Paediatric Inflammatory Multisystem Syndrome Temporally Associated with Sars-Cov-2: A Review and Our Experience in a Secondary Hospital in Spain

Introduction: Paediatric multisystem inflammation syndrome temporally associated with SARS-COV-2 PIMS-TS was described in 2020 as an increased incidence of paediatric patients with cardiogenic shock and acute myocarditis associated with SARS-COV2. This disease has similarities and can manifest as Kawasaki Disease (KD). The aim of the study was to document the cardiovascular characteristics of the novel multisystem inflammatory syndrome in children and to share our experience. Methods: A descriptive study is presented including children with diagnosis of PIMSTS at a secondary hospital. Children 0 to 15 years of age admitted to a hospital between from May 2020 to May 2021 were included and the data, including demography, clinical status, biochemical markers, echocardiography findings, treatment and evolution, were extracted from the clinical history of the patients. Results: 7 children were included from a secondary hospital. The mean age was 8 years and 71% were boys. The most common cardiovascular complications were cardiovascular shock with hypotension and the reduction in over a half of the patients in the left ventricular ejection fraction was reported. It was observed a high elevation of acute phase reactants at the admission. In 2 children were found coronary alterations. Polymerase chain reaction (PCR) for SARS-COV-2 was positive in 28% whereas immunoglobulin G (IgG) was positive in 100% cases. Conclusion: Covid-19 disease is asymptomatic in children in most cases but cardiovascular involvement is common if PIMS-TS is presented. Despite the need of intensive care support, mortality is uncommon and our study shows that these patients can be treated in a hospital with Paediatric Intensive Critical Unit level 2 benefiting from combined, specific treatment.


Paediatric
multisystem inflammation syndrome temporally associated with Sars-Cov-2 (PIMS-TS) was described in April 2020 in London, where an increased incidence of paediatric patients with cardiogenic shock and acute myocarditis associated with SARS-COV2 was observed.Initially 8 patients were described and were admitted to the Paediatric Intensive Care Unit (PICU) with symptoms of cardiogenic shock and fever.They had been previously exposed to SARS-COV2 [1].Since then, several studies have been reported describing the clinical spectrum of this disease, collected by The Royal College of Paediatrics and Child Health and the Center for Disease Control and Prevention, which includes fever of at least 3 days, abdominal pain and myocardial involvement, among others.This disease accounts for less than 1% of paediatric patients affected by COVID due to it is usually asymptomatic or mild [2].Despite prevalence is currently unknown, although more than 600 cases have been reported today.
This disease has similarities to KD and can manifest phenotypically as complete or incomplete KD.According to the different series, between 22 and 65% of the reported cases present a similar phenotype.Other series of cases have described it as a clinic similar to toxic shock syndrome or macrophage activation syndrome [3,4].In adult patients, the infection affects the respiratory system almost entirely, although in 20% of cases affectation has been described myocardial involvement.In children with PIMS-TS, morbidity and mortality lies in the involvement of the cardiovascular system secondary to inflammation caused by the SARS-COV2 virus, which can cause acute myocarditis, ventricular dysfunction, cardiogenic shock, arrhythmias, pericardial effusion or coronary involvement through coronary aneurysms or ischemic phenomena.In severe cases, admission to the PICU may be necessary.Several theories have been postulated about the origin of the disease.The most widely accepted is that it occurs due to a hyperimmune reaction secondary to COVID infection in genetically predisposed individuals that, as is seen in KD, triggers a cytokine storm with systemic hyperinflammation whose target organ is the heart.Cardiac involvement is produced by myocardial invasion of the virus that generates autoantibodies against these cells, producing specific T lymphocytes and autoantibodies that also produce endothelial and microvascular dysfunction.All of this leads to the activation of the coagulation cascade, increasing the risk of thrombosis and increasing cellular damage [5].
However, in children polymerase chain reaction (PCR) is only positive in a third of cases, while IgG is positive in half of the cases to 90%, depending on the series described.It is characteristic symptoms occur between two and four weeks after the infection has passed which suggests that it is a postinfectious complication.Most of the initially affected patients are usually healthy and the average age is between 8 and 11 years, unlike the KD that are less than 5 years.This disease is more frequent in black and hispanic patients.[2,[6][7][8][9][10].The syndrome is presented by persistent fever lasting more than three days in almost 100%.Systemic involvement is presented with gastrointestinal, cutaneous, renal, neurological or respiratory manifestations.Gastrointestinal involvement (abdominal pain or diarrhoea) occurs in 71-90% of patients and cutaneous or conjunctival manifestations (40-60%) are usually present.

