Risk Factors Associated with Mortality in Patients with Covid-19 View PDF

The appearance of a new coronavirus disease in December 2019 (COVID-19) in the city of Wuhan, China, and its accelerated spread around the world, became a public health emergency in several countries and later on the 11 March 2020 was declared a pandemic by the World Health Organization (WHO), having to date (May 2021) more than 170 million infected and 3.53 million deaths. The family of coronaviruses is wide, but only three of them have caused outbreaks of diseases characterized by severe acute respiratory syndrome in humans: SARS-CoV in 2002 in Guangdong-China, MERS-CoV in 2012 in Saudi Arabia and lastly the SARS-CoV-2 in 2019 in Wuhan-China. Likewise, all three are highly pathogenic, however, SARS-CoV-2 is more transmissible than the rest [1].

The clinical characteristics of patients with COVID-19 are varied, from asymptomatic patients, through subjects with fever, non-productive cough, shortness of breath, muscle aches, fatigue, anosmia, ageusia and diarrhea, to more severe conditions such as insufficiency respiratory tract requiring admission to the intensive care unit (ICU) [2]. Although the majority of patients show mild symptoms, there is a small population that develops clinical manifestations of severity and complications that lead to fatal results. This depends on risk factors such as being male, being older than 60 years associated with the presence of comorbidities. Among the most frequent comorbidities observed in patients with COVID-19 are arterial hypertension, cardiovascular diseases, type 2 diabetes mellitus, chronic obstructive pulmonary disease (COPD), and obesity [3].

Acute respiratory distress syndrome (ARDS) was described as the main cause of death in severe patients with COVID-19, however, recent studies have explained that the excessively pro-inflammatory immune reaction called "cytokine storm" is the pathophysiological basis and that it predisposes to coagulopathies, venous thrombosis, and pulmonary embolism that ultimately lead to multi-organ failure. In relation to the above, altered values of inflammatory biomarkers and cell damage are identifiable risk factors that can help predict the clinical course of patients infected with the SARS-CoV-2 virus [4].

Taking into account the absence of a standardized treatment, the congestion of health systems and with the intention of improving triage and prioritizing the most vulnerable patients, the present article aims to carry out a review of the published bibliography on the factors of risk associated with mortality in patients with COVID-19.

In the present work of systematic review, articles in English and Spanish published from May 7, 2020 to April 28, 2021 on the search sites PubMed, Scielo and Google Scholar were used. The clinical question was used: What are the risk factors associated with mortality in patients with COVID-19? PEO question: Population: COVID-19 patients, Exposure: Risk factors, Result: Mortality. The keywords were: “coronavirus infections” (MeSH Term), in combination with “risk factors” and “mortality” (used in PubMed and Google Scholar); "Coronavirus infections" together with "COVID-19", "risk factors" and "mortality" (used in Scielo) (Annex 1). This work is in the health priorities "Communicable diseases: Respiratory infections and pneumonia", according to the "Health research priorities 2019-2023 of the National Institute of Health".

Inclusion criteria:

• Articles in Spanish or English published in the last 5 years that include any of the following keyword combinations in the title or abstract: Coronavirus or COVID-19 infections along with risk factors and mortality; "Coronavirus infections" together with "risk factors" and "mortality".
• Articles that analyze other non-communicable comorbidities as risk factors for mortality from COVID-19.
• Articles that analyze prognostic factors in conjunction with mortality from COVID-19.

Exclusion criteria:

• Protocols and preprints.
• Systematic reviews.
• Letters to the editor.
• Studies addressing COVID-19 treatments.
• Articles that are not directly related to the topic.

Of the 76 articles found, 22 articles were discarded because they did not meet our criteria for combinations of keywords in the title or in the abstract, and they were also withdrawn: 3 protocols, 8 preprints, 10 systematic reviews, 1 letter to the editor, 3 studies that addressed the treatment of COVID-19 and 10 articles for not having a direct relationship with the subject of review. A total of 57 articles were discarded, therefore 19 articles remained for this bibliographic review. Of the 19 articles chosen, all had research results to be analyzed and 4 additional review articles were considered for theoretical - conceptual aspects that are related to the objective of this study: Risk factors associated with mortality from COVID-19 infection (Figure 1).

19 studies were included for this study. Table 1 presents the main characteristics of the 19 selected studies, appreciating the publication period from 2020 to 2021. The studies were developed in people of different sexes, ages, countries, socioeconomic sectors and with different comorbidities. The samples were varied, showing a population of between 415,008 to 52 participants. Table 2 shows the importance, strength and weaknesses of the 14 selected studies, appreciating the period from 2020 to 2021.

Table 1: Titles, authors and design of research works related to risk factors associated with mortality in patients with COVID-19.

