Characteristics and clinical outcomes of adolescents infected by SARS-CoV-2: a systematic review

ABSTRACT Objective: To verify the COVID-19 clinical characteristics, associated comorbidities, and outcomes in adolescents. Data source: This is a systematic review study based on articles published between 2020 and 2022 in the United States National Library of Medicine - PubMed (MedLine), Virtual Health Library – VHL (LILACS), Science Direct, Web of Science, and Scopus (Elsevier) databases. The study was registered in the International Prospective Register of Systematic Reviews, under No. CRD42022309108. Data synthesis: A total of 1188 studies were identified. After applying the selection criteria, 13 articles were included. Prevalence was 25%; mild cases were predominant; and fever, cough, headache, anosmia, nasal congestion, and ageusia were frequent. Fever and cough were proportionally higher in hospitalized cases: 81 and 68%, respectively. Dyspnea (odds ratio [OR] 6.3; confidence interval 95%[CI] 2.8–14.3), fever (OR 3.8; 95%CI 2.0–7.4), and cough (OR 3.4; 95%CI 2.0–6.0) were associated with severe cases. Up to 28% required intensive care and 38% required mechanical ventilation. Pre-existing comorbidities increased the risk of hospitalization and death. Severe cases were associated with the risk of death (relative risk [RR] 4.6; 95%CI 2.8–7.5). The black, mixed, and indigenous races/skin colors represented risk groups, as well as residents of poorer regions. Conclusions: The review provided a better understanding of the disease profile and may favor the development of public policies, in addition to contributing to the current literature in the field of adolescent health.


INTRODUCTION
In the general population, the clinical manifestations of COVID-19 are very heterogeneous, ranging from asymptomatic cases to severe respiratory conditions. 1,23][4][5] However, adolescents with chronic health conditions or who are immunosuppressed may develop severe acute respiratory syndrome (SARS).These conditions result in worse prognoses. 6,7[10] However, this number can reach 25 to 30% in underdeveloped countries. 6,8,10urrently, the clinical characteristics and outcomes of the infection in adolescents are still unknown in many national and international territories. 1,5,6,10There is no consensus in the literature on this matter.The proportion of asymptomatic and symptomatic cases and the prevalent symptoms are not evident, nor are the prevalence and mortality, need for admission to the intensive care unit (ICU), use of mechanical ventilation (MV), and comparison of the infection with other age groups. 6,9,108]10 Therefore, this article presents a systematic review aimed at verifying the COVID-19 clinical characteristics, associated comorbidities, and outcomes in adolescents.

METHOD
This is a systematic literature review carried out on electronic databases to identify publications on COVID-19 clinical characteristics, associated comorbidities, and outcomes in adolescents.The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO), under No. CRD42022309108.
The articles included were focused on adolescents aged 10 to 19 years, regardless of gender.Data collection occurred in April 2022, considering information since January 2020, and conducted by two independent researchers.
The electronic journal databases of the US National Library of Medicine of the National Institutes of Health (PubMed), Virtual Health Library (VHL), Science Direct, Web of Science, and Scopus were consulted.The Population, Exposure, Comparator, and Outcomes (PECO) strategy was used to elaborate the research question. 11,12The combinations of descriptors and keywords in English were constructed according to the Medical Subject Headings (MeSH): (adolescent OR adolescents OR teenager OR teenagers) AND (COVID-19 OR "COVID-19 Virus Disease" OR "COVID-19 Virus Infection" OR "Coronavirus Disease 19" OR "SARS-CoV-2 Infection") AND ("signs and symptoms" OR "health profile").
Observational cross-sectional, case-control, or cohort studies were selected.Articles in English, Portuguese, and Spanish and those with access to full-text versions were eligible.For this review, the population aged less than 10 years or 20 years and older was not considered adolescent.Thus, our adolescent age group included patients from 10 to 19 years-old.Clinical trials, quasi-experimental studies, case studies, literature reviews, governmental documents, preprints, press releases, qualitative studies, and studies involving animals were excluded.
An initial screening was performed based on the titles and abstracts of all the articles found, in line with the inclusion and exclusion criteria and that answered some of the study questions; themes that were not consistent with the study were excluded, for example, those that dealt exclusively with cases and profile of pediatric multisystemic inflammatory syndrome or vaccines.The identification, screening, eligibility, and inclusion process of the articles found complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. 13he selection and evaluation of papers were autonomously conducted by two researchers (CG Campos and LA Muniz).The full texts were thoroughly reviewed, observing the criteria for inclusion.A database was created in Microsoft Word 2016, and the extracted variables were the following: reference, year of publication, country, study design, sample description, associated comorbidities, clinical characteristics, tests performed for diagnosis, outcomes, methodological quality, and level of evidence.
To assess the methodological quality of the articles selected, the questionnaire proposed by Downs and Black was used, consisting of 27 items in the form of questions, which cover the methodological evaluation of the studies, including internal validity, external validity, and statistical power.Five items of this instrument were not used, as they refer to experimental studies evaluation.3][14] This evaluation was conducted by two independent researchers.Disagreements between them were resolved in a plenary session with a third researcher.The level of scientific evidence of the studies was classified according to the Agency for Healthcare Research and Quality (AHRQ) categorization. 12