Cardiac involvement
In children with PIMS-TS, cardiac involvement is frequent [1].Several series describe that in KD between 2-7% of patients may present with cardiovascular shock secondary to myocardial dysfunction, vasoplegia and systemic hypotension, but in PIMS-TS approximately 40-50% of patients may present shock and half of the patients usually require admission to the ICU [4,8,11].
Cardiac involvement occurs almost entirely through elevation of proBNP or troponins, while echocardiography, which is the basic test in these patients, usually does not show alterations.The most frequent alteration is a decrease in the left ventricular ejection fraction (LVEF) affected in 30-60% of patients and according to some series, 80% of cases recovered during hospitalization after treatment.Of these patients, a third during their admission presented severe myocardial dysfunction, with a decrease in LVEF of less than 30%.The alteration of the myocardial wall motility was observed in some patients and no abnormalities were found in the tissue Doppler.The most frequent valve alteration is mitral regurgitation (42%), while other valvular affectations are not frequent.Pericardial effusion was detected in 28% of the patients.Coronary involvement varies as well.Up to 25% of patients can detect dilatation of the coronary arteries (defined as Z>2), with the left main coronary being the most frequent.Coronary aneurysms were only seen in 8% of the patients.Giant coronary aneurysms were not detected.
Up to a third of patients may present ECG alterations similar to myocarditis, such as alterations in repolarization or lengthening of the PR interval, among others.72% recovered their manifestations during hospitalization.Necrosis Q waves are rare.
Cardiac magnetic resonance imaging can be useful to delineate myocardial lesions or establish the prognosis of the disease, although there is little experience in this regard.In the study by Valverde et al.Cardiac magnetic resonance imaging was performed in 14% of the patients in the sample and myocardial edema was detected in a third, pericardial effusion in 20% and myocardial fibrosis in no case [8].
Abdominal ultrasound was performed in half of the patients and no alterations were observed in 60% of the patients.Among the patients with abnormalities, the most frequent was ascites (20%) followed by lymphadenopathy, ileitis and colitis.patients and unlike KD, troponins are elevated in more than 90% of patients.[12][13][14][15].

Treatment
Currently there are no clinical trials that determine which is the gold standard, so given the similarity to other diseases mentioned above, similar therapies have been administered [16,17].The most frequently used medication is intravenous immunoglobulins (IVIG), which have been used in only 80% of cases.In 30% of the cases, glucocorticosteroids (GC) (mainly methylprednisolone) were used and in the refractory cases, biological therapy was used as an adjunct in 15%.8 Other studies show different data.
In his sample of 614, an observational cohort study was conducted and 40% of the patients received IVIG in monotherapy compared to 33% combined with GC.In this study, no evidence was found that the treatment was more effective in reducing severe disease, recommending the monotherapy use of GC, IVIG or a combination of both [18].The most widely used biological drugs were Anakinra, Infliximab and Tocilizumab.Currently the guidelines (Figure 1) recommend in case of mild disease the use of IVIG at 2mg / kg, moderate risk associated with glucocorticoids at 2mg/ kg and in severe disease, associated with steroids megadoses at 30mg/kg [19].Until now, biologic treatment is reserved for refractory cases, but we used them early depending on the biochemical pattern in the blood test performed periodically and the severity of disease.

