Multisystemic Inflammatory Syndrome Temporally Associated with COVID-19 in a Regional Pediatric Hospital from México

Round 1

Reviewer 1 Report

Authors reported the detail of clinical data concerning the multisystemic inflammatory syndrome associated with COVID19 infection, especially paying attention to the comparison to multisystemic inflammatory state of Kawasaki disease. Basically, this report is interesting.

However, they showed only the data of MIS-C and there are no data about the Kawasaki disease. It is very hard to compare these diseases without control (Kawasaki disease) data.

Authors should make comprehensive answer some questions, and some corrections are also needed for the publication to journal.

 

1.         Because the title of table 1 and 3 are same, it is very difficult to understand the aim of these tables. I guess that Table 1 shows the summary of symptoms of early stage of MIS-C, and Table 3 shows the detail of the result of some investigations in MIS-c. Authors should change the titles of table 1 and 3 or change the contents of these tables to make the purpose of each table clear.

2.         Page 3 Table 3 →Table 2?

3.         Page 3 line 102～103 Some data shown in Result are not the same in Tale 3(2?). Median were shown in the result, but the data shown in the table are unclear. Please correct or make them clear.

4.         Page 4 Line 106 acute kidney Injury →acute kidney injury or Acute Kidney Injury ?

5.         Page 4 Line 106 Please show the “criteria for acute kidney injury” in detail or add the reference of it.

6.         Table 3 “Pharmacologic therapy”: Intravenous immunoglobulin 29(??) Why authors showed “??” in the frequency (%) . Please explain the reason about it.

 

Author Response

Point-by-point response to the reviewer’s comments 

pediatrrep-2201854

 

We appreciate the comments of the reviewers who helped us to improve the presentation of the manuscript. Therefore, we specify the changes made below for each observation.

 

Reviewer 1.

 

Authors showed only the data of MIS-C and there are no data about the Kawasaki disease. It is very hard to compare these diseases without control (Kawasaki disease) data.

R= To help understand the main differences identified between KD and MIS-C, we include the following paragraph in the introduction (line 38-45):

First reports in 2020, compared MIS-C symptoms to those of KD (fever mucocutaneous features and cardiac sequelae), but the recent Clinical Guidance emitted by the American College of Rheumatology (version 3), discusses the differences between MIS-C and KD phenotypes that are worthy to mention. First, this guide stands out that the incidence of KD is higher in Japan and East Asia, and it is common in children under 5 years old. Also, the clinical presentations of left ventricular dysfunction and shock are more characteristic of patients with MIS-C than KD, and gastrointestinal and neurologic are more frequent in MIS-C patients [3].

Ref 3. Henderson, L.A.; Canna, S.W.; Friedman, K.G.; Gorelik, M.; Lapidus, S.K.; Bassiri, H.; Behrens, E.M.; Kernan, K.F.; Schulert, G.S.; Seo, P.; Son, M.B.F.; Tremoulet, A.H.; VanderPluym, C.; Yeung, R.S.M.; Mudano, A.S.; Turner, A.S.; Karp, D.R.; Mehta, J.J. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 3. Arthritis & rheumatology 2022, 74(4), e1–e20. https://doi.org/10.1002/art.42062

 

 Specific Comments

1. Because the title of table 1 and 3 are same, it is very difficult to understand the aim of these tables. I guess that Table 1 shows the summary of symptoms of early stage of MIS-C, and Table 3 shows the detail of the result of some investigations in MIS-c. Authors should change the titles of table 1 and 3 or change the contents of these tables to make the purpose of each table clear.

1. Thank you for the observation, the title of Table 1 was changed to “Summary of symptoms at hospital admission”, and the title of Table 3 was changed to “Clinical characteristics of MIS-C patients during hospital stay ”
2. Page 3 Table 3 →Table 2?
3. The number of Table 2 was corrected in page 3. Also, we reviewed all tables, their titles, and numbering. We apologize for the typo errors throughout the manuscript.
4. Page 3 line 102～103 Some data shown in Result are not the same in Tale 3(2?). Median were shown in the result, but the data shown in the table are unclear. Please correct or make them clear.

R= Data in each clinical history was reviewed and corrected in the text as follows (lines 105–113): “The serum CRP concentrations were found in the normal range (< 5 mg/dL) in 7 patients (13.4%) and only in 3 (5.7%) patients the PCT levels were under 0.1 ng/mL. On the other hand, the median for platelet values was found in the normal range (184 x 10⁹ cells/L) and only in 18 patients (34.6%), the platelet values were below the lower limit (150 x 10⁹ cells/L). Lymphopenia was present in 37 patients (71.1%). In 17 patients (32.7%) serum sodium levels were found below the lower limit (<135 mEq/L), although the average was in the normal range”.