The prospective studies found the following:

Rutten JJS, et al. (2020) [5], Conducted a prospective cohort study with the objective of describing the symptoms and analyzing mortality in residents with clinical suspicion of COVID-19 and comparing them between the group of residents with confirmed COVID-19 with the group ruled out of COVID-19 by means of a TR-PCR test, in addition to analyzing risk factors for mortality in residents with confirmed COVID-19. Residents with a clinical suspicion of COVID-19 based on medical evaluation with RT-PCR results were included and residents who did not have a diagnosis of COVID-19 available from March 18 to May 13, 2020 were excluded. of the final study was 4007 residents, of which 1,538 were confirmed cases of COVID-19 and 2,469 were discarded. The results showed that 42% of the COVID-19 + residents died in 30 days (95% CI 39% -44%) versus 15% of the COVID-19 residents - (95% CI 14% -17% ), in addition, COVID-19 + residents were 3 times more likely to die within 30 days than COVID-19 residents - [Adjusted relative risk 3.14, 95% CI 2.7-3.6; P <.001]. Of the men with COVID-19 +, 52% died within 30 days (95% CI 48% -56%) versus 36% of women with COVID-19 + (95% CI 33% -39%); dementia, decreased kidney function, and Parkinson's disease were all associated with a high mortality rate in residents with COVID-19 +. In conclusion, the mortality rate in residents with confirmed COVID-19 was 3 times higher, also COVID-19 disproportionately affects men and mortality was almost double for men than for women [5].

The cohort study, divided into derivation cohorts and validation cohorts by Bertsimas D, et al. (2020) [6], Aims to develop and validate the personalized mortality risk calculator for hospitalized patients with COVID-19. The study comprises 33 different hospitals in southern Europe and the United States, considering a sample of 3,062 patients consisting of adult patients who were admitted to the hospital with a SARS-CoV-2 infection confirmed by the chain reaction test. polymerase (PCR) of nasopharyngeal samples. 22 characteristics were collected that included patient demographic information, comorbidities, vital signs on admission, and laboratory results. Risk factors that were not systematically recorded were excluded, omitting characteristics whose values are missing more than 40%. The results show that, compared to survivors, non-survivors tend to be older (mean age 80 vs. 64) and more commonly male (62.7% vs. 58.4%), in addition to the prevalence of comorbidities such as cardiac arrhythmias, chronic kidney disease and diabetes are higher in non-survivors (9.61%, 4.21% and 15.62% vs. 5.56%, 1.74% and 11.42%, respectively). On the other hand, when the BUN is above 25 mg / dL in elderly patients, the risk of death increases; C-reactive protein (CRP) above 160 mg / L, the high risk does not change and is higher in the elderly; an oxygen saturation below 93% increases the risk of mortality rapidly and tends to accelerate the older one is; serum glucose levels above 180 mg / dL increase the risk, particularly in the elderly; an aspartate aminotransferase (AST) at levels above 65 U / L increases the risk; a platelet count below 50 x 103 / uL increases the risk, between 50 x 103 / uL and 180 x 103 / uL the risk is slightly elevated (more for the elderly); the mean corpuscular volume (MCV) between 90 and 94 fL increases the risk moderately and the risk is increased when the leukocyte count is above 10 x 103 / uL, generally in the elderly. In conclusion, the mortality risk calculator for COVID-19 is highly accurate for hospitalized patients confirmed with COVID-19 [6].

The study carried out by Alizadehsani R, et al. (2020) [7], With a prospective design, sought to analyze risk factors and clinical outcomes to identify critically ill patients, provide correct treatment, and prevent mortality. With a sample of 319 patients with flu symptoms recruited from March 3, 2020 to April 8, 2020 during the COVID-19 pandemic, 32 symptoms were selected including fever (p = 1.99E-12), dyspnea ( p = 2.99E-11), weakness (p = 3.16E-11), tremors (p = 1.01E-09), fatigue (p = 6.60E-09), dry cough (p = 9.53E-09), anorexia (p = 1.68E-08), anosmia (p = 5.46E-08), ageusia (p = 1.19E-07), dizziness (p = 2.10E-05) and sweating (p = 2.15E-05). The results showed a significant association between old age (p = 2.82E-05), history of heart disease (p = .00654) and history of cancer (p = .012863) and mortality from COVID-19 compared to healthy subjects; blood group O + showed protective characteristics against mortality from COVID-19 (p = .0057); Regarding symptoms, anosmia (p = .010612), dry cough (p = .011324), ageusia (p = .011741), fever (p = .024933) and anorexia (p = .038981) are significantly related to COVID -19 regarding mortality compared to healthy subjects. In conclusion, age, blood type O +, heart disease, anosmia, and dry cough are the most crucial factors in patient mortality [7].

