Copyright
©The Author(s) 2020.
World J Clin Cases. Nov 6, 2020; 8(21): 5250-5283
Published online Nov 6, 2020. doi: 10.12998/wjcc.v8.i21.5250
Published online Nov 6, 2020. doi: 10.12998/wjcc.v8.i21.5250
Table 1 Hypothesized mechanism for the lower susceptibility of children to coronavirus disease-2019
| Factor involved | Explanation |
| ACE2 receptor | The ACE2 receptor is necessary for the entry of the COVID-19 into the cells. It is postulated that in children the development, function, or activity of this protein could be lower. Also, ACE2 receptors are up-regulated in those with chronic obstructive pulmonary disease or hypertension, which may partially explain more serious disease in those with comorbid conditions. |
| Reduced exposures | Children may have fewer opportunities than adults to be exposed to the virus or to those with COVID-19. Children have fewer outdoor activities and make fewer international trips, making infection less likely. Compared to adults, children have had less lifetime exposure to toxins such as cigarette smoke and air pollution, factors which may affect the health of an individual’s epithelium. |
| Comorbidities | Compared to adults, children have a low rate of comorbidities and most children with COVID-19 infection are young and previously healthy. |
| Other viruses | Children are susceptible to a wide variety of viral illnesses. The presence of other viruses may limit COVID-19 infection by competitive mechanism. In addition, cross-reactive antibodies generated by exposure to other viruses may cause a partial protective response. |
| Inflammatory response | Children have fewer pro-inflammatory cytokines secretion than adults. This may mean that adults experience a more pronounced inflammatory response than children with a similar exposure to SARS-CoV-2. |
| Immune response | Children have a more active innate immune response than adults. The innate immune system, which acts earlier than the adaptive immune response, is more active in children, and may prevent more serious illness. Natural involution of the thymus over time leads to a decline in circulating naïve T cells. Due to this normal process, immune systems in adults are less able to be adaptive than those of children. |
Table 2 Hypothesized pathophysiological mechanisms for cardiac injury in coronavirus disease-2019
| Mechanism | Explanation |
| COVID-19–related myocarditis | SARS-CoV-2 may directly cause myocardial damage by entering cardiomyocytes using the ACE2 receptor, a human cell receptor with a strong binding affinity to the virus spike protein of SARS-CoV-2 (highly expressed in the heart). The virus is also capable of active CD8+ T lymphocytes migrate to the cardiomyocytes and cause myocardial inflammation through cell-mediated cytotoxicity. There is evidence demonstrating that SARS-CoV-2 infects the myocardial tissue. |
| Deregulated immune response & cytokine storm | SARS-CoV-2 infection may lead to deregulated immune response with higher neutrophil-lymphocyte-ratio, lower levels of both T helper and T suppressor cells, and higher expression of pro-inflammatory cytokines (IFN-γ, TNF, IL-1, IL-6 and IL-18), which are released into the circulation. This cytokine storm syndrome has a role in cardiovascular system injury, causing multi-system inflammation and multi-organ failure with direct cardiotoxicity and rapid onset of severe cardiac dysfunction, hemodynamically instability and vascular leakage with peripheral and pulmonary edema. |
| Oxygen supply and demand imbalance | Myocardial injury may result from the imbalance between oxygen supply and demand due to a severe acute respiratory distress syndrome and systemic hypotension with myocardial hypo-perfusion in association with increased cardio metabolic demand in the myocardial tissue. This can result in myocytes hypoxia and necrosis. |
| Thromboembolic events | The systemic inflammation secondary to the cytokine storm also causes endothelial dysfunction and increases the procoagulant activity of the blood, which can further contribute to the formation of multi-organ micro thrombi and also occlusive thrombi over a ruptured coronary plaque. |
| Cardiotoxicity of drugs used against SARS-CoV-2 | Off-label drugs available for COVID-19 treatment can produce myocardial dysfunction, severe systemic hypotension, QT prolongation with ventricular arrhythmia and AV block |
