Comprehensive approach, basic-clinical-psychosocial, for respiratory diseases (SARS-CoV-2 model)

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'''Comprehensive approach (basic-clinical-psychosocial)'''</div>

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'''for respiratory diseases (SARS-CoV-2 model)'''</div>

'''Natalia Andrea Arbeláez-Alvarez<sup>1,4</sup>, Sandra Constanza Cañón-Buitrago<sup>1,2</sup>, Paula Tatiana Uribe-Echeverry<sup>1,3</sup>, Juan Carlos Carmona-Hernandez<sup>1,4*</sup>'''

<sup>1</sup>Grupo de Investigación Médica, Universidad de Manizales, Facultad Ciencias de la Salud, e-mail: [mailto:narbelaez57263@umanizales.edu.co narbelaez57263@umanizales.edu.co]

<sup>2</sup>Línea de Investigación Salud Mental y Suicidio, e-mail: [mailto:sandraka@umanizales.edu.co sandraka@umanizales.edu.co]

<sup>3</sup>Línea de Investigación Biología Molecular y Genética, e-mail: [mailto:puribe@umanizales.edu.co puribe@umanizales.edu.co]

<sup>4</sup>Línea de Investigación Metabolismo-Nutrición-Polifenoles (MeNutrO)

'''<sup>*</sup>Correspondence''': Juan Carlos Carmona-Hernandez; Universidad de Manizales, Carrera 9 # 19-03, Manizales 170001, Phone number: +57 300 586 8133. Colombia. E-mail: jucaca[mailto:@umanizales.edu.co @umanizales.edu.co]
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==Abstract==

Clinical manifestations in patients affected by severe acute respiratory syndrome coronavirus 2 have been reported and its management has been suggested and followed by different international protocols. Due to the nature of the pandemic, the World Health Organization was active from the beginning of the epidemiological event and the different national entities throughout the world shared success stories in relation to treatment. Considering diagnostic and treatment tools, not only for this viral manifestation in the world, it is advisable to make a comprehensive evaluation of the challenge faced by health administration entities. The study and management of the medical event from different fields of knowledge offers a greater number of possibilities in the health management system, which can lead to a more efficient treatment of the disease. This review is highlights the importance of the analysis of SARS-CoV-2, focused on clinical, molecular and psychosocial aspects. With the search equations developed in different databases and search engines, more than 1,450 documents were found that had common characteristics. With the use of delimitation tools, 47 documents were analyzed and reported, highlighting the importance of a multidimensional analysis of an epidemiological event.

'''Keywords''': SARS-CoV-2; Inflammatory markers; Anxiety-Depression

==Introduction==

The impact of SARS-(Severe Acute Respiratory Syndrome)-CoV-2 has been established among the most notorious pandemics ever recorded in human history, with almost 115 million confirmed cases and more than 2.56 million deaths. since March 2021 (1, 2). The World Health Organization (WHO) estimated, for Colombia, that treatment would be required for nearly 500,000 patients, which would probably collapse the national hospital infrastructure (3). The reports of SARS-CoV-2 in Colombia (cases: 4,903,304, deaths: 124,743, new cases: 2,141 and new deaths: 95), evidenced an urgent need to appease and control the pandemic situation (2). Therefore, greater understanding of the molecular behavior and biopsychosocial impact of the virus, of the interactions between the host and the pathogen were needed to help identifying reliable and effective strategies for diagnosis, control, and treatment and to prevent the spread of the infection (1, 4). This review seeks to highlight molecular aspects of SARS-CoV-2 to correlate them with basic-clinical aspects from a multidisciplinary approach (Molecular Biology, Clinical and Psychosocial), as well as visualize the social impact of the pandemic, as a basis for understanding the dynamics of future outbreaks and develop informed strategies to treat, control and prevent these types of diseases and other epidemiological events.

