of COVID-19 associated acute respiratory failure is outlined in figure 5 . The principles of management and end goals of respiratory therapy are the same as for other causes of acute respiratory failure in children. 33, 35, 36 Patients who have SpO2 < 90% will need supplemental oxygen, non-invasive ventilation or intubation and mechanical ventilation based on severity. Intubation protocols with special precautions for patients with COVID-19 should be developed based on resources available. 37, 38 Ventilator strategies as outlined in figure 5 will help in the management of COVID-19 PARDS and ARDSNet protocols for PEEP/FiO2 may be followed. In a retrospective study in children prior to the COVID-19 pandemic, use of lower PEEP relative to FiO2 than what is recommended by the ARDSNet model resulted in higher mortality. [38] [39] [40] In addition to recommendations in figure 5 , intravascular volume expansion should be avoided in patients without hypotension. Adequate mean arterial pressure should be maintained, and inotropic support provided as needed, and nutritional support must be adequate. 38, 41 Patients who have refractory hypoxemia may need treatment such as inhaled nitric oxide, high-frequency oscillatory ventilation, or extracorporeal membrane oxygenation (ECMO) as recommended in the management of PARDS from other causes.

II: COVID-19 specific management:

1. Rapid spread of infection from SARS-CoV-2 can occur during various aerosol generating procedures (AGP). Appropriate personal protection equipment (PPE) should be used by all staff and visitors. Special precautions should be taken to minimize spread during AGP such as coughing and sneezing, use of non-invasive ventilation including HFNC, bag-mask ventilation, intubation, tracheal suction, planned or accidental extubation, chest physiotherapy, cardiopulmonary resuscitation, and use of nebulized medications outside of a closed circuit. 38 2. Antiviral therapy: Remdesivir is an antiviral medication that is an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), which is essential for viral replication. Remdesivir is approved by the Food and Drug Administration (FDA) for treatment of patients > 12 years old hospitalized with COVID-19, who weigh ≥ 40 kg, and is FDA authorized via EUA for use in hospitalized patients < 12 years of age or weigh between 3.5 to <40kg. 42,43 In neonates <3.5 kg, use should be directed by recommendations from infectious disease consultants upon weighing the risks versus benefits. Intravenous remdesivir is most beneficial if used early in the course of illness (<10 days) and has been shown to reduce symptom duration in adults but does not appear to reduce mortality. There are few studies in children, but remdesivir appears to be well tolerated. 44, 45 Lyophilized powder formulation should be used in children <40 kg as it contains half the amount of sulfobutylether-β-cyclodextrin sodium salt, an excipient in remdesivir which is cleared through the kidneys and can accumulate in patients with decreased renal function.

Children weighing ≥3.5 kg and <40kg should receive a loading dose of 5 mg/kg on day one followed by 2.5 mg/kg/dose once daily. For those >40 kg, a loading dose of 200 mg is recommended on day one followed by 100 mg daily. Duration of therapy is five days or until hospital discharge, whichever is earlier, and ten days for those who require mechanical ventilation or ECMO. Laboratory monitoring during remdesivir therapy should include CBC, CMP, PT/INR at baseline, day five of therapy, and more often if there is concern for toxicity.

