Relationship between obesity and the occurrence of negative outcome in patients hospitalized with COVID-19: integrative literature review

Objective: To verify the relationship between obesity and the occurrence of negative outcomes in hospitalized patients. Methodology: An integrative review was carried out using the National Library of Medicine of the National Institutes of Health (PubMed) and the Virtual Health Library (VLH/BVS) database. Results: It was observed that obese patients are 2 to 5 times more likely to need Invasive Mechanical Ventilation (IMV) when admitted to the Intensive Care Unit. Patients with high BMI (obese) and who needed mechanical ventilation had a mortality rate above 60%. The risk increases as the patient has other pathologies, this fact is shown that mortality by COVID-19 has multifactorial causes. Conclusion: The study showed that obesity is a risk factor associated with the increased development of the severe form of the disease, usually associated with other pathologies (hypertension, diabetes and cardiovascular diseases). That is, obesity increases the likelihood of unfavorable outcomes.


Introduction
In Wuhan, China, at the end of 2019 was observed a series of cases of a new virus that caused respiratory infections.
Since then the SARS-CoV-2 (new coronavirus), according to the data released by World Health Organisation, already infected over 215 millions people around the world, what has already resulted in 4,48 millions of deaths. In Brazil, according to the data released by Brazilian government, it's 578.326 deaths already, reaching a 2.8% death rate. (OMS, 2021;BRASIL, 2020) The new coronavirus possess an single-stranded RNA enveloped and the transmission is realized human by human, although in China the bats were stablished as an important reservoir of the virus. The most common clinic symptoms are: fever and cough; but can include dyspnea, headache, muscle pain and fatigue. Is estimated that 20% of the cases are serious, with a 3% death rate. The COVID-19's complications (respiratory failure, acute respiratory distress syndrome (ARDS), sepsis, septic shock, thromboembolism, and/or multiple organ failure), happens mainly in patients with comorbidities such as hypertension, obesity, diabetes, cardiovascular disease, chronic lung disease, among others. (Hu et al., 2017;Wang, Tang, Wei, 2020;Wang, Horby, Hayden, Gao; The (re) emergence of the virus has caused several impacts in many areas of society, such as economy and education, but mostly in the health area. The most critical structural limitation during the pandemic in the country was the low number of ICU beds and mechanical fans needed to deal with the serious cases of the disease, furthermore there were difficulties in the acquisitions of the medicines (sedatives, neuromuscular and cardiotonic blockers), as well as the rising of the prices, with and increase up to 200% in relation to the usual price. The State University of Campinas estimates that an implantation of an ICU bed is something around R$ 180.000,00, and the daily cost of it is between R$ 2.500,00 and R$ 3.000,00. (UNICAMP, 2020;Paiva, et al,. 2020;Holanda & Pinheiro, 2020;Saraiva, et al., 2020) Given that the damages caused to the patient health and the financial impact related to the treatment of serious cases, it's necessary the identification of the predictive risk factors to the development of the severe stage of the disease. Between the factors we can highlight obesity, given that results between other things in a disregulated immune answer, through the increasing of inflamatory cells, for exemple, impacting among other things the pulmonary functions. (Kulcsar et al, 2019;Dixon et al, 2018).
Being the obesity a prevalent desease in the world population, the information about the impact of this risk factor as for the negative outcome of the desease, could be a great value for the directing of the clinic decision, as the rationing of the resources and consequently a reduction of the costs related to this assistance. In this way, the objective of this integrative revision is to verify the relation between obesity and the occurrencies of negative outcome in hospitalized patients.

