Introduction

Although children and adolescents have a lower risk of infection and severity of coronavirus disease 2019 (COVID-19) compared to adults, in the presence of comorbidities, the risk of developing more severe forms of this disease is higher¹. Studies have shown that some underlying medical conditions such as asthma, immunosuppression, Type 1 diabetes, obesity, cardiovascular disease, congenital circulatory anomalies, neurodevelopmental disorders, anxiety or fear-related disorders, and depressive disorders have been related to an increased rate of fatal health outcomes²,³.

Some studies have reported a low incidence of COVID-19 in children and adolescents around the world: from the total cases of COVID-19, the World Health Organization estimated that 8.5% were children aged under 18 years⁴, UNICEF reported that 21% of cases occurred in individuals under 20 years⁵, and a Mexican nationwide study reported that 2% were cases under 15 years⁶.

In Europe, half of the children and adolescents with antibodies against SARS-CoV-2 have experienced symptoms; other studies in Latin America reported that most cases of young people were asymptomatic⁷. Hospitalization due to severe COVID-19 disease in children is rare, and the respiratory symptoms of these inpatients are more apparent than in infected children in the community. Fatality cases in hospitalized children are relatively low at 1%, compared to 27% across all other age groups⁸. Another study reported that < 5% of affected individuals are known to be children and <1% of those required ventilatory support⁹.

Scientific evidence has shown that most children with SARS-CoV-2 infection have been asymptomatic or had mild COVID-19 symptoms, and few children are at risk of severe COVID-19; however, some children with comorbidities have had a severe illness and have shown a higher risk of death¹⁰. Although COVID-19 in children is usually mild, in exceptional cases, they can become seriously ill and need hospitalization and intensive care. One adverse outcome has been termed multisystem inflammatory syndrome in children (MIS-C), characterized by fever, severe inflammation, and multisystem disorders, causing approximately 1-2% of overall mortality¹¹. These adverse outcomes have been observed mainly among children with comorbidities. This study aimed to assess the risk of hospitalization and death in children and adolescents with COVID-19 and comorbidities living in Mexico.

Methods

Results

From the total 6,303,932 COVID-19 cases accumulated until July 9, 2022, the percentage of pediatric cases under 18 years was 6% (n = 366,542 analyzed in this study) and the average age was 10.98 years. Table 1 shows the general characteristics of Mexican children with COVID-19. From the total number of cases analyzed, the average age was 10.98 years, and 50.66% of the cases were males and most cases (54.57%) were reported by the MoH providers caring for the uninsured, followed by providers of the Mexican Institute of Social Security (IMSS, for its Spanish acronym) caring for social security beneficiaries (36.33%) (Table 1).

Table 2 shows that of the total studied population (n = 366,542), most cases had COVID-19 diagnosis only (92.70%), and 7.30% reported at least one comorbidity or risk factor. Regarding cases without comorbidities (n = 339,780), most were treated as ambulatory patients (96.50%), only 3.52% were hospitalized, and 0.20% died; in contrast, from the total cases with at least one comorbidity (n = 26,762), 86.0% were ambulatory patients, 14.03% were hospitalized, and 1.90% died. Regardless of the presence of comorbidities, the crude percentage of hospitalization was 4.29% (15,729 hospitalized/366,542 infected), and the percentage of death was 0.32% (1,191 deaths/366,542 infected).

Table 2 also shows the percentage of pediatric COVID-19 cases with comorbidities and risk factors across health-care services and the percentage of comorbidities by age groups. From the total cases with at least one comorbidity, the most frequent NCD was asthma (34.0%), followed by immunosuppression (6.48%), diabetes (5.15%), cardiovascular disease (4.83%), hypertension (4.01%), CKD (2.45%), and the most frequent modifiable risk factor was obesity (32.84%). Regarding specific comorbidity and health-care services used, COVID-19 cases with asthma, diabetes, cardiovascular diseases, hypertension, and obesity were significantly more treated as ambulatory cases than hospitalized (p ≤ 0.013, in all cases); a significantly higher percentage of cases with immunosuppression were hospitalized (57.29%) compared with those treated as ambulatory patients (42.71%) (p = 0.000). Furthermore, CKD was the comorbidity with a higher percentage of death (7.61%), followed by cardiovascular disease (6.80%) and immunosuppression (6.63%). When comparing the percentage of death versus hospitalization by comorbidity, all comorbidities showed significantly higher percentages of hospitalization than death (p = 0.000).

