SEQUELS OF COVID-19: AN INTEGRATIVE LITERATURE REVIEW

The strong affinity between the Spike protein of the SARS-CoV-2 virus and the angiotensin-converting enzyme 2 receptor is postulated as one of the main reasons for the high viral transmission rate, leading the WHO to declare COVID-19 as a Public Health Emergency of International Concern and to adopt measures to contain viral spread. Moreover, due to the virus's pathophysiological mechanism, non-specific symptoms, atypical progression, especially in the elderly and immunocompromised, and a faster and more lethal progression are observed. Additionally, as knowledge about the natural history of the virus infection has advanced, persistent symptoms and/or sequelae causing


INTRODUCTION
Viruses rely on the infrastructure and metabolism of the host cell throughout their replication cycle, particularly the cytoskeleton and the cell membrane (CORTINES, 2019).They utilize, to varying degrees, the cell's synthesis system, leading to the transfer of the viral genome to others.Viruses are composed, at least, of a nucleic acid genome, either RNA or DNA, and a protein coat.Many of them have an additional outer membrane called an envelope (ANDINO, 2017;MAERTENS, 2022).
Viral transmission occurs indirectly through contact with secretions/excretions from an infected animal or directly through mechanical or biological vectors.There is also a vertical transmission (colostrum, perinatal, or transplacental) from the mother to the offspring.The other forms are referred to as horizontal transmission (ANDINO, 2017;LI, 2022).
The virus reproduction process involves mechanisms of adhesion, penetration, and viral uncoating; synthesis of polyproteins, genomic replication, assembly, and exocytosis of new virions (DE ALMEIDA et al., 2020).
Regarding the SARS-CoV-2 virus, the replicative cycle begins with the interaction of the Spike glycoprotein, located on the viral envelope, with the cellular receptor Angiotensin-Converting Enzyme 2 (ACE2) present on the surface of the target cell.This interaction is responsible for the virus tropism towards the host cell, leading to its adhesion (DE ALMEIDA et al., 2020;LAMERS, 2022).
Based on evidence, it is postulated that SARS-CoV-2 infection can start in the upper respiratory tract, such as the nasal epithelium.Thus, the endocytosis pathways, associated with viral adhesion and penetration steps, will depend on the expression of endocytic proteins, such as GTPase (abundant in the nasal epithelium), and proteins https://www.nucleodoconhecimento.com.br70 RC: 101554 Disponível em: https://www.nucleodoconhecimento.com.br/lei/pedido-genericoinvolved in macropinocytosis (present in pneumocytes) (LAMERS, 2022;GONZALEZ et al., 2023).SARS-CoV-2 can be classified as a virus belonging to the Coronaviridae family and the betacoronavirus group, similar to MERS (Middle East Respiratory Syndrome) and SARS (Severe Acute Respiratory Syndrome), responsible for causing an acute respiratory disease known as COVID-19 (OMS, 2022).
Given the widespread distribution of ACE2 in multiple organs, there is a possible reason for the high transmission rate of SARS-CoV-2, which spread to almost all continents, leading to the World Health Organization (WHO) declaring it a Public Health Emergency of International Concern (PHEIC) on January 30, 2020 (YESUDHAS et al., 2021).Following this point, there was a need to adhere to measures to contain viral spread.
Thus, the main measures adopted were personal distancing of at least one meter, the use of personal protective masks, and the isolation of infected individuals.Additionally, the WHO provides basic rules to follow to avoid contagion, emphasizing points such as avoiding closed spaces and large gatherings, hand hygiene with soap and water or alcohol, and avoiding touching eyes, mouth, and nose (OMS, 2022).
In line with the mentioned pathophysiological mechanism, it is possible to observe that the presented symptoms result from an inflammatory process affecting the endothelium of various organs.The exaggerated release of pro-inflammatory cytokines such as interleukins 1 and 6 (IL-1 and IL-6) and interferon-α (TNF-α) causes damage to endothelial functions, resulting in thrombosis, fluid extravasation, and loss of the pulmonary, hepatic, renal, cardiac, and central nervous system endothelial barrier (LIBBY, 2020).
Most infected individuals will have mild presentations of the disease, with symptoms such as fever, malaise, mild shortness of breath, fatigue, myalgia, cough, sore throat, headache, nasal congestion, diarrhea, nausea, and vomiting.On the other hand, vulnerable patients, such as immunocompromised and elderly individuals, may have https://www.nucleodoconhecimento.com.br71 RC: 101554 Disponível em: https://www.nucleodoconhecimento.com.br/lei/pedido-generico an atypical condition with a rapid and severe progression, potentially leading to death.Thus, the main symptoms are characteristic of an Influenza-like Illness (ILI); however, when there is progression to a severe syndrome, it is termed Severe Acute Respiratory Syndrome (SARS), characterized by dyspnea/respiratory distress or persistent chest pressure or O2 saturation less than 95% in ambient air or cyanosis in lips and face (ISER et al., 2020).
As knowledge about the natural history of SARS-CoV-2 infection has advanced, systemic involvement sequelae have been observed, characterized by modifications in the functioning and/or form of cells and/or organs, resulting in permanent or nonpermanent dysfunctions in the individual (CHAVES et al., 2021).
In this regard, sequelae in the Central Nervous System (CNS) have already been observed, manifested as behavioral changes, anosmia, and an increased incidence of stroke.In the cardiovascular system, there are reports of acute cardiac injury, myocarditis, vascular inflammation, arrhythmias, as well as elevation of cardiac enzymes associated with systemic or localized inflammatory response in arterial plaques.In the liver, hepatic failure and microvascular steatosis can occur.In the kidneys, possibilities of tubular necrosis and renal failure.Coagulation disorders, such as thrombotic alterations, an increased likelihood of severe thrombocytopenia, and disseminated intravascular coagulation, can also be found (CAMPOS et al., 2020).
The study of post-acute infection indicates that persistent symptoms and/or sequelae may manifest differently, depending on the severity of the acute condition, showing differences between patients who were hospitalized in the Intensive Care Unit (ICU) and those outside the ICU (ALBU et al., 2021).