Common adverse reactions to remdesivir include reversible transaminase elevations and J o u r n a l P r e -p r o o f hypersensitivity reactions. Bradycardia and hypotension have been reported in adults but may have been related to concomitant use of other medications. 46 Contraindications to its use are hypersensitivity to remdesivir or any component of the formulation. Remdesivir is not recommended in children older than 28 days with estimated glomerular filtration rate <30 mL/min, and in full-term neonates with serum creatinine level 1 mg/dL or greater and should be used with caution in those with baseline alanine transaminase (ALT) levels more than 5 times the upper limit of normal. Transaminases might be elevated due to COVID-19 and if remdesivir is used it should be discontinued if ALT levels increase to more than 10 times the upper limit of normal or if ALT elevation is accompanied by signs or symptoms of liver inflammation. Dose adjustments will be needed for those on ECMO or renal replacement therapy (RRT) because of interactions between remdesivir and the circuits which can cause significant changes in pharmacokinetics of the drug. J o u r n a l P r e -p r o o f platelet count is recommended. 38 When not contraindicated, pharmacologic thromboprophylaxis combined with mechanical thromboprophylaxis with sequential compression devices are recommended. Anticoagulant thromboprophylaxis with low molecular weight heparin is recommended in patients who have elevated D-dimer levels or clinical risk factors for venous thromboembolism. Children who are at high risk for venous thromboembolism include those who are critically ill, with a history of thromboembolism, or those who have increased inflammatory markers (CRP>150 mg/l, D-dimer >1500 ng/ml, IL-6 >100pg/ml, ferritin >500 ng/ml), and should be treated with subcutaneous low molecular weight heparin (< 2months:

1.5mg/kg/dose every 12 hours; > 2 months: 1mg/kg/dose every 12 hours) to achieve Anti-Xa factor levels of 0.5-1 IU/mL. 56 Children who are clinically unstable or have severe renal impairment should receive continuous intravenous infusion of unfractionated heparin as anticoagulant thromboprophylaxis using pediatric heparin nomogram to guide therapy. 57,58

Patients with MIS-C commonly have myocarditis, and occasionally, in severe acute COVID- 19 . Presentation and management are the same as that for myocarditis from other infections.

 Pathophysiology and diagnosis of PARDS from COVID-19 is the same as PARDS from other causes.

 Intensivists must be familiar with additional precautions to be taken during intubation and aerosol generating procedures. 13-20 years of age while MIS-C is higher in the 6-12-year age group. 61 MIS-C has been associated with more severe outcomes in children older than 5 years while severe acute COVID-19 is associated with worse outcomes in children < 1 year of age. 68, 69 Higher values of D-dimer, CRP, ferritin, lower platelet and absolute lymphocyte count have been shown to be predictive of severe MIS-C. Higher neutrophil to lymphocyte ratio, higher CRP, and lower platelet count have been observed in MIS-C compared to COVID-19. 61 Mucocutaneous signs and symptoms on presentation are seen in almost two-thirds of patients with MIS-C, but only in 10% of patients with COVID-19. 61 Abdominal pain and vomiting can occur in sixty percent of patients with MIS-C and of such severity as to be mistaken for acute appendicitis. 60 The possibility of MIS-C coexisting with acute appendicitis should be considered. 70, 71 Patients with severe acute COVID-19 can present with gastrointestinal symptoms but usually not as severe as that seen in patients with MIS-C.

Feldstein and colleagues reported gastrointestinal symptoms on presentation in ninety percent of patients with MIS-C compared to fifty eight per cent of patients with severe acute COVID- 19. 61 Abdominal imaging in patients with MIS-C have demonstrated inflammation including mesenteric adenopathy, mesenteric edema, ascites, bowel wall thickening and gallbladder wall thickening (Fig.6 ).