Concerning the age groups, from the total study population, the group between 12 and 17 years old showed the highest percentage of COVID-19 (54.23%), and cases <5 years presented a higher proportion of hospitalization (14.57%) and death (1.19%) than other age groups (Table 2).

Table 3 shows the likelihood of hospitalization or dying among pediatric patients with comorbidities or risk factors compared to those without comorbidities. Pediatric patients with COVID-19 and NCD comorbidities had 5.65 times greater risk of hospitalization than those without any NCD diagnosis or no risk factors. Immunosuppression is the NCD that poses the greatest hospitalization risk (OR 22.06), followed by CKD (OR 11.36), cardiovascular disease (OR 5.66), and diabetes (OR 4.51). Patients with obesity also had a greater risk of hospitalization of 2.15. Regarding mortality risk, pediatric patients with NCDs and modifiable risk factors presented 11.01 times higher likelihood of death than those without comorbidities. The highest risk was observed in the case of CKD (OR 12.57), followed by cardiovascular disease (OR 6.87) and diabetes (OR 5.83), while asthma was found to be a significant protective factor against death (OR 0.50). Further, considering the odds of hospitalization and death by age groups: COVID-19 cases lower than 5 years old showed significantly higher probabilities of hospitalization (OR 5.45) or death (OR 7.63) than those between 5 and 11 years old. However, the age group between 12 and 17 years old showed a significantly lower probability of hospitalization (OR 0.66) and slightly and non-significant higher odds of death than cases between 5 and 11 years (1.10; p = 0.271).

Table 4 shows the odds of hospitalization in COVID-19 patients with comorbidities or modifiable risk factors by age group. In the group of patients under 5 years old, those with underlying comorbidity had an overall 4.59 times likelihood of hospitalization greater than those without comorbidities, and considering the odds by each comorbidity, the highest risk for hospitalization was observed for immunosuppression (OR 13.41) and cardiovascular disease (OR 6.52); patients between 5 and 11 years had an overall risk of hospitalization of 6.52 higher than those without comorbidities, and the highest risk of hospitalization was observed in patients with immunosuppression (OR 27.03) and CKD (OR 6.12); in the age group between 12 and 17 years, the overall likelihood of hospitalization was 5.70 times greater than in patients without comorbidities, and the highest risk was in immunosuppression (OR 28.27), CKD (OR 16.90), and diabetes (OR 6.71) (Table 4).

Table 5 shows the odds of death in patients with COVID-19 and comorbidities or risk factors by age group. Patients under 5 years had 7.79 times higher overall likelihood of death than those without comorbidities, and this likelihood was higher for cardiovascular diseases (OR 7.09) and CKD (OR 6.75); the group aged between 5 and 11 years had an overall higher risk of death of 14.50-fold risk of death than children without comorbidities, as well children with immunosuppression and CKD had 6.69 and 6.00 times, respectively, higher risk of death; finally, in the group of children between 12 and 17 years their overall risk of death was 11.36 times greater than in those without comorbidities, and the highest risk was observed in CKD (OR 19.57) and immunosuppression (OR 11.42) (Table 5).

Discussion

This study highlights that the percentage of total accumulated COVID-19 cases under 18 years old was 6%. From the total of this population, more than seven of each hundred cases also reported at least one comorbidity and presented a risk of hospitalization and death close to six-fold and over 11-fold, respectively, compared with cases without comorbidities. Immunosuppression, CKD, cardiovascular diseases, and diabetes were comorbidities that significantly increased the risk of hospitalization and death, and obesity was a modifiable risk factor that also increased the risk of severity of COVID-19. Moreover, considering the odds of hospitalization and death by age groups (Tables 4 and 5, respectively), the COVID-19 cases between 5 and 11 years old that reported at least one comorbidity showed the greatest risk of both outcomes of interest.

The Mexican pediatric population studied here showed a lower percentage of COVID-19 than other pediatric populations worldwide. The WHO data suggests that children under 18 years old represent 8.5% of the total COVID-19 cases in the world⁴, UNICEF by July 2022 showed that from a total of confirmed cases of COVID-19 reported by 102 countries, 21% happened in patients under 20 years old⁵. In contrast, our pediatric population showed higher percentages of COVID-19 than other countries: in China, the percentage of laboratory-confirmed cases among children under 19 years of age was of 2%¹³; in England, between January to May 2020, pediatric cases under 16 years old were 4%¹⁴; in Italy, by March 2020, only 1% were children under 18 years of age¹⁵. Another Mexican nationwide study, updated in October 2020, also studied the pediatric population under 15 years old independently of comorbidities. This study showed a lower prevalence of COVID-19 (2%) but a higher prevalence of hospitalization and death (13.5% and 1.4%, respectively)⁶.