Methods
This work is an integrative review based on the research question: "What is the relationship between obesity and the occurrence of negative outcomes in patients hospitalized for COVID-19?". This was delimited by the PICO strategy (acronym for Patient, Intervention, Comparison, Results). The steps taken in preparing the study were: elaboration of the research question, sampling or search in the literature of primary studies, data extraction, evaluation of primary studies, interpretation of results, presentation of the review.
The primary studies were searched from january to 2021, in the following databases: National Library of Medicine of the National Institutes of Health (PubMed) and Virtual Health Library (VLH / BVS).
The controlled descriptors selected in the Health Sciences Descriptors (HSD) of the Virtual Health Library (VLH / BVS) and HSD in PubMed were "Obesity, CoronavirusInfections, Hospitalization, Mortality, Intensive Care Units, Respiration, Artificial" (in English). The descriptors were combined using the Boolean operators, which obtained the following searches: "Obesity AND CoronavirusInfections AND Hospitalization AND Mortality OR Intensive Care Units OR Respiration, Artificial".
The inclusion criteria were articles whose main and / or secondary objective was to verify and/or establish the correlation between obesity and negative outcomes in patients hospitalized with COVID-19. Regarding the period, foram selecionados artigos publicados no ano de 2020. The search was conducted in Portuguese, Spanish and English. The exclusion criteria were: studies carried out in emergency rooms and outpatient services in hospitals, case reports and studies, pregnant and pediatric patients.
The choice of articles was divided into three stages: 1) Search for articles using descriptors in the databases, filtering the period.
2) Reading of titles and abstracts by two independent reviewers who decided to include or exclude the article. In case of disagreement, a third reviewer was invited.
3) Reading of the articles in full by the reviewers, in order to identify whether the article answered the proposed question.
Articles were identified in the four databases. After applying the criteria, 308 articles were excluded, for the following reasons: Duplicates (136), Secondary Studies and / or Case Report (12), No Answer To The Proposed Questions (83), Studies in Outpatients (16) and studies with pregnant women and pediatric patients (22). Thus, 39 articles were qualified for this review.

Results
The information extracted from the primary studies included in the review is shown in Table 1. Research, Society and Development, v. 10, n. 13, e165101321038, 2021 (CC BY 4.0)  Descriptive study, with reduced sample size, and non-differentiation of BMI calculation between adipose and muscle tissue. Research, Society and Development, v. 10, n. 13, e165101321038, 2021 (CC BY 4.0)  Obesity was related to admission to the ICU, but it was not related to death from COVID-19.
Patients who were referred to the ICU, but who were not admitted due to wear and tear on the healthcare system.
Among the observed data shown in the table above, there is a prevalence of males (77%) with an average age of 61 years, demonstrating that this is an elderly population. When evaluating the incidence of obese patients hospitalized by Covid-19, the mean was 33%, compared to obese patients who required Invasive Mechanical Ventilation (IMV) it was approximately 37%.

