In this study, we analyzed the severe and hospitalized COVID-19 cases in the state of Pará that occurred in the year 2020, as reported and investigated in the SIVEP-GRIPE platform of the Ministry of Health, which carries out surveillance of acute and severe respiratory syndromes of hospitalized patients, regardless of the etiological agent.
The study population presented lethality in 42.47% of hospitalized patients, much higher than that for Brazil (32.35%) , with a predominance of males in general (59.05%) and in the deceased group (62.20%), with higher odds of death (OR 1.198: CI 1.111–1.293). It is noteworthy that several studies have shown that the incidence of infected women is most often higher when evaluating all cases (i.e., mild, moderate, and severe); however, these same studies show that, in terms of deaths, the predominance is in males [30–32], corroborating the results herein that severe cases were more common in men, as well as deaths.
One study has cited that the higher occurrence of severity and death in men is associated with greater expression of ACE2, which may explain how SARS-CoV-2 can have a greater impact on this gender .
Two meta-analyses have shown that the lethality of COVID-19 is concentrated in older individuals [34, 35], similar to the results observed in this study by the Mann-Whitney test, but in the multivariate regression model, older age was not associated with death. We believe that the other variables influenced. Studies have indicated that older people have more chronic diseases, which are most often risk factors for complications of COVID-19, as well as a weakened immune response due to immunosenescence; which is a natural deterioration of the immune response, causing changes in immune memory, as well as in the production and actions of certain defense cells such as T-cells. Thus, clinical presentations are atypical, such as an absence of fever, which is the main sign of infection, impairing adequate screening of the disease in this age group . A study has highlighted that being aged over 60 years is a risk factor for mortality and can still be potentiated in the presence of some chronic diseases. Thus, advanced age is associated with most causes of death from chronic and infectious diseases, and it is no different for COVID-19 .
The predominant clinical features in the study population included cough (79.69%), fever (78.02%), dyspnea (74.48%), respiratory distress (63.02%), O2 saturation ≤ 95% (48.86%), and sore throat (34.01%), being similar to the results of other studies evaluating severe and hospitalized cases [38, 39]. In terms of the clinical characteristics associated with mortality, we observed dyspnea (81.52%), respiratory distress (65.10%), and O2 saturation ≤ 95% (56.03%); in addition, the odds ratio dyspnea (OR 1.899; CI 1.737–2.076) presented almost twice as many chances for death. This result has also been observed in other studies [40, 41].
Respiratory distress and oxygen saturation changes can occur without the presence of dyspnea; however, dyspnea usually occurs as a consequence of respiratory distress and oxygen saturation changes, which may indicate pulmonary hypoxia in COVID-19. The O2 saturation below 95% already indicates signs of severity directly associated with the pathological process of SARS-CoV-2, which causes a cytokine storm or macrophage activation syndrome, which leads to an inflammatory cascade causing a state of generalized pulmonary hypercoagulability, causing hypoxia and injury to lung tissue. Thus, for the management of cases, laboratory markers such as D-dimer, prothrombin time, platelet aggregates, macro platelets, C-reactive protein, lactate, ferritin, serum amyloid A, and liver enzymes become essential, with changes in the levels of these markers having been cited in studies as predictors for mortality [42, 43].
In the chi-square test, all comorbidities were associated with mortality except for asthma; while those in the regression were being a carrier of another lung disease, kidney disease, diabetes, and immunodeficiency. Similar to the results of other studies, we also highlighted that the presence of chronic diseases is an important predictor of mortality [44–46]. One study has highlighted that, in diabetic individuals, the highest rate of inflammatory processes is due to the constant recognition of glucose by type C lectin receptors. Hypertensives, usually grouped with other diseases, are treated with drugs to reduce blood pressure mainly by Angiotensin-Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB), leading to increased ACE2 expression, which is used by SARS-CoV-2 to enter human cells. To date, studies have shown that individuals with these conditions and affected by COVID-19 have a controlled release of pro-inflammatory cytokines and unbalanced immune response, leading to the cytokine storm phenomenon .
Having another chronic pneumopathy, such as Chronic Obstructive Pulmonary Disease (COPD), increases the chances of severe COVID-19 forms by up to five times, according to a meta-analysis . In terms of immunodeficiency, a study has shown the chances of progression to severity in COVID-19 being increased by up to 3.39 times, as directly associated with opportunistic infections that can cause other systemic complications, influenced by severity and mortality, as b-lymphocyte deficiency prevents the storm of inflammatory cytokines; however, it facilitates secondary infections, such as bacterial infections, with chances of sepsis [49, 50].
It has been shown that asthma is not significantly associated with mortality. A study in 1526 patients with COVID-19, both hospitalized and non-hospitalized, showed the prevalence of only 14% of asthma patients in hospitalized patients, finding no association between asthma and disease severity and longer hospitalization time; furthermore, the continuous use of initiatory corticosteroids did not influence mortality, severity, and/or hospitalization . A meta-analysis provided no clear evidence of increased risk of COVID-19 diagnosis, hospitalization, severity, or mortality due to asthma .