OBJECTIVE
To present an integrative literature review, covering the years 2021 and 2022, on the main sequelae of COVID-19.

METHOD
An integrative literature review was carried out on the sequelae of COVID-19, in the research databases Scientific Electronic Library Online -SciELO, Biblioteca Virtual em Saúde-VHL and PubMed.To achieve this, initially, on October 19, 2022, the health descriptors "SARS-CoV-2", "COVID-19" and "Sequelas e Reabilitação" were used, joined by the logical connector "AND".Furthermore, time filters were applied, setting the publication period between 2021 and 2022; language, for publications in Portuguese and English; and type of study, with which articles from "Systematic Review", "Prevalence Study" and "Qualitative Research" were selected.
At the end of these stages, 23 articles were obtained from the VHL, 03 articles from PubMed and 01 article from SciELO.Finally, an article selection stage was carried out with the inclusion criteria being articles that were available in full and that corresponded to the research objectives and the exclusion criteria being articles that were incomplete or that did not meet the objective.Thus, 06 articles remained in the VHL, and 01 in SciELO.
In a second stage, on December 8, 2022, a new search was carried out, this time using the descriptor "Post-COVID-19 Syndrome", repeating all the steps previously described.At the end of this stage, 06 articles were added to the VHL and 01 to PubMed, totaling the sample space for the integrative review of 14 articles.
Finally, on December 28, 2022, with the aim of better systematizing the choice of articles for this review, the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology was used.This methodology provides a flowchart (Figure 1) in three stages: "Identification", "Screening" and "Included", where in each of them the number of excluded articles in each database is recorded, and those that will continue for the subsequent stage of analysis until the final quantity that will be used in the review.
In the "Identification" stage, time, language, type of study and topic filters were applied.
In the "Triage", publications were excluded after reading the title and abstract and, after https://www.nucleodoconhecimento.com.br73 RC: 101554 Disponível em: https://www.nucleodoconhecimento.com.br/lei/pedido-genericoreading the full text, publications that did not meet the research objectives.The "Included" stage consolidates the total number of articles, in each database, to be worked on in the review (MOHER et al., 2009).

RESULTS
The main results related to the pathophysiology of persistent COVID-19 are based on the theory of immunological phenomena secondary to infection, abnormal immune response and the presence of viruses in immunologically privileged locations.Adding to this, evidence of a causal relationship between COVID-19 and Subacute Thyroiditis (SAT) was found.Furthermore, SARS-CoV-2 shows signs of having the capacity to trigger a greater number of complications and hospitalizations in patients with vitamin D deficiency.Such findings were summarized in Table 01 together with the methods and conclusions obtained in the articles selected for this review.
Table1.Summary of results found in articles selected in 2021 and 2022
The quality of evidence from the studies included in this review is low, with a high risk of bias and extensive heterogeneity in terms of disease prevalence.Furthermore, its external validity is very limited, with no control groups and limited studies including children.There is a need to carry out new controlled prospective cohort studies that include different populations and risk contexts.