Cortés-Tellés A, et al. (2020) [8] Conducted a single-center, observational, and ambispective cohort study to identify risk factors associated with mortality and outcomes in hospitalized Mexican patients with COVID-19. They included 200 patients between March 28 and June 30, 2020 who were admitted with an acute respiratory illness and were diagnosed with COVID-19, collected information about age, sex, medical history and symptoms from inception to hospital admission, Furthermore, mortality was defined as survivors and non-survivors at the time of the analysis. The results show that there was a general mortality rate of 82.5%, of which 32 patients (72.7%) died in the ICU compared to 39 patients (92.7%) who died in a different area of the hospital; Compared to survivors, non-survivors of COVID-19 had a high proportion of patients older than 65 years (43% vs 18%, p <0.001); Compared to survivors, non-survivors had a significant increase in heart rate (107 vs 98, p = 0.022) and respiratory rate (30 vs 28, p = 0.003), a low baseline oxygen saturation (SpO2) (73 % vs 89%, p <0.001) and SpO2 / FiO2 (348 vs 424, p <0.001), in addition, mortality in non-survivors who did not receive ICU care was higher (92.8% vs 72.7%, p = 0.014); compared to survivors, leukocyte levels (13.1 vs 9.4, p <0.001), neutrophil-lymphocyte ratio (RNL; 12.3 vs 6.3, p <0.001), procalcitonin (0.47 ng / mL vs 0.14 ng / mL, p <0.001) and C-reactive protein (203 ng / L vs 128 ng / L, p <0.001) were significantly higher in the group of non-survivors; D-dimer levels were double in non-survivors (1,025 ng / mL vs 505 ng / mL, p = 0.002); basal glucose, CK, CK-MB, highly sensitive troponin-T, and lactate dehydrogenase (LDH) were markedly higher in non-survivors; in the group of non-survivors, the absolute lymphocyte count was lower (0.9 vs 1.1, p = 0.021), as was the lymphocyte-CRP ratio (4.4 vs 9.0, p <0.001), total proteins and serum albumin (2.9 g / dL vs 3.5 g / dL, p <0.001) than in the group of survivors; In addition, the survivors had more signs and symptoms of the disease, although the non-survivors showed higher intensity. In conclusion, the findings found may be useful for decisions to be made to improve outcomes and prognosis with COVID-19 [8].

The objective of the study carried out by R-H Du and collaborators of the single-center case cohort type was to search for and identify the clinical and laboratory parameters associated with mortality in patients with COVID-19. 179 patients were recruited between December 25, 2019 and February 7, 2020, who were hospitalized with a probable and confirmed diagnosis of COVID-19 at the Wuhan Pulmonary Hospital. The results showed that 21 patients (11.7%) worsened in a short period of time and died of multiple organ failure, especially respiratory failure and heart failure, and the average duration from admission to death was 13.7 ± 8.3 days (range of 3-33 days); the patients who died were much older than the surviving group (70.2 ± 7.7 years vs 56.0 ± 13.5 years; p <0.001); In the group of deceased, more patients had hypertension (61.9% vs 28.5%; p = 0.005) and cardiovascular or cerebrovascular disease (57.1% vs 10.8%; p <0.001); dyspnea, fatigue, sputum production and headache were more frequent in the deceased than in the survivors (85.7% vs 44.9% (p <0.001), 61.9% vs 36.7% (p = 0.033), 57.1% vs 27.2% ( p = 0.010) and 23.8% vs 7.6% (p = 0.033), respectively); deceased patients had a higher respiratory rate than survivors (p = 0.016); the deceased had more leukocytes and neutrophils than the survivors; the deceased had decreased lymphocytes compared to the survivors; Furthermore, the analysis revealed that age 65 years, CD3 + CD8 + T cell ?75 cellsxμL − 1, cardiac troponin I ?0.05 ngxmL − 1, myoglobin> 100 ngxL − 1, creatinine ?133 μmolxL − 1, D-dimer ?0.5 mgxL− 1 and PaO2 <60 mmHg were associated with death in patients with COVID-19. In conclusion, they identified four predictors of high mortality among the general population with COVID-19: age older than 65 years, pre-existing or current cardiovascular or cerebrovascular diseases, CD3 + CD8 + ?75 cellsxμL − 1 and cardiac troponin I ?0.05 ngxmL −1 [9].

