Case Series of Multisystem Inflammatory Syndrome (MIS-C) in Children during the SARS-CoV-2 Pandemic in Latvia

Round 1

Reviewer 1 Report

I read with pleasure the case series presented by Racko et al titled “Case Series of Multisystem Inflammatory Syndrome (MIS-C) in Children During the SARS-CoV-2 Pandemic in Latvia”. This brings further information in the era of COVID-19 where children are affected.

I do have several concerns regarding the data presentation as noted below:

Introduction:

• The sentence: “Most of the children had a mild or moderate course of the disease and were treated at home, but 83 patients had more severe manifestations, necessitating hospitalization at Riga Children's Clinical University.” Unclear to me what to make out of this sentence and how the number 83 came since there was not specific mention in the methods or results section.
• The following sentence: “All 13 had temperature ≥ 38.0 C for longer than 24 hours at the time of presentation” – this is not the true definition of the MIS-C. Please rephrase to the WHO/CDC definition of the MIS-C in this and following sentences.

Results:

• 1.1. – The term Asperger syndrome is no longer used terminology as per DSM-5 criteria. Please change to Autism Spectrum Disorder.
• 1.2 - This sentence is not clear - what is the definition of symptomatic as per the authors? It appears only 5 were symptomatic of the 13, however, all 13 patients exhibited every system involvement. This is contradictory and needs to be clarified.
• 1.3 – The authors say that the myocarditis was diagnosed 2 by ECG and 1 by MRI – unfortunately, this is not the way to diagnose myocarditis – please clarify.
• Table 2. Under EKG- please specify arrhythmias and AV dissociations.
• Under the Echo – please mention if there were any patients who had coronary artery dilation/ectasia, this is an important information in the table and in the discussion.
• 1.4. – This is unclear and confusing with the number of symptomatic patients – goes back to the prior comment above 3.1.2.
• 1.5. – The median length of stay is 13 days, this appears to be much longer stay duration in general across the world when compared to this specific population per author. Is there a specific reason why they had to stay for such a long duration? Most of the studies have patients stay for ~1 week.

Discussion:

• The sentence: “Neither the children's parents nor the outpatient doctors associated these conditions with COVID-19. SARS-CoV-2 infection in children is usually experienced relatively mildly.” This is not a clear sentence, please rephrase for easy reading.

Author Response

Dear Reviewer,

On behalf of all co-authors, I would like to thank you very much for the comments and suggestions on our draft manuscript, which helps to improve the article. Thank you for pointing out the unclear sentences. We have carefully studied the suggestions and rewritten the manuscript based on your suggestions. 

About the comments:

1. The sentence from the introduction: “Most of the children had a mild or moderate course of the disease and were treated at home, but 83 patients had more severe manifestations, necessitating hospitalization at Riga Children's Clinical University.” Unclear to me what to make out of this sentence and how the number 83 came since there was not specific mention in the methods or results section.

Response - Before mentioning and starting the main purpose of the article about our mis-c patients, we wanted to highlight the general data on the number of cases in the acute covid-19 phase, so we mentioned the total numbers, like by March 2021 a total number of Covid-19 cases in Latvia were 90,997 patients, of which 8.7% or 7883 were children. And of all these children only 83 required inpatient care in the acute phase of the disease.

2. 1.1. – The term Asperger syndrome is no longer used terminology as per DSM-5 criteria. Please change to Autism Spectrum Disorder.

Response - Thank you for pointing this out. I have corrected the terminology.

3. About 1.2 in the result section - This sentence is not clear - what is the definition of symptomatic as per the authors? It appears only 5 were symptomatic of the 13, however, all 13 patients exhibited every system involvement. This is contradictory and needs to be clarified.

Response - We mentioned in the results in 3.1.1. “demographic characteristics” and in 3.1.4. “link to SARS-CoV-2” that only 5 out of all 13 mis-c patients were symptomatic during the acute Covid-19 phase. This is not meant about the period of mis-c presentation.

4. 1.3 – The authors say that the myocarditis was diagnosed 2 by ECG and 1 by MRI – unfortunately, this is not the way to diagnose myocarditis – please clarify.

