ABSTRACT

This study aimed to describe the characteristics of multisystemic inflammatory syndrome associated with COVID-19 (MIS-C) in the first three years of the pandemic in children in a pediatric hospital in Peru. We conducted an observational, descriptive study with data from 73 patients and described the clinical and laboratory characteristics, treatment and complications according to the wave of the pandemic and whether they had shock. The median age was 6 years, gastrointestinal and mucocutaneous manifestations were frequent in the three waves. Kawasaki disease-like phenotype was present in 34 (46.6%) patients and 21 (28.8%) patients developed shock. The most commonly used treatment was immunoglobulin (95.9%), followed by acetylsalicylic acid (94.5%) and corticosteroid (86.3%). Five (7%) patients had coronary aneurysm and 17 (23.3%) were admitted to the intensive care unit (ICU). Patients with shock had greater laboratorial alteration and need for mechanical ventilation. In conclusion, MIS-C has decreased in the first three years of the pandemic, possibly due to COVID-19 vaccination in children.

Keywords:
COVID-19; SARS-CoV-2; Multisystem Inflammatory Syndrome in Children; Kawasaki Disease; Intravenous Immunoglobulin

KEY MESSAGES

Motivation for the study. There are few studies describing the variation of COVID-19-associated multisystem inflammatory syndrome (MIS-C) in Peru across pandemic waves.

Main findings. Cases of MIS-C decreased during the first three years of the pandemic, with higher frequency in the second wave with clinical features similar to Kawasaki disease.

Implications. MIS-C is a post-infectious complication of SARS-CoV-2. Its diagnostic suspicion is important weeks after peak infections, especially in children who have not yet received COVID-19 vaccines.

Keywords:
COVID-19; SARS-CoV-2; Multisystem Inflammatory Syndrome in Children; Kawasaki Disease; Intravenous Immunoglobulin

INTRODUCTION

Multisystemic inflammatory syndrome in children (MIS-C) is a post-infectious complication of SARS-CoV-2 ¹1. Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 2020;20(11):e276-88. doi: 10.1016/S1473-3099(20)30651-4.
https://doi.org/10.1016/S1473-3099(20)30... , which appeared weeks after the peak of COVID-19 infections in different countries ²2. Payne AB, Gilani Z, Godfred-Cato S, Belay ED, Feldstein LR, Patel MM, et al. Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2. JAMA Netw Open. 2021;4(6):e2116420. doi: 10.1001/jamanetworkopen.2021.16420.
https://doi.org/10.1001/jamanetworkopen....

3. Ruvinsky S, Voto C, Roel M, Fustiñana A, Veliz N, Brizuela M, et al. Multisystem Inflammatory Syndrome Temporally Related to COVID-19 in Children From Latin America and the Caribbean Region: A Systematic Review With a Meta-Analysis of Data From Regional Surveillance Systems. Front Pediatr. 2022;10:881765. doi: 10.3389/fped.2022.881765.
https://doi.org/10.3389/fped.2022.881765...

4. Buonsenso D, Perramon A, Català M, Torres JP, Camacho-Moreno G, Rojas-Solano M, et al. Multisystemic Inflammatory Syndrome in Children in Western Countries: Decreasing Incidence as the Pandemic Progresses?: An Observational Multicenter International Cross-sectional Study. Pediatr Infect Dis J. 2022;41(12):989-993 doi: 10.1097/INF.0000000000003713.
https://doi.org/10.1097/INF.000000000000...

5. Holm M, Espenhain L, Glenthøj J, Schmidt LS, Nordly SB, Hartling UB, et al. Risk and Phenotype of Multisystem Inflammatory Syndrome in Vaccinated and Unvaccinated Danish Children Before and During the Omicron Wave. JAMA Pediatr. 2022;176(8):821-3. doi: 10.1001/jamapediatrics.2022.2206.
https://doi.org/10.1001/jamapediatrics.2... ^-66. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA. 2020;324(3):259-69. doi: 10.1001/jama.2020.10369.
https://doi.org/10.1001/jama.2020.10369... . It is a rare disease with an incidence of 4.9 cases/million person-months in children under five years of age and 6.3 cases/million person-months in children aged six to ten years ²2. Payne AB, Gilani Z, Godfred-Cato S, Belay ED, Feldstein LR, Patel MM, et al. Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2. JAMA Netw Open. 2021;4(6):e2116420. doi: 10.1001/jamanetworkopen.2021.16420.
https://doi.org/10.1001/jamanetworkopen.... .