The retrospective studies found the following:

Silva I, et al. (2021) [10] Conducted a retrospective cohort-type study that aimed to verify and analyze the demographic impact and comorbidities as risk factors for admission to the ICU and mortality among the adult Brazilian population. Out of a total of 1,048,575, they were left with a population of 159,704 patients between 20 and 59 years of age, of whom they had information about their mortality and admission to the ICU, the information was collected on February 26 (1st case of COVID -19 in Brazil) as of October 9, 2020. The results showed that 4.2% (n = 43,662) of patients required admission to the ICU and 3.3% (34,704) died; age had no significant association with mortality or ICU admission (p> 0.05); obesity was the variable most strongly associated with admission to the ICU and death, obesity increases the risk of mortality by 88.9%; diabetes was not a predictor of mortality unlike obesity; chronic cardiovascular disease was a risk factor for admission to the ICU, but not for mortality; the number of years of education was not identified as a risk factor for mortality; living in rural or peri-urban areas increases the risk of mortality than living in urban areas; All non-white races had an increase in the death rate due to COVID-19 (56.4% in mixed race to 75.6% in black race); found that women were more likely to survive than men; death rates from COVID-19 were higher in men than in women. In conclusion, sex, demographic characteristics, and comorbidities were predictors of ICU admission and mortality in Brazilian adults with COVID-19 [10].

The study carried out by Incerti D, et al. (2021) [11] was a retrospective cohort that sought to develop a prognostic model to identify and quantify risk factors for mortality in patients admitted to hospital for COVID-19. They recruited 17 086 patients between February 20 and June 5, 2020, these had as inclusion criteria being over 18 years of age, having a diagnosis of COVID-19 and giving positive to the diagnostic test for SARS-CoV-2. The results showed that mortality is higher at high and low levels of temperature and systolic blood pressure and that there was a strong negative relationship between oxygen saturation and mortality that is present only below approximately 95%; age was the most important predictor and that laboratory results and vital signs tend to be more important predictors than comorbidities or demographic factors; positive relationship between high levels of BMI and mortality, the most important laboratory results associated with mortality were troponin I, LDH and platelets. In conclusion, age was the strongest predictor of mortality, and vital signs and laboratory results added prognostic information beyond age [11].

Cobre A de F, et al. (2020) [12] carried out a retrospective cohort study that aimed to investigate the risk factors associated with delay in diagnosis and mortality in patients with COVID-19 in Rio de Janeiro, Brazil. They collected information from 3 656 patients who tested positive for COVID-19 between February and April 2020, taking into account the social development index (IDS) that classified it into two groups: low social index and high social index. The results showed that male patients were more likely to die from COVID-19 than females (OR = 0.150 [95% CI, 0.051-0.440]; P = 0.001). The age groups that were statistically associated with death were: 70-79 years (OR = 1.495 [95% CI, 1.121-1.994]; p = 0.006), 80-89 years (OR = 3.146 [95% CI, 2.256 -4.387]; p <0.001) and 90-99 years (OR = 5.100 [95% CI, 2.024-12.852]; p = 0.001). Patients from regions with a low IDS were more likely to die from COVID-19 (OR = 1,833 [95% CI, 1,565-2,148]; p <0.001). A delay in diagnosis of more than eight days was also a risk factor for death (OR = 3.537 [95% CI, 2.769-4.519]; p <0.001); also the ages between 40-49 years (OR = 3.226 [95% CI, 1.561-6.668]; p = 0.002), 50-59 years (OR = 5.341 [95% CI, 2.625-10.865]; p = 0.000) and 60-69 years (OR = 13.280 [95% CI, 6.662-26.474]; p = 0.000) became factors associated with the probabilities of mortality from COVID-19. In conclusion, the risk factors for COVID-19 were associated with the male gender, age under 60 years and patients living in regions with a low IDS such as favelas, in addition to the delay between the onset of symptoms and diagnosis beyond 8 days it can increase mortality rates [12].

Sáez-García MA, et al. (2020) [13], carried out an observational, descriptive, cross-sectional and retrospective research aimed at analyzing the clinical variables associated with hospital deaths in patients who died in the first quarter of 2020, and their relationship with the presence or not of COVID-19. They considered a sample of 371 deaths collected during the first four months of 2020 and did not have any exclusion criteria. In the results, a higher percentage of deceased men (53.1%) compared to women (46.9%) was observed; those who died from positive COVID-19 practically doubled their stay (10.1%) compared to negative COVID-19 (5.5%); Of all the dead, 39 (10.5%) died in the emergency room, 296 (79.8%) in the hospital ward and 36 (9.7%) in the ICU; 67% of the deceased presented poor general condition upon admission, the percentage increased to 81.9% in positive COVID-19 cases; HTA was present in 70.5% of failures due to COVID-19; diabetes present in 36.5% of cases, compared to 26% of COVID-19 negative deaths; asthma present in 4.8% of positive COVID-19 deaths compared to 2% of negative COVID-19; cancer was present in 31% of positive COVID-19 and in 19.9% of negative COVID-19. In conclusion, the highest mortality rates in patients with COVID-19 occurred in patients older than 70 years [13].

