COVID-19 and cardiac complications:Myocarditis and multisystem inflammatory syndrome in children

Coronavirus is an important pathogen causing disease in humans and animals.At the end of 2019,an investigation into an increase in pneumonia cases in Wuhan,Hubei Province,China,found that the cause was a new coronavirus.This disease,which spread rapidly across China and caused an outbreak worldwide,resulted in a pandemic.Although this virus has previously been referred to as 2019-nCoV,which causes coronavirus disease 2019(COVID-19),later it was named severe acute respiratory syndrome coronavirus 2.Children were usually asymptomatic and rarely severely affected.In April 2020,reports from the United Kingdom indicated that children may have Kawasaki disease or a clinical condition similar to toxic shock syndrome.This clinical picture was later defined as multisystem inflammatory syndrome in children.Since then,similarly affected children as well as cases with other cardiac complications have been reported in other parts of the world.In this review,we aimed to evaluate COVID-19 in terms of cardiac involvement by reviewing the literature.

Esophageal ulcer and multisystem inflammatory syndrome after COVID-19:A case report

BACKGROUND Multisystem inflammatory syndrome in adults(MIS-A)is a rare but severe disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 infection.It develops in adults with inflammation of different organs including the gastrointestinal tract,heart,kidneys,skin and hematopoietic system.CASE SUMMARY We present a 58-year-old Chinese man diagnosed with MIS-A.His chief complaints were fever,generalized fatigue and anorexia,accompanied with rashes on his back.Further examination showed cardiac,renal and liver injury.He had melena and gastroscopy indicated esophageal ulcer and severe esophagitis.Repeated blood and sputum culture did not show growth of bacteria or fungi.Antibiotic treatment was stopped due to unsatisfactory performance.His condition improved after prednisone and other supportive treatment.CONCLUSION Gastrointestinal involvement in MIS-A is not uncommon.Intestinal involvement predominates,and esophageal involvement is rarely reported.Esophageal ulcer with bleeding could also be a manifestation of MIS-A.

Pediatric multisystem inflammatory syndrome associated with COVID-19: Insights in pathogenesis and clinical management

The pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has been a major challenge to be faced in recent years.While adults suffered the highest morbidity and mortality rates of coronavirus disease 2019,children were thought to be exclusively asymptomatic or to present with mild conditions.However,around April 2020,there was an outbreak of a new clinical syndrome related to SARS-CoV-2 in children-multisystemic inflam-matory syndrome in children(MIS-C)-which comprises a severe and uncon-trolled hyperinflammatory response with multiorgan involvement.The Centers for Disease Control and Prevention considers a suspected case of MIS-C an individual aged<21 years presenting with fever,high inflammatory markers levels,and evidence of clinically severe illness,with multisystem(>2)organ involvement,no alternative plausible diagnoses,and positive for recent SARS-CoV-2 infection.Despite its severity,there are no definitive disease management guidelines for this condition.Conversely,the complex pathogenesis of MIS-C is still not completely understood,although it seems to rely upon immune dysregu-lation.Hence,in this study,we aim to bring together current evidence regarding the pathogenic mechanisms of MIS-C,clinical picture and management,in order to provide insights for clinical practice and implications for future research directions.

Age-adjusted NT-proBNP could help in the early identification and follow-up of children at risk for severe multisystem inflammatory syndrome associated with COVID-19(MIS-C)

