Influence of sex on disease severity in children with multisystem inflammatory syndrome and COVID-19 in Latin America

Influence of sex on disease severity in children with multisystem inflammatory syndrome and COVID-19 in Latin America

Martin Brizuela1, Jacopo Lenzi2, Rolando Ulloa-Gutiérrez3, Omar Yassef Antúnez-Montes4, Jorge Alberto Rios Aida5, Olguita del Aguila6, Erick Arteaga-Menchaca7, Francisco Campos8, Fadia Uribe8, Andrea Parra Buitrago9,10, Lina Maria Betancur Londoño9, Jessica Gómez-Vargas11, Adriana Yock-Corrales11, Danilo Buonsenso12,13,14

1Pediatric Infectious Disease, Hospital Isidoro Iriarte, Quilmes, Buenos Aires, Argentina; 2Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Italy; 3Infectious Disease Department, Hospital Nacional de Niños “Dr. Carlos Sáenz Herrera”, CCSS, San José, Costa Rica; 4Departamento de Docencia e Investigación, Instituto Latinoamericano de Ecografía en Medicina (ILEM), Ciudad de Mexico, Mexico; 5Clínica Jas Médica, Lima, Perù; 6Unidad de Infectología Pediátrica del Hospital Nacional Edgardo Rebagliati Martins-Lima-Peru; 7Hospital General Regional 200 IMSS, Mexico; 8Hospital Madre Niño San Bartolome, Lima, Peru; 9Hospital Pablo Tobon Uribe Medellin, Colombia; 10Fundacion Neumologica Colombiana, Bogotà, Colombia; 11Pediatric Emergency Department, Hospital Nacional de Niños “Dr. Carlos Sáenz Herrera”, CCSS, San José, Costa Rica; 12Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; 13Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Rome, Italy; 14Global Health Research Institute, Istituto di Igiene, Università Cattolica del Sacro Cuore, Rome, Italy

Received 5 February 2021; accepted 23 March 2021

Summary. Data from adult studies show that COVID-19 is more severe in men than women. However, no data are available for the pediatric population. For this reason, we performed this study aiming to understand if sex influenced disease severity and outcomes in a large cohort of Latin-American children with COVID-19 and multisystem inflammatory syndrome (MIS-C). We found that a higher percentage of male children developed MIS-C (8.9% vs 5% in females) and died (1.2% and 0.4% in females), although on multivariate adjusted analyses the only statistically significant difference was found in need of hospitalization, with females less frequently admitted compared with boys (25.6% vs 35.4%). This data are preliminary and need further independent studies to better assess the role of sex.

Keywords. COVID-19, MIS-C, MIS, sex, gender, children.

Influenza del sesso sulla gravità della malattia nei bambini con sindrome infiammatoria multisistemica e COVID-19 in America Latina

Riassunto. I dati degli studi sugli adulti dimostrano che il COVID-19 si manifesta in modo più grave negli uomini che nelle donne; tuttavia, per la popolazione pediatrica non sono disponibili dati. Per questo motivo abbiamo condotto questo studio, con l’obiettivo di capire se il sesso ha influenzato la gravità e gli esiti della malattia in un’ampia coorte di bambini latino-americani con COVID-19 e sindrome infiammatoria multisistemica (MIS-C). Abbiamo notato che una più alta percentuale di bambini maschi ha sviluppato MIS-C (8,9% vs 5% nelle femmine) ed è morta (1,2%, vs 0,4% nelle femmine), sebbene nell’ambito di analisi multivariate aggiustate l’unica differenza statisticamente significativa sia stata identificata nella necessità di ospedalizzazione, con le femmine ricoverate con minor frequenza rispetto ai maschi (25,6% vs 35,4%). Questi dati sono preliminari e necessitano di ulteriori studi indipendenti per poter valutare meglio il ruolo del sesso.

Parole chiave. COVID-19, MIS-C, MIS, sesso, genere, bambini.

Introduction

Over a year after the description of the first cases of COVID-19 in China, several aspects of this pandemic are still unclear; among these, the different clinical impact of COVID-19 in females and males. Early data from China showed that men were more frequently infected by COVID-19 than women, and that men with underlying diseases (diabetes, hypertension and cardiovascular disease) developed a severe condition, with an increased mortality rate.1 Similar findings were reported in Italy, and were subsequently confirmed in almost all other Countries.