==Method==

A basic search and reading of academic information was carried out to identify the feasibility, to know and to interpret what type of information would be in the scope of the research and size the problem. Subsequently, an advanced search of the information was carried out using the bibliographic sources Elsevier, Nature, Up to date, PubMed, Google Scholar, MEDLINE, Embase and Web of Science. The advanced inquiry was based on search equations which included, connected and excluded terms of interest for the literature review such as: COVID-19, immunology, diagnosis and clinical treatment. For the construction of the search equations, advice was obtained from the resources area of the library of the University of Manizales. Search equations were used such as: “COVID 19 AND inflammatory markers”, “COVID 19 AND immunology”, “cell OR animal, diagnoses AND COVID 19”, “COVID 19 AND sequencing”, “origin AND COVID 19 AND Hubei”, “AND COVID 19”, “clinical treatment AND COVID 19”, “suicide AND COVID 19 AND isolation”, and finally “COVID 19 AND bioethics”.

==Results==

The search returned 1,458 results; scientific publications were included from January 1, 2019 to December 10, 2023. Only publications that focused on the molecular, immunological, psychosocial, and clinical characteristics for SARS-CoV-2 were considered. Reference lists of relevant studies were examined to identify missing publications. In total 47 bibliographic references were considered potentially eligible; they were recovered for full text review. Search results were limited to publications in Spanish, Portuguese and English. Conference abstracts and commentaries were excluded.

==Generalities==

Coronaviruses (CoV) are a diverse group of single-stranded RNA viruses that infect various vertebrates; these were detected in humans in the 1960s (5). CoVs cause upper respiratory tract diseases (6). At the beginning of the 21st century, new infections caused by zoonotic transmission of highly pathogenic strains of beta coronavirus begin to emerge. The first severe acute respiratory syndrome virus (SARS-CoV-1) was detected in 2002 and the Middle East respiratory syndrome-related coronavirus (MERS-CoV) in 2012, both showing high mortality with 10% and 34% respectively (6, 7). SARS-CoV-2 is a new betacoronavirus, similar to SARS-CoV-1, that emerged at the end of 2019 in Hubei Province in China (8). It is the cause of coronavirus disease 2019 (COVID-19), which generated multisystem compromises in millions of patients (4).

By March 11, 2020, SARS-CoV-2 had infected more than 100,000 people in more than 100 countries around the world and caused 4,000 deaths (9). The World Health Organization declared the situation a pandemic, the first in history due to a coronavirus (10). Since then, infections have grown exponentially in different countries and continents, largely due to increasing globalization and rapid international travel. The WHO epidemiological reports showed globally: Total cases: 83,424,394, total deaths: 2,096,353, new cases: 68,695 and new deaths: 2,092. The situation at the department of Caldas/Colombia (Date: 2021-08-21, total cases: 99,509, total deaths: 2,219, total new cases: 47, total new deaths evidencing the impact generated by the pandemic (2). The community also expressed consequences at a socioeconomic level due to the numerous absences from work, schools closing and less employment opportunities. Due to COVID-19 or preventive isolation, and in the psychosocial field due to the impact generated by the loss of a loved one, the possibility of presenting the disease in a severe form or even dying, also due to social isolation and the new functioning of the world (9). The ability to quickly control the pandemic from its beginning was limited by factors, such as the lack of detailed knowledge of the biology of SARS-CoV-2 and the host, the poor diagnosis and rapid identification of cases, and the lack of treatments. clearly effective (5).

==SARS-COV-2 approach from the perspective of molecular biology==

A novel coronavirus (CoV) began circulating in Wuhan City, Hubei province, China, around December 2019 in patients who had been possibly exposed to foodborne transmission from wild animals (3, 11). Initially, the impact of the virus on humans was not well understood (6). The virus was isolated, identified and sequenced on 01/05/2020, from a hospitalized patient in Wuhan<sup>10</sup>. The coronaviruses that have caused epidemic and pandemic outbreaks of respiratory disease, including SARS, MERS, and COVID-19, in human populations belong to a subgroup of ''Betacoronaviruses'' known as ''Sarbecoviruses ''(1). Members of this group of coronaviruses are abundant in bats, pangolins, and other mammals (12). As these species harbor different coronaviruses and have close contacts with each other, frequent recombination can be experienced even between different strains, leading to diversification and easy possibility of infection to humans (13).