MIS-C appears lately (>5 years), and its representative manifestations are gastrointestinal such as abdominal pain and mucocutaneous such as conjunctival injection and polymorphous exanthema ⁷7. Pérez-Gómez HR, Morfín-Otero R, González-Díaz E, Esparza-Ahumada S, León-Garnica G, Rodríguez-Noriega E. The Multifaceted Manifestations of Multisystem Inflammatory Syndrome during the SARS-CoV-2 Pandemic. Pathogens. 2022;11(5):556. doi: 10.3390/pathogens11050556.
https://doi.org/10.3390/pathogens1105055... . For this reason, it has similar symptomatology to Kawasaki disease (KD), toxic shock syndrome or hemophagocytic lymphohistiocytosis ¹1. Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 2020;20(11):e276-88. doi: 10.1016/S1473-3099(20)30651-4.
https://doi.org/10.1016/S1473-3099(20)30... ^,88. Godfred-Cato S, Abrams JY, Balachandran N, Jaggi P, Jones K, Rostad CA, et al. Distinguishing Multisystem Inflammatory Syndrome in Children From COVID-19, Kawasaki Disease and Toxic Shock Syndrome. Pediatr Infect Dis J. 2022;41(4):315-23. doi: 10.1097/INF.0000000000003449.
https://doi.org/10.1097/INF.000000000000... . The most frequent complications are cardiovascular which are the main reasons for admission to pediatric intensive care units (PICU) ⁹9. Acevedo L, Piñeres-Olave BE, Niño-Serna LF, Vega LM, Gomez IJA, Chacón S, et al. Mortality and clinical characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with covid-19 in critically ill patients: an observational multicenter study (MISCO study). BMC Pediatr. 2021;21(1):516. doi: 10.1186/s12887-021-02974-9.
https://doi.org/10.1186/s12887-021-02974... ^,1010. Fernández-Sarmiento J, Acevedo L, Niño-Serna LF, Boza R, García-Silva J, Yock-Corrales A, et al. Risk Factors Associated with Intensive Care Admission in Children with Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome (MIS-C) in Latin America: A Multicenter Observational Study of the REKAMLATINA Network. J Intensive Care Med. 2024;08850666241233189. doi: 10.1177/08850666241233189.
https://doi.org/10.1177/0885066624123318... . The clinical-epidemiological characteristics of MIS-C varied during the pandemic ⁴4. Buonsenso D, Perramon A, Català M, Torres JP, Camacho-Moreno G, Rojas-Solano M, et al. Multisystemic Inflammatory Syndrome in Children in Western Countries: Decreasing Incidence as the Pandemic Progresses?: An Observational Multicenter International Cross-sectional Study. Pediatr Infect Dis J. 2022;41(12):989-993 doi: 10.1097/INF.0000000000003713.
https://doi.org/10.1097/INF.000000000000... ^,1111. Jain PN, Acosta S, Annapragada A, Checchia PA, Moreira A, Muscal E, et al. Comparison of Laboratory and Hemodynamic Time Series Data Across Original, Alpha, and Delta Variants in Patients With Multisystem Inflammatory Syndrome in Children. Pediatr Crit Care Med. 2022;23(8):e372. doi: 10.1097/PCC.0000000000002976.
https://doi.org/10.1097/PCC.000000000000... . In France, children with MIS-C had less severe disease throughout the waves of COVID-19 ¹²12. Kechiche R, Borocco C, Bajolle F, Belot A, Poignant S, Lachaume N, et al. Multisystem inflammatory syndrome in children during the COVID-19 waves: data from the Juvenile Inflammatory Rheumatism cohort. Front Pediatr. 2023;24(11):1126985. doi: 10.3389/fped.2023.1126985.
https://doi.org/10.3389/fped.2023.112698... , similar to India ¹³13. Angurana SK, Kumar V, Nallasamy K, Kumar MR, Naganur S, Kumar M, et al. Clinico-Laboratory Profile, Intensive Care Needs and Short-Term Outcome of Multisystem Inflammatory Syndrome in Children (MIS-C): Experience during First and Second Waves from North India. J Trop Pediatr. 2022;68(5):fmac068. doi: 10.1093/tropej/fmac068.
https://doi.org/10.1093/tropej/fmac068... ⁾ and Argentina ¹⁴14. Gentile A, Juárez MDV, Romero Bollon L, Aprea V, Matteucci E, Falaschi A, et al. Comparison of Epidemiologic and Clinical COVID-19 Profiles in Children in Argentina, During Circulation of Original and Variant (Alpha, Gamma and Lambda) Strains. Pediatr Infect Dis J. 2023;42(2):136. doi: 10.1097/INF.0000000000003776.
https://doi.org/10.1097/INF.000000000000... . This was probably related to the diagnosis and treatment that each country was able to implement according to its available resources ¹²12. Kechiche R, Borocco C, Bajolle F, Belot A, Poignant S, Lachaume N, et al. Multisystem inflammatory syndrome in children during the COVID-19 waves: data from the Juvenile Inflammatory Rheumatism cohort. Front Pediatr. 2023;24(11):1126985. doi: 10.3389/fped.2023.1126985.
https://doi.org/10.3389/fped.2023.112698... ^,1313. Angurana SK, Kumar V, Nallasamy K, Kumar MR, Naganur S, Kumar M, et al. Clinico-Laboratory Profile, Intensive Care Needs and Short-Term Outcome of Multisystem Inflammatory Syndrome in Children (MIS-C): Experience during First and Second Waves from North India. J Trop Pediatr. 2022;68(5):fmac068. doi: 10.1093/tropej/fmac068.
https://doi.org/10.1093/tropej/fmac068... ^,1515. Ensinck G, Gregorio G, Flores RM, Crowe CI, Clerico Mosina P, Curi C, et al. Consensus on treatment of multisystemic inflammatory syndrome associated with COVID-19. Arch Argent Pediatr. 2021;119(4):S198-211. doi: 10.5546/aap.2021.S198.
https://doi.org/10.5546/aap.2021.S198... ⁾ and by vaccination against SARS-CoV-2 and by the type of variant that predominated in each wave of the pandemic ⁵5. Holm M, Espenhain L, Glenthøj J, Schmidt LS, Nordly SB, Hartling UB, et al. Risk and Phenotype of Multisystem Inflammatory Syndrome in Vaccinated and Unvaccinated Danish Children Before and During the Omicron Wave. JAMA Pediatr. 2022;176(8):821-3. doi: 10.1001/jamapediatrics.2022.2206.
https://doi.org/10.1001/jamapediatrics.2... .