| Deleterious effects of inotropes and mechanical ventilation | Mechanical ventilation in critically ill children is another possible cause of cardiovascular adverse effects, such as a decrease in cardiac output due to decreased venous return to the right heart, right ventricular dysfunction, and impaired left ventricular elastics. Increased right ventricular after-load due to the pulmonary infection can be worsened by mechanical ventilation with high PEEP, leading to right ventricular failure and subsequent myocardial injury. Inotropes can provoke an increased cardio metabolic demand during an hypoxemic condition, |
| Pre-existing Heart diseases | Patients with pre-existing heart diseases have increased morbidity and mortality related to viral infection It is reasonable to assume that patients with underlying heart diseases with low cardiopulmonary reserve are susceptible to cardiac injury, and once such patients are infected with COVID-19, myocardial ischemia or infarction, and left ventricular systolic dysfunction or ventricular arrhythmia are more likely to occur, ultimately leading to a sudden deterioration. |
Table 3 Different case-definitiosns for the novel hyperinflammatory syndrome described during coronavirus disease-2019 pandemic
| Royal College of Pediatrics and Child Health (United Kingdom) | World Health Organization | Centers for Disease Control and Prevention (United States) |
| A child presenting with persistent fever, inflammation (neutrophilia, elevated CRP, and lymphopenia) and evidence of single or multiorgan dysfunction (shock, cardiac, respiratory, kidney, gastrointestinal, or neurological disorder) with additional clinical features, including children fulfilling full or partial criteria for Kawasaki disease 2 | Children and adolescents 0-19 yr of age with fever > 3 d AND 2 of the following: (1) Rash or bilateral nonpurulent conjunctivitis or mucocutaneous 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, APTT, elevated D-dimers); (5) Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain). | An individual aged < 21 yr presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (> 2) organ involvement (cardiac, kidney, respiratory, hematologic, gastrointestinal, dermatologic, or neurological). 1Fever > 38.0 °C for ≥ 24 h or report of subjective fever lasting ≥ 24 h. |
| And exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus (waiting for results of these investigations should not delay seeking expert advice) | And elevated markers of inflammation such as ESR, CRP, or procalcitonin. | And no alternative plausible diagnoses |
| And SARS-CoV-2 PCR test results may be positive or negative | And no other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes | And positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or COVID-19 exposure within the 4 wk prior to the onset of symptoms |
| And evidence of COVID-19 (RT-PCR, antigen test, or serology positive), or likely contact with patients with COVID-19 | Additionally, 1some individuals may fulfil full or partial criteria for Kawasaki disease but should be reported if they meet the case definition for MIS-C. |
Table 4 Differential characteristics between Kawasaki disease and the novel Pediatric Multisystem Inflammatory Syndrome in children with SARS-CoV-2 infection
| Characteristic | Kawasaki disease | PMIS |
| Age | 6 mo-5 yr (most cases under 2-yr-old) | School-aged children (mean age 9-yr-old) |
| Sex | Male predominance | Male = Female |
| Race | Asiatic | African/Caribbean |
| Region | Most cases at Asia | Most cases at Europe and America. No asiatic cases |
| Seasonality | Spring-Autum | Regional incidences associated with the larger regional COVID-19 outbreaks |
| Related with acute infection | Yes | 2-4 wk after primary infection (can occur also during acute phase) |
| Incomplete KD criteria | Up to 30% | < 25% |
| Gastrointestinal symptoms | Uncommon | Almost 100% |
| KD shock syndrome | 2%-7% | 50%-60% |
| Increased inflammatory biomarkers (CRP, Procalcitonin, Ferritin) | ++ | ++++ |
| Lymphocyte count | Lymphopenia rare | Lymphopenia in up to 80% |
| Platelet count | Thrombocytosis | Thrombocytopenia |
| Coagulation indexes | Normal values | Increased indexes; Very increased Dimer-D levels |
| Increased cardiac biomarkers | Natriuretic peptides (> 50%) ++; cTn (< 20%-30%) +/- | Natriuretic peptides (87%) ++++; cTn (73%) ++++ |
| Myocardial dysfunction | < 1% | Up to 52% |
| Coronary arteries anomalies | 25% without adequate treatment | 15% |
| IVIG resistance | 10%-20% | 50%-60% |
| Biologic therapy | Very rare | 15 % |