4.         Page 4 Line 106 acute kidney Injury →acute kidney injury or Acute Kidney Injury ?

R= The term “Acute Kidney Injury” was changed to “Acute Kidney Injury” in Table 3 and in line (119).

5.         Page 4 Line 106 Please show the “criteria for acute kidney injury” in detail or add the reference of it.
6. We included the criteria for AKI as follows (lines 118–120). The 15.4% (n=8) presented criteria for Acute Kidney Injury according to RIFLE criteria (Risk, Injury, Failure, Loss, End stage), defined as a 50% increase in serum creatinine at 24 hours [15].

Ref. 15: Ricci, Z.; Cruz, D.N.; Ronco, C. Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria. Nat Rev Nephrol 2011 7(4), 201–208. https://doi.org/10.1038/nrneph.2011.14

6. Table 3 “Pharmacologic therapy”: Intravenous immunoglobulin 29(??) Why authors showed “??” in the frequency (%). Please explain the reason about it.
7. We apologize for this mistake, the exact frequency and percentage (n=51, 98%) were changed in Table 3 and in the text (line 127).

Reviewer 2 Report

see below

Comments for author File: Comments.pdf

Author Response

A point-by-point response to the reviewer’s comments 

pediatrrep-2201854

 

We appreciate the comments of the reviewers who helped us to improve the presentation of the manuscript. Therefore, we detailed the changes made below for each observation.

1. Line 48: the age range is actually 0-19, instead 10

R= Thanks for the observation, we correct this range (0–19) in line 55.

2. Line 79: Correlations studies among collected data (demographics, presenting symptoms, lab biomarkers, organ system complications, clinical outcomes) would be of interest.

R= Initially we looked for correlations, however, we found no statistical differences with the variables of interest (age, sex, PICU stay, MIS-C severity etc.) given our limited sample size.

3. Line 88/102/103: percentages are missing.

R= The percentages were included in the text as follows:

Lines 95–97: More male cases were diagnosed with MIS-C (33 males and 19 females, 63.4% vs 36.6% respectively)....

Lines 106 – 113: The serum CRP concentrations were found in the normal range (< 5 mg/dL) in 7 patients (13.4%) and only in 3 (5.7%) patients the PCT levels were under 0.1 ng/mL. On the other hand, the median for platelet values was found in the normal range (184 x 109 cells/L) and only in 18 patients (34.6%), the platelet values were below the lower limit (150 x 109 cells/L). Lymphopenia was present in 37 patients (71.1%). In 17 patients (32.7%) serum sodium levels were found below the lower limit (<135 mEq/L), although the average was in the normal range.

4. Line 93-95: provide more information about patients with underlying diseases (age, time of diagnosis- before or during hospitalization/acute phase/on treatment?)

R = The detailed information about underlying diseases was included in lines 135 – 161:

The 88.2% (n=46) were discharged in a mean time of 8 days, without clinical data of complications. However, 3 patients were discharged at 11 days for MIS-C severity related to PICU stay, the use of vasopressors, and respiratory support. Three patients had the longest hospital stay (15 to 25 days) related to underlying diseases. A severe MIS-C case was identified in a female patient diagnosed in 2017 with high-risk myeloid lymphoblastic leukemia, aged 10 years, with isolated relapse in the second-line protocol, who was admitted to PICU in February 2021 for febrile neutropenia, respiratory dis-tress (intercostal indrawing and polypnea) with severe thrombocytopenia and elevated acute phase reactants (PCR = 3.8 mg/dL). After IVIG and methylprednisolone treat-ment, she was discharged on day 23 with a normal echocardiogram.

Mortality (n=2) was observed in two patients. One male child with Down Syndrome (8 years old) was diagnosed with pre-B Acute Lymphoblastic Leukemia in April 2019. On October 2020, he was admitted due to neutropenia and cervical abscess, with history of COVID-19 infection 4 weeks ago which was confirmed by PCR. At admission, he pre-sents fever of more than 3 days of evolution, elevated D-dimer (2000 mg/mL), without data of bacteremia. Chest tomography reports pneumonia with focal lobar interstitial condensation lesions, predominantly bilateral at baseline. During the hospital stay, he was clinically stable with supplemental oxygen support. Intravenous gamma globulin (1 gr/kg/dose; 20 gr total) and methylprednisolone (2 mg/kg/day for 14 days) were administered. He was discharged on day 25 with a normal echocardiogram. One week later, this patient was readmitted for septic shock and died. The other case was a female patient with congenital cardiopathy of 1 year old, post-operated of patent ductus artery-us with a history of perinatal asphyxia that required hospitalization for a month. She had a positive antigen test for SARS-CoV-2, with torpid evolution, septic shock, and cardiogenic shock, which required broad-spectrum antimicrobial and antifungal management as well as management with vasoactive amines. After 25 days, hemodynamic and respiratory deterioration was observed without improvement, presenting septic and cardiogenic shock, and death.