BACKGROUND Multisystem inflammatory syndrome in children(MIS-C) has emerged as a new disease associated with COVID-19 that presents in acute critically ill children with acute cardiovascular dysfunction.AIM To determine whether the age-adjusted N-terminal pro-brain natriuretic peptide(NT-proBNP) value(Z-log-NT-proBNP) is associated with severe MIS-C and myocardial dysfunction.METHODS A retrospective study was conducted which included children with MIS-C managed at our institution between April 1,2020,and February 28,2022.We divided the population into groups depending on severity based on pediatric intensive care unit(PICU) admission.We compared Z-log-NT-proBNP values across these groups and analyzed Z-log-NT-proBNP dynamics during the onemonth follow-up.RESULTS We included 17 participants [median age 3(2-9) years] and seven(41%) required PICU admission.All(100%) of these cases presented very high(Z-log > 4) levels of NT-proBNP at the time of admission compared to only 5(50%) patients with non-severe MIS-C(P = 0.025).NT-proBNP was significantly correlated with highsensitive Troponin I levels(P = 0.045),Ross modified score(P = 0.003) and left ventricle ejection fraction(P = 0.021).CONCLUSION Raised NT-proBNP,specifically very high values(Z-log-NT-proBNP > 4) could help in the early identification of MIS-C patients with myocardial dysfunction requiring inotropic support and PICU admission.

Multisystem Inflammatory Syndrome-Neonate: Biochemical Parameters as Early Marker of Adverse Neurodevelopmental Outcome

Background: Pregnant women and newborns are highly susceptible to Covid-19, manifesting as multisystem inflammatory syndrome-New-born (MISC-N) in many babies born to Covid positive mothers. The relationship between Covid-19 infection during pregnancy and neonatal neurodevelopmental outcome, if any, is unclear necessitating a follow-up study in this aspect. Methods: 16 babies with MIS-N, born to symptomatic Covid antibody positive mothers were enrolled. Demographic profile, treatment details and biochemical parameters were analyzed with neurodevelopmental follow-up. Results: 25% mothers received 2 doses of Covid vaccine;50% had oligohydramnios and 75% received antenatal steroids. 87.5% were preterm of which 62.5% required surfactant with ventilator support and 75% required ionotropic support. Significant association was found between the antibody level and D-dimer levels with the ferritin and LDH levels of the baby (p 0.05);gestational age with LDH and D-dimer levels (p 0.05) and Covid antibody level of the baby vs the duration of ventilator requirement (P-value-0.0009). D-dimer values of babies were positively associated with both maternal antibody and D-dimer levels. Neurodevelopmental follow-up done at 6 months of corrected gestational age showed 37.5% were normal, 37.5% hypertonic and 25% hypotonic. HINE score was below 60 in 62.5%. Development assessment using Bayley-III showed a delay in the motor domain (62.5%), cognitive domain (56.25%) and language domain (62.5%). Conclusion: Neurodevelopmental problems occur in babies born to Covid positive mothers and should be stratified as “high risk”. Anticipatory guidance to prospective mothers for preterm care should be given. Covid antibody titre and D-dimer levels may help to predict the NICU stay, ventilator requirement and the adverse neurodevelopmental outcomes in these babies.

Treatment of multisystem inflammatory syndrome in children

Background Multisystem inflammatory syndrome in children(MIS-C),a relatively uncommon but severe pediatric complication,is associated with coronavirus disease 2019(COVID-19).A variety of treatment approaches,including intravenous immunoglobulins(IVIGs),glucocorticoids(GCs)and biologic agents,such as anakinra and infliximab,have been described for the management of COVID-19-related MIS-C.Anticoagulant therapy is also important.However,a well-developed treatment system has not been established,and many issues remain controversial.Several recently published articles related to the treatment of MIS-C have been released.Hence,in this review,we identified relevant articles published recently and summarized the treatment of MIS-C more comprehensively and systematically.Data sources We reviewed the literature on the treatment of MIS-C through 20 September 2023.The PubMed/Medline,Web of Science,EMBASE,and Cochrane Library databases were searched with the combination of the terms"multisystem inflammatory syndrome","MIS-C","PIMS-TS","therapy","treatment","drug","IVIG","GCs","intravenous immunoglobulin","corticosteroids","biological agent",and"aspirin".Results The severity of MIS-C varies,and different treatment schemes should be used according to the specific condition.Ongoing research and data collection are vital to better understand the pathophysiology and optimal management of MIS-C.Conclusions MIS-Cis a disease involving multiple systems and has great heterogeneity.With the accumulation of additional experience,we have garnered fresh insights into its treatment strategies.However,there remains a critical need for greater standardization in treatment protocols,alongside the pressing necessity for more robust and meticulously conducted studies to deepen our understanding of these protocols.