Several hypotheses have been made to support these differences, although no definite conclusions have been reached yet. Disparities in sex-specific disease outcomes may be due to sex-specific steroids and the activity of X-linked genes, which modulate the innate and adaptive immune response to virus infection and affect the immune response.2 Sex-related pre-existing comorbidities, such as hypertension, cardiovascular disease and diabetes, can play a role, since they are associated with severe outcomes, and are more frequent in men.3 In addition, hormonal and genetic factors can affect the expression of ACE2 (the receptor of SARS-CoV-2),4-6 microRNAs expressions and transcription,7 and the vitamin D3 activity.8

However, whether or not such differences between sexes are present in the pediatric population has not yet been the subject of any analysis. Major pediatric papers mainly focus on age as a risk factors of disease severity but, to our knowledge, no sex-assessing sub-analyses have been described.9-15 Since sex hormones or specific habits/conditions (alcohol, type-2 diabetes, and cardiovascular disease) are less pronounced in the pediatric population, in particular in infants and young children, such analysis can provide indirect evidence on the effect of hormones on COVID-19. Therefore, we performed this study with the aim to understand whether sex affects disease severity and outcomes in a large cohort of Latin-American children with multisystem inflammatory syndrome (MISC) and COVID-19.

Materials and methods

Study design and participants

This study is part of an ongoing independent project – already presented elsewhere12 – which assesses COVID-19 and MIS-C in Latin American children, with a previously published paper describing an initial group of 409 children with confirmed COVID-19.14 For this study we performed a sub-analysis of a previously used dataset,15 in order to evaluate the effect of sex on disease severity. The remaining variables are those previously described, and include age, gender, symptoms, imaging, underlying medical conditions, need for hospital and NICU/PICU admission, respiratory and cardiovascular support, other viral co-infections, drugs used to treat COVID-19, development of MIS-C and type of organ involvement, and outcome.

SARS-CoV-2 infection was confirmed through a positive PCR test with nasopharyngeal swab.

MIS-C was defined according to the CDC criteria (available at https://www.cdc.gov/mis-c/hcp/): an individual aged <21 years (we only subjects younger than 18) presenting with: i) fever; ii) laboratory evidence of inflammation; iii) evidence of clinically severe disease, requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); iv) no plausible alternative diagnoses; and v) positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposed to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.

The study was reviewed and approved by the DOMINGO (CoviD in sOuth aMerIcaN children-study GrOup) core group and approved by the Ethics Committee of the coordinating center and by each participating center (Mexico: COMINVETICA-30072020-CEI0100120160207; Colombia: PE-CEI-FT-06; Peru: No. 42-IETSI-ESSALUD-2020; Costa Rica: CEC-HNN-243-2020). The study was conducted in accordance with the Declaration of Helsinki and its amendments. No personal or identifiable data were collected during the study.

Statistical analysis

Summary statistics were presented as counts and percentages. The association between female sex and COVID-19 clinical outcomes was preliminarily evaluated with crude odds ratios (ORs) and 95% confidence intervals (CIs). A confounding adjustment was performed using a propensity score approach based on inverse-probability weighting. More specifically, we considered the following covariates, potentially related with the outcomes and unbalanced across males and females: age, pre-existing medical conditions, immunosuppressant at the time of diagnosis, primary or secondary immunodeficiency, chemotherapy over the last 6 months, pyrexia (≥38.0 °C/≥100.4 °F), days between the onset of symptom and the diagnosis, administration of systemic corticosteroids, intravenous immunoglobulin therapy, lower respiratory tract infection, and diagnosis of MIS-C. Clustered standard errors were used to account for the multicenter design of the study. All data were analyzed using the Stata 15 software (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC). The significance level was set at 5%, and all tests were 2-sided.

Results

The characteristics of the 990 patients enrolled in the study – both overall and by sex – are summarized in Table 1.

Children were enrolled in Peru (383), Costa Rica (299), Argentina (253), Colombia (43), and Mexico (12). Among the 484 females, 313 (64.7%) had fever, 223 (46.1%) signs of upper respiratory tract infection, 143 (29.5%) diarrhea and/or vomiting, 86 (17.8%) signs of lower respiratory tract infection, and 52 (10.7%) headache; 39 (8.1%) had chest X-ray abnormalities, 124 (25.6%) were hospitalized, 20 (4.1%) were admitted to ICUs, 49 (10.1%) received respiratory support, and 2 (0.4%) died; 24 (5%) were diagnosed with MIS-C. Among the 506 males, 53 (10.5%) had chest X-ray abnormalities, 179 (35.4%) were hospitalized, 27 (5.3%) were admitted to ICUs, 69 (13.6%) received respiratory support, and 6 (1.2%) died; 45 (8.9%) were diagnosed with MIS-C. Systemic steroids (38, 7.9%) and intravenous immunoglobulins (21, 4.3%) were used in similar proportions of females and males.

Table 2 shows the results of the crude and adjusted analyses, demonstrating the association between sex and clinical outcomes. Following an adjustment obtained with a weighting approach based on propensity scores, the only significant outcome was the access to the hospital: girls were admitted less frequently than boys (OR = 0.82, p <0.001).