| Long-term Cardiac sequel | < 5% with adequate treatment | 5.5% |
| PICU admission | 4%-5% | 75% |
| Mechanical Ventilation | Very rare | 22 % |
| ECMO support | Extremely rare | 4%-5% |
| Exitus or Sequelae | < 1% | 2% |
Table 5 Summary of the data about cardiovascular involvement reported by the case series with more than 10 children with Pediatric Multisystem Inflammatory Syndrome
| Author | Feldstein | Dufort | Miller | Capone | Kaushik | Cheung | Riollano-Cruz | Verdoni | Whittaker | Ramcharan | Hameed | Toubiana | Belhadjer | Grimaud | Pouletty | Moraleda |
| Demographic | ||||||||||||||||
| Country | United States | United States | United States | United States | United States | United States | United States | Italy | United Kingdom | United Kingdom | United Kingdom | France | France & Sw | France | France | Spain |
| Size | 186 | 99 | 44 | 33 | 33 | 17 | 15 | 10 | 58 | 15 | 35 | 21 | 35 | 20 | 16 | 31 |
| Age | 8.3 | 8.4 | 7.3 | 8.6 | 10 | 8 | 12 | 7.5 | 9 | 8.8 | 11 | 8 | 10 | 10 | 10 | 7.6 |
| Male Sex | 115 (62%) | 53 (53%) | 20 (45%) | 20 (60%) | 20 (60%) | 8 (47%) | 11 (73%) | 7 (70%) | 25 (43%) | 11 (73%) | 27 (77%) | 9 (43%) | 18 (51%) | 10 (50%) | 8 (50%) | 18 (58%) |
| Commorbidity | 59 (31%) | 35 (35%) | 16 (36%) | 4 (9%) | 16 (48%) | 3 (17%) | 5 (33%) | 0 (0%) | 7 (12%) | 0 (0%) | 0 (0%) | 0 (0%) | 10 (28.5%) | 0 (0%) | 6 (37.5%) | 10 (32%) |
| Cardiovascular involvement | ||||||||||||||||
| Shock | NR | 32 (32%) | NR | 16 (48%) | 21 (63%) | 13 (76%) | 13 (87%) | 5 (50%) | 27 (46%) | 10 (66%) | 21 (60%) | 12 (57%) | 28 (80%) | 20 (100%) | 11 (68%) | 15 (48%) |
| ECG alterations | 22 (12%) | 59 (59%) | 22 (50%) | NR | NR | 16 (94%) | 2 (13%) | NR | 4 (7%) | 9 (60%) | NR | 2 (10%) | 1 (3%) | NR | NR | 7 (23%) |
| Increased cTn | 77/153 (50%) | 63/89 (71%) | NR | 33 (100%) | 33 (100%) | 14 (82%) | 13 (87%) | 5/9 (55%) | 34/50 (68%) | 15 (100%) | 35 (100%) | 17 (81%) | 35 (100%) | 20 (100%) | 11/11 (100%) | NR |
| Increased pro-BNP | 94/128 (74%) | 74/82 (90%) | NR | 33 (100%) | 33 (100%) | 15 (88%) | 13 (87%) | 10 (100%) | 24/29 (83%) | 15 (100%) | 35 (100%) | 14/18 (78%) | 35 (100%) | 15/15 (100%) | 16 (100%) | 22 (71%) |
| Myocardial dysfunction | 70 (38%) | 51 (52%) | 22 (50%) | 19 (58%) | 22 (63%) | 6 (35%) | 7 (57%) | 5 (50%) | 18 (31%) | 12 (80%) | 15 (43%) | 16 (76%) | 35 (100%) | 20 (100%) | 7 (43%) | 15 (48%) |
| Coronary artery involvement | 15 (8%) | 9 (9%) | 0 (0%) | 16 (48%) | 0 (0%) | 7 (41%) | 3 (20%) | 2 (80%) | 8 (14%) | 14 (93%) | 6 (20%) | 8 (38%) | 6 (17%) | 0 (0%) | 3 (18%) | 3 (10%) |
| Treatment | ||||||||||||||||
| Mechanical ventilation | 37 (20%) | 10 (10%) | 1 (2%) | 6 (18%) | 5 (15%) | 0 (0%) | 3 (20%) | 0 (0%) | 25 (43%) | 4 26%) | 7 (20%) | 11 (52%) | 22 (62%) | 8 (40%) | 2 (12%) | 6 (19%) |
| Inotropic support | 90 (48%) | 61 (62%) | 22 (50%) | 25 (75%) | 17 (51%) | 10 (59%) | 8 (53%) | 2 (20%) | 29 (50%) | 10 (67%) | 20 (57%) | 15 (71%) | 28 (80%) | 19 (95%) | 6 (38%) | 15 (48%) |
| ECMO support | 8 (4%) | 4 (4%) | 0 (0%) | 0 (0%) | 1 (3%) | 0 (0%) | 1 (6%) | 0 (0%) | 3 (5%) | 0 (0%) | 2 (6%) | 0 (0%) | 10 (28%) | 0 (0%) | 0 (0%) | 0 (0%) |
| IVIG | 144 (77%) | 69 (70%) | 36 (81%) | 33 (100%) | 18 (54%) | 13 (76%) | 12 (80%) | 8 (80%) | 41 (70%) | 10 (66%) | 35 (100%) | 21 (100%) | 25 (71%) | 20 (100%) | 15 (93%) | 20 (65%) |
| Steroids | 91 (49%) | 61 (62%) | 42 (95%) | 23 (70%) | 17 (51%) | 15 (92%) | 3 (20%) | 10 (100%) | 37 (64%) | 5 (33%) | 35 (100%) | 10 (48%) | 12 (35%) | 2 (10%) | 4 (25%) | 21 (68%) |
| Antiplatelet | 0 (0%) | 0 (0%) | 0 (0%) | 29 (87%) | 0 (0%) | 4 (24%) | 2 (13%) | 2 (20%) | 0 (0%) | 11 (73%) | 0 (0%) | 21 (100%) | 0 (0%) | 0 (0%) | 15 (93%) | 0 (0%) |
| Anticoagulation | 87 (47%) | 0 (0%) | 40 (90%) | 14 (42%) | 32 (97%) | 11 (64%) | 15 (100%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 23 (65%) | 0 (0%) | 0 (0%) | 0 (0%) |
| Biologics | 38 (21%) | 0 (0%) | 8 (18%) | 7 (21%) | 12 (36%) | 0 (0%) | 14 (93%) | 0 (0%) | 11 (19%) | 0 (0%) | 0 (0%) | 0 (0%) | 3 (9%) | 2 (10%) | 2 (12%) | 0 (0%) |
| Outcomes | ||||||||||||||||
| PICU admission | 148 (80%) | 79 (80%) | 22 (50%) | 26 (79%) | 33 (100%) | 15 (88%) | 14 (93%) | 5 (50%) | 29 (50%) | 10 (67%) | 25 (69%) | 17 (81%) | 35 (100%) | 20 (100%) | 7 (44%) | 20 (65%) |
| Full recovery | 182 (98%) | 97 (98%) | 44 (97%) | 24 (73%) | 29 (88%) | 16 (94%) | 13 (88%) | 10 (100%) | 56 (98%) | 12 (80%) | 33 (97%) | 21 (100%) | 25 (71%) | 20 (100%) | 14 (88%) | 30 (97%) |
