Enhancing understanding of SARS-CoV-2 infection among individuals with Down syndrome: An integrative review

ABSTRACT BACKGROUND: Down syndrome (DS) is a non-rare genetic condition that affects approximately 1 in every 800 live births worldwide. Further, it is associated with comorbidities, anatomical alterations of the respiratory tract, and immunological dysfunctions that make individuals more susceptible to respiratory infections. OBJECTIVE: To systematize the current scientific knowledge about the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among individuals with DS. DESIGN AND SETTING: This integrative review was conducted at the Universidade Federal de São Carlos, São Paulo, Brazil. METHODS: This review was conducted in the following databases: the Virtual Health Library (Biblioteca Virtual em Saúde, BVS), PubMed, and Web of Science, using MeSH descriptors. The search included English or Portuguese studies published between January 1, 2020, and October 14, 2022. RESULTS: A total of 55 articles from 24 countries were selected, comprising 21 case-control or cohort studies, 23 case reports or series, and 11 narrative reviews or opinion studies. The articles were grouped into five categories: previous comorbidities, coronavirus disease 2019 (COVID-19) clinical features and evolution, cytokine storm and interleukins, living in institutions as a risk factor, and behavioral actions as a protective factor against SARS-CoV-2 infection. CONCLUSION: Individuals with DS are more susceptible to COVID-19 infection due to variables such as previous comorbidities, immunological factors, and their habitable environments. These aspects confer a higher risk of infection and an unfavorable clinical course. The precise pathways involved in the pathophysiology of COVID-19 in individuals with DS are not clear, thus requiring further studies. SYSTEMATIC REVIEW REGISTRATION: The Open Science Framework registered the research protocol (https://osf.io/jyb97/).

approaches. 7 The lack of systematized information on how the disease affects this population is a barrier to discussing the specific risk of coronavirus disease 2019 . 8

OBJECTIVE
This integrative review aimed to systematize the current scientific knowledge about the behavior of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among individuals with DS. In particular, to enhance understanding of the subject and identify gaps in the area.

Research design
This integrative literature review was conducted per the literature 9-11 based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement (PRISMA). 12 The research protocol was registered in the Open Science Framework (https:// osf.io/jyb97/). 13 Six steps were followed to ensure methodological rigor: Two independent authors performed the searches on the databases. The compatibility of the material found was checked and then entered into the Rayyan software (Cambridge, United States, https:// www.rayyan.ai/). Duplicate studies were identified and excluded using Rayyan. Title and abstract screening were applied to identify relevant studies in blind mode by two reviewers. When there was disagreement or doubt, a third reviewer was consulted. Finally, the articles were selected after a consensus discussion. The selected studies were read in their entirety. Further, with the help of the eligibility criteria, they were included or excluded from this review.

Eligibility criteria
This review included papers published in English or Portuguese between January 1, 2020, and October 14, 2022. Manuscripts that discussed the infection of SARS-CoV-2 in individuals with DS, regardless of the methodology and type of study, were included.
The exclusion criteria were: articles without adherence to the theme; not involving humans; in different languages; and duplicated texts in the databases.

Data extraction and quality assessment
Data from the selected studies were extracted using a form (Supplemental file available at https://doi.org/10.6084/ m9.figshare.21277452.v4), 16 which made it possible to summarize the information, verify the validity of the studies, and identify the relationships in the data. The following information was collected: authors, country of origin or year of publication, journal, study method, main results, and study conclusions.
The quality of the studies was evaluated and categorized by the level of evidence using the following criteria, modified from Melnyk and Fineout-Overholt: 17 I -a systematic review with meta-analysis of randomized controlled trials; II -randomized controlled trial; III -non-randomized controlled trial; IV -case-control or cohort study; V -a systematic review of descriptive or qualitative studies; VI -descriptive or qualitative study (including case reports and case series); VII -narrative review or expert opinion.
The authors reviewed the final studies independently and then worked collaboratively to establish the discussed categories. This inductive categorization allowed us to identify the main themes from the articles' results. 18