In infected human samples, one study found that more than 60% of all transcriptomes were of viral origin, demonstrating the overwhelming alteration of SARS-CoV-2 cell biology upon infection of human cells. The genetic material of SARS-CoV-2 is of the RNA type; the genome is composed of a single, non-segmented strand of positive polarity (+ssRNA) with a size of 29,903 kilobases (14). Regarding its dimensions, it is reported that the diameter of this type of virus varies between 80-120 nanometers (15). The virus encodes four structural proteins: The spicula (S) protein gives the virus its characteristic crown appearance and is very important in its pathogenesis, as it contains the binding domain for the cellular receptor, angiotensin-converting enzyme 2 (ACE2), present in human host cells, the envelope protein, the membrane protein, and the nucleocapsid protein (16).

In a study, complete genome sequences of SARS-CoV-2 were obtained in five patients in the early phase of the outbreak, which were reported as almost identical, sharing a sequence similarity of 79.6% with SARS-CoV-1, and from 96% with the complete genome to that of a bat coronavirus sequenced in 2013 (17). But a change in a base pair led to the amino acid being changed, therefore, the protein and biochemical behavior of the virus changed. Molecular evolutionary analyzes of the SARS-CoV-2 reference genome indicated that it originated from virus reservoirs in nonhuman mammals, such as bats, through recombination and purifying selection (6).

Among the problems that arose with SARS-CoV-2, one of the most relevant was the presentation of several variants circulating worldwide. Some had mutations in the surface spike protein, which mediates viral binding to human cells and is a target of natural and vaccine-induced immunity since the first sequenced mutation (D614G) was presented in Africa (14, 18). This fact set off alarm bells, since it was clear that the variants represented anomalous behavior, more virulent, pathogenic and with the ability to evade the immune response, especially innate immunity (18). This variant showed that they were going to have a challenge to control and appease the pandemic with vaccination. Currently more variants have been generated among the most relevant are B.1.1.7 (Alpha) lineage, known as 20I/ 501Y.V1. first identified in the United Kingdom in late 2020 and B.1.617.2 (Delta) lineage, known as 20A/S:478K, identified in India in late 2020 (19).

From a previous study, it was stated that the fact of presenting infection with endemic coronaviruses, prior to SARS-CoV-2, showed a decrease in severity, which became a central axis for continuing with vaccination (20). It should be noted that what allowed the rapid development of the vaccine for SARS-CoV-2 was the previous experience with SARS-CoV-1 and that when evaluating the efficacy, not only the antibodies had to be taken into account. These antibodies decrease over time, as do immunoglobulins A, but cellular immunity that interferes with different epitopes and is given by CD4 and CD8 lymphocytes is maintained (21). The only way to be prepared for variants was to perform sequenced genomic surveillance to quickly identify them and take preventive measures. In Colombia this work was slow due to the availability of sequencing, having a total of 1,446 compared to other countries that had, at the time, more than 100,000 sequencing, as was the case of China (22).

==SARS-COV-2 approach from a clinical perspective==

The early recognition of infection in suspected SARS-CoV-2 patients allowed the timely initiation of appropriate prevention and control measures (13). The typical clinical symptoms of these patients were fever, dry cough, breathing difficulties (dyspnea), headache and pneumonia (17). The initial guidelines of the National Institute of Health of Colombia established, the presence of fever as a necessary condition to assume infection by SARS-CoV-2/COVID-19, sufficient evidence showed that in up to 10% of cases, the infection (3). It could occur without fever, however, in most cases patients presented a clinical syndrome similar to influenza. For these reasons, it was useful for the clinician to consider the infection with two or more suggestive symptoms of respiratory infection. Additionally, the presence ageusia or anosmia was reported as frequent (33.9%) (3).