| Cardiac sequelae | 0 (0%) | 0 (0%) | 0 (0%) | 9 (27%) | 2 (6%) | 1 (6%) | 1 (6%) | 0 (0%) | 0 (0%) | 3 (20%) | 0 (0%) | 0 (0%) | 19 (29%) | 0 (0%) | 2 (12%) | 0 (0%) |
| Death | 4 (2%) | 2 (2%) | 1 (2%) | 0 (0%) | 1 (3%) | 0 (0%) | 1 (6%) | 0 (0%) | 1 (2%) | 0 (0%) | 1 (3%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (3%) |
Table 6 Description of the case or case series of cardiac involvement in pediatric patients without pre-existing cardiac condition and coronavirus disease-2019
| Ref. | Mechanism | Description |
| Dong et al[16] | Myocardial injury | Nationwide case series of 2135 pediatric patients with COVID-19 reported to the Chinese Center for Disease Control and Prevention. Cardiovascular involvement was found in 13 patients with myocardial injury or heart failure. No deaths were reported. |
| Cui et al[115] | Myocardial injury | Description of a 55-d-old otherwise healthy female case with COVID-19 in China. Abnormal myocardial enzyme values on admission and increased troponin I indicated myocardial injury. The patient evolved favourably. |
| Del Barba et al[116] | Myocardial injury | A 38-d-old male tested positive for SARS-CoV-2 and developed mild cardiovascular inflammation. An increase in troponin T was observed and a cardiac magnetic resonance was also performed which showed a minimal amount of pericardial effusion. The patient evolved favourably. |
| Gnecchi et al[117] | Myocardial injury | A previously healthy 16-yr-old boy presented at the emergency department with fever and chest pain. The ECG showed inferolateral ST-segment elevation and the echocardiogram showed hypokinesia of the inferior and anterolateral segments of the left ventricle, with preserved function (EF 52%). Troponin I was very increased. Cardiac MRI supported the diagnosis of myocarditis. On day 3 of illness a nasopharyngeal swab test confirmed SARS-CoV-2 infection. The patient presented a full recovery on day 12 of illness. |
| Craver et al[122] | Myocardial injury | The authors reported a previously healthy 17-yr-old male that presented with sudden cardiac death. The autopsy showed diffuse myocarditis with mixed inflammatory infiltrate with a predominance of eosinophil as the cause of the death. |
| Sun et al[123] | Myocardial injury | In a small series of 8 critically ill patients infected by SARS-CoV-2, the authors reported the case of a 13-mo-old male who developed heart failure within a multiple organ failure with full recovery after support therapy (plasmapheresis and oxygen). |
| Su et al[124] | Myocardial injury | Clinical data from nine previously healthy children and their 14 families were collected, including general status, clinical, laboratory test, and imaging characteristics. In this study, they found six children with high CK-MB, which means that SARS-CoV-2 could cause heart injury. All children presented a full recovery. |
| Kesici et al[119] | Myocardial injury | A 2-yr-old, otherwise healthy boy with a history of respiratory distress secondary to COVID-19 developed cardiogenic shock the second day of hospitalization. The patient presented elevated cardiac Troponin and severe left ventricular failure on echocardiography. The patient required ECMO support and presented cardiac arrest. The autopsy confirmed a dilated cardiomyopathy secondary to viral myocarditis with SARS-CoV-2 RT-PCR positivity in the cardiac tissue as the cause of the death. |
| Giacomet et al[118] | Myocardial injury | A 2-mo-old boy presented with fever, vomiting and diarrhoea within a confirmed SARS-CoV-2 infection. The cardiac work-up revealed increased Troponin I and NT-proBNP levels and mild left ventricular dysfunction on echocardiogram. IL-6 was elevated. After therapy with IVIG the patient presented a rapid full recovery. The clinical diagnosis was myocarditis. |
| Rodriguez-Gonzalez et al[114] | Pulmonary hypertension | A 6-mo-old male with history of small bowel disease presented with a pneumonia, cardiogenic shock and severe hypoxemia. Cardiac biomarkers and IL-6 were increased, and echocardiography showed severe pulmonary hypertension and severe right ventricular failure. Pulmonary thromboembolism was ruled-out through angio-CT scan. The patient received inotropic and respiratory support and improved rapidly with full recovery after the initiation of Tocilizumab. SARS-CoV-2 infection was confirmed by serology. |