Due to the epidemiological change of MIS-C in recent years ⁴4. Buonsenso D, Perramon A, Català M, Torres JP, Camacho-Moreno G, Rojas-Solano M, et al. Multisystemic Inflammatory Syndrome in Children in Western Countries: Decreasing Incidence as the Pandemic Progresses?: An Observational Multicenter International Cross-sectional Study. Pediatr Infect Dis J. 2022;41(12):989-993 doi: 10.1097/INF.0000000000003713.
https://doi.org/10.1097/INF.000000000000... , it is important to understand how the characteristics of MIS-C have varied during the pandemic in Peru, in order to improve care protocols for future scenarios and avoid complications in patients. This study aimed to describe the characteristics of MIS-C during the first three years of the pandemic in a pediatric hospital in Peru according to the wave and the development of shock.

THE STUDY

We conducted an observational, descriptive and retrospective study. The study population consisted of hospitalized patients diagnosed with MIS-C between April 2020 and December 2022 at the Instituto Nacional de Salud del Niño-Breña (INSN-B) in Lima, Peru. INSN-B is one of the pediatric hospitals with the highest resolution capacity located in Lima, with different specialties and subspecialties, including the pediatric intensive care unit (PICU) for critical patients. The INSN-B is a state institution that belongs to the Peruvian Ministry of Health (MINSA) and serves the population with or without comprehensive health insurance (SIS) and is one of the most representative institutions in Peru, both in terms of care and research ¹⁶16. Atamari-Anahui N, Ccorahua-Rios MS, Rodriguez-Camino MC, Santander-Cahuantico AC, Pacheco-Mendoza J. Bibliometric Analysis of Scientific Production in Scopus by the Instituto Nacional de Salud Del Niño-Breña, Peru, 2010-2019. Journal of Hospital Librarianship. 2022;22(2):108-20. doi: 10.1080/15323269.2022.2054601.
https://doi.org/10.1080/15323269.2022.20... .

MIS-C was diagnosed based on World Health Organization (WHO) criteria ¹1. Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 2020;20(11):e276-88. doi: 10.1016/S1473-3099(20)30651-4.
https://doi.org/10.1016/S1473-3099(20)30... , similar to previous reports ¹²12. Kechiche R, Borocco C, Bajolle F, Belot A, Poignant S, Lachaume N, et al. Multisystem inflammatory syndrome in children during the COVID-19 waves: data from the Juvenile Inflammatory Rheumatism cohort. Front Pediatr. 2023;24(11):1126985. doi: 10.3389/fped.2023.1126985.
https://doi.org/10.3389/fped.2023.112698... ^,1313. Angurana SK, Kumar V, Nallasamy K, Kumar MR, Naganur S, Kumar M, et al. Clinico-Laboratory Profile, Intensive Care Needs and Short-Term Outcome of Multisystem Inflammatory Syndrome in Children (MIS-C): Experience during First and Second Waves from North India. J Trop Pediatr. 2022;68(5):fmac068. doi: 10.1093/tropej/fmac068.
https://doi.org/10.1093/tropej/fmac068... . Patients with diagnosis of MIS-C at emergency admission or during hospitalization were included. We excluded patients with SARS-CoV-2 infection and KD criteria without MIS-C criteria (three patients), those diagnosed with another disease (one with thrombotic thrombocytopenic purpura, one with Takayasu arteritis and two with dengue) and those referred to another hospital (three patients).

We did not calculate sample size due to the limited number of cases since this is a rare disease. Data collection was performed by four researchers distributed in two independent groups. Discrepancies were resolved by a fifth researcher performing the review again.

Study variables

The study variables were age (years), sex (male and female), intradomiciliary contact with SARS-COV-2 infected person (yes or no), type of SARS-CoV-2 test: real-time polymerase chain reaction (RT-PCR), antigenic and serologic (IgM and IgG), comorbidities, time of illness (days), gastrointestinal symptomatology (abdominal pain, vomiting, diarrhea, nausea), mucocutaneous (polymorphous exanthema, conjunctival injection, changes in the oral cavity, edema of palms and soles, desquamation of fingers and cervical lymphadenopathy), respiratory (upper respiratory symptoms, respiratory distress), neurological and clinical phenotype (fever and inflammation, similar to KD and shock), based on previous reports ⁶6. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA. 2020;324(3):259-69. doi: 10.1001/jama.2020.10369.
https://doi.org/10.1001/jama.2020.10369... ^,1717. Izquierdo G, Cofré F, Poli C, Delpiano L, Conca N, Verdugo P, et al. Recomendaciones para la sospecha diagnóstica y manejo del Síndrome Inflamatorio Multisistémico (SIM-COVID-19) en contexto pandemia SARS-CoV-2. Abril 2021. Rev Chil Infectol. 2021;38(3):370-80. doi: 10.4067/S0716-10182021000300370.
https://doi.org/10.4067/S0716-1018202100... ^,1818. Alvarado-Gamarra G, Aguila O del, Dominguez-Rojas J, Chonlon-Murillo K, Atamari-Anahui N, Borcic A, et al. Fenotipos clínicos del síndrome inflamatorio multisistémico pediátrico asociado a COVID-19 (SIM-C). Andes Pediatr. 2022;93(6):841-50. doi: 10.32641/andespediatr.v93i6.4084.
https://doi.org/10.32641/andespediatr.v9... .