It is necessary to remember that up to 17% of COVID-19 cases presented relevant gastrointestinal symptoms (diarrhea as the most frequent symptom and less frequently abdominal pain and emesis). The findings in the most severe cases, such as: the persistence of respiratory symptoms for a period of more than eight days or their tendency to worsen, contributed efficiently to the diagnosis (8, 15). The suspicion of COVID-19 increased if the individual reported close contact with people suspected or with confirmed infection as established by the Colombian National Institute of Health (23).

The most common diagnosis in patients with SARS-CoV-2/COVID-19 was severe pneumonia (10). The risk factors for poor prognosis in patients with SARS-CoV-2/COVID-19 infection included people over 60 years of age, history of smoking, respiratory failure, pre-existing comorbidities such as cardiovascular diseases (mainly arterial hypertension 55.6%), diabetes, chronic respiratory diseases and cancer (24). Other risk factors are also included, such as asthma, kidney disease, autoimmune disease, hypothyroidism and malnutrition, which had not had a significant association (25). The main complications associated with the infection were acute respiratory deficiency syndrome, acute renal failure, myocardial and hepatic dysfunction, neurological alterations, additionally infections with special emphasis on pneumonia associated with mechanical or nosocomial ventilation (26, 27).

The diagnosis of COVID-19 was initially to confirm close contact with previously diagnosed patients, but, due to rapid spread, the National Health Commission of China formulated a diagnosis and treatment program for the new coronavirus pneumonia, on February 17, 2020 (28). The WHO accepted this diagnosis considering that the confirmation of viral pneumonia, through computed tomography, was evidence for the diagnosis of the infection only when it was accompanied by the confirmation of the presence of the virus, through the chain reaction reverse transcription polymerase (28). It was based on the fact that this is a highly sensitive molecular biology tool that allows analyzing the presence of RNA sequences with high specificity (29).

The tests that confirmed the presence of SARS-CoV-2 in human samples, from the upper or lower respiratory tract, were based on amplification of viral nucleic acids. In this case, a real-time PCR (RT-PCR), based on fluorescent TaqMan probes, since the first reported by Corman ''et al''. (2020) from the Charité Institute of Virology (Berlin, Germany) to those standardized in Thailand, Japan and China (25). Although there were several protocols, most countries implemented the protocol designed by the US Centers for Disease Control (8, 29, 30).

Therefore, it was important to integrate these paraclinical tests with PCR tests in patients with a high suspicion of infection and a moderate to severe stage of the disease. It was not recommended to diagnose SARS-CoV-2/COVID-19 solely with RT-PCR, nor for contact tracing (31). In patients with Covid-19, the stage cases were standardized as mild pneumonia, severe pneumonia, acute respiratory distress syndrome, sepsis and septic shock (32). For early detection, in the department of Caldas (Colombia), a protocol was established to increase sensitivity and specificity, based on three waves of PCR, ruling out the identification of the Spicula protein, because it was the one that acquired the most mutations over time. At the time, this protocol was based on identifying envelope protein E, DNA-dependent ribonucleases, nucleocapsid gene, and ribonuclease P, which is part of the non-structural proteins of the virus (33).

==SARS-COV-2 approach from a psychosocial perspective==

Beyond the health (biological-clinical) impact, the social consequences of the COVID-19 pandemic were dramatic (34). Social isolation was shown to severely affect the health of isolated individuals and was (and is currently still associated) with stress, anxiety, and mood disorders (35). The World Bank estimated that the number of people living below the international poverty lines, for low- and upper-middle-income countries (USD 3.20/day and USD 5.50/day respectively), would increase. Moreover, the WB highlighted that countries with high poverty and inequality figures would contribute the largest proportion of the new group of poor communities (15, 36).