| Samuel et al[120] | Arrhythmia | Thirty-six pediatric patients with active PCR positive SARS-CoV-2 infection were included in the study. No patients presented pre-exiting cardiac condition. Of them 6 cases developed significant arrhythmias (non-sustained ventricular tachycardia in 5 and sustained atrial tachycardia in 1). All were self-resolving episodes, and 3 of them were started on prophylactic anti-arrhythmic therapy. Four of them presented abnormal echocardiograms with mild dilation/dysfunction of the left ventricle that recovered at discharge. |
| Xia et al[121] | Arrhythmia | The authors reported the clinical, laboratory, and chest CT features of 20 pediatric inpatients with COVID-19 infection confirmed by pharyngeal swab COVID-19 nucleic acid test. The authors observed self-limited ECG alterations in four of these patients during admission (Sinus tachycardia, Atrial arrhythmia, First-degree atrioventricular block, atrial and ventricular premature beats). The patients did not require any treatment and presented a full recovery. |
Table 7 Description of the case or case series of cardiac involvement in pediatric patients with pre-existing cardiac condition and coronavirus disease-2019
| Authors | Description |
| Grafmann et al[158] | A 16-yr-old girl with history of treated congenital mitral valve disease with pulmonary hypertension, atrial arrhythmias and mitral valve stenosis, who is admitted for signs of respiratory infection positive for SARS-CoV-2 which produced no signs of myocardial involvement with a full recovery. |
| Zheng et al[161] | A 8-mo and 1-yr-old boys with pre-existing congenital heart disease, presented critical COVID-19 with increased cardiac enzymes, requiring mechanical ventilation and venous-venous hemodiafiltration. These two patients presented the more aggressive SARS-CoV-2 infection among the 25 patients reported in this case series. They presented a full-recovery. |
| Krishnan et al[157] | A 3-yr-old boy with Down syndrome, repaired atrioventricular septal defect (AVSD), and pulmonary hypertension was presented a critical case of COVID-19 confirmed by PCR test. He received methylprednisone, azithromycin, and hydroxychloroquine, and continuous positive airway pressure. The patients presented prolongation of the QTc interval on electrocardiogram with posterior full recovery. |
| Salik et al[159] | A 15-d-old baby girl was diagnosed with Tetralogy of Fallot prenatally. The infant's mother was diagnosed with COVID- 19 postpartum. On day 7 of life, the infant experienced desaturation to SpO2 60–65%, tachypnea, worsening cyanosis. A COVID nasopharyngeal swab was positive; and the infant exhibited frequent spells requiring supplemental oxygen. Due to sustained hypoxemia with SpO2 55%-65%, so it was decided that Blalock- Taussig shunt placement with good clinical evolution. |
| Russell et al[160] | A 3-yr-old female patient with history of heart transplant in 2017 for congenital dilated cardiomyopathy. In the first week of March she developed a mild clinical picture consisting of rhinorrhoea and a productive cough and nasal congestion that did not require hospital admission. Several weeks later, in a review by protocol, COVID 1 PCR was performed with positive results. The patient evolved favourably. |
| Linnane et al[156] | A 10-yr-old boy with a background of double inlet left ventricle, pulmonary atresia, atrial septal defect, and a right aortic arch. He proceeded to have a bidirectional Glenn procedure and completed a total cavopulmonary connection via an extra cardiac fenestrated Fontan surgery at 3 yr and 10 mo. He was admitted for signs of respiratory infection positive for SARS-CoV-2. The patient required admission to intensive care, with gradual improvement and good evolution. |
| Sabatino et al[176] | An Italian, observational, multi-center survey of patients with congenital heart disease affected by COVID-19 was conducted and included two pediatric-aged patients. The first patient is one year old with a history of transposition of great arteries, pulmonary atresia and ventricular septal defect. The second patient had pulmonary atresia and ventricular septal defect and the third patient had a transposition of great arteries. No increase in mortality was observed in this group, with full recovery of all patients. |
| Xia et al[128] | The authors reported the clinical, laboratory, and chest CT features of 20 pediatric inpatients with COVID-19 infection confirmed by pharyngeal swab COVID-19 nucleic acid test. Two patients presented a pre-existing cardiac condition and survived previous surgery for atrial septal defect. The patients did not require any intensive treatment and presented a full recovery. |