Rodríguez-Zúñiga MJM, et al. (2020) [14] conducted a retrospective cohort study with the objective of describing the main factors associated with mortality in hospitalized patients with SARS-CoV-2 pneumonia in a public hospital in Lima, Peru. 122 adult patients with clinical suspicion or with confirmation of COVID-19 were included with rapid and / or molecular tests, demographic, clinical, laboratory, tomographic and treatment variables were analyzed. The results show that the majority of critical patients died (p <0.001); age, hypertension and BMI are associated with a higher risk of mortality in COVID-19 patients; low levels of SatO2 and PaO2 / FiO2 in AGA were related to a higher risk of death; CRP, INL, and DD were associated with an increased risk of death; the greater the lung involvement, the greater the risk of death; the administration of corticosteroids, LPV / r and prophylactic ENX is associated with higher mortality; prolonged and pulsed corticosteroid treatment are associated with an increased risk of death; hospital admission with a severe or critical condition is associated with 7 and 16 times more, respectively, the relative risk of death compared to a moderate condition. In conclusion, the factors age, BMI, HTN, PaO2 / FiO2 index and exposure to corticosteroids and LPV / r are associated with mortality in addition to high doses of corticosteroids associated with an increased risk of death [14].

Valenzuela Casquino K, et al. (2020) [15] carried out an observational, descriptive and retrospective investigation in order to determine the factors associated with mortality and outcomes in patients hospitalized for COVID-19 in the Intermediate Care Unit of the Uldarico Rocca Fernández Hospital. They studied the medical records of 71 patients admitted to the intermediate care unit (NICU) diagnosed with COVID-19 between July 1 and September 30, 2020, excluding patients with an uncertain outcome. The results show that 76.47% of the deceased were older adults versus 23.53% who were adults, highlighting the association between mortality and age over 60 years (p <0.05); Furthermore, 82.35% of the deceased were men (n = 42) and 17.65%, women (n = 9); oxygen saturation <80% taken at admission was associated with higher mortality, compared to the group of survivors (p <0.0025). The highest percentage of hospitalized patients who died (49.02%, n = 25) had an intermediate hospital stay (p <0.025); of the deceased, 19 (37.25%) had a history of arterial hypertension (p> 0.1), 15 (29.41%) had diabetes mellitus (p> 0.05) and 33.33% were obese (p> 0.5). In conclusion, the study suggests that the factors associated with a fatal prognosis are age over 60 years, arriving at the emergency room with oxygen saturation less than 80%, and a long hospital stay [15].

Yupari IL, et al. (2020) [16] and collaborators carried out a descriptive study, with a quantitative approach and correlational, retrospective and cross-sectional design in order to analyze the biological, social and clinical factors of mortality risk in hospitalized patients with COVID-19 in the Trujillo district, Peru. They had a sample of 64 patients chosen from March to May 2020. The results show that the deceased patients had an average age of 64.67 years; more men died (85.7%); retirees were the most frequent (28.6%); the deceased had approximately 9.7 (+/- 9.9) days of average length of stay in hospital until their death; In deceased patients, the mean temperature recorded was 37.6 ° C ± 0.9; dyspnea, abnormal lung auscultation, and abnormal X-ray findings were present in deceased patients. Pulmonary in 47.6%, 47.6% and 33.3% respectively; the deceased patients experienced the symptoms of fever, malaise, cough and respiratory distress in 81.0%, 57.1%, 52.4% and 90.5% respectively; in deceased patients, cardiovascular disease (including hypertension) predominated in 42.9%, diabetes and cancer in 14.3% in both comorbidities. In conclusion, the most significant risk factors for mortality within the biological factors are age older than 60 years and the male sex, within the social factors none were included in the model and within the clinical factors, cough, respiratory distress and as a comorbidity, Diabetes [16].

Zhang N, et al. (2020) [17] Conducted a retrospective cohort study with the objective of describing the clinical characteristics of diabetic patients with COVID-19 and investigating the risk factors that influence prognosis, especially the impact of different antidiabetic drugs. They took a sample of 52 patients who were admitted between January 25 to February 14, 2020, during the outbreak of the pandemic. The results were that 23.1% were admitted to the ICU, 28.8% had life-threatening complications, and 8 patients died, with a mortality rate of 15.4%. Of the 52 diabetic patients, 8 (15.4%) died within a mean time of 10.5 days (IQR 9.0–13.0) from admission to the day of death. Causes of death include ARDS (8, 15.4%), followed by septic shock (2, 3.8%) and finally AMI (1, 1.9%). In conclusion, diabetic patients with poor follow-up and treatment of their disease tend to have higher mortality rates, as well as the presence of comorbidities and advanced age [17].