PIMS-TS
is related to thrombotic phenomena, therefore acid acetylsalicylic (AAS) is associated with an antiplatelet dose more frequently or an anti-inflammatory dose.In patients with high risk of thromboembolism, indicated as clinical severity, giant coronary aneurysms or obesity, treatment with heparin was started, which according to the different series varies around 40%.
One third of the patients required inotropic support, which was the most frequent dopamine, followed by norepinephrine, milrinone, epinephrine and dobutamine.In other series, this percentage can rise to 80%.If therapy is not effective, the use of extracorporeal membrane oxygenation (ECMO) may be necessary (less than 1% of patients).Despite the clinical severity in some patients, the clinical evolution is favorable in most cases, with less than 1% mortality [4,8,20,21].

Material and methods
A retrospective descriptive study is presented with a total of 7 patients with a final diagnosis of PIMS-TS at the Hospital General Universitario de Castellón (Valencian Community, Spain), with PICU level 2. The data were extracted from the clinical history of the patients.retrospectively from May 2020 to May 2021.All patient data were deidentified with respect to dates of birth or dates of discharge or death.Children with persistent fever, inflammation (neutrophilia, elevated C-reactive protein), and evidence of cardiovascular compromise (shock, acute cardiac dysfunction), who may also present with multi-organ dysfunction (respiratory, renal, gastrointestinal, or neurological) were included (Table 1).
This may include children who meet the full or partial criteria for KD.The inclusion criteria were broad to include centers using both the Royal College of Paediatrics and Child Health (pediatric multi-system inflammatory syndrome temporally associated with SARS-CoV-2) and the Centers for Disease Control and Prevention case definitions diseases.Inclusion did not require proof of SARS-CoV-2 infection.Data from 7 patients between 4 and 12 years of age were examined.Patient data were divided into demographic data and clinical presentation, laboratory findings and treatment, and finally cardiac involvement.Standard international normal ranges were used to decide the cutoff point whether laboratory markers were elevated or not, and for echocardiographic findings, z-values were derived from the data provided.

Demographics
A total of 7 patients from Hospital General Universitario de Castellón (Castellón, Valencian Community) were included.The median age was 8 years (4 to 12 years) and 71% were male.None of the patients had underlying disease or heart disease.The mean admission of the patients was 14 days.Of the 7 patients, 6 were Caucasian and 1 Arab. 1 patient presented positive CPR on admission, 3 patients presented positive IgM and all presented positive IgG.The mean time between acute SARS-COV2 infection and the appearance of SIMPED symptoms was 4 weeks.
The most frequent symptoms presented by all our patients was fever of 5 days of evolution with cardiogenic shock, systemic hypotension and abdominal pain, followed by phenotypic presentation of Kawasaki-like by 4 patients, most frequently incomplete (Rash, hyperemic conjunctival, branched tongue, lymphadenopathy or periungeal desquamation).None of our patients presented respiratory symptoms (Table 1).

Analytics
Most of the admitted patients showed a significant elevation of inflammation markers.In all our patients, a determination of IL-6, IL-1, CRP, PCT and Ferritin was performed upon admission.Mean IL-6 was 240 while IL-1 was 184,3.The mean CRP was 227 and the mean PCT was 5.3, being only negative in one patient.Ferritin on average was 643 and ESR on average was 44.5.The markers of cardiac involvement were also elevated in our patients upon admission.All patients presented elevation of NT-ProBNP, whose mean was 15428 and troponins were also elevated in all patients with a mean of 125.All inflammatory parameters progressively normalized until discharge, except ESR, which in most of the patients' cases increased slightly.The parameters of cardiac involvement were also normalized.Regarding the haematological analytical parameters, 3 patients had leukocytosis and 4 patients had leukopenia.One of the patients had thrombopenia, while the rest had normal values or at the high limit of normality of platelets.Coagulation was normal and we observed a significant elevation of D-dimers (mean 4312) that normalized in only one patient at discharge (Table 1).