| Simpson et al[155] | They presented seven children with congenital heart disease and COVID-19. Three patients had atrioventricular canal defect and trisomy 21, one had double inlet left ventricle with Fontan palliation by cardiac transplant 8 years ago, one had hypertrophic cardiomyopathy, one history of anomalous left coronary artery from the pulmonary artery surgically repaired at 2-mo-of-age. Four of the seven developed cardiac arrhythmias or new electrocardiogram abnormalities. All seven developed acute decompensation, with one death in an 18-yr-old with hypertrophic cardiomyopathy. |
| Climent et al[162] | A 5 mo-old infant with personal history of Hurler syndrome and severe dilated cardiomyopathy with myocardial dysfunction presented a worsening of his cardiac status during SARS-CoV-2 infection, leading to cardiac arrest and death after 72 h of admission. |
Table 8 Classification of Congenital heart diseases regarding the risk of severe coronavirus disease-2019 based on their anatomical and physiological characteristics
| High risk of poor outcomes with COVID-19 | Low risk1 of poor outcomes with COVID-19 | ||
| Physiological stage B | Physiological stage A | Physiological stage A | NYHA FC I symptoms |
| Mild hemodynamic squeal | No hemodynamic or anatomic squeal | ||
| Mild valvular disease | No arrhythmias | ||
| Trivial or small shunt | Normal exercise capacity | ||
| Arrhythmia not requiring treatment | Normal renal/hepatic/pulmonary function | ||
| Abnormal objective cardiac limitation to exercise | |||
| Physiological stage C | NYHA FC III symptoms | ||
| Significant valvular disease moderate or greater ventricular dysfunction | |||
| Moderate aortic enlargement | |||
| Venous or arterial stenosis. | |||
| Mild-moderate hypoxemia/cyanosis | |||
| Hemodynamically significant shunt | |||
| Arrhythmias controlled with treatment | |||
| Mild-Moderate Pulmonary hypertension | |||
| End-organ dysfunction that is responsive to therapy. | |||
| Physiological stage D | NYHA FC IV symptoms | ||
| Severe aortic enlarge | |||
| Arrhythmias refractory to treatment | |||
| Severe hypoxemia (associated with cyanosis) | |||
| Severe pulmonary hypertension | |||
| Eisenmenger syndrome | |||
| Refractory end-organ dysfunction | |||
Table 9 Classification of surgical and catheter-based procedures based on their relevance for the prognosis of the patients with congenital heart diseases and genetic heart diseases
| Emergency cases (Not delay more than 24-48 h) | Urgent cases (Not delay more than days to weeks) | Elective cases (Delay > 2 mo) |
| Surgical or catheter procedures | ||
| ECMO in hemodynamically unstable patient | Transposition of great vessels | |
| PDA stent in unstable patient on prostaglandin treatment | Norwood procedure for hypoplastic left heart syndrome | Valvular regurgitations managed medically |
| Thrombosed shunt | Truncus arteriosus | Slow progressive aortic stenosis scheduled for Ross procedure |
| Pericardial tamponade | Obstructive lesions stabilized with prostaglandins | Pre-Fontan catheterization with adequate saturations on room air (> 75%) |
| Rashkind procedure | Glenn procedure with decreasing saturations (< 75%) | |
| Heart transplant | Persistent heart failure in shunts on maximal anti congestive therapy | |
| Obstructed total anomalous pulmonary venous return | Endocarditis in hemodynamically stable patient | |
| ALCAPA | ||
| Stenotic right ventricle-Pulmonary artery conduit with severe ventricular dysfunction | ||
| Electrophysiological procedures | ||
| Emergency cases (Not delay more than 24-48 h) | Urgent cases (Not delay more than days to weeks) | Elective cases (Delay > 2 mo) |
| Cardiac arrest in association with pre-excited atrial fibrillation | Primary prevention defibrillator implants after life-threatening ventricular arrhythmia | Tilt-table test |
| Arrhythmia causing need for ECMO | Cardiac resynchronization therapy | Implantable loop recorder implants |
| Incessant arrhythmia with severe ventricular dysfunction | Ablation for medically refractory ventricular tachycardia | Ablation of stable arrhythmias adequate managed with drugs without cardiomyopathy |
| Pacemaker insertion for advanced AV-block | Ablation of SVT though to contribute to cardiomyopathy | Upgrades of devices |
| Defibrillator implant for secondary prevention of sudden death | Generator replacements with > 6 wk of battery remaining | |