Cai Y, et al. (2020) [18] Conducted a single-center cohort study at the Renmin Hospital of Wuhan University in Wuhan, China and aimed to investigate the clinical characteristics of diabetic patients coexisting with COVID-19 and examine the association between a history of diabetes and / or Fasting Serum Glucose (FGG) Levels with COVID-19 Mortality in a Selected Cohort of Patients in Wuhan, China. The sample consisted of 941 patients diagnosed with COVID-19, selected from January 20 to February 20, 2020. The results show that mortality in patients with pre-existing diabetes was higher than in patients without pre-existing diabetes (21/123 [17 , 1%] vs. 76/818 [9.3%]; P = 0.012); the difference in mortality was more pronounced between patients with SAG higher and lower than 7 mmol / L (/ 51/245 [20.1%] vs 46/696 [6.6%]; P <0.001); Among subjects with diabetes, mortality in patients with SAG ≥ 7.0 mmol / L (15/75 [20%]) was higher than in patients with FBG <7.0 mmol / L (6/48 [12.5 %]); Among subjects without diabetes, mortality in patients with FBG ≥ 7.0 mmol / L was markedly higher than in patients with FBG <7.0 mmol / L (36/167 [21.6%] vs 40/651 [6.1%]; P <0.001); the mortality rate of older patients was higher, especially for those older than 60 years; for patients with a history of diabetes, high mortality was very closely correlated with hyperglycemia; for patients without diabetes, higher mortality was also related, to some extent, to hyperglycemia; a significantly higher risk of death was evidenced in patients with COVID-19 with advanced age, hypertension, diabetes, coronary heart disease, cerebrovascular disease, chronic kidney failure, COPD, chronic heart failure, high levels of CRP and PCT, GSA ≥ 7 mmol / L. In conclusion, although the history of diabetes was associated with mortality in hospitalized COVID-19 patients, SAG ≥ 7.0 mmol / L was an independent risk factor for death from COVID-19 [18].

Huang Y, et al. (2020) [19] and colleagues conducted a retrospective, single-center study at Tongji Hospital with the objective of describing the clinical characteristics of patients without diabetes who were discharged or died from COVID-19 infection in two hospitals in Wuhan, China. in addition to evaluating the associations between fasting plasma glucose levels and COVID-19 mortality in these patients. The sample collected was 151 cases with COVID-19 that were admitted to two centers, from January 1 to February 28 at Tongji Hospital, in addition the patients had no history of diabetes and their levels of glycosylated hemoglobin (HbA1c) they were less than 6.0% and fasting glucose (GSA) levels were less than 6.1 mmol / L. The results showed that the non-survivors were older in years than the survivors; the percentage of male patients was higher in non-survivors than in survivors (P = 0.0067); Compared to survivors, non-survivors were more likely to have underlying medical conditions including hypertension (60.0% vs. 28.7%, P = 0.019) and chronic lung disease (40.0% vs. 7.4 %, P = 0.0015); non-survivors had higher body temperature (36.9 vs 36.5 ?, P = 0.014) and lower percutaneous oxygen saturation (SpO2) (92% vs 97%, P = 0.010) than survivors entry; Laboratory results showed that GSA levels were significantly higher in non-survivors compared to survivors (5.86 vs 5.03 mmol / L, P = 0.0003). Meanwhile, non-survivors have higher AST (40 vs. 23 IU / L, P = 0.0003), BUN (7.6 vs. 4.3 mmol / L, P <0.0001), Cr (84 vs. at 69 umol / L, P = 0.028) and eTFG levels (93 vs 64 ml / h · 1.73 m2, P = 0.0032). In conclusion, compared to survivors, non-survivors were combined with more comorbidities, more severe infection, and worse liver, kidney, and heart function, and fasting plasma glucose levels were significantly associated with the risk of death in even patients. with normal levels of GSA and HbA1c [19].

Caliskan T, et al. (2020) [20] and collaborators carried out an observational and retrospective study, in order to explore the prevalence of smoking rates and comorbidities and to evaluate the relationship between them and the severity of the disease and mortality in hospitalized patients with COVID-19 . They collected a sample of 565 hospitalized patients with COVID-19 and 248 hospitalized patients without COVID-19 as the control group, the collection was from March 15 to May 10, 2020 and they were divided into groups: intensive care unit group (UCI), survivor and non-survivors. The results showed that the non-survivors were older than the survivors (p <0.0001); current and former smokers were more frequent in non-survivors (p <0.0001); COPD, diabetes, dementia, coronary artery disease, hypertension, CRF, CHF, and arrhythmia were significantly more frequent among non-survivors than among survivors (p <0.05); there was no difference between non-survivors and survivors in terms of asthma (p> 0.05); logistic regression analysis indicated that older age (OR, 1.082, 95% CI: 1.056-1.109, p <0.0001), COPD (OR, 3.213, 95% CI: 1.224-8.431, p = 0.018) , coronary artery disease (OR, 6.252; 95% CI: 2.171-18.004; p = 0.001) and ICC (OR, 5.917; 95% CI: 1.069-32.258; p = 0.042), were significantly associated with mortality; current smoking (OR, 13.014; 95% CI: 5.058-33.480; p <0.0001) and previous smoking (OR, 6.507; 95% CI 2.731-15.501; p <0.0001) were risk factors for mortality ; diabetes, dementia, hypertension, CHF, and arrhythmia were not significantly associated with mortality (p> 0.05). In conclusion, smoking, old age, COPD and coronary heart disease were risk factors for admission to the ICU and mortality in hospitalized patients treated for COVID-19, while asthma, diabetes, dementia, hypertension, CRF and arrhythmia were not associated with admission to the ICU or with mortality. Finally, CHF was not a risk factor for admission to the ICU; however, it was a risk factor for mortality [20].