Clinical practice guidelines in multisystem inflammatory syndrome(MIS-C)related to COVID-19:a critical review and recommendations

Background Multisystem inflammatory syndrome in children(MIS-C)is a serious health condition that develops from and is linked to coronavirus disease 2019.MIS-C is considered a multi-organ dysfunction involving cardiac,renal,respiratory,hematologic,gastrointestinal and neurological symptoms and groups of signs and symptoms such as rash or bilateral non-purulent conjunctivitis,hypotension or shock and acute gastrointestinal problems,which require immediate therapeutic intervention to prevent the aggravation of the patient’s health condition.MIS-C is relatively new in the field of evidence-based medicine;however,there are several clinical guidelines for good clinical practice.For every disorder,the guidelines have different suggestions.Hence,based on the current status of the evidence,recommendations have been combined to form a unified guideline for therapeutic management.Methods This paper compares and evaluates the current MIS-C-specific clinical practice guidelines(namely,American Academy of Pediatrics,American College of Rheumatology,Helen DeVos Children’s Hospital Foundation,Children’s Hospital of The King’s Daughters,and the Infectious Diseases Society of America).The compiled literature was then assessed by the authors separately,and an algorithm was proposed for each disorder,taking into consideration the various guidelines proposed for the management of the disorder.Results The features of MIS-C patients are unified;this is very helpful in managing its symptoms and decreasing mortality rates.In addition,recommendations for pharmacological treatment for MIS-C symptoms are formulated after cross-comparison across five different guidelines.Conclusions This study provides a general interpretation of the results in the context of other evidence and implications for future research.It proposes a unified guideline based on the current evidence,with the best potential to maintain suitable clinical standards in the Saudi Arabian Ministry of Health.

Multisystem inflammatory syndrome in pediatric COVID-19 patients:a meta-analysis

Background We aimed to systematically review the clinical and laboratory features of patients with the multisystem inflam-matory syndrome in pediatrics diagnosed during the COVID-19 pandemic.Data sources A literature search in Web of Science,PubMed,Scopus,and Science Direct was made up to June 29,2020.Results Analysis of 15 articles(318 COVID-19 patients)revealed that although many patients presented with the typical multisystem inflammatory syndrome in pediatrics,Kawasaki-like features as fever(82.4%),polymorphous maculopapular exanthema(63.7%),oral mucosal changes(58.1%),conjunctival injections(56.0%),edematous extremities(40.7%),and cervical lymphadenopathy(28.5%),atypical gastrointestinal(79.4%)and neurocognitive symptoms(31.8%)were also com-mon.They had elevated serum lactic acid dehydrogenase,D-dimer,C-reactive protein,procalcitonin,interleukin-6,troponin I levels,and lymphopenia.Nearly 77.0%developed hypotension,and 68.1%went into shock,while 41.1%had acute kidney injury.Intensive care was needed in 73.7%of cases;13.2%were intubated,and 37.9%required mechanical ventilation.Intravenous immunoglobulins and steroids were given in 87.7%and 56.9%of the patients,respectively,and anticoagulants were utilized in 67.0%.Pediatric patients were discharged after a hospital stay of 6.77 days on average(95%CI 4.93-8.6).Conclusions Recognizing the typical and atypical presentation of the multisystem inflammatory syndrome in pediatric COVID-19 patients has important implications in identifying children at risk.Monitoring cardiac and renal decompensation and early interventions in patients with multisystem inflammatory syndrome is critical to prevent further morbidity.