Other countries have reported higher percentages of COVID-19 than our pediatric population: in Canada, by July 2022, among the population of children between 0 and 11 years old, the percentage of them with COVID-19 was 10.5%, and among those between 12 and 19 years was of 8.4%¹⁶; in the United States, between March 2020 and June 2022, among the population under 18 years old, the percentage with COVID-19 was of 15.5%¹⁷; further, from March to December 2020, from a total of laboratory-confirmed cases of COVID-19 among population between 0 and 24 years old: 57.4% of cases occurred in young adults aged from 18 to 24 years old, 7.4% in preschoolers (0-4 years), 10.9% in elementary school (5-10 years), 7.9% in middle school (11-13 years), and 16.4% in high school (14-17 years)¹⁸.

Regarding severity and fatality health outcomes related to COVID-19 among children and adolescents, our findings are similar to other worldwide reports. By July 2022, UNICEF reported that, of the total deaths in 90 countries, 0.40% were in children and adolescents under 20 years⁵. In the United States, by December 2020, from a total of pediatric COVID-19 cases, 11.7% were hospitalized, and 3.6% presented severe illness¹. In the international network cohort using European primary care records (France, Germany, and Spain), South Korean and US claims, and hospital databases between January and June 2020 among children and adolescents under 18 years old: from the total diagnosed cases, 4% were hospitalized¹⁹. In a US cohort of pediatric patients under 19 years old, 11.7% were hospitalized for COVID-19, and 31.1% experienced severe COVID-19, showing that patients with one or more chronic conditions presented 3.27 times higher risk of severe COVID-19 than those with none¹. In a Mexican report from February 2020 to March 2021, the proportion of case fatality was below 0.3% in the population between 1 and 20 years old and 2.2% in infants under 1-year old¹⁰. Moreover, our results are inconsistent with what is reported in the scientific literature regarding the fact that the age group from 5 to 11 years old showed the highest probabilities of hospitalization and death than those cases under 5 years or those between 12 and 17 years old.

Regarding the comorbidities that most raised the risk of severity by COVID-19 among our Mexican pediatric population: asthma was the most prevalent comorbidity (34%); although immunosuppression was only prevalent in 6.48% of COVID-19 cases, this disease increased the risk of hospitalization by 22.06 times, and death by 5.78 times, compared to COVID-19 pediatric cases without comorbidities; the second most prevalent disease was obesity (32.84%), which increased the risk of hospitalization by 2.15 times, and death by 3.17 times; moreover, our findings also highlight that after immunosuppression: CKD, cardiovascular disease, and diabetes were the diseases that most increased the risk of hospitalization and death. These results are partially consistent with a cross-sectional study done in more than 900 US hospitals that included patients with COVID-19 aged 18 years or younger: 28.7% had underlying medical conditions, asthma being the most common (10.2%), neurodevelopmental disorders (3.9%), anxiety or fear-related disorders (3.2%), depressive disorders (2.8%), and obesity (2.5%). The main risk factors associated with hospitalization were type 1 diabetes (adjusted risk ratio (aRR) of 4.60) and obesity (aRR of 3.07); further, the risk factors for severe COVID-19 were type 1 diabetes (aRR, 2.38) and cardiac and circulatory congenital anomalies (aRR, 1.72)². In a Mexican study with 1443 pediatric patients under 19 years old, 3.3% were admitted to the intensive care unit, 1.8% required assisted mechanical ventilation, and mortality was of 1.9%, where the main risk factors for mortality were pneumonia (OR of 6.45), intubation (OR of 8.75), immunosuppression (OR of 3.66), and cardiovascular disease (OR of 3.1)³.

In this study, asthma was the most frequent comorbidity, significantly increasing the risk of hospitalization (OR 1.30; 95% confidence interval [CI] 1.17-1.45; p = 0.000), but in contrast, this comorbidity was related with a significant reduction in the risk of death (OR 0.50; 95%CI 0.29-0.85; p = 0.010). There is concern that asthma is a risk factor for developing severe COVID-19 and increases the risk of death in the pediatric population; however, some systematic reviews and meta-analyses have shown that asthma is not an independent factor that significantly increases the risk of hospitalization, care unit admission, or death in children and adult population²⁰,²¹. In contrast, other studies have shown that asthma could be a non-statistically significant protective factor in preventing severe COVID-19. This may be explained by the fact that people with asthma receive treatments that favor low production of IFN-α, thus having a protective role of eosinophils in the airway as well as the immunomodulatory properties of inhaled steroids²² and montelukast²³.