We also considered laboratory characteristics, treatment (immunoglobulin, corticosteroid, acetylsalicylic acid, vasopressors/inotropes, anticoagulation and antibiotics), complications (echocardiographic alterations, admission to PICU and invasive mechanical ventilation, macrophage activation syndrome) and hospitalization time (days) (Table S1).

The variables were described in a general way (period 2020-2022), according to the first three waves by COVID-19 (first: March - December 2020, second: January - September 2021, third: December 2021 - January 2022) ¹⁹19. Araujo-Castillo R. Dos años de pandemia, una batalla que aún no termina. Acta Médica Peru. 2022;39(1):3-6. doi: 10.35663/amp.2022.391.2374.
https://doi.org/10.35663/amp.2022.391.23... and according to the shock phenotype (MIS-C with need of support with inotrope/vasopressor or fluid resuscitation >20 ml/kg).

Procedure and statistical analysis

We identified the records of the patients included in the study and then we proceeded to review and collect the information from their medical records in the hospital archive. A data collection form was used, after approval and authorization of the project by the hospital’s institutional research committee.

The STATA v.16 program (StataCorp LP, College Station, Texas, United States) was used for data analysis. Categorical variables were described by absolute and relative frequencies and quantitative variables by mean and standard deviation (SD) or median and interquartile range (IQR) according to the normality assessment with the Shapiro-Wilk test.

Ethical aspects

The study was approved by the INSN-B Research Ethics Committee (No. 078-2022-CIEI-INSN) and the protocol was registered in the PRISA platform of the National Institute of Health (code: EI00002522). Informed consent was not requested because we opted for the permission of the institution for the collection of data from the medical records; we respected the confidentiality of the data by using numerical codes. Some characteristics of the first eight patients in the study were published in the Revista Peruana de Medicina Experimental y Salud Pública ²⁰20. Coll-Vela LED, Zamudio-Aquise MK, Nuñez-Paucar H, Bernal-Mancilla RR, Schult-Montoya SC, Ccorahua-De La Paz M, et al. Síndrome inflamatorio multisistémico asociado a COVID-19 en niños: serie de casos en un hospital pediátrico de Perú. Rev Peru Med Exp Salud Publica. 2020;37(3):559-65. doi: 10.17843/rpmesp.2020.373.6126.
https://doi.org/10.17843/rpmesp.2020.373... .

FINDINGS

Of the 73 patients with MIS-C, about 50% were diagnosed during the second wave (Figure 1) and the last patient was diagnosed in April 2022 (third wave). The median age was 6 years (IQR: 2 - 9, range: 3 months - 16 years) and was higher in the second and third waves. Five participants (6.9%) were less than one year old, 23 (31.5%) one to four years, 32 (43.8%) five to nine years and 13 (17.8%) older than 10 years. More than half were male and 61 (83.6%) patients had intradomiciliary contact with a person infected with SARS-COV-2. Sixty-one (83.6%) had any positive SARS-CoV-2 test (6/59 RT-PCR, 3/49 antigenic, 17/56 IgM and 52/64 IgG) and 12 had negative tests with positive intradomiciliary contact to SARS-CoV-2. Two patients had comorbidities (one neurogenic bladder and one unilateral hydronephrosis). The median time of illness was 5 days (IQR: 4-7) and was longer in the third wave (Table 1).

Gastrointestinal (abdominal pain and vomiting) and mucocutaneous (polymorphous exanthema and conjunctival injection) manifestations were frequent during all three waves, while respiratory and neurological manifestations were frequent during the second wave. The KD-like phenotype was frequent in all three waves and was reported in 34 (46.6%) patients followed by the shock phenotype in 21 (28.8%) patients.

Blood tests showed mild anemia: 10.5 g/dL (IQR: 9.7-11.2), and elevated leukocytes: 12,500/mm³ (IQR: 7330-16,390), neutrophils: 8772/mm³ (IQR: 5057.7-12,002), erythrocyte: sedimentation rate: 39.5 mm/h (IQR: 27.5-49), C-reactive protein: 18.2 mg/dL (IQR: 11.8-24.8), liver enzymes, fibrinogen: 558 mg/dL (IQR: 493.3-651.5), D-dimer: 4.2 mg/L (IQR: 2.3-7.1), ferritin: 402 ng/mL (IQR: 234.5-538.5) and lactate dehydrogenase: 547 U/L (IQR: 432-665) (Table 2).

Intravenous human immunoglobulin was used in 70 (95.9%) patients with a dose of 1 to 2gr/kg (minimum: 9 grams; maximum: 100 grams) and was administered to all patients during the first wave. Corticosteroids (methylprednisolone) were more frequently used during the second wave in 34 (97.1%) patients. The dose was 1-2mg/kg for five days, and 10-30mg/kg as a pulse dose (14 patients) in those with signs of clinical deterioration for three days. Acetylsalicylic acid was used in 69 (94.5%) patients, 47 (64.4%) received prophylactic anticoagulation and 57 (78.1%) antibiotics, the latter two decreased their use during each wave.

Regarding complications, five developed coronary aneurysm and three developed left ventricular dysfunction. Two patients required intubation in the emergency room, 17 (23.3%) were admitted to PICU (mean 5.8+/-3 days) and 11 (15.1%) required invasive mechanical ventilation (mean 4+/-1 day). Ten (15.1%) patients had macrophage activation syndrome, six (8.2%) had pneumonia, two had pancreatitis and one had deep vein thrombosis of the extremities. The median length of hospitalization was 10 days (IQR: 8-14) and no patient died during hospitalization.