DISCUSSION
COVID-19 has a variable clinical presentation. 28,29In adolescents, there are reports of asymptomatic cases, cases of severe respiratory failure, and deaths. 15,22In this study, we discuss the clinical profile and the main associated comorbidities and outcomes in the age group from 10 to 19 years.
Rev Paul Pediatr. 2024;42:e2022241 In adolescents, the prevalence of the disease varies between 20 and 30%; however, it may be even higher in poorer countries with low human development indexes, unknown until now, in several national and international regions. 4,6,17,22,30Compared to other age groups, teenagers are often less infected than the adult population.In contrast, the COVID-19 prevalence in adolescents appears to be higher than that observed in children.It is hypothesized that the transmission of the disease to adolescents occurs mainly through infected adults and household contacts, since adults are more exposed to the virus in the workplace, in transport, and on the streets and are, therefore, more frequently infected. 17,22,30On the American continent, 13% of all cases are in adolescents. 16,26Nearly 80% of those infected are asymptomatic or mild cases, and 20% are severe. 30Pinto Júnior et al. verified that asymptomatic cases account for 76% of those infected. 22However, the study by Afonso et al. observed that 45% of the adolescents are asymptomatic and that, among the symptomatic, most are cases of flu syndrome. 17In this review, the proportion of symptomatic patients varies from 40 to 70%. 17,19,22,23However, there is still no consensus in the literature on the prevalence of symptomatic and asymptomatic cases, considering that global testing in adolescents is not usual. 22,23,26he most common clinical manifestations in mild cases are headache (42%), cough (41%), fever (35%), and myalgia (30%), according to Fiocruz. 30Maciel et al. showed that cough (40%) and fever (26%) are prevalent symptoms and data from the United States Centers for Disease Control and Prevention reinforce what was found, mentioning fever in 56% and cough in 54% of cases. 31Likewise, Xia et al. cited the occurrence of cough and fever in 65% and 60%, respectively, of the infected adolescents. 32In the current study, fever are predominant in severe and critical cases, in 80%.However, at the beginning of the infection, fever may be low or absent, manifesting itself only days after contamination. 15,22,24,30Cough may appear in mild cases, from 10 to 70%, but it is higher in severe cases, with approximately 70%. 20,27In non-hospitalized adolescents, anosmia, nasal congestion, and ageusia are also recurrent, and nausea, vomiting, diarrhea, abdominal pain, myalgia, arthralgia, and fatigue have variable frequencies. 17,20,22,30In severe cases, adolescents may present SARS; this condition increases the probability of ICU admission, MV use, and death. 21,23,27,30here are also reports of cases that develop into pediatric multisystemic inflammatory syndrome (P-MIS). 7In the analysis of the articles, it is noticed that the symptoms associated with the need for hospitalization are fever, cough, dyspnea, and peripheral oxygen saturation (SpO 2 ) <95%; 21,27 of which dyspnea, cough, and fever increased the risk of ICU admission, use of MV, and death. 21,23,27Although children, teenagers, and adults have similar symptoms of COVID-19, children and teenagers often have a less severe infection than adults. 17,22While signs and symptoms of upper and lower respiratory system involvement are frequent in adolescents and adults, gastrointestinal symptoms are frequently present in children. 15,23,24tudies available to date show that lower airway involvement in COVID-19 infection appears uncommon in children; on the contrary, skin rashes and difficulty eating or inappetence are more prevalent.However, even if they are more asymptomatic, children and adolescents can develop P-MIS and SARS associated with COVID-19, manifesting a severe form of the disease, implying the need for hospital care, local availability of medical materials and equipment, and trained teams in disease management. 15,19,21,23,27imilar to adults and children, adolescents with comorbidities are more vulnerable to severe disease. 301][22][23] However, age is already a significant predictive factor for a higher occurrence of severity and mortality from COVID-19, with the elderly with chronic disease being more susceptible to severe form; consequently, high mortality rates are observed in this age group. 20,27,30A meta-analysis found severe COVID-19 in 5.1% of adolescents with comorbidities and in 0.2% of those without comorbidities (RR 1.8; 95%CI 1.3-2.5). 30The presence of comorbidities also increases death risk and length of stay, regardless of age. 19,20,23,27According to data from the Brazilian Ministry of Health, 6% of adolescents who died from COVID-19 and 63% of those who needed invasive ventilatory support in 2021 had -Dyspnea, fever, and cough are associated with severe cases and hospitalization.
-Severe cases are associated with the risk of death.
-Preexisting comorbidity increases the risk of hospitalization and death.
-Patients with chronic respiratory, neurological, cardiac, metabolic, or immunosuppressed diseases are at greater risk of hospitalization and death.
-The risk of hospitalization and death is greater with each additional comorbidity, dose-response relationship.
-Blacks, mixed race, indigenous peoples, and residents of poorer regions are risk groups.
