Outcomes of SARS-CoV-2 and Seasonal Viruses Among 2 Million Adults Hospitalized for Severe Acute Respiratory Infection During the COVID-19 Pandemic in Brazil

Abstract

Background

The outbreak of the COVID-19 pandemic has had a profound impact on the circulation of seasonal respiratory viruses. This study aimed to compare the outcomes of SARS-CoV-2 and seasonal viruses in adults hospitalized with severe acute respiratory infection during the COVID-19 pandemic.

Methods

This population-based cohort study included patients aged >18 years hospitalized for severe acute respiratory infection in Brazil between February 2020 and February 2023. The primary outcome was in-hospital mortality. A competing risk analysis was used to account for competing events.

Results

In total, 2 159 171 patients were included in the study. SARS-CoV-2 was the predominant virus (98.7%). Among patients testing positive, the cumulative incidence of in-hospital mortality was 33.1% for SARS-CoV-2, 31.5% for adenovirus, 21.0% for respiratory syncytial virus, 18.7% for influenza, and 18.6% for other viruses. SARS-CoV-2 accounted for 99.3% of the deaths. Older age, male sex, comorbidities, hospitalization in the northern region, and oxygen saturation <95% were the common risk factors for death among all viruses.

Conclusions

In this large cohort study, individuals infected with SARS-CoV-2 or adenovirus had the highest risk of mortality. Irrespective of the virus type, older age, male sex, comorbidities, hospitalization in vulnerable regions, and low oxygen saturation were associated with an increased risk of fatality.

Acute upper and lower respiratory infections are a significant cause of morbidity and mortality worldwide and pose a considerable public health burden [1, 2]. These infections, primarily caused by viruses, encompass a broad spectrum of respiratory illnesses, ranging from mild common colds to severe respiratory syndromes. In a prepandemic study based on the Global Burden of Disease study, Jin et al [2] reported that the estimated number of cases of upper respiratory tract infections reached >17 billion in 2019, accounting for approximately 43% of all illnesses and injuries in the study. The COVID-19 pandemic has further highlighted the potential of respiratory viruses to cause widespread devastation.

The emergence of SARS-CoV-2 and the implementation of public health measures to curb the spread of the virus have significantly affected the transmission of respiratory viruses and drastically altered viral epidemiology [3–6]. While some studies have reported a higher fatality rate for SARS-CoV-2 infection than for the seasonal flu [7–9], few studies have directly compared the burden of COVID-19 with other common seasonal viruses, such as respiratory syncytial virus (RSV) and adenovirus. We recently demonstrated in a Brazilian pediatric cohort that children who contracted SARS-CoV-2 had the highest in-hospital mortality risk when compared with those who contracted seasonal viruses [10]. Although it is widely believed that SARS-CoV-2 will eventually become a seasonally endemic pathogen, there is limited information about the equilibrium dynamics of SARS-CoV-2 and seasonal viruses in this new scenario [11, 12]. Understanding the transition of SARS-CoV-2 to endemicity, continuous circulation, and interaction with seasonal viruses is crucial for designing effective preventive and control strategies [13]. In this population-based retrospective cohort study, we used a Brazilian national epidemiologic surveillance system to compare the clinical outcomes and risk factors of death among hospitalized adults with severe acute respiratory infection (SARI) related to SARS-CoV-2 and other common seasonal viruses.

METHODS

Study Design and Participants

This is a population-based retrospective cohort study. We analyzed all hospitalized patients with SARI recorded in the Influenza Epidemiological Surveillance Information System (SIVEP-Gripe). The inclusion criterion was patients aged >18 years registered in the database between February 2020 and February 2023. Information regarding the included and excluded cases is shown in Figure 1. To further ascertain the robustness of our analysis, we performed a sensitivity analysis of the excluded cases, which is provided in the Supplementary material.

Data Source

SIVEP-Gripe is a comprehensive Brazilian database that tracks cases of SARI nationwide [14, 15]. The reporting of SARI is mandatory, and the database receives information from patients admitted to public and private hospitals. The detailed information regarding the SIVEP-Gripe database—including the reporting form and data dictionary, codes, and all deidentified data—is publicly available at https://opendatasus.saude.gov.br/dataset. Additional information is provided in the Supplementary material.

Covariables and Definitions

Demographic data were collected for the analysis, such as age, sex, ethnicity, education level, and geographic macroregion of the country. Age was stratified into 4 groups (19–29, 30–59, 60–79, and ≥80 years). The Brazilian Institute of Geography and Statistics classifies the Brazilian population into 5 ethnicities: White, Black, Brown, Asian, and Indigenous [16]. Brazil is geopolitically divided into 5 macroregions: North, Northeast, Central-West, Southeast, and South. These macroregions have historical social, economic, and health system capacities and coverage differences. Education was categorized into 5 levels based on completion: illiterate, elementary school, middle school, high school, and college.

Clinical data were collected, including birth date, date of symptom onset, and date of admission. Also recorded were signs and symptoms of presentation (fever, cough, respiratory distress, gastrointestinal, and reduced oxygen saturation), occurrence of nosocomial infection, and the presence of preexisting comorbidities (asthma, diabetes, obesity, immune deficiency, and malignancy, as well as heart, pulmonary, kidney, neurologic, and hematologic diseases). For analysis, the presence of comorbidity was categorized into 4 levels according to the number of preexisting medical conditions.