Patients with the shock phenotype were older with a median age of eight years (IQR: 5-9), had greater respiratory distress and neurological symptoms compared to those who did not develop shock (Table 1). In addition, greater inflammatory alterations (increased c-reactive protein and ferritin), alteration of liver enzymes, hematological alterations (lower hemoglobin, lymphopenia and mild thrombocytopenia) and coagulation alterations (fibrinogen and D-dimer) were found in this group of patients (Table 2). The use of second dose immunoglobulin was higher (47.6%) and all used vasopressors and antibiotics (Table 3). Echocardiographic alterations were more frequent in these patients and they had longer hospitalization time, 14 days (IQR: 11-16).

DISCUSSION

Our study showed that the frequency of MIS-C varied during the first three years of the pandemic and was characterized by gastrointestinal and mucocutaneous symptoms. Treatment mainly consisted of immunoglobulin and corticosteroids, and those with shock had more complications.

We found that more cases were diagnosed during the second wave, which is similar to what was reported in a hospital in India ¹³13. Angurana SK, Kumar V, Nallasamy K, Kumar MR, Naganur S, Kumar M, et al. Clinico-Laboratory Profile, Intensive Care Needs and Short-Term Outcome of Multisystem Inflammatory Syndrome in Children (MIS-C): Experience during First and Second Waves from North India. J Trop Pediatr. 2022;68(5):fmac068. doi: 10.1093/tropej/fmac068.
https://doi.org/10.1093/tropej/fmac068... , but a study in France reported more cases during the first wave ¹²12. Kechiche R, Borocco C, Bajolle F, Belot A, Poignant S, Lachaume N, et al. Multisystem inflammatory syndrome in children during the COVID-19 waves: data from the Juvenile Inflammatory Rheumatism cohort. Front Pediatr. 2023;24(11):1126985. doi: 10.3389/fped.2023.1126985.
https://doi.org/10.3389/fped.2023.112698... . This difference could be explained by the fact that the high peak of infection in Peru occurred during the second wave in addition to the softening of social distancing measures due to economic recovery and increased movement of people, including children ¹⁹19. Araujo-Castillo R. Dos años de pandemia, una batalla que aún no termina. Acta Médica Peru. 2022;39(1):3-6. doi: 10.35663/amp.2022.391.2374.
https://doi.org/10.35663/amp.2022.391.23... . MIS-C has been reported four to six weeks after the peak of COVID-19 infection ¹1. Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 2020;20(11):e276-88. doi: 10.1016/S1473-3099(20)30651-4.
https://doi.org/10.1016/S1473-3099(20)30... , which is related to what was reported in France during the first wave ¹²12. Kechiche R, Borocco C, Bajolle F, Belot A, Poignant S, Lachaume N, et al. Multisystem inflammatory syndrome in children during the COVID-19 waves: data from the Juvenile Inflammatory Rheumatism cohort. Front Pediatr. 2023;24(11):1126985. doi: 10.3389/fped.2023.1126985.
https://doi.org/10.3389/fped.2023.112698... .

Variants may also influence the frequency of MIS-C cases. In Peru, the identification of variants began during the second wave (2021) with the Lambda/Gamma/Delta variant predominating; the Omicron variant was the most prevalent during the third wave, ¹⁹19. Araujo-Castillo R. Dos años de pandemia, una batalla que aún no termina. Acta Médica Peru. 2022;39(1):3-6. doi: 10.35663/amp.2022.391.2374.
https://doi.org/10.35663/amp.2022.391.23... where fewer MIS-C cases were recorded despite a high peak of infections. Vaccination may have influenced the decrease in MIS-C cases during the third wave. The effect of vaccination was reported during the wave for the Delta variant in children aged 12-18 years in the United States ²¹21. Zambrano LD, Newhams MM, Olson SM, Halasa NB, Price AM, Boom JA, et al. Effectiveness of BNT162b2 (Pfizer-BioNTech) mRNA Vaccination Against Multisystem Inflammatory Syndrome in Children Among Persons Aged 12-18 Years - United States, July-December 2021. MMWR Morb Mortal Wkly Rep. 2022;71(2):52-8. doi: 10.15585/mmwr.mm7102e1.
https://doi.org/10.15585/mmwr.mm7102e1... , and during the wave for the Omicron variant in Denmark ⁵5. Holm M, Espenhain L, Glenthøj J, Schmidt LS, Nordly SB, Hartling UB, et al. Risk and Phenotype of Multisystem Inflammatory Syndrome in Vaccinated and Unvaccinated Danish Children Before and During the Omicron Wave. JAMA Pediatr. 2022;176(8):821-3. doi: 10.1001/jamapediatrics.2022.2206.
https://doi.org/10.1001/jamapediatrics.2... .

In Peru, vaccination (Pfizer-BioNTech) started in children aged 12-17 years in November 2021 and 5-11 years in January 2022. In our study, two patients with MIS-C had received vaccination against COVID-19, a 14-year-old male (vaccinated in November 2021, one dose) who developed disease five months later (he was IgG positive), and an 11-year-old male (vaccinated in February 2022) who developed the disease eight days later, but had positive IgG and IgM serology at diagnosis.