A GERIA-COVID study conducted by Ménager P, et al. (2020) [21] and collaborators of an observational and longitudinal type aimed to determine whether the regular use of vitamin K antagonists (VKA) before COVID-19 was associated with higher mortality compared to not using VKA among frail older adults hospitalized for COVID-19. The sample acquired was 82 patients who had to be hospitalized in the geriatric acute care unit of the University Hospital of Angers, France, in March-June 2020 together with patients older than 80 years, diagnosed with COVID-19 by RT- Chest PCR or CT and information on the use of VKA. The results showed that there was a trend of more frequent VKA use before COVID-19 in those who did not survive to day 7 (33.3% versus 8.2%, p = 0.056); in addition to a direct association between regular VKA use before COVID-19 and 7-day mortality; Although it is considered not to use VKA as a reference (RR = 1), the RR of mortality in those who use VKA regularly was 5.68 [95% CI: 1.17; 27.53] (p = 0.0312); COVID-19 patients who used VKA regularly had shorter survival times than those who did not use VKA. In conclusion, the main finding is that regular VKA use prior to COVID-19 was associated with a lower survival rate in frail elderly patients hospitalized with COVID-19 [21].

The purpose of the study carried out by Barragán BS, et al. (2020) [22] and collaborators of mixed ecological design was to indicate the possible influence of vaccination coverage with Calmette-Guérin bacilli (BCG) on indicators of mortality and morbidity due to COVID-19 in countries with an epidemic curve. consolidated. The sample obtained was from 45 countries and this was divided into two: BCG coverage> 60% and BCG coverage <60% with high income, collected on June 1, 2020, among the inclusion criteria are: countries with a consolidated epidemiological curve and countries that have BCG vaccination coverage. The results showed that in countries with coverage greater than 60% and current universal vaccination policy, in contrast to countries with zero% coverage, the reduction of mortality and morbidity indicators and an increase in deaths and preventable or avoided cases attributable to BCG vaccination It is broad and significant (p <0.01) mainly in countries with lower middle income and upper middle income and in countries with coverage less than 60% versus zero% coverage (both groups with high income), with reduction (except fatality with similar behavior p> 0.01) of mortality rate and incidence and increase of deaths and preventable cases (p <0.01) in favor of those vaccinated. In conclusion, BCG vaccination coverage greater than 60%, maintenance of universal vaccination policies, is associated with a greater reduction in mortality indicators, morbidity due to COVID-19 [22].

Ferrándiz Espadin R, et al. (2021) [23] and collaborators carried out a longitudinal, descriptive and analytical study of a case model, and its objective was to describe and analyze mortality from Covid-19 based on social aspects: economic, sociodemographic, health and social development indicators, of the first countries affected at the beginning of the pandemic. The sample obtained was from 63 countries, taking into account that the selection was from countries with at least 60 days of follow-up, at least 500 confirmed COVID-19 patients and being representative countries in the condition of the pandemic in their regions. The results showed in the first 30 days that the pandemic affected the countries, there are a diversity of variables related to mortality such as poverty, economic well-being and people's concept of life such as alcohol consumption, wealth distribution , corruption and the feeling of happiness and human development; But later on, many of these variables are decanted, leaving poverty, economic well-being, longevity of life of people and the moment the disease appears as sustainable variables; Furthermore, it can be observed that the highest rates of corruption and inequality are important early with mortality of intermediate range, following the pattern of poverty among others; Finally, obesity was related to mortality at 75 days and in a very relevant way and that the higher the diagnosis of cases, the lower the mortality. In conclusion, the analysis carried out at the beginning of the COVID-19 pandemic allows us to appreciate that in countries with higher life expectancy and where there was a higher prevalence of people with higher rates of obesity and chronic lung diseases had a significantly higher risk of mortality at the beginning of the pandemic with respect to countries where communicable diseases predominate [23].