| Pacemaker generator replacement for pacing-dependent patients | Pacemaker implant for sinus node dysfunction, non-high-grade AV block and tachy-brady syndrome in middle symptomatic patients | |
| Defibrillator generator replacement for patients with appropriate defibrillator therapies. | ||
| Ablation of supra ventricular arrhythmias causing hemodynamic deterioration and WPW syndrome associated with cardiac arrest | ||
| Transvenous lead extraction |
Table 10 Recommendations for the management of pediatric cases of genetic heart diseases during coronavirus disease-2019 pandemic
| Disease | Recommendations for management during COVID-19 pandemic |
| General recommendations | Preventive measures to minimize SARS-CoV-2 infection: Social distancing, hand-washing, facial mask. Limit outpatient clinic visits and electrophysiological and surgical procedures to life-threatening arrhythmias requiring immediate treatment, non-deferrable treatments and urgent diagnostic devices. Rule-out the presence of ventricular arrhythmia or heart failure when common overlapping COVID-19 symptoms appear: Dyspnea, syncope, cough, fatigue. Aggressive management of fever, diarrhoea and adrenergic stress as the main triggers for cardiac complications. Balance fluid and electrolyte intake according to clinical status. Influenza, pneumococcal and respiratory syncytial virus vaccination are recommended to reduce the possibility of co-infection of COVID-19. Consider at home management as first option whenever possible. Consider initial hospitalization for closely monitoring and intensive treatment in high-risk patients for heart failure or sudden cardiac death episodes. Pediatric cardiologist evaluation is highly advised when hospitalization is required. Careful use of specific COVID-19 treatment (antivirals and immunomodulatory drugs). Not discontinue usual cardiac basal. |
| LQTS | Avoid hyper-adrenergic states as triggers of Ventricular Tachycardia and Torsade de Pointes. Fever is not a main issue in LQTS. Aggressive control of fever is only recommended for LQTS type-2 cases. Beta-blocker therapy must be continued. QT prolonging drugs should be avoided. Flecainide can interact with antivirals but must not be discontinued. Avoid and correct dehydration states with ion alterations, overall potassium). Check serum electrolyte levels (especially potassium) in case of vomiting and diarrhoea. Keep potassium level above 4mEq/l with potassium supplements. Consider hospitalization in high-risk patients: Previous syncope. High-risk mutation. Infants younger than 1 year-old. Whenever an in-hospital admission is needed, a careful QT monitoring and a telemetric system should be used. Specific therapies for COVID-19 that are known to prolong the QT interval, specially hydroxychloroquine, azithromycin and ritonavir, should be avoided or used with caution. |
| Brugada | Aggressive management of Fever is the main issue. All patients should self-treat with paracetamol immediately if they develop signs of fever and stay at home. Consider hospitalization in high-risk patients: Children without an ICD and with previous syncope, spontaneous Brugada type-1 pattern on ECG, persistent fever despite paracetamol treatment at home, presence of palpitations or syncope. Management in the hospital should include monitoring of ECG abnormalities and arrhythmia as well as efforts to reduce the body temperature. If an ECG shows the type 1 Brugada ECG pattern, then the patient will need to be observed until fever and/or the ECG pattern resolves. If all ECGs show no sign of the type 1 Brugada ECG pattern, then they can go home. Specific drugs for COVID-19 do not influence on Brugada syndrome patients. |
| CPVT | At present, there are no data suggesting that patients with CPVT are at increased risk of infection with COVID-19. Avoid hyper-adrenergic states as triggers of Ventricular Tachycardia. Whenever possible, avoid the use of adrenaline in situations of ventricular tachycardia/ventricular fibrillation (VT/VF). Adrenaline is contraindicated in the event of cardiac arrest. Beta-blocker therapy must be continued. QT prolonging drugs should be avoided. Flecainide can interact with antivirals but must not be discontinued. An increased heart rate alone (pacing-induced), as an important symptom of fever or stressful circumstances, does not appear to be sufficient for the induction of ventricular arrhythmias. The antiviral or immunomodulatory therapy proposed for COVID-19 is not expected to influence on CPVT patients. |