Considering that the Latin America scenario is one of extremely complex and precarious political situations, with critical economic situations and marked gender inequalities; the arrival of the pandemic was an event that aggravated social inequalities and revealed its harshness and action. It generated social demand for change, for example, the massive demonstrations (riots) in Colombia in March 2021 (37). In Latin American countries the response to the health, social and economic crisis, generated by SARS-CoV-2, presented greater difficulties (38). Given predictions that the recession could be worse than the Great Financial Depression of the 1930s, if COVID-19 resulted in an equivalent financial crisis, suicide rates were expected to by 5% in middle- and high-income countries (34, 37).

Mental health conditions during pandemics have historically affected healthcare personnel; much of the burden falls on health systems, generating a lot of anxiety, stress and depression in health personnel (39). In order to evaluate mental health problems during the global crisis due to COVID 19, a study was carried out that included 1,257 health workers, doctors and nursing staff from 20 hospitals in Wuhan and 14 hospitals in other regions of China (40). It was reported that 50% of the participants presented depression, 45% anxiety, 34% insomnia and 72% anguish. It should be noted that these symptoms occurred with a greater degree of severity in personnel who were in primary care, diagnosis schemes, and treatment and follow-up of patients with confirmed or suspected SARS-CoV-2 infection (40). Symptoms increased and/or were exacerbated by the lack of availability of quality personal, protective equipment, burnout, fear of becoming infected or infection in their loved ones, and working in high-risk establishments (41).

Social distancing measures generated a positive impact by reducing the spread of the disease and preventing the chain of viral transmission, but it also generated fear, sleeping disorders, anxiety and gave rise to psychological dysregulations such as stress-related disorders (35). Preventive isolation led to an increase in gender violence, including feminicides, reaching high numbers in the countries of the Latin-American region (42). It is also noteworthy that virtual activities can (and did during the pandemic) help reduce the experience of loneliness, especially for vulnerable individuals such as children and adolescents. In times of the COVID-19, in Colombia, there was an incentive for social connection through virtual media within family groups and academic communities (43).

More than 50% of the world's COVID-19 cases were concentrated in Latin America; this region registered the highest fatality and mortality rates from the virus (44). This fact frames that when humanity faces communicable diseases, whether in the Middle Ages or in the current era, the most affected populations are the same, that is, those who live in conditions of poverty and marginalization leaving communities more exposed and more vulnerable to becoming infected, getting sick or dying. These inequalities are given by structural social conditions, such as the types of democracy, economy, and the ways in which power and resources are inefficiently distributed in the Latin American society, which became more acute during the pandemic (37, 38).

The experience facing the challenge of COVID-19 in Latin American health systems, characterized by their segmentation, fragmentation, inequalities in access, and inefficiencies in health care, increased the need to strengthen integrated and coordinated health systems, to mitigate the likelihood of adverse mental health outcomes and to control the increasing suicide mortality (39, 45). In the objective of consolidation health systems, a crucial aspect was the strengthening of primary health care and the implementation of vaccines (44).

This effort was required to demonstrate vaccines effectiveness facing ethical and credible discussions related mainly to the use and origin of the different vaccines that were being produced in different countries. A large part of the population was against vaccination due to lack of knowledge, safety and myths about them (46). Despite the efforts of science to obtain vaccines that contributed to controlling the devastating effects of SARS-CoV-2 new challenges arose, among them, the refusal of a part of the population to receive the vaccine (47). The multivariate model on vaccination acceptance showed different characteristics that predicted being or not in the group of undecided to receive the vaccination. They were: having a higher education level, being single, hearing negative information about the vaccine, hearing information about the safety of the vaccine and not knowing where the vaccines were applied (26).