Table 4. Main risk factors for hospitalization, disease severity, or death from COVID-19 in adolescents.some comorbidity. 6Patients with chronic pulmonary, metabolic, neurological, cardiac, and immunosuppressive diseases are more likely to be hospitalized and experience complications from COVID-19. 23,26,27,31In many of these diseases, chronic inflammation, poor immune response, and underlying cardiorespiratory pathologies contribute to the need for hospitalization and the worsening of cases. 16,32,33ccording to some surveys, contamination by COVID-19 is prevalent among black, mixed-race, and indigenous peoples, as well as among inhabitants of the poorest regions worldwide. 17,22,25,26,27The accentuated inequalities and socioeconomic vulnerabilities in many countries may have impacted the access to information, the lack of protective equipment, and the difficulty in accessing health services. 26,27,34Likewise, the need for income led many adults and adolescents to the front lines during the pandemic, as many of them worked in essential services (supermarkets, bakeries, delivery services), exposing themselves more to contamination.It is evident that the living conditions affected them in a way that made them more exposed to illness and death. 30,35The scenario of social inequality is also repeated in other age groups since the mortality of children by COVID-19 is more common in poor countries; about 92% of global deaths from COVID-19 among children and adolescents occurred in low-and middle-income countries. 36,37cientific evidence shows that the effective way to prevent severe COVID-19 is vaccination. 30It is imperative that adolescents receive the complete immunization schedule, as vaccine is 94% (95%CI 90-96) effective in preventing hospitalization and 98% (95%CI 93-99) effective in avoiding ICU admissions and need for life support. 34,36There is also the possibility that the vaccine reduces the risk of sequelae, P-MIS, and Long COVID. 30,36Vaccination also reduces the number of severe cases and deaths in adults and children, while minimizing disease transmission.Thus, vaccinating children and adults interferes with the indirect protection of the adolescent population, as it will increase vaccination coverage and decrease the circulation of the virus and its variants, decreasing secondary cases or possible new cases. 36,37t is noticeable that the number of new cases and deaths due to COVID-19 are decreasing globally, although the pandemic is not over.A new variant, more virulent and transmissible, can appear at any time; hence the importance of preventive measures. 30,34,36Therefore, in high-incidence regions, adolescents should be advised to avoid crowds and use masks, especially those with preexisting diseases. 34Besides, due to the flow of various types of respiratory viruses, associated with the low sensitivity of self-tests, and the high cost and scarcity of laboratory exams, frequent testing of symptomatic adolescents is unfeasible in some countries. 30Thus, any symptomatic case identified should be isolated and monitored.Also, the management of adolescent health care in the context of the COVID-19 pandemic should be performed based on the training of primary care teams since most positive cases are mild or moderate, enabling these teams to address them.In addition, it is necessary to develop a set of effective interventions for the adolescent community, expanding health education and encouraging vaccination. 30,33,36he current systematic review was carried out based on observational studies, which can be considered a research limitation.However, the evaluation of the methodological quality of the articles was conducted according to the recommended methods for this type of study.Hence, the research contributed to a better understanding of the profile of adolescents affected by COVID-19, fostering other studies on the topic.
The results show a possible clinical profile of COVID-19, associated comorbidities, and outcomes in adolescents.Fever, cough, headache, anosmia, nasal congestion, and ageusia were prevalent in mild cases.In hospitalized patients, fever and cough were more frequent, as well as dyspnea and SpO 2 <95%.There was an association between previous comorbidities and disease severity, including a dose-response relationship, increasing hospitalization risk, need for intensive care, use of MV, and death.Contamination is prevalent in black, mixed-race, and indigenous people, as well as in inhabitants of poorer regions.The study permitted a better understanding of the disease profile in adolescents.Thus, it can contribute to the elaboration of public health policies and interventions, and to current literature in the field of adolescent health.

Figure 1 .-
Figure1.Research flowchart: identification, screening, eligibility, and inclusion of the scientific articles in the systematic review, according to PRISMA.13

Table 1 .
Articles published between January 2020 and April 2022.

Table 2 .
Associated comorbidities, clinical characteristics, and test performed for the COVID-19 diagnosis.

Table 3 .
22tcomes found in adolescents infected by SARS-CoV-2.Alharbi et al.18Two participants were admitted to the ICU.One female, 12 years old, without comorbidities, no need of MV, hospitalized for 43 days, 14 in the ICU, and was discharged.The second adolescent developed P-MIS, he was male, 12 years old, neuropath, used MV, and died.*Clementeetal.19Themedianhospitalization time was five days (IQR: 2-20).One patient required ICU.There are no death records.Previous use of glucocorticoids is associated with a greater chance of hospitalization (OR 3.5; p=0.001).The comorbidities were not analyzed.*PintoJúnioret al.2229.3% of prevalence.32% of cases presented comorbidities.24% were symptomatic at the time of examination.