Severe acute respiratory syndrome coronavirus 2-induced multisystem inflammatory syndrome in children

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced multisystem inflammatory syndrome in children(MIS-C)is a life-threatening illness that has been reported in the United States and Europe.It affects multiple organ systems and often requires patient admission to an intensive care unit.Although some features of MIS-C overlap with Kawasaki disease,MIS-C is more common among older children and adolescents,more often affects cardiovascular and gastrointestinal systems,and more frequently presents with elevated inflammatory markers.Rapid and complete clinical recovery is possible in nearly all patients following immunomodulation therapy.Thus far,MIS-C pathophysiology and long-term prognosis are not sufficiently clear;further studies are needed.

Delayed inflammatory pulmonary syndrome: A distinct clinical entity in the spectrum of inflammatory syndromes in COVID-19 infection?

BACKGROUND During the second wave of the coronavirus disease 2019(COVID-19)pandemic,a subset of critically ill patients developed delayed respiratory deterioration in the absence of new infection,fluid overload or extra-pulmonary organ dysfunction.AIM To describe the clinical and laboratory characteristics,outcomes,and management of these patients,and to contrast this entity with other post COVID-19 immune dysregulation related inflammatory disorders.METHODS This was a retrospective observational study of adult patients admitted to the medical intensive care unit of a 2200-bed university affiliated teaching hospital,between May and August 2021,who fulfilled clearly defined inclusion and exclusion criteria.Outcome was assessed by a change in PaO_(2)/FiO_(2) ratio and levels of inflammatory markers before and after immunomodulation,duration of mechanical ventilation after starting treatment,and survival to discharge.RESULTS Five patients developed delayed respiratory deterioration in the absence of new infection,fluid overload or extrapulmonary organ dysfunction at a median interquartile range(IQR)duration of 32(23-35)d after the onset of symptoms.These patients had elevated inflammatory markers,required mechanical ventilation for 13(IQR 10-23)d,and responded to glucocorticoids and/or intravenous immunoglobulin.One patient died(20%).CONCLUSION This delayed respiratory worsening with elevated inflammatory markers and clinical response to immunomodulation appears to contrast the well described Multisystem Inflammatory Syndrome–Adults by the paucity of extrapulmonary organ involvement.The diagnosis can be considered in patients presenting with delayed respiratory worsening,that is not attributable to cardiac dysfunction,fluid overload or ongoing infections,and associated with an increase in systemic inflammatory markers like C-reactive protein,inteleukin-6 and ferritin.A good response to immunomodulation can be expected.This delayed inflammatory pulmonary syndrome may represent a distinct clinical entity in the spectrum of inflammatory syndromes in COVID-19 infection.

Multi-Systemic Inflammatory Syndrome in Children

The objective of our work is to study the multi-systemic inflammatory syndrome (PIMS) in children, to determine its frequency, by analyzing the epidemiological, clinical, paraclinical, therapeutic, and evolutionary profile of these patients. A retrospective study spanning a period of 2 years from April 2020 to March 2022. It concerns all children under the age of 16 admitted and cared for in the pediatric emergency department of the university hospital Hassan II of Fez for multi-system inflammatory syndrome (PIMS). Twenty cases of PIMS were collected over this period. Multi-system inflammatory syndrome in children has been described in temporal association with COVID-19, usually within 2 to 6 weeks of illness or exposure. The age of the patients varies between 8 months and 15 years. All patients presented with fever and cutaneous signs, followed by digestive signs and neurological signs. The inflammatory syndrome is frankly positive in all patients who had a COVID-19 PCR and/or positive serology. The treatment is based on the administration of immunoglobulins in association with corticosteroid therapy and non-specific antibiotic therapy in the majority of cases (80%). The evolution was favorable. PIMS should be considered in all children presenting with a clinical and/or biological inflammatory syndrome associated with COVID-19.