Cardiac involvement
The cardiological evaluation was performed by echocardiography during their initial evaluation during their admission and all the patients presented cardiac involvement (Table 2   The evaluation of systolic function was performed by determining the left ventricular ejection fraction (LVEF) derived from M mode, classified using a qualitative scale.57% the patients had systolic dysfunction, estimated by TeichHoltz LVEF.
None of our patients had an LVEF less than 50% and this parameter normalized during admission in all patients (Figure 2B).The most common valve disease detected in our series was mild mitral regurgitation (MR) in 57% of patients, followed by mild tricuspid regurgitation (TR) in 45% of patients.
In the echocardiographic evaluation of the coronary arteries, 2 children found alterations (29%) described as not giant aneurysms in the main coronary arteries (Figure 2 C and D). ( examination.In our series, cardiac magnetic resonance imaging or cardiac computed tomography were not performed on the acute period due to good visualization of the coronary arteries on 2d echo in paediatric patients, but in patients with coronary lesions, coronary CT scan were performed to scan the whole coronary arteries.
No myocardial biopsy or cardiac catheterization was performed.An ECG was performed in all patients and repolarization abnormalities were detected in 71%.There were no arrhythmias in any patient.

Treatment
All patients received acetylsalicylic-acid (ASA) at anti-inflammatory doses initially and subsequently at antiplatelet doses.They also received exonaparin or sodium heparin.Those patients with coronary aneurysms required megabolus doses of corticosteroids.All the patients received corticosteroids and 85% received gamma globulins (IVIG).
No patient was treated with antivirals.Biological therapy was reserved for those patients who presented signs of severity, such as coronary involvement.In the two patients with coronary involvement, Anakinra was administered.Due to the clinical situation of the patients, inotropic support therapy was started in 71% of the cases, adrenaline being the drug most frequently administered.
Our patients were also treated with antibiotic therapy, with Cefotaxime being the most frequent drug used.

Outcome
The clinical evolution of our patients was favorable.All our patients were discharged with the resolution of the clinic and a little improvement in one of them, or at least no complications added to the initial lesions during the follow up until now.Admission to the PICU was required by 85% of our patients due to the clinical situation and the need for close monitoring.There were no deaths and no patient required mechanical ventilation or extracorporeal circulation oxygenation membrane.Cardiac surgery was not required.