The median age was six years, lower than that reported by other studies ⁹9. Acevedo L, Piñeres-Olave BE, Niño-Serna LF, Vega LM, Gomez IJA, Chacón S, et al. Mortality and clinical characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with covid-19 in critically ill patients: an observational multicenter study (MISCO study). BMC Pediatr. 2021;21(1):516. doi: 10.1186/s12887-021-02974-9.
https://doi.org/10.1186/s12887-021-02974... ^,1818. Alvarado-Gamarra G, Aguila O del, Dominguez-Rojas J, Chonlon-Murillo K, Atamari-Anahui N, Borcic A, et al. Fenotipos clínicos del síndrome inflamatorio multisistémico pediátrico asociado a COVID-19 (SIM-C). Andes Pediatr. 2022;93(6):841-50. doi: 10.32641/andespediatr.v93i6.4084.
https://doi.org/10.32641/andespediatr.v9... ⁾ and higher in later waves, a trend similar to that reported in Argentina ¹⁴14. Gentile A, Juárez MDV, Romero Bollon L, Aprea V, Matteucci E, Falaschi A, et al. Comparison of Epidemiologic and Clinical COVID-19 Profiles in Children in Argentina, During Circulation of Original and Variant (Alpha, Gamma and Lambda) Strains. Pediatr Infect Dis J. 2023;42(2):136. doi: 10.1097/INF.0000000000003776.
https://doi.org/10.1097/INF.000000000000... . Gastrointestinal and mucocutaneous manifestations were the most frequent, in agreement with other studies ¹²12. Kechiche R, Borocco C, Bajolle F, Belot A, Poignant S, Lachaume N, et al. Multisystem inflammatory syndrome in children during the COVID-19 waves: data from the Juvenile Inflammatory Rheumatism cohort. Front Pediatr. 2023;24(11):1126985. doi: 10.3389/fped.2023.1126985.
https://doi.org/10.3389/fped.2023.112698... ^,1313. Angurana SK, Kumar V, Nallasamy K, Kumar MR, Naganur S, Kumar M, et al. Clinico-Laboratory Profile, Intensive Care Needs and Short-Term Outcome of Multisystem Inflammatory Syndrome in Children (MIS-C): Experience during First and Second Waves from North India. J Trop Pediatr. 2022;68(5):fmac068. doi: 10.1093/tropej/fmac068.
https://doi.org/10.1093/tropej/fmac068... . These characteristics were reported since the first cases in the United Kingdom ⁶6. Whittaker E, Bamford A, Kenny J, Kaforou M, Jones CE, Shah P, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA. 2020;324(3):259-69. doi: 10.1001/jama.2020.10369.
https://doi.org/10.1001/jama.2020.10369... , and are also found in reports from Denmark ⁵5. Holm M, Espenhain L, Glenthøj J, Schmidt LS, Nordly SB, Hartling UB, et al. Risk and Phenotype of Multisystem Inflammatory Syndrome in Vaccinated and Unvaccinated Danish Children Before and During the Omicron Wave. JAMA Pediatr. 2022;176(8):821-3. doi: 10.1001/jamapediatrics.2022.2206.
https://doi.org/10.1001/jamapediatrics.2... , United States ¹¹11. Jain PN, Acosta S, Annapragada A, Checchia PA, Moreira A, Muscal E, et al. Comparison of Laboratory and Hemodynamic Time Series Data Across Original, Alpha, and Delta Variants in Patients With Multisystem Inflammatory Syndrome in Children. Pediatr Crit Care Med. 2022;23(8):e372. doi: 10.1097/PCC.0000000000002976.
https://doi.org/10.1097/PCC.000000000000... ⁾ and Latin America ³3. Ruvinsky S, Voto C, Roel M, Fustiñana A, Veliz N, Brizuela M, et al. Multisystem Inflammatory Syndrome Temporally Related to COVID-19 in Children From Latin America and the Caribbean Region: A Systematic Review With a Meta-Analysis of Data From Regional Surveillance Systems. Front Pediatr. 2022;10:881765. doi: 10.3389/fped.2022.881765.
https://doi.org/10.3389/fped.2022.881765... ^,1010. Fernández-Sarmiento J, Acevedo L, Niño-Serna LF, Boza R, García-Silva J, Yock-Corrales A, et al. Risk Factors Associated with Intensive Care Admission in Children with Severe Acute Respiratory Syndrome Coronavirus 2-Related Multisystem Inflammatory Syndrome (MIS-C) in Latin America: A Multicenter Observational Study of the REKAMLATINA Network. J Intensive Care Med. 2024;08850666241233189. doi: 10.1177/08850666241233189.
https://doi.org/10.1177/0885066624123318... .

Children with MIS-C developed laboratory alterations such as elevation of inflammatory markers, hematological and coagulation disorders, particularly in patients with the shock phenotype in agreement with previous reports ⁹9. Acevedo L, Piñeres-Olave BE, Niño-Serna LF, Vega LM, Gomez IJA, Chacón S, et al. Mortality and clinical characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with covid-19 in critically ill patients: an observational multicenter study (MISCO study). BMC Pediatr. 2021;21(1):516. doi: 10.1186/s12887-021-02974-9.
https://doi.org/10.1186/s12887-021-02974... ^,1818. Alvarado-Gamarra G, Aguila O del, Dominguez-Rojas J, Chonlon-Murillo K, Atamari-Anahui N, Borcic A, et al. Fenotipos clínicos del síndrome inflamatorio multisistémico pediátrico asociado a COVID-19 (SIM-C). Andes Pediatr. 2022;93(6):841-50. doi: 10.32641/andespediatr.v93i6.4084.
https://doi.org/10.32641/andespediatr.v9... . These alterations are produced by an imbalance in the immune system due to the binding of SARS-CoV-2 to ACE-2 receptors in the endothelial cells of the vascular system, causing inflammation and systemic coagulation ¹1. Jiang L, Tang K, Levin M, Irfan O, Morris SK, Wilson K, et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. Lancet Infect Dis. 2020;20(11):e276-88. doi: 10.1016/S1473-3099(20)30651-4.
https://doi.org/10.1016/S1473-3099(20)30... .