Response - Thank you for pointing this out. I corrected the information. Three patients out of all 13 had signs of myocarditis by elevated cardiac biomarkers in conjunction with clinical signs and ecg and echocardiographic findings, and one of them was diagnosed with myocarditis by cardiac MRI.

5. About 1.5. – The median length of stay is 13 days, this appears to be much longer stay duration in general across the world when compared to this specific population per author. Is there a specific reason why they had to stay for such a long duration? Most of the studies have patients stay for ~1 week.

Response - Hospitalization was longer due to the general condition of the children. Seven patients of all 13 required admission to the PICU, three patients had cardiac involvement. Similarly to our study, Tolunay et al. also reported median duration of hospitalization 12,5 days in an article “Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A case series experience in a Tertiary Care Hospital of Southern Turkey”.

With the best regards from Latvia,

I. Račko

Reviewer 2 Report

This is a very well written case series. It adds important information to the medical a literature about MIS-C in children infected with COVID -19. Please give normal laboratory values in Table 2. Please also discuss the most appropriate methods to diagnose this condition and how this applies to these cases.

Author Response

Dear Reviewer,

On behalf of all co-authors, I would like to thank you very much for the comments and suggestions on our draft manuscript, it helps to improve the article. We have corrected the manuscript based on your suggestions. 

About the comment to discuss the most appropriate methods to diagnose this condition and how this applies to these cases. 

Response - Following the CDC and WHO guidelines for MIS-C, we mentioned in the introduction - “All 13 had documented fever > 38.0 C for ≥ 24 hours at the time of presentation, severe illness involving more than two organ systems, and laboratory evidence of inflammation; equally, they all were linked to SARS-CoV-2 infection.” And in the methods we describe that “The present study is a case series that includes all patients with a temporal relation to SARS-CoV-2 infection and other main diagnostic criteria of MIS-C published by the US Centers for Disease Control and Prevention (CDC).” We excluded alternative possible diagnoses. 

With the best wishes from Latvia,

I. Račko

Reviewer 3 Report

It is an interesting study reflecting the presence of MIS-c at Latvian children population.

It would be very interesting to also discuss the estimated incidence of COVID disease among Latvian children.

How  did the authors decide to follow up the children included in the study?

How long was treatment prescribed in children included in the study?

Author Response

Dear Reviewer,

On behalf of all co-authors, we are grateful for your consideration of this manuscript, and we also very much appreciate your interest and your questions.

1. It would be very interesting to also discuss the estimated incidence of COVID disease among Latvian children.

Response - The estimated incidence of the COVID-19 disease among the Latvian children is about 210.86 per 10’000.

1. How  did the authors decide to follow up the children included in the study?

Response - We decided to follow up not only the MIS-C patients, but also children after the acute Covid-19 without subsequent multisystemic manifestations. At the beginning of the pandemic there was very little information about the disease so we started to look after the first cases. Responding to worldwide data that the disease may not fully resolve even months after the end of the acute phase, we decided to keep following them, to evaluate and study the possible short and long-term consequences.

1. How long was treatment prescribed in children included in the study?

Response - All patients received IVIG once. Glucocorticosteroids were continued by outpatients with gradual dose reductions, also Aspirin was continued until the next supervision of a cardiologist. Antibiotics received for a maximum of 14 days. Patients who received anticoagulants according to the indications received them for different time periods from 4 to 13 days.

With the best wishes from Latvia,

I. Račko

Round 2

Reviewer 1 Report

The authors have satisfactorily responded to all my concerns. I do suggest the following sentence be included in the discussion section where the longer hospitalization was noted.

"Hospitalization was longer due to the general condition of the children. Seven patients of all 13 required admission to the PICU, three patients had cardiac involvement. Similarly to our study, Tolunay et al. also reported median duration of hospitalization 12,5 days in an article “Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19: A case series experience in a Tertiary Care Hospital of Southern Turkey”.

Author Response

Dear Reviewer,

On behalf of all co-authors, I would like to thank you very much for the suggestions on our draft manuscript. We have corrected the manuscript based on your suggestions.

Reviewer 2 Report

Thank you for addressing all of the reviews concerns.

Author Response

Dear Reviewer,

On behalf of all co-authors, I would like to thank you very much for giving the opportunity to submit a revised draft of our manuscript.