 

5. Line 106/107: define shock and acute kidney injury criteria

R= We included the criteria for AKI as follows (lines 118–120). The 15.4% (n=8) presented criteria for Acute Kidney Injury according to RIFLE criteria (Risk, Injury, Failure, Loss, End stage), defined as a 50% increase in serum creatinine at 24 hours [15].

Ref. 15: Ricci, Z.; Cruz, D.N.; Ronco, C. Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria. Nat Rev Nephrol 2011 7(4), 201–208. https://doi.org/10.1038/nrneph.2011.14

6. Line 109: define vasoactive support

R= We change the term for “vasopressor support” in lines (120–121) and in Table 3 we specified the monotherapy and combined therapy. 

7. Line 113: add the duration of treatment

R= The duration of treatment was specified in lines (127–130) as follows:

Fifty-one cases (98%) were treated with gamma globulin (2 g/kg of weight/day during 12 h with a maximum dose of 80 gm), 96.1% (n=50) with methylprednisolone (2 mg/kg of weight/day during 14 days), and 88% with acetylsalicylic acid (50 mg/kg of weight/day during 8 weeks up to follow-up echocardiogram without alterations).

8. Line 115: what does retroviral treatment mean?

R= We apologize for this mistake. We change the term “retroviral” to “antiviral” and we specified the treatment used (line 131-132).

9. Line 116: min and max days of hospitalization? What happened to the 11.2% of patients?

R= We included hospital stay information in line (115), indicating min and max values. We mentioned the evolution of the remained cases (n=6) in lines 135 – 161.

10. Sodium although measured is not referred in results section

R= We added sodium values in Table 3 and mentioned in lines 111–13 as follows:  In 17 patients (32.7%) serum sodium levels were found below the lower limit (<135 mEq/L), although the averange was in the normal range (Table 2)

11. Table 3. The title does not fit to the data displayed. Bleeding episodes are not included in the text – type/ severity of bleeds? Where were these attributed to? Furthermore, mortality is higher than in text commented

R= The title of table 3 was changed to: “Outcomes during hospital stay of MIS-C patients”

Bleeding episodes were reviewed in all patients and we correct the results in Table 3, including one episode of gastrointestinal bleeding. In lines 116–118 we added: “and one case manifested upper gastrointestinal bleeding as a complication requiring aminergic management and 3 days in the PICU”

Mortality was observed in two cases, which corresponds to 3.8%. This data was corrected in Table 3.

12. Line 124: Display exactly the differences

R= We mention the main differences in discussion as follows (lines 167–168): “as SARS-CoV-2 positivity, age of presentation, males proportion, and less cardiac involvement”

13. Line 128: Is there a possible explanation for superiority of men?

R= We added an explanation in the discussion as follows:

Lines 171–176: The majority of the cases reported correspond to men, with a proportion of 1.5 to 1 (men-women, respectively) as previously reported in the general population [18,19]. A higher prevalence of MIS-C in males has been reported in the Mexican population, although the reason is not clear, it could be due to a higher risk to develop COVID-19 and it has been hypothesized that specific immune defects could predispose to MIS-C in males [20,21].

14. Line 131: It would be if interest to present the number of your patients <5years old, who were included in the study

R= The number of children under 5 years (19 children) was mentioned in lines 96–97.

 

Round 2

Reviewer 1 Report

I think revised version of this paper is acceptable for the publication.

Author Response

We appreciate the revisions made to our manuscript.

Reviewer 2 Report

2. Line 79: Correlations studies among collected data (demographics, presenting symptoms, lab biomarkers, organ system complications, clinical outcomes) would be of interest.

 

R= Initially we looked for correlations, however, we found no statistical differences with the variables of interest (age, sex, PICU stay, MIS-C severity etc.) given our limited sample size.

The absence of correlations among collected data is also a interesting result and is worth mentioning

Author Response

Response to Reviewer 2 Comments

1. The absence of correlations among collected data is also an interesting result and is worth mentioning

R. We included two sentences as follows:

Lines 91 – 92

We analyzed associations between the variables of interest (age, sex, PICU stay, and MIS-C severity).

Lines 135 to 137

In the correlation analysis, no significant associations were observed when analyzing the frequency of the characteristics at admission according to age, sex, admission to the PICU, or MIS-C severity due to our small sample size.