Treatment consisted in the use of immunoglobulin, corticoids and acetylsalicylic acid, which is similar to the management of KD ²²22. McCrindle Brian W, Rowley Anne H, Newburger Jane W, Burns Jane C, Bolger AF, Gewitz M, et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association. Circulation. 2017;135(17):e927-99. doi: 10.1161/CIR.0000000000000484.
https://doi.org/10.1161/CIR.000000000000... ⁾ and according to the management of MIS-C in Latin American countries such as Chile ¹⁷17. Izquierdo G, Cofré F, Poli C, Delpiano L, Conca N, Verdugo P, et al. Recomendaciones para la sospecha diagnóstica y manejo del Síndrome Inflamatorio Multisistémico (SIM-COVID-19) en contexto pandemia SARS-CoV-2. Abril 2021. Rev Chil Infectol. 2021;38(3):370-80. doi: 10.4067/S0716-10182021000300370.
https://doi.org/10.4067/S0716-1018202100... and Argentina ¹⁵15. Ensinck G, Gregorio G, Flores RM, Crowe CI, Clerico Mosina P, Curi C, et al. Consensus on treatment of multisystemic inflammatory syndrome associated with COVID-19. Arch Argent Pediatr. 2021;119(4):S198-211. doi: 10.5546/aap.2021.S198.
https://doi.org/10.5546/aap.2021.S198... . The patients that required a second dose of immunoglobulin did not show clinical improvement 36 hours after the first dose, they had persistent fever or developed shock or macrophage activation syndrome.

The use of antibiotics was high at the beginning of the pandemic; patients with severe MIS-C or COVID-19 who were most at risk of receiving such treatment ¹⁸18. Alvarado-Gamarra G, Aguila O del, Dominguez-Rojas J, Chonlon-Murillo K, Atamari-Anahui N, Borcic A, et al. Fenotipos clínicos del síndrome inflamatorio multisistémico pediátrico asociado a COVID-19 (SIM-C). Andes Pediatr. 2022;93(6):841-50. doi: 10.32641/andespediatr.v93i6.4084.
https://doi.org/10.32641/andespediatr.v9... ^,2020. Coll-Vela LED, Zamudio-Aquise MK, Nuñez-Paucar H, Bernal-Mancilla RR, Schult-Montoya SC, Ccorahua-De La Paz M, et al. Síndrome inflamatorio multisistémico asociado a COVID-19 en niños: serie de casos en un hospital pediátrico de Perú. Rev Peru Med Exp Salud Publica. 2020;37(3):559-65. doi: 10.17843/rpmesp.2020.373.6126.
https://doi.org/10.17843/rpmesp.2020.373... . In our study, antibiotics were used more during the first and second waves because of the risk of bacterial infection; however, it was lower in the third wave, a trend similar to that reported in France ¹²12. Kechiche R, Borocco C, Bajolle F, Belot A, Poignant S, Lachaume N, et al. Multisystem inflammatory syndrome in children during the COVID-19 waves: data from the Juvenile Inflammatory Rheumatism cohort. Front Pediatr. 2023;24(11):1126985. doi: 10.3389/fped.2023.1126985.
https://doi.org/10.3389/fped.2023.112698... . This is explained by the fact that as the waves passed, diagnosis and treatment improved, avoiding the use of antibiotics, since MIS-C is a post-infectious viral complication.