==Discussion==

The current outpatient and health conditions in Colombia indicate the entrance to a new era in the research and treatment of SARS-CoV-2, which has been prolonged and was thought to be almost extinct. New studies and recommendations would benefit different communities if there was an integrated paradigm for the understanding of this and other diseases. Simple causal relationships between pathophysiology and symptoms that address and explain diseases and chronic health conditions, such as persistent SARS-CoV-2, are becoming increasingly urgent (48). It is also necessary to emphasize the dualistic understanding of physical versus mental illness and, likewise, incorporate existing knowledge about functional somatic symptoms to provide improved explanations and treatments (48). SARS-CoV-2 is such a complex disease that requires an evaluation with systemic thinking seeking to achieve true progress in understanding the pandemic at the population level, as well as at the level of individual pathology from different points of view and scientific approaches (49).

Patients, health professionals, and general public were (and are in a certain way at the present time) exposed to great psychological stress, developing various psychiatric symptoms and maladaptive responses, such as anxiety, fear, depression and insomnia (50).  Current knowledge and long-term intervention studies indicate that the biological aspects and clinical outcomes of SARS-CoV-2 infection are largely limited. Approaching the pandemic based only on lessons learned from previous outbreaks of infectious diseases and the biology of another corona virus represents the only basis for explaining aspects of public mental health in this pandemic. Besides that, the translation of therapeutic strategies that improve responses to confront stress could lighten the burden it produced (and currently causes). Longitudinal studies will be the basis for obtaining more information on the possible consequences and more effective integral treatment of the outbreak (50, 51).

From the above, it is highlighted that providing accurate information, professional advice and social support can significantly help address these post-pandemic problems (50). In addition, psychiatric and psychological services also play a fundamental role in the general control of the disease and suggest that the negative impact itself can last longer than the pandemic itself and its consequences. In a three-year follow-up study of the SARS outbreak in 2003, 23% of healthcare workers still reported moderate or major depressive symptoms (50).

Considering a more vulnerable population, it is emphasized that young people may experience not only short-term but also long-term consequences of the stressors of SARS-CoV-2 (51). The opening of cities and the uncontrolled restoration of some daily activities caused spikes in new cases, which also generates waves of expectations and frustration, especially among young people who do not know how to cope. It is necessary to underline the notorious urgency of psychological monitoring of children and adolescents in quarantine, hospitalization and prolonged medical treatment, especially for those who suffer domestic violence, which grow in the same proportion as unemployment, financial bankruptcy and social inequalities (51, 52).

Health authorities and the government must treat the post-pandemic effects as a public health problem and not as disease with short-lived results. However, more research investment is needed to evaluate the impact of the stressors of the SARS-CoV-2 pandemic on the developing brains of young people, so that mental health outcomes can be prevented or mitigated by offering integral support and/or appropriate treatment (53). The need to monitor these children, adolescents, and also, their families, and caregivers is also urgent in order to develop strategies to mitigate, in the long term, the effects of the recent pandemic and other long-term (or long treatment) diseases (51, 53).

==Conclusion==

Achieving a comprehensive knowledge (biological-clinical-psychosocial) about what has happened with the management of SARS-CoV-2 allows for a more efficient diagnosis and treatment of this and other epidemiological events. This was due to a lack of planning and organization in the initial control of the virus and allowed for uncontrolled transmission and spread. It is also relevant because future pandemics are almost inevitable and the preparation of health personnel is essential. The shortage in genomic surveillance, the lack of effective strategies at first-level hospitalization in Colombia shows that being a developing country leads to major problems managing future threats with a pandemic situation. Emerging variants cause the greatest source of concern due to current epidemiological data, vaccine development and antibodies and cellular immunity that are still unknown.

==Acknowledgments==

The authors appreciate the time and valuable contribution of the database advisory team and bibliographic managers of the library at University de Manizales (Caldas – Colombia).

==Funding None==

This research did not receive funding from agencies of any type or sector.

==Informed Consent Statement ==

No informed consent was required for this type of bibliographical research.

==Data Availability Statement ==

Data supporting the findings of this work will be upon request from the corresponding author.

==Conflicts of Interest ==

All authors declare no conflict of interest with any private or public institution.

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