This study also identified that people vaccinated against influenza died less than the unvaccinated (13.46%, p < 0.01). The OR showed a lower risk in the vaccinated (OR 0.714; CI 0.637–0.801), confirmed also in the survival analysis, showing shorter survival period in the unvaccinated cases (p < 0.01). In a study in Italy that analyzed data from elderly people over 65 years who were vaccinated or not vaccinated against influenza, a simple linear regression was performed to predict the percentage of deaths from COVID-19. They showed a moderate to strong negative correlation (r = − 0.5874, n = 21, P = .0051), which means that where there were higher rates of influenza vaccination, there were fewer deaths from COVID‐19. A significant regression equation was found [F (1.19) = 10.01, P = 0.01], with an R2 value of 0.3450. The percentage of COVID-19 deaths in each region decreased by 0.3450 for each percentage unit of elderly people over 65 years of age vaccinated against influenza , similar to the results of this research.
A study in Brazil with a sample of 92,664 patients having COVID-19, of whom about one-third received the influenza vaccine, showed that influenza-vaccinated patients were 8% less likely to be in the intensive care unit, 18% less likely to require mechanical ventilation, and 17% less likely to die . The research by Yang et al.  showed that COVID-19 patients who had not received an influenza vaccination in the last year had a 2.44× chance (95%CI: 1.68–3.61) of hospitalization and a 3.29× chance (95%CI: 1.18–13.77) of longer ICU stay, when compared to those who were vaccinated. The results were also controlled to take into account age, race, gender, hypertension, diabetes, chronic obstructive pulmonary disease, obesity, coronary artery disease, and congestive heart failure. These analyses suggest that influenza vaccination is potentially protective against moderate to severe cases of COVID-19 infection. This protective effect is valid regardless of the presence of comorbidity.
Another study in Brazil considering 472,688 hospitalized cases of COVID-19 showed, in a regression, almost twofold higher odds ratios for invasive ventilation, ICU admission, and death in unvaccinated cases .
Concerning the deceased group, ICU admission (38.71%) and invasive ventilatory support (32.05%) had high significance. For predicting mortality, it was observed that invasive ventilatory support presented an OR of 6.627 (CI 5.780–7.597) and admitted to ICU boarding school had an OR of 1.764 (CI 1.588–1.959). In a study of 164 critically followed patients admitted to the ICU in Mexico, the majority were men (69%), with mean age of 57.3 years. A total of 38.4% presented hypertension and 32.5% presented diabetes; all received invasive ventilation for an average time of 11 days, with lethality of 51.85%, death before 30 days, and a median survival of 25 days. The authors concluded that the time of hospitalization, an increase in c-reactive protein, were predictors for ICU lethality by COVID-19 . Thus, the outcomes of ICU and invasive ventilation were associated with death, as well as being influenced by other risk factors such as male gender and pre-existing illness. A cohort study in Brazil also independently associated the need for supplemental oxygen on admission and invasive ventilation with increased chances of death in hospitalized cases of COVID-19 .
Studies that identify predictors of death, like our study for example, allow for better clinical evaluation and prediction of disease severity. One study for example created a strategy to predict the severity and mortality of COVID-19 in hospitalized patients, a risk score, which included ge, blood urea nitrogen, number of comorbidities, C-reactive protein, SpO2/FiO2 ratio, platelet count, and heart rate. The model had high discriminatory value (AUROC 0.844, 95% CI 0.829–0.859). It is implemented in a freely available online risk calculator (https://abc2sph.com/) . These tools are essential to contribute to the clinical practice of case management and treatment, which can have an impact on reducing mortality from the disease.
There is also a limitation for those vaccinated against influenza, as the form only has the options “yes” or “no”, regarding whether they had been vaccinated in the last year—after all, in Brazil, the influenza vaccination campaign is annual. Thus, there is a risk of bias, due to the analysis of retrospective secondary data. Another point to be highlighted as a limitation is the absence of continuous data such as temperature, blood saturation levels, blood pressure, because the answers were binary and the database does not have these measured values for each case. We also emphasize that we did not perform the interaction between the predictors that might or might not have similar or different results.
The treatment and management of hospitalized cases were based on oxygen therapy and other known care for critically ill patients, and that were already carried out in the surveillance and care flow for acute and severe respiratory syndromes in Brazil, which has existed since 2009. However, it is worth noting the limitation of the types of treatment of the cases, which we believe was not different between the cases because the SARS protocol already exists in Brazil.
The cases refer to those who were hospitalized, and most were confirmed by laboratory criteria; however, the results of the clinical characteristics and outcome associated with death were similar to the literature. The lethality of the hospitalized patients was higher than that of those hospitalized in Brazil overall, which may be associated with the factors of vulnerability of the region or weaknesses in epidemiological surveillance in the notification and closure of investigations, such that the surveillance predominantly focuses on investigating deaths, influenced by the high demand for service and few professionals trained in health surveillance in the region, as well as the turnover of professionals in epidemiological surveillance both at the state and municipal level. The main author is an epidemiologist in the state, and has experienced all these weaknesses first-hand.