DISCUSSION
According to Martín-Garrido ( 2022), persistent COVID-19 or Long COVID-19 Syndrome is defined as the presence of signs and symptoms that continue or develop after acute COVID-19 and is a significant finding that affects different organs and body systems.According to the aforementioned author, it is postulated that the explanation of pathophysiogenesis is based on three theories: immunological phenomena secondary to infection, abnormal immunological response and the presence of viruses in privileged locations.
Regarding immunological phenomena secondary to infection and abnormal immune response, the term "cytokine storm" has been used to describe the high level of inflammatory cytokines present in patients with severe COVID-19.This inflammatory state can both worsen pre-existing conditions and cause new ones, leading to the consequences of COVID-19 (BRITISH SOCIETY FOR IMMUNOLOGY, 2020).
The most frequent sequel was fatigue, cited both by Martín-Garrido (2022) and Albu et al. (2021).One of the possible explanations would be the severity of the clinical condition, the cytokine storm in the acute phase and the medications used, such as corticosteroids (LAM et al., 2009).Another result would be that this sequel directly impacts quality of life, mainly by influencing physical and cognitive activities that are essential in everyday life (CEBAN et al., 2022).Finally, fatigue is one of the main influencers of psychological complications, according to Albu et al. (2021).
Regarding psychological disorders, Kozato et al. (2021) documented the case of a man with no prior history of any psychiatric disorder, but with type 2 diabetes mellitus, systemic arterial hypertension, non-alcoholic fatty liver disease, smoking and alcoholism in the past, who, after acquiring the COVID-19 infection, needed to stay 8 days in the ICU and developed panic attacks, insomnia, auditory and tactile hallucinations.
Regardless of gender, group or region, there was a high prevalence of depression, anxiety, insomnia and psychiatric disorders (KULAGA, 2021;FONTES et al., 2022;CÉNAT et al., 2021).However, neuropsychiatric symptoms can be triggered by several microorganisms in addition to COVID-19.
According to Sousa et al. (2022), the presence of isolated or concomitant symptoms of depression, anxiety, insomnia, stress and post-COVID-19 somatization in healthcare professionals is notable.These data are supported by the study carried out by Pappa et al. (2020) in which these symptoms were the main complications found in these professionals during the COVID-19 pandemic.Therefore, this is a population particularly vulnerable to psychiatric disorders, as they are directly involved in the diagnosis and management of patients, being placed under extreme demands that threaten professional resilience.(2021), who described and qualitatively evaluated the relationship between Acute Disseminated Encephalomyelitis (ADEM) and COVID-19, relating the degree of severity of the infection with the outcomes.In general, classic ADEM has a higher incidence in children, however in cases preceded by SARS-COV-2 infection there was a predominance of the adult population.This discrepancy would be a consequence of children's lower propensity for infection, as well as the development of asymptomatic or mild disease.In any case, the percentage of pediatric cases, 30% of the total, suggests the need for neurological monitoring in the post-COVID-19 evaluation of children.As for the adult public, it was found that the average age was around 50 years old, when in the classic ADEM it  (MANZANO et al., 2021;WANG et al., 2022;ZELADA-RIOS et al., 2021).Zhang et al. (2021) identified the main mechanisms of smell disturbances in SARS-COV-2 infection: olfactory cleft syndrome with mucosal obstruction, post-viral anosmia syndrome, cytokine storm and impairment of sense due to direct damage to olfactory neurons and /or impaired perception in the smell center of the brain.Furthermore, as the coronavirus is one of the many pathogens that cause Post Viral Olfactory Dysfunction (PVOD) and given the strong impact of anosmia on patients' quality of life, it is necessary to establish a protocol for its treatment, as was also said by Chaves et al. (2021).
The study by Christensen et al. (2022) demonstrated the causal relationship between COVID-19 and subacute thyroiditis (SAT).The clinical characteristics found in SAT were varied and general, such as palpitations, anxiety, heat intolerance, insomnia, weight loss, agitation, irregular menstruation, fever, asthenia, tremors, hyperreflexia greater number of complications and length of stay were found in patients with vitamin D deficiency.Furthermore, 46.8% of deficient patients died, compared to 29.4% of those who were insufficient and 5.5% of those who were sufficient.These data support the understanding that higher serum concentrations of vitamin D are associated with reduced risk and severity of COVID-19 (MERCOLA et al., 2020).However, it has not been proven that deficiency of this vitamin can occur as a sequelae of COVID-19.