Compared with adults, the proportion of COVID-19 cases in the pediatric population has been lower, which could be explained by significant differences in the immune system. Children have a robust innate immune response, being the first-line defense against SARS-CoV-2, with more natural killer cells (NKC). In addition, children have ‘trained immunity,' which involves epigenetic reprogramming of innate immune cells, including NKCs, following exposure to certain stimuli, including infections and vaccines, leading to ‘memory'²⁴,²⁵. Children also have a higher proportion of lymphocytes and absolute numbers of T and B cells²⁶. Another proposed immunological explanation is that children are less capable of mounting the pro-inflammatory cytokine storm, which plays an important role in the pathogenesis of severe COVID-19 and is responsible for multiorgan failure in critically ill patients²⁶-²⁹. In contrast to this theory, other studies have highlighted that hospitalized children with COVID-19 have higher serum levels of IL-17A and IFN-γ but not TNF-α or IL-6; therefore, children are not less prone than adults to develop a cytokine storm and ARDS²⁸.

The transmission of SARS-CoV-2 among children is a major concern. However, early studies suggest that children, due to their milder symptoms, do not contribute much to the spread of SARS-CoV-2 since the risk of transmission from an asymptomatic individual with SARS-CoV-2 infection is less than the risk from a symptomatic individual³⁰. In Norway, a prospective study showed a minimal transmission of SARS-CoV-2 among children and adults, finding a percentage of transmission of SARS-CoV-2 child-to-child of 0.9% and child-to-adult of 1.7%, supporting that people under 14 years of age are not the main carriers of SARS-CoV-2 transmission³¹. In this regard, a different expression of angiotensin-converting enzyme 2 (ACE2) receptor in children and adults has been proposed as a factor implicated in the reduced transmission and morbidity of SARS-CoV-2 observed at young ages. Furthermore, children have fewer ACE2 receptors in the respiratory tract than adults³², and these are only in the upper respiratory tract; this could explain why young children are less susceptible to SARS-CoV-2 infection³³ and why they present less severe disease than adults³⁴.

Although the proportion of COVID-19 cases in pediatrics is lower than in adults, some infected children can also develop serious complications, such as MIS-C, which cause inflammation of the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs³⁵. Thus, the vaccination of children is also justified as a strategy to reach herd immunity³⁶ and to avoid severe COVID-19. However, although Mexico's MoH has announced the vaccination against SARS-CoV-2 in children and adolescents, the Mexican National Health and Nutrition Survey for COVID-19 showed that the refusal and hesitancy to vaccinate against COVID-19 had been related to age, being more elevated among people of 60 and older (34.4% and 11.7%, respectively). However, these percentages had also been elevated among adolescents between 10 and 19 years (28.2% and 6.7%, respectively)³⁷. The threshold of 65-70% of the population with flock immunity is the prerequisite to ending this pandemic, either through vaccinations or natural infection; however, widely circulating virus variants and vaccination indecision make this threshold challenging to reach. In addition, novel variants with increased transmissibility and enhanced immune evasion changed the herd-immunity calculation. From an epidemiological perspective, unvaccinated children could become the virus shelter when adults achieve immune protection, given that most COVID-19 cases in children are mild and asymptomatic³⁶,³⁸.

The most important limitation of this study is that comorbidities collected in the Mexican COVID-19 surveillance system were also frequent diseases of the adult population¹², and specific health conditions in pediatric COVID-19 cases were probably underreported. In addition, the prevalence of confirmed COVID-19 cases found in this study could be underestimated since the pediatric population tends to be asymptomatic or shows mild symptoms of the disease³⁴. On the other hand, Mexico has performed few tests to detect SARS-CoV-2: in May 2020, the Organization for Economic Cooperation and Development reported that Mexico only executed 0.6 tests per thousand inhabitants, while other countries performed a greater number of tests, such as Iceland (146.6), Luxembourg (75.8), Lithuania (52.0), Israel (45.4), and Portugal (41.9)³⁹.

In conclusion, although Mexican children and adolescents have presented much lower percentages of SARS-CoV-2 infection and fatality rates than adults, the pediatric population with comorbidities has presented higher percentages of fatality outcomes. Therefore, children and adolescents with comorbidities should be vaccinated to avoid risks and to prevent transmission of SARS-CoV-2 in schools or communities.