| Cardiomyopathies | Avoid hyper-adrenergic and dehydration states that can provoke or increase left ventricular outflow obstruction leading to syncope and sudden cardiac death in HCM. Avoid hyper-adrenergic states with increased energetic and oxygen consumption leading to a worsening the myocardial function and decompensated heart failure in DCM. Consider hospitalization in high risk patients: Basal left ventricular outflow tract obstruction, end stage cardiomyopathies, decompensated HF with no response to intensification of oral treatment at home, syncope Hospital management include balance fluid and electrolyte intake according to the clinical status. Predisposition to Pulmonary edema. Negative hydric balance in case of pulmonary edema in DCM. Positive hydric balance in case of LVOTO in HCM. ECG monitoring watching for VA. QT monitoring, especially in patients on disopyramide and COVID-19 therapies). Echocardiography is mandatory to assess LVOTO and myocardial function. |
Table 11 Potential cardiovascular side-effects of the different drugs used against severe acute respiratory syndrome coronavirus 2 infection
| Drugs | Cardiovascular adverse effect | Cardiovascular monitoring |
| Hydroxychloroquine | Vomiting with low-potassium levels. QT-prolonging and TdP. Conduction abnormalities; Heart block. Myocardial injury and Cardiomyopathy. | Monitor QTc interval, specially when using in combination with other QT-prolonging drugs and CYP3A4-inhibiting drugs. Monitor myocardial function by echocardiography and pro-BNP levels. |
| Azithromycin | QT-prolonging and TdP. Moderate CYP3A4 inhibitor. | Monitor QTc interval, specially when using in combination with other QT-prolonging drugs and CYP3A4-inhibiting drugs. |
| Lopinavir/Ritonavir | Vomiting with low-potassium levels. PR-prolonging. QT-prolonging and TdP. Major CYP3A4 inhibitor. | Monitor QTc interval, specially when using in combination with other QT-prolonging drugs and CYP3A4-inhibiting drugs. |
| Remdesivir | Limited data. Severe Hypotension and cardiac arrest after loading dose in Ebola patients. Possible CYP3A4 inducer. | Monitor Hemodynamics with infusion. Carful with unstable patients. |
| Steroids | Exacerbation of Lymphopenia. Can induce hypertension. | Monitor Hemodynamics with infusion. Monitor LVOTO in HCM by echocardiography. Careful in HCM. |
| Tocilizumab | Hypertension. Volume retention. Hypersensitivity. Increased lipid profile. | Monitor Hemodynamics with infusion. Monitor myocardial ischemia (ECG; Troponin). Careful in patients with myocardial dysfunction, chamber dilation or pulmonary edema. |
Table 12 Summary of the recommendations that should be kept in mind when treatment with prolonging-QT interval are going to be used during coronavirus disease-2019 pandemic
| Step-by-step approach to administer prolonging-etc drugs during SARS-CoV-2 infection | |
| 1 | QTc intervals should be monitored at baseline and at 4 h after the administration of any QTc-prolonging drug. |
| 2 | QTc interval monitoring previously to combine any drugs prolonging the QTc interval or CYP3A4-inhibiting drugs. |
| 3 | QTc interval monitoring in patients with Known LQTS, acquired QT prolongation, or conditions associated with acquired QT prolongation (e.g, use of other QT-prolonging drugs, underlying heart disease, bradycardia, liver and renal disease electrolyte alterations…) |
| 4 | Serum potassium, calcium and magnesium should be evaluated at baseline and monitored and optimized daily. |
| 5 | Avoiding hypokalaemia is not enough. Patients with acquired LQTS or patients using a combination of QT-prolonging drugs should have a high serum potassium level (5 mEq/L). |
| If QTc increases by > 60 milliseconds or absolute QTc > 500 milliseconds (or > 530-550 milliseconds if QRS > 120 milliseconds) is observed | |
| 1 | Consultation with a pediatric cardiologist (“QT specialist”) for guidance in case of important QT prolongation. A careful balance of pros and cons should guide the decision to discontinue therapy. |
| 2 | Intensified ECG monitoring |
| 3 | Raising potassium levels |
| 4 | Correct QT-prolonging factors (calcium, magnesium, potassium…) |
| 5 | Consider to increase beta-blocker dosage |
- Citation: Rodriguez-Gonzalez M, Castellano-Martinez A, Cascales-Poyatos HM, Perez-Reviriego AA. Cardiovascular impact of COVID-19 with a focus on children: A systematic review. World J Clin Cases 2020; 8(21): 5250-5283
- URL: https://www.wjgnet.com/2307-8960/full/v8/i21/5250.htm
- DOI: https://dx.doi.org/10.12998/wjcc.v8.i21.5250