Cardiovascular impact of COVID-19 with a focus on children: A systematic review

BACKGROUND Since the beginning of the pandemic,coronavirus disease-2019(COVID-19)in children has shown milder cases and a better prognosis than adults.Although the respiratory tract is the primary target for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),cardiovascular involvement is emerging as one of the most significant and life-threatening complications of SARS-CoV-2 infection in adults.AIM To summarize the current knowledge about the potential cardiovascular involvement in pediatric COVID-19 in order to give a perspective on how to take care of them during the current pandemic emergency.METHODS Multiple searches in MEDLINE,PubMed were performed using the search terms“COVID-19”or“SARS-CoV-2"were used in combination with“myocardial injury”or"arrhythmia"or“cardiovascular involvement”or"heart disease"or"congenital heart disease"or“pulmonary hypertension”or"long QT"or“cardiomyopathies”or“channelopathies”or"Multisystem inflammatory system"or"PMIS"or“MIS-C”or”Pediatric multisystem inflammatory syndrome"or"myocarditis"or"thromboembolism to identify articles published in English language from January 1st,2020 until July 31st,2020.The websites of World Health Organization,Centers for Disease control and Prevention,and the Johns Hopkins Coronavirus Resource Center were reviewed to provide up to date numbers and infection control recommendations.Reference lists from the articles were reviewed to identify additional pertinent articles.Retrieved manuscripts concerning the subject were reviewed by the authors,and the data were extracted using a standardized collection tool.Data were subsequently analyzed with descriptive statistics.For Pediatric multisystemic inflammatory syndrome temporally associated with COVID-19(PMIS),multiple meta-analyses were conducted to summarize the pooled mean proportion of different cardiovascular variables in this population in pseudo-cohorts of observed patients.RESULTS A total of 193 articles were included.Most publications used in this review were single case reports,small case series,and observational small-sized studies or literature reviews.The meta-analysis of 16 studies with size>10 patients and with complete data about cardiovascular involvement in children with PMIS showed that PMIS affects mostly previously healthy school-aged children and adolescents presenting with Kawasaki disease-like features and multiple organ failure with a focus on the heart,accounting for most cases of pediatric COVID-19 mortality.They frequently presented cardiogenic shock(53%),ECG alterations(27%),myocardial dysfunction(52%),and coronary artery dilation(15%).Most cases required PICU admission(75%)and inotropic support(57%),with the rare need for extracorporeal membrane oxygenation(4%).Almost all of these children wholly recovered in a few days,although rare deaths have been reported(2%).Out of PMIS cases we identified 10 articles reporting sporadic cases of myocarditis,pulmonary hypertension and cardiac arrythmias in previously healthy children.We also found another 10 studies reporting patients with preexisting heart diseases.Most cases consisted in children with severe COVID-19 infection with full recovery after intensive care support,but cases of death were also identified.The management of different cardiac conditions are provided based on current guidelines and expert panel recommendations.CONCLUSION There is still scarce data about the role of cardiovascular involvement in COVID-19 in children.Based on our review,children(previously healthy or with preexisting heart disease)with acute COVID-19 requiring hospital admission should undergo a cardiac workup and close cardiovascular monitoring to identify and treat timely life-threatening cardiac complications.

Gastrointestinal and hepatic involvement during COVID-19 pandemic: A focus on pediatric population and possible future implications

Since the coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has rapidly spread worldwide,there is still limited knowledge about this condition and its natural history.Children have been relatively spared during COVID-19 pandemic but a novel syndrome known as multisystem inflammatory syndrome(MIS-C)has emerged,following a SARS-CoV-2 infection in children and adolescents.This syndrome can lead to shock and multiple organ failure requiring intensive care.Although COVID-19 clinical research focuses on respiratory symptoms,extrapulmonary involvement such as gastrointestinal(GI)and hepatic manifestations should also be considered.In fact,GI and hepatic involvement play an important role among the most common presenting symptoms of both pediatric and adult COVID-19 and MIS-C.This involvement can not only be one of the most common presenting clinical features but also one of the sequelae of these syndromes.Abdominal ultrasonography monitoring could be very useful to identify a potential involvement of the GI tract and liver.Moreover,long-term follow-up is needed and would be essential to define the long-term outcomes of these patients.