Cardiac complications characterized MIS-C during the initial phase ²³23. McArdle AJ, Vito O, Patel H, Seaby EG, Shah P, Wilson C, et al. Treatment of Multisystem Inflammatory Syndrome in Children. N Engl J Med. 2021;385(1):11-22. doi: 10.1056/NEJMoa2102968.
https://doi.org/10.1056/NEJMoa2102968... ^,2424. Son MBF, Murray N, Friedman K, Young CC, Newhams MM, Feldstein LR, et al. Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes. N Engl J Med. 2021;385(1):23-34. doi: 10.1056/NEJMoa2102605.
https://doi.org/10.1056/NEJMoa2102605... . In our study, five (7.0%) patients developed coronary aneurysm and three (4.2%) left ventricular dysfunction, none had coronary artery dilatation. This low frequency may be explained by the fact that there were fewer severe cases resulting in less admission to PICU and need for mechanical ventilation in contrast to other studies ³3. Ruvinsky S, Voto C, Roel M, Fustiñana A, Veliz N, Brizuela M, et al. Multisystem Inflammatory Syndrome Temporally Related to COVID-19 in Children From Latin America and the Caribbean Region: A Systematic Review With a Meta-Analysis of Data From Regional Surveillance Systems. Front Pediatr. 2022;10:881765. doi: 10.3389/fped.2022.881765.
https://doi.org/10.3389/fped.2022.881765... ^,1212. Kechiche R, Borocco C, Bajolle F, Belot A, Poignant S, Lachaume N, et al. Multisystem inflammatory syndrome in children during the COVID-19 waves: data from the Juvenile Inflammatory Rheumatism cohort. Front Pediatr. 2023;24(11):1126985. doi: 10.3389/fped.2023.1126985.
https://doi.org/10.3389/fped.2023.112698... ^,1313. Angurana SK, Kumar V, Nallasamy K, Kumar MR, Naganur S, Kumar M, et al. Clinico-Laboratory Profile, Intensive Care Needs and Short-Term Outcome of Multisystem Inflammatory Syndrome in Children (MIS-C): Experience during First and Second Waves from North India. J Trop Pediatr. 2022;68(5):fmac068. doi: 10.1093/tropej/fmac068.
https://doi.org/10.1093/tropej/fmac068... ^,2323. McArdle AJ, Vito O, Patel H, Seaby EG, Shah P, Wilson C, et al. Treatment of Multisystem Inflammatory Syndrome in Children. N Engl J Med. 2021;385(1):11-22. doi: 10.1056/NEJMoa2102968.
https://doi.org/10.1056/NEJMoa2102968... ^,2424. Son MBF, Murray N, Friedman K, Young CC, Newhams MM, Feldstein LR, et al. Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes. N Engl J Med. 2021;385(1):23-34. doi: 10.1056/NEJMoa2102605.
https://doi.org/10.1056/NEJMoa2102605... ; however, patients with shock had more cardiac alterations and complications similar to other reports ⁹9. Acevedo L, Piñeres-Olave BE, Niño-Serna LF, Vega LM, Gomez IJA, Chacón S, et al. Mortality and clinical characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with covid-19 in critically ill patients: an observational multicenter study (MISCO study). BMC Pediatr. 2021;21(1):516. doi: 10.1186/s12887-021-02974-9.
https://doi.org/10.1186/s12887-021-02974... ^,1111. Jain PN, Acosta S, Annapragada A, Checchia PA, Moreira A, Muscal E, et al. Comparison of Laboratory and Hemodynamic Time Series Data Across Original, Alpha, and Delta Variants in Patients With Multisystem Inflammatory Syndrome in Children. Pediatr Crit Care Med. 2022;23(8):e372. doi: 10.1097/PCC.0000000000002976.
https://doi.org/10.1097/PCC.000000000000... ^,1818. Alvarado-Gamarra G, Aguila O del, Dominguez-Rojas J, Chonlon-Murillo K, Atamari-Anahui N, Borcic A, et al. Fenotipos clínicos del síndrome inflamatorio multisistémico pediátrico asociado a COVID-19 (SIM-C). Andes Pediatr. 2022;93(6):841-50. doi: 10.32641/andespediatr.v93i6.4084.
https://doi.org/10.32641/andespediatr.v9... ^,2424. Son MBF, Murray N, Friedman K, Young CC, Newhams MM, Feldstein LR, et al. Multisystem Inflammatory Syndrome in Children - Initial Therapy and Outcomes. N Engl J Med. 2021;385(1):23-34. doi: 10.1056/NEJMoa2102605.
https://doi.org/10.1056/NEJMoa2102605... . No patient died during hospitalization but other studies have reported a lethality rate between 1 to 9% ⁹9. Acevedo L, Piñeres-Olave BE, Niño-Serna LF, Vega LM, Gomez IJA, Chacón S, et al. Mortality and clinical characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with covid-19 in critically ill patients: an observational multicenter study (MISCO study). BMC Pediatr. 2021;21(1):516. doi: 10.1186/s12887-021-02974-9.
https://doi.org/10.1186/s12887-021-02974... ^,1313. Angurana SK, Kumar V, Nallasamy K, Kumar MR, Naganur S, Kumar M, et al. Clinico-Laboratory Profile, Intensive Care Needs and Short-Term Outcome of Multisystem Inflammatory Syndrome in Children (MIS-C): Experience during First and Second Waves from North India. J Trop Pediatr. 2022;68(5):fmac068. doi: 10.1093/tropej/fmac068.
https://doi.org/10.1093/tropej/fmac068... ^,1414. Gentile A, Juárez MDV, Romero Bollon L, Aprea V, Matteucci E, Falaschi A, et al. Comparison of Epidemiologic and Clinical COVID-19 Profiles in Children in Argentina, During Circulation of Original and Variant (Alpha, Gamma and Lambda) Strains. Pediatr Infect Dis J. 2023;42(2):136. doi: 10.1097/INF.0000000000003776.
https://doi.org/10.1097/INF.000000000000... ^,1818. Alvarado-Gamarra G, Aguila O del, Dominguez-Rojas J, Chonlon-Murillo K, Atamari-Anahui N, Borcic A, et al. Fenotipos clínicos del síndrome inflamatorio multisistémico pediátrico asociado a COVID-19 (SIM-C). Andes Pediatr. 2022;93(6):841-50. doi: 10.32641/andespediatr.v93i6.4084.
https://doi.org/10.32641/andespediatr.v9... .

The study was limited by the fact that it was retrospective and was conducted in a single hospital; therefore, these findings cannot be generalized to other institutions in Peru. It was not possible to identify the type of SARS-CoV-2 variant in each patient, which would have served to better characterize each group; however, the cases were temporally related to the COVID-19 waves. In spite of this, this study has the strength of describing characteristics of a considerable series of MIS-C cases from a national pediatric referral hospital during the first three years of the pandemic, since the Peruvian health system had limited human, material and logistic resources.

In conclusion, the frequency of MIS-C cases in INSN-B varied during the first three years of the pandemic. The clinical manifestations and treatment were similar to those described by other studies, and patients with shock had greater laboratory alterations and cardiac complications.

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