Discussion
Although COVID-19 infection in children is asymptomatic or mild in most cases, the potentially serious complication of PIMS-TS should be taken into account [2].Despite the fact that many of the symptoms and signs in our patients are reminiscent of diseases with KD, KDSS, myocarditis, toxic shock syndrome or macrophage activation syndrome, the truth is that it is an independent entity with clinical differences that occurs in genetically predisposed individuals and mediated by superantigens like KD and KDSS.
KDSS is a disease that occurs in less than 5% of patients with KD and is characterized by myocardial dysfunction with cardiovascular shock sings and marked systemic hypotension, also producing coronary involvement in those patients who are not adequately treated with IVIG.The difference between the PIMS-TS and the KDSS lies in several points.In the first, we know the causal agent, while in the second it is infrequent.Furthermore, coronary heart disease incidence in untreated KD patients can rise to 50-75% without treatment (5% with treatment), while in PIMS-TS patients it usually occurs in 25% of patient's cases despite treatment.However, we currently do not have data in untreated patients with PIMS, so it is possibly higher [ 9,20,21].
In our cohort, the incidence of cardiac involvement was 100%, while that of cardiac dysfunction and shock was 57%, similar to studies with more patients to date.We did not find arrhythmias in any of our patients, although there were alterations in repolarization similar to those found in viral myocarditis.
All patients presented a significant elevation of acute phase reactants, including IL-6, CRP, and ESR, reflecting the significant proinflammatory status of the disease.These mean values were slightly higher than in other studies, as were troponins and NT-ProBNP.Troponin elevation was slight while NT-ProBNP was marked.In most of the studies described, the patients present with leukopenia, whereas in our case it only manifested itself in half of the patients, with marked leukocytosis in the other half.One of our patients presented clinically with pancytopenia, and no such patients had been previously described [7][8][9][10][11].
Cardiac evaluation by echocardiography was crucial for the diagnosis.The most frequently detected alteration was mild MR, which occurred in 71% of the patients.Coronary involvement was 29% of the patients.Although the studies to date are small, this is an above-average incidence.Patients with coronary involvement were treated with Anakinra, the anti-IL-1 most commonly used in patients with PIMS-TS.
Most of our patients received treatment with GC and IVIG in combination.Currently, the latest study to date shows that there are no significant differences between the joint or separate administration of these drugs with respect to the evolution of the disease, although the studies are observational and do not have enough patients to draw solid conclusions.In the observational study carried out in France by Ouldali et al. with 181 patients they do conclude that this combined therapy improves the clinical course [22].
These results are similar to those found in the largest studies to date.Although the majority of patients were cared for in hospitals with PICU level 3, our study shows that these patients can be treated in a hospital with PICU level 2 owing to not all patients require ECMO and may benefit from combined drug treatment.
Although the pathogenesis of the disease remains unknown, a hyperinflammatory state that produces endothelial damage with consequent thrombotic microangiopathy has been observed.This hyperinflammatory state produces a cytokine storm that occurs at the expense of the elevation of IL-6, IL-1 or TNFalpha, which induce an excessive inflammatory response and affect the cardiomyocyte.
Elevated IL-6 has been associated with a worse prognosis in adult patients with COVID19 [5].Another similarity that we found with PIMS is that in the KKSS the elevation of IL-6 rises to similar values, well above the KD [20].However, it remains unknown in those patients with normal levels of IL-6 which molecule is involved.Currently, adult patients with severe symptomatic COVD19 and elevated IL-6 are administered targeted therapy with Tocilizumab.However, in most hospitals the determination of the rest of the aforementioned pro-inflammatory cytokines is not carried out.Future studies should focus on determining whether in those genetically predisposed patients in whom a certain proinflammatory cytokine is specifically elevated, be it IL-6, IL-1 or TNF alpha among others, and we can apply selective molecular therapies against them.In addition, we encourage investigating therapies effect on coronary aneurysms due to the importance of comorbidity in children.
This study has some limitations.This is a small case series with few patients whose data were collected in a period in which diagnostic criteria for the disease are still being established.In addition, the therapy selected in each patient was individualized, instead of following a standardized protocol or clinical decisions based on randomized clinical trials that are currently not available.

Conclusion
Covid-19 disease is asymptomatic in children in most cases but cardiovascular involvement is common if multisystem inflammatory syndrome associated with the Covid-19 pandemic is presented.Cardiac involvement could be manifested in multiple ways, such as myocardial dysfunction, valve inflammation, coronary dilation (ecstasy or aneurysms).As KD, it's due to systemic inflammation, which leads to different clinical manifestations.Clinical evolution was good in all the patients, some of them needed long term surveillance to know follow up of the coronary injuries.Despite the necessity of intensive care support mortality is uncommon and our study shows that these patients can be treated in a hospital with Paediatric Intensive Critical Unit level 2 benefiting from combined, specific anti-inflammatory and biologic treatment.We strongly believe that probably in the near future, patients will be selected for specific anti-inflammatory treatments based on biochemical markers.This is a small group of patients, so it'll be necessary larger studies with randomized group of patients.

Figure 1 :
Figure 1: Adapted diagrams of management of PIMS based in risk criteria and treatment.(Mahmoud S, Fouda EM, Kotby A, Ibrahim HM, Gamal M, El Gendy YG, et al.The "Golden Hours" Algorithm For the Management of the Multisystem Inflammatory Syndrome in Children (MIS-C).Glob Pediatr Health.2021;8:2333794X21990339).

Table 2 :
Cardiac Involvement and Treatment.