Table 2: Importance, strength and weaknesses of research work related to risk factors and mortality in patients with COVID-19.

In this review, the relationship between risk factors of different natures and mortality in patients with COVID-19 was investigated, having different results and finding concordant information between several articles or obtaining discrepant data between different investigations. This can be explained by the heterogeneity of the studies regarding: type of population (elderly, male, with DM, with hypertension, obese, with neoplasms, smokers, rural or urban residents, retirees, low socioeconomic level), design (prospective, retrospective), countries (from Europe, Asia, America), determined risk factors and sample size.

The significant risk factors that coincided in more number of studies were mostly intrinsic to the patient with less possibility of modifying. The risk factors highlighted by this review, considering the number of studies and the level of evidence are: Age over 60 years, which was a risk factor for COVID-19 mortality in 16 of 19 studies [6-21], the reasons why advanced ages are frequently associated with mortality from COVID-19 could be explained by the fact that in these patients the presence of comorbidities, polypharmacy and a decrease in the immune response is common, which favors a pro-inflammatory state without regulation and subsequent complications up to death [2]. Likewise, the male sex was associated with mortality from COVID-19 in 8 of 19 studies [5,6,10,12,13,15,16, and 19], this can be explained in part because men tend to ignore the manifestations clinics no longer go to health centers, attending already in more advanced periods of the disease and when the underlying disease has become too complicated [13-16]. On the other hand, we found that prolonged hospital stay is also a relevant risk factor. This association was found in 6 of 19 studies [5,9,13, and 15-17], it has been described that the number of days hospitalized it may increase due to the number of serious complications that the patient presents and their referral to the ICU [5,13, and 17] or because there is a delay in their diagnosis [12]. Also, the association with comorbidities increases the mortality rates due to COVID-19, in this sense, we have cardiovascular diseases [6,7,9,16,18, and 20] such as arrhythmias, coronary diseases, congestive heart failure and even HBP [5,13-16,18, and 19], in addition metabolic diseases such as diabetes mellitus [6,13, and 15-18] and obesity [10,15, and 23] are also of great relevance when thinking about deaths from COVID-19, likewise, pre-existing lung diseases such as asthma [13] and COPD [19,20, and 23] can worsen the initial symptoms of SARS-CoV-2 infection and ultimately lead to death. we have chronic kidney disease [5,6], dementia [5], cerebrovascular disease [9] and cancer [7,13, and 16] as comorbidities that influence a fatal outcome. Now, the signs and symptoms that appear at the beginning of the disease in the same way affect the final clinical picture, since for example the presence of fatigue, headache, sputum production [9], anosmia [7], dry cough [7,16], dyspnoea [9,16], malaise [13,16], fever [11,16,19], decreased oxygen saturation [6,8,11,14,15, and 19] and increased both heart rate [8] and respiratory rate [8,9] can serve as predictors of severity and mortality in patients with COVID-19. It is also necessary to mention that biomarkers can help us predict the future of our patient given that increased levels of BUN [6,19], CRP [6,8,14, and 18], glucose [6,8,18, and 19] , AST [6,19], leukocytes [6,8, and 9], neutrophils [9], PCT [8,18], D-dimer [8,9, and 14], CK, CK-MB [8], myoglobin [9], troponin [8,9, and 11] and LDH [8,11] are factors associated with mortality in patients with COVID-19 as well as decreased values of total proteins, albumin [8], platelets [11] and lymphocytes [8,9]. Finally, risk factors were also studied in particular, such as living in rural or peri-urban areas [10], a low socioeconomic level [12,23], black and mixed race [10], prolonged use of corticosteroids and in high doses [14], retired patients [16], smokers or ex-smokers [20], VKA use [21], and low BCG vaccination coverage [22].

In conclusion, the risk factors associated with death from COVID-19 are varied: Age over 60 years, male gender, presence of signs and symptoms at the onset of the disease such as dry cough, dyspnea, general malaise, increased heart and respiratory rate and decrease in oxygen saturation less than 92%, presence of comorbidities such as cardiovascular and cerebrovascular diseases, hypertension, diabetes, obesity, cancer, COPD and asthma, alteration of biomarkers such as increased CRP, glucose, PCT , leukocytes, D-dimer, troponin, LDH and decreased platelets and lymphocytes, and lastly sociodemographic aspects such as low socioeconomic status, black race, mixed race, and low BCG vaccination coverage.

At the same time, early identification of risk factors associated with COVID-19 mortality can help better stratify patients who come to the emergency, as well as provide a better approach to treatment.

The author declares that he has no conflicts of interest of any kind, that the work has been approved by the ethics committee responsible for the workplace and does not declare means of financing the work carried out outside of his own.

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