Discussion

In this study, we aimed to assess the impact of sex on disease severity in a large cohort of Latin American children with COVID-19 and MIS. We found that a higher percentage of male children developed MIS (8.9% vs 5% in females) and died (1.2% vs 0.4% in females), although – upon multivariate adjusted analyses – the only statistically significant difference was found to be the need for hospitalization, with females less frequently admitted than males (25.6% vs 35.4%). Overall, this preliminary data highlights the fact that females can experience a milder disease compared with boys, as suggested in adults. In other reports,6 females were more frequently affected by hyposmia or anosmia and taste dysfunction compared with males; unfortunately, we did not assess these parameters in this study. In our cohort, children had no comorbidities such as hypertension, obesity or type-2 diabetes, therefore these behavioral factors, traditionally more frequent in males, could not have contributed to the described differences. Also, considering that sex hormones may have less impact in children, different microRNAs expressions due to sex hormones would not be involved as well.

An explanation of the disparity in sex-specific disease outcomes can be found in the activity of X-linked genes, as previously suggested,6 which modulate the innate and adaptive immune response to virus infection and affect the immune response. In addition, the male predominance in the COVID-19 pandemic could be partially explained by the sex-specific expressions of TMPRSS2.6

The activity and expression of the human angiotensin-converting enzyme 2 (ACE2) – the functional receptor for the severe acute respiratory syndrome coronavirus (SARS-CoV) – can also explain some differences. Age-related differences have been already suggested in a review.16 In rodents, pulmonary ACE2 expression is developmentally regulated, being at its highest at an early age and at its lowest when mice reach adulthood. Studies in rat lungs confirmed that ACE2 is predominantly expressed in the alveolar and bronchiolar epithelium, with the ACE2 expression dramatically reduced with age in both genders, with old male rats showing a more pronounced decrease.16 Also, hormonal and genetic factors could lead to ACE2 over-expression in the female sex. Gagliardi et al.6 reported that the SARS-CoV infection induces ACE2 down-regulation through the binding of the viral Spike protein to ACE2, thus reducing ACE2 expression in the lung, and triggering acute respiratory failure.17

Vitamin D has also received attention in the context of the immune pathogenesis of COVID-1917 and Pagano et al. hypothesized that the synergy between vitamin D3 and estrogen could affect the sex differences in the outcome of COVID-19 patients.18,19 However, no rigorous data is yet available on these issues and, in our data series, vitamin D levels have not been reported.

Sex may play a major role in the severity and persistence of the symptoms after the first diagnosis of acute COVID-19. In adults, long COVID has been described, and it seems more frequent in women.20-21 International experts highlighted the possibility of this disease in childhood as well, and recent reports seem to confirm that long COVID may affect children too.22-24 Since autoimmunity has been suggested as a potential pathogenic trigger – and considering the higher frequency of autoimmune disorders in children – the role of sex in long COVID, including in children, is a priority research topic for the next months.

Our study has limitations to be considered. First, it was not initially developed to specifically understand how sex could affect disease severity, therefore the variables included – as well as the study power – were not tailored to this subject. Also, blood tests, hormones and vitamin D were not tested, and therefore not analyzed. Lastly, there isn’t a control group of adult patients from the same area to compare sex differences in the various age groups. However, this study is the first to specifically assess the role of sex in children with COVID-19 and MIS.

In conclusion, we found a slightly more severe course of COVID-19 and MIS occurring in males than in females in our cohort of Latin American children. This data is preliminary, and further independent studies are needed to better assess the role of sex. In light of the growing evidence on long COVID in children, it is important to start including sex as an important potential variable of symptoms severity or persistence in COVID-19 children.

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24. Buonsenso D, Espuny Pujol F, Munblit D, et al. Clinical characteristics, activity levels and mental health problems in children with long COVID: a survey of 510 children. Preprints [Internet]. 2021. Available from: https://www.preprints.org/manuscript/202103.0271/v1.

Author contribution statement: DB conceptualized; DB, AY, MB wrote the first draft of the paper. JL performed statistical analyses. All the authors contributed to the writing of the final version, saw last version and approved it.

Conflict of interest: the Authors declare no conflicts of interest.

Funding: no funds received.

Ethic statement: ethical approval was obtained from each participating center (codes provided in section ‘Material and methods’).

Informed consent: a signed statement of informed consent to publish patient data was obtained from all the parents or legal guardians of the children participant to the research.

Availability of data and material: available upon request.

Correspondence to:

Danilo Buonsenso

Department of Woman and Child Health and Public Health

Fondazione Policlinico Universitario A. Gemelli

Largo A. Gemelli 8

00168 Rome, Italy

email: danilobuonsenso@gmail.com