RESULTS
A total of 477 studies were identified in the databases in the initial search. After applying the eligibility criteria, 55 manuscripts were selected for this review. The selection process and exclusion reasons are described in Figure 1. The articles included were named A1 through A55.
The selected articles are described in Table 2, which summarizes their location of origin, type of study, and level of evidence.
The studies were conducted in 24 different countries. The United States of America (USA) comprises the highest number of studies (n = 16), followed by Brazil (n = 9), Spain (n = 8), and Italy (n = 6). We did not find studies with evidence levels I, II, III, or V. All 55 selected studies consisted of a case report or case series, cohort, case-control, review, or expert opinion with evidence levels IV, VI, and VII, respectively.
We organized these 55 manuscripts per the similarity of data and themes, grouping them into five categories as reported in  37 Illouz et al. 31 described a change in the endocytosis process in individuals with DS related to some genes located on chromosome 21, including Amyloid Beta Precursor Protein (APP), known to mediate dementia in these individuals. This gene is also involved in viral trafficking, changing endosomal fusion, which may be one factor that favors a higher risk of COVID-19 in individuals with DS and dementia. 31 Epilepsy was a relevant comorbidity in individuals with intellectual disability and COVID-19, 21 and it was more common in individuals with DS. 7,19,25,30,37 It was indirectly associated with an unfavorable outcome related to other comorbidities and care challenges.
Heart defects were recurrent in DS individuals with COVID-19, mainly in the pediatric age group. [20][21][22][23][24][26][27][28][29]35,36,[40][41][42][43][44][45] Children with DS seem more likely to be exposed to severe COVID-19 than those without DS. 46 Simpson et al. 24 presented a case series of seven children, three of whom had DS, a heart defect, and COVID-19. In addition to the corrected tetralogy of Fallot, one of these infants had hypothyroidism and obstructive sleep apnea and died 2.5 months after a SARS-CoV-2   infection. 24 The other cardiopathies mentioned were primarily septal defects that were associated with severe infection and prolonged hospitalization. 24,26,27,36,[40][41][42]44 Some studies stated whether the heart defect was surgically corrected, while others did not, making it difficult to conclude if surgical treatment of the heart disease changes the natural progression or outcome of the COVID-19 disease.
Sleep apnea was a comorbidity associated with obesity and heart disease and was also prevalent in the pediatric age group. 22,24,36,40,42 Apnea has been linked to a more severe course of COVID-19, ventilatory support, prolonged hospitalization, and death. 24  One study described SARS-CoV-2 and tuberculosis coinfections, 23    A4, A5, A23, A28, A40.

Behavioral actions as a protective factor against SARS-CoV-2 infection
It shows that specific behavioral patterns in individuals with DS may be a protective factor against infection by SARS-CoV-2.
in the immunopathogenesis of the disease, the authors detected negative regulation of the NLR family pyrin domain containing 3 gene (NLRP3), which is involved in the immune system and is critical in maintaining homeostasis against infections. This would hypothetically contribute to the co-occurrence of viral and bacterial infections. 53 Individuals with DS were four times more likely than the general population to acquire the SARS-CoV-2 infection. 21 They had a more severe clinical course and required more hospitalization 52,[55][56][57][58][59][60][61] and intensive care unit (ICU) treatments. 28 36 and multisystem inflammation syndrome (MIS-C) 40 were observed in two pediatric patients.

SARS-CoV-2 infection severity may be related to long COVID-19
or post-COVID conditions. 32,50 The risk of mortality was also higher. 21,56,59,61,63,64 In the cohort study by Semenzato et al., 56  High levels of inflammation seem to predispose to more severe disease and affect vaccine response in these individuals, proving to be a risk factor in the COVID-19 protection of individuals with DS and requiring greater attention to the doses and security measures. 50,69 Fourth category: Living in institutions as a risk factor Considering that some individuals with DS live in communities or institutions, this population has been assigned as a COVID-19 risk group due to the ease of viral transmission. 25,33,70,71 More populated places seem to be associated with higher infection rates. 70 In a cohort of 543 individuals with intellectual disabilities, 56 of whom had DS, the trisomy of 21 represented a higher risk for COVID-19 infection. 72 The demographic profile of institutionalized individuals with DS has been described as slightly different from that of individuals with intellectual disabilities due to other etiologies. Individuals with trisomy are usually younger and more likely to have dementia, hearing loss, or be overweight. 73 These variables might be linked to a higher vulnerability to COVID-19.

Fifth category: Behavioral actions as a protective factor against SARS-CoV-2 infection
Since the COVID-19 pandemic started, behavioral actions have been a vital tool to prevent infection by SARS-CoV-2. In this context, Russo et al. 74

Study limitations
This study has some limitations. Vaccination is currently the most effective strategy to prevent contamination by COVID-19 and its unfavorable outcomes among individuals with DS, as well as in the general population.
Maintaining good hygiene by cleaning the hands regularly and thoroughly disinfecting surfaces frequently, especially those often touched, such as door handles, faucets, and phone screens is important. Environmental measures such as avoiding spaces that are closed, crowded, or involve close contact should also be encouraged.
To improve ventilation at home or school, it is recommended to bring in as much outdoor air as possible, for example, by opening windows; increasing air filtration in the heating, ventilation, and air conditioning systems by changing filters frequently and using filters that are properly fitted and provide higher filtration; using portable high-efficiency particulate air cleaners; and turning on exhaust fans or using other fans to improve airflow. Appropriate use of masks should still be considered in settings with multiple exposure risks.