CONCLUSION
The sequelae of COVID-19 are disorders generated by the SARS-CoV-2 virus that remain for a long time even after the infectious condition has resolved, affecting patients' lives and their daily tasks.
Fatigue and dyspnea were the most cited sequelae in the studies evaluated.However, others may be evident, such as psychological and neurological disorders.This variety of sequelae and severity, regardless of the course of the infection, demonstrates the need for a thorough evaluation within a specific rehabilitation center.Furthermore, there is evidence that there are factors that can worsen the disease and increase the chances of complications, such as vitamin D deficiency, which is an object of analysis for future studies.
Therefore, the development of new scientific research is necessary to specify the sequelae and deepen knowledge about them, understanding their behavior over the   v. 33, n. 4, p. 397-412, 2022.
https://www.nucleodoconhecimento.com.br80 RC: 101554 Disponível em: https://www.nucleodoconhecimento.com.br/lei/pedido-genericoIn the review by Alemanno et al. (2021), when investigating the impact of COVID-19 on the cognitive functions of hospitalized patients and using neuropsychological assessment instruments such as the Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and Hamilton Rating Scale for Depression (HRSD), a correlation was observed between cognitive impairments and age, with severity being greater in older patients.Changes were observed in the visuospatial/executive domains, naming, short and long-term memory, abstraction, orientation, depression and anosmia, however, according to Schou et al. (2021), it is unclear whether early cognitive deficits are related to the long-term effects of COVID-19.Regarding sequelae related to the CNS, Zamani et al. (2022) aimed to determine the profile and possible mechanisms for triggering inflammatory diseases in the context of COVID-19, namely: immune-mediated inflammation with migration of inflammatory agents to the CNS; intrathecal or systemic synthesis of autoantibodies resulting from molecular mimicry/immunological hyperactivity; direct hematogenous viral invasion by disruption of the blood-brain barrier; direct neuronal invasion via the cribriform plate/bulb or other cranial nerves, this mechanism having a direct relationship with olfactory involvement.These pathophysiological mechanisms explain the results found by Zelada-rios et al.
https://www.nucleodoconhecimento.com.br81 RC: 101554 Disponível em: https://www.nucleodoconhecimento.com.br/lei/pedido-generico would be between 33 and 41 years old (Zelada-Rios et al., 2021), this fact was explained by the higher frequency of cases of COVID-19 in the elderly population and the influence of infection severity on the development of ADEM.Furthermore, Manzano et al. (2021) found a relationship between the development of ADEM and Acute Hemorrhagic Leukoencephalitis (AHLE) after SARS-COV-2 infection.Thus, with respect to time, the development of ADEM and AHLE occurred within 15 to 30 days, with encephalopathy (confusion, lethargy and difficulty waking up after sedation), focal motor, focal sensory, cranial, cerebellar and of seizure the main neurological signs and symptoms.Thus, it was evidenced that post-COVID-19 ADEM cases share several symptoms of the classic model, with the following differences: onset of COVID-19 and ADEM symptoms (25 days post-COVID-19 and 7-14 days in the classic), more advanced age distribution of patients (median of 44 years in post-COVID-19 and more commonly in children in the classic), lower recovery rate, distribution of the most frequent brain lesions in the periventricular white matter and corpus callosum and lower frequency of lesions in the deep substantia nigra https://www.nucleodoconhecimento.com.br82 RC: 101554 Disponível em: https://www.nucleodoconhecimento.com.br/lei/pedido-generico and goiter.The lack of specificity of the clinical picture makes diagnosis difficult in the initial course of COVID-19, corroborating the findings that 16 of the 17 cases found by Christensen et al. (2022) were diagnosed at times when the patient no longer had respiratory symptoms, much less Systemic Inflammatory Response Syndrome (SIRS).In this case, the mechanism of how SAT is triggered by the Sars-Cov-2 virus is not yet known.Lastly, Siamak et al. (2021) presented satisfactory results on the relationship between low levels of vitamin D and worsening of COVID-19 infection.In this study, patients were divided into groups of vitamin D deficiency, insufficiency and sufficiency.A https://www.nucleodoconhecimento.com.br83 RC: 101554 Disponível em: https://www.nucleodoconhecimento.com.br/lei/pedido-genericoyears.This practice should aim to create effective protocols for diagnosing patients who acquired COVID-19 and were left with sequelae.https://www.nucleodoconhecimento.com.br85 RC: 101554 Disponível em: https://www.nucleodoconhecimento.com.br/lei/pedido-genericoMANZANO, Giovanna S. et al.Acute disseminated encephalomyelitis and acute hemorrhagic leukoencephalitis following COVID-19: systematic review and meta-synthesis.Neurology-Neuroimmunology Neuroinflammation, v. 8, n.6, 2021.MARTÍN-GARRIDO, I.; MEDRANO-ORTEGA, F. J. Beyond acute SARS-CoV-2 infection: A new challenge for Internal Medicine.Revista Clínica Española (English Edition), 2022.MERCOLA, Joseph; GRANT, William B.; WAGNER, Carol L. Evidence regarding vitamin D and risk of COVID-19 and its severity.Nutrients, v. 12, n. 11, p. 3361, 2020.MOHER, David et al.Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement.Annals of internal medicine, v. 151, n.