Advances in understanding Kawasaki disease-related immuno-inflammatory response and vascular endothelial dysfunction

Kawasaki disease(KD)is a systemic vasculitis of unknown etiology,which tends to involve coronary arteries and can lead to acquired heart disease in children.The immuno-inflammatory response and vascular endothelial dysfunction are important causes of coronary artery disease in patients with KD.Multisystem inflammatory syndrome in children(MIS-C)is a rare inflammatory disease in children identified in recent years,which is caused by severe acute respiratory syndrome coronavirus 2 infection;this disease overlaps with KD.This review examines research progress concerning the immuno-inflammatory response and vascular endothelial dysfunction associated with KD,as well as differences between KD and MIS-C.

Similarities and diferences between multiple infammatory syndrome in children associated with COVID‑19 and Kawasaki disease: clinical presentations, diagnosis, and treatment

Background Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has been spreading rapidly around the world,while“multisystem inflammatory syndrome in children”(MIS-C)is a new type of syndrome that has now been reported in many countries.Similar and different characteristics between KD and MIS-C have been reported in a variety of literature.We aimed to focus on reviewing clinical presentations,diagnosis,and treatment of KD and MIS-C.Methods We searched articles in the electronic databases,including the Cochrane Library database,EMBASE,and MEDLINE with the keywords“multiple inflammatory syndrome”and/or“COVID-19”and/or“Kawasaki disease”and“children”.Results Main presentations of MIS-C and KD include fever,rashes,mucous membrane involvement,conjunctivitis,hands and feet erythema/edema,and cervical lymphadenopathy.However,compared with the highest incidence of KD among some Asian countries,MIS-C is common among Black and Hispanic children.MIS-C is common in older children and teenagers,whereas classic KD is common in children under five years of age.Gastrointestinal symptoms,shock,and coagulopathy are common in MIS-C patients but are not common in classic KD.Cardiac manifestations are more common than KD,including myocarditis with cardiac dysfunction and coronary artery dilation or aneurysms.Severe cases in MIS-C present with vasodilated or cardiogenic shock that requires fluid resuscitation,muscular support,and even mechanical ventilation and extracorporeal membrane oxygenation(ECMO),whereas KD rarely presents with these manifestations and requires these treatments.Increased serum ferritin,leukopenia,lymphopenia and thrombocytopenia are common in MIS-C.However,thrombocytosis is a characteristic feature of KD.Intravenous immunoglobulin(IVIG)and moderate-high dose aspirin are still a standard recommended treatment for KD.In addition to the above-mentioned medications,steroids and biological drugs are frequently used in patients with MIS-C.Most of the children with KD have a good prognosis;however,the long-term clinical outcomes of MIS-C are not clear.Conclusions The overall presentation and treatment of MIS-C appear to overlap with KD.However,there are still great differences between the syndromes,and it is controversial to say whether MIS-C is a new entity or is a“severe type”of KD.

Immune response to SARS-CoV-2 in children: A review of the current knowledge

Host immune responses to severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),especially in children,are still under investigation.Children with coronavirus disease 2019(COVID-19)constitute a significant study group of immune responses as they rarely present with severe clinical manifestations,require hospitalization,or develop complications such as multisystem inflammatory syndrome in children(MIS-C)associated with SARS-CoV-2 infection.The deciphering of children’s immune responses during COVID-19 infection will provide information about the protective mechanisms,while new potential targets for future therapies are likely to be revealed.Despite the limited immunological studies in children with COVID-19,this review compares data between adults and children in terms of innate and adaptive immunity to SARS-CoV-2,discusses the possible reasons why children are mostly asymptomatic,and highlights unanswered or unclear immunological issues.Current evidence suggests that the activity of innate immunity seems to be crucial to the early phases of SARS-CoV-2 infection and adaptive memory immunity is vital to prevent reinfection.