Cardiorespiratory involvement, and the need for vasoactive agents were observed in fifty six percent, sixty seven percent, and forty five percent respectively in patients with MIS-C compared to nine, twelve, and nine percent respectively in patients with severe acute COVID-19 in a case series of 1,116 patients studied by Feldstein et al. 61 Belay and colleagues reported hypotension (51%), shock (37%), cardiac dysfunction (31%), and myocarditis (17%) in the largest cohort of J o u r n a l P r e -p r o o f patients with MIS-C reported thus far. 60 Mucocutaneous lesions and conjunctival injection and laboratory markers of BNP and IL-6 were associated with coronary artery abnormalities. 61, 68 The incidence of coronary artery dilation and aneurysms (CAA) in MIS-C is four to twenty four percent. 60, 61, [72] [73] [74] In patients with KD, the risk of coronary artery thrombosis is directly related to size of CAA and increases exponentially above a z-score of 10. 75, 76 Depressed left ventricular function (LV) has been noted in a third of patients. 60,61 Similar to patients with other causes of poor cardiac function, children with MIS-C or severe acute COVID-19 with LV dysfunction are at risk for intracardiac thrombosis. 77 Knowledge of duration of persistence of abnormalities in inflammatory markers, troponin, D-dimer, LV dysfunction, and CAA is limited because of lack of consistent follow-up protocols and patient compliance. In the small number of children seen in follow-up so far, most of the abnormalities return to normal. 61, 78 Respiratory complications in MIS-C can be like those seen in severe acute COVID-19 with some differences. Lower respiratory infection was reported in seventeen percent of patients with MIS-C compared to thirty six percent of patients with severe acute COVID-19. Severe respiratory disease without cardiovascular involvement was observed in twenty four percent of MIS-C compared to seventy one percent of patients with severe acute COVID-19 in the study by inflammation, and hypoalbuminemia are seen more often in patients with MIS-C compared to those with severe acute COVID-19, likely contributing to third spacing and pleural effusion in patients with MIS-C.

The diagnostic pathway for MIS-C recommended by the American College of Rheumatology is a clinically useful tool. 50 The tier 1 and tier 2 evaluations shown in figure 9 are a comprehensive list of tests for evaluation of MIS-C. Recommendations for laboratory studies for patients in the ICU include daily CBC, basic metabolic panel, and D-dimer, troponin every six hours, and BNP every forty-eight hours and adjusted in frequency based on clinical condition. Recommendations for monitoring of cardiac complications in MIS-C in addition to those listed in tier 2 include the following: 1. EKG every forty-eight hours in hospitalized patients or more frequently for those with conduction abnormalities and again at follow-up. 2. Echocardiogram repeated one to two weeks and four to six weeks after initial presentation. Patients with LV dysfunction and coronary artery aneurysm require more frequent echocardiography. 3. Cardiac MRI two to six months after the acute illness to assess for myocardial fibrosis and scarring.

Patients who do not meet all the criteria for diagnosis of MIS-C should be evaluated for diseases with similar presentations, such as KD, toxic shock syndrome or hemophagocytic lymphohistiocytosis.

Treatment should be directed at supportive care of multi-organ dysfunction and mitigation of the underlying inflammatory process. The treatment of MIS-C as recommended by the American College of Rheumatology is outlined in figure 10 . 50 Additional treatment guidelines: J o u r n a l P r e -p r o o f 1. Initial treatment with IVIG and glucocorticoids is associated with lower risk of left ventricular dysfunction, shock, and decreased need for adjunctive therapy than with IVIG alone. 80 2. Anakinra 1-2mg/kg/d should be considered in patients in whom corticosteroids are contraindicated.

3. High dose anakinra, > 4mg/kg/d is recommended for those refractory to treatment with IVIG with or without steroids. In some cases, anakinra as high as 10 mg/kg/day (max 100 mg/ dose) through subcutaneous or intravenous routes divided every six to twelve hours may be needed. If the patient does not show improvement with this regimen, the diagnosis of MIS-C should be reconsidered. 9. Consultation with infectious disease, immunology and cardiology subspecialists is recommended for all patients. Hematologists and endocrinologists may also be needed to guide anticoagulation and steroid management.

MIS-C may be especially difficult to differentiate from KD despite well-established diagnostic criteria. 62, 81 The following are differences between MIS-C and KD:

1. MIS-C is common among black and Hispanic children while incidence of KD is highest in children of Asian descent.

2. MIS-C is reported in children from three months to twenty years with those older than five years more severely affected while KD is usually seen in children less than five years of age.  Intensivists should be familiar with the differential diagnosis for MIS-C and especially its differentiation from Kawasaki disease.

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