Discussion
The surveys carried out in the USA corresponded to 37.5% (15) of the studies included in this review, while 35.89% (14) studies were carried out in European countries. Although Vasconcelos et al., (2020) demonstrate that China stood out in scientific production related to COVID-19, presenting the largest number of publications related to the topic in 2019 and 2020, the leading role of obesity-related research in the US may be a reflection of the high incidence of this comorbidity, being present in 35% of the North American population, as described by De Sousa et al., (2008). Thus, there was greater concern about the implications of the correlation between obesity and the occurrence of COVID-19 in the context of the pandemic.
Regarding the adopted methodology, 89.7% (35) of the studies were carried out through retrospective data review.
According to Fernandes et al, (2005), among the weaknesses/limitations of this type of study there is the information bias and the inability to control confounding variables (lack of information), this fact corroborates the data collected from the studies in this review where the potential or the real lack of information was one of the points most evident as limitations in the studies, along with the sample size and the difficulty of measuring outcomes in a pandemic scenario.
There was great variation in the number of patients in the populations studied, with samples ranging from 53 to 89,450 participants, with an average of 3864 participants per survey. Regarding the characteristics of the population, the average age was 61 years among the studies, this information was not found in 04 studies. The prevalence of older adults in the samples is evident, which according to the authors may also have corroborated for the outcomes. Matsudo et al, 2000 says that there is evidence in the literature that aging brings neuromotor, metabolic and anthropometric variations to the population.
In the studies analyzed, there was a prevalence of males in 77% (30) of the researches, only 01 article did not take gender into account. This is consistent with some studies that confirmed that men have characteristics that enhance the disease, due to greater disregard for health and low use of primary and secondary care, being at greater risk of clinical decompensation (Camarano, 2002;Almeida et al., 2015).
For the definition of obesity, the classification proposed by the WHO was used, in which the BMI that determines obesity is above 30kg/m3. It was possible to identify the information on the prevalence of obesity in 37 studies, 01 there was no information on the number of obese patients in relation to the population studied, and in another study, the BMI value >24kg/m² was considered for statistical analysis purposes. That would fit the overweight classification, according to the WHO. The percentage incidence of obese patients hospitalized by Covid in the extracted data ranged from 0.7% to 81%, with a mean of 33%. Even before the new coronavirus pandemic, obesity was already considered a global challenge, however, with the restrictions established by governments and health promotion/protection entities that aimed to reduce the circulation of the virus, there was na increase in the sedentary and weight gain (Posso et al., 2020).
Insulin resistance, changes in metabolism, hyperglycemia, and increased inflammatory markers are just some of the changes Obesity itself is a metabolic entity characterized by changes related to its occurrence. This, combined with vascular and pulmonary alterations, as well as the increased expression of the angiotensin 2 converting enzyme, and the adipose tissue itself, which can behave as a means for intense viral replication, thus creating na exacerbated immune response, make this comorbidity na important predictive and prognostic factor for understanding the course of the disease and its severity (Saryer et al., 2020;Guzik et al., 2020;Shah et al., 2021).
Of the evaluated articles, 23 brought data from obese patients who had severe complications, some of them evaluating more than one outcome: invasive mechanical ventilation (IMV) (n 9) and/or admission to the intensive care unit (n 9) and/or occurrence of severe pneumonia (n 2), or only outcomes defined as severe (n 3). The percentage of obese hospitalized patients who required IMV ranged from 15.7 to 64.1%, with na average of approximately 37%, while the percentage of obese patients with covid who were admitted to the ICU ranged from 17.9% to 62, 5% with na average of 41%.
And the relationship between obesity and mortality was assessed in 24 articles, with a death rate ranging from 9% to 65.7%, with a mean death rate of 29.7%. It is worth noting that among the articles mentioned, there were 02 (two) studies that showed the relationship between obesity and the IMV and mortality outcomes, stratifying by degree of obesity according to the WHO classification, in these it was shown that the greater the degree of obesity, the higher the percentage of patients who evolve with IMV and death.
Regarding statistical associations (odds ratio, relative risk and hazard ratio), 06 (six) studies evaluated the correlation between obesity and IMV in 100% of them there was a statistical correlation, which showed that obese patients are 2 to 5 times more likely to need VMI. When the outcome evaluated was admission to the ICU, in all 06 (six) articles that evaluated this outcome, there was a positive correlation, as the occurrence of obesity makes the patient with COVID 1.5 to 4.7 times more likely to be admitted to the intensive care unit. In one of the studies where there was stratification by race, only obese blacks were associated with intensive care. The occurrence of death in obese patients was evaluated in 29 articles, of which 17 (58.6%) showed a significant correlation between obesity and increased mortality, one of the studies showed na 8fold increase in the chances of death in obese patients.
Some studies report that when considering a scenario of mechanical ventilation, obese patients would be subject to longer periods of intubation, greater difficulty in weaning from mechanical ventilation and handling by professionals in nonspecialized health centers, factors that could contribute for unfavorable outcomes (Severin et al., 2020;Stefan et al., 2020). Muscogiuri et al., (2020), points out that patients with COVID with a BMI value above 30 kg / m² and who were referred for mechanical ventilation had a mortality rate of 60.9%. Furthermore, it was also observed that the recommendation and need for mechanical ventilation increased with the degree of obesity, which may explain the variability between studies. In addition, it is difficult to obtain the patients' BMI data, since most of the time this value is obtained in na estimated way during hospitalization.
In the study by Thomsom et al. (2020), the absence and unclear criteria for admission to the intensive care units (ICU) would be a confounding factor in the analysis of admitted patients. In this regard, some scores created to assess hospitalized patients with COVID are already available, which aim to identify those who need intensive support in less time, helping clinical decision-making in a stressful and low-resource context Kumar et al., 2020) Louie et al. (2011) and Dawood et al. (2009) reported during the H1N1 influenza epidemic a large proportion of hospital admissions and mortality were associated with obesity, and now a growing number of studies suggest that the outcomes of obese patients are worse compared to non-obese patients. Obese individuals who became infected with the coronavirus. It is a fact that mortality from COVID has multifactorial causes, among which we can highlight: diabetes, cardiovascular, cerebrovascular, pulmonary diseases and advanced age are some of the predictors already identified (Muscogiuri et al., 2020;Li et al., 2020;Du et al., 2020;Kang et al., 2020;Ruan et al., 2020;Grasselli et al., 2020).

Conclusion
According to the studies analyzed, they showed that obesity increases the incidence of unfavorable outcomes, such as increased ICU admission, increased intubation and invasive mechanical ventilation, that is, obesity is a risk factor for the development of the severe form of the disease. The findings of this study also concluded that mortality was associated in 50% of the studies. It is important to mention that obesity is usually associated with several other pathologies, such as: hypertension, diabetes and cardiovascular diseases, which are also a risk factor for the development of the severe form of COVID -19. Therefore, there is a need for studies that seek to correlate to which dangers obese individuals and those with comorbidities are exposed.