Exposure of Interest

The primary exposure of interest was laboratory-confirmed viral etiology.

Outcomes

The primary outcome was the in-hospital mortality rate. The clinical course was reported in terms of respiratory support (none, noninvasive oxygen support, and invasive ventilation), admission to the intensive care unit (ICU), recovery, death, and ongoing clinical situation. The date of death or discharge was recorded.

Statistical Analysis

The analysis was conducted in 3 stages. Initially, we described the clinical, demographic, and epidemiologic characteristics of patients with SARI according to their viral etiology. In this stage, we used summary statistics to describe the clinical and demographic characteristics, presenting the data as mean and SD, median and IQR, and count and proportion. Comparisons between groups were performed with the F test and chi-square test, as appropriate.

Second, we assessed the effect of viral etiology on the survival of patients with SARI. To achieve this, we conducted a competing risk survival analysis using the cumulative incidence function [17] and the Fine-Gray model [18] to estimate the cumulative incidence of the primary outcome over time. In-hospital mortality was considered the primary outcome, whereas hospital discharge was considered a competing event. Finally, we performed a multivariate competing risk survival analysis to determine the independent risk factors for death for each viral etiology. All models were adjusted for sex, ethnicity, educational level, year of admission, region of hospitalization, oxygen saturation at admission, and comorbidities. The results are presented as adjusted hazard ratios (HRs) and 95% CIs. All statistical tests were 2-tailed, and statistical significance was set at P < .05.

Ethical Aspects

We accessed the data in SIVEP-Gripe, which is already deidentified and publicly available. The study was approved by the Federal University of Minas Gerais institutional review board (CEP 6.127.414). The study followed the STROBE guidelines (Strengthening the Reporting of Observational Studies in Epidemiology) for observational cohort studies.

RESULTS

Participants and Case Defining

Between 16 February 2020 and 21 February 2023, 3 515 224 cases of SARI were recorded in the SIVEP-Gripe surveillance database. From this pool of individuals, we excluded 411 484 (11.7%) who were <18 years of age at the time of admission and 456 182 (13%) whose test results were still pending. Additionally, we excluded 362 691 (10.3%) who tested negative for SARI, 104 925 (3%) whose test results were missing from the database, and 10 295 (0.3%) whose SARI was attributed to nonviral causes. Furthermore, we excluded 8127 (0.2%) for whom the test was not performed and 2433 (0.07%) whose test results were inconclusive. Consequently, the final sample comprised 2 159 171 adult patients hospitalized for SARI.

Epidemic Curve

Figure 2 illustrates the prevalence of viral etiology over time, categorized by year of admission. The first laboratory-confirmed case of SARS-CoV-2 infection in Brazil was reported on 16 February 2020. From the 14th epidemiologic week of 2020 onward, SARS-CoV-2 infection became the predominant cause of illness, maintaining a prevalence of >90% throughout the entire year of 2020. During the second year of the pandemic, SARS-CoV-2 infection continued to be the predominant cause of illness until around the 43rd epidemiologic week, when influenza became prevalent. However, with the emergence of the Omicron wave, SARS-CoV-2 infection once again became the predominant cause of illness in all age groups in 2022.

Demographic and Clinical Characteristics

The demographic and clinical characteristics of the 2 159 171 patients hospitalized with SARI, according to viral etiology, are shown in Table 1. Within the time frame of the study, there was an absolute predominance of cases positive for SARS-CoV-2 (98.7%), followed by influenza (1%), RSV (0.1%), adenovirus (0.01%), and other viruses (0.2%). The mean age of the patients at admission was 59.9 years (SD, 17.5). Patients with RSV were older at admission and had higher rates of comorbidities.

Regarding clinical outcomes, 696 537 patients (37.5%) were admitted to the ICU, 1 064 784 (58.1%) required noninvasive oxygen support, and 373 073 (20.4%) required invasive ventilation. The overall hospital mortality rate was 31.4% (672 899/2 143 941) among the patients with available information. Patients positive for SARS-CoV-2 had lower baseline oxygen saturation, higher rates of ICU admission and oxygen support, and higher in-hospital mortality rates. Patients who were adenovirus positive also had high rates of ICU admission and in-hospital mortality.

Risk Factors of Fatal Outcome

Figure 3 illustrates the cumulative incidence function according to viral etiology. The estimated probability of a fatal outcome at 30 days of hospitalization according to viral strain was 33.1% for SARS-CoV-2, 31.5% for adenovirus, 21.0% for RSV, 18.7% for influenza, and 18.6% for other viruses. The results of the univariate competing risk survival analysis for the risk factors associated with mortality in the entire cohort indicated that a positive test result for SARS-CoV-2, adenovirus, and RSV was consistently associated with an elevated risk of death (Figure 4). After adjusting for the covariates of interest, a positive test result for SARS-CoV-2 or adenovirus remained significantly associated with a higher risk of fatal outcomes (Supplementary Figure 1). Additionally, we conducted a competing risk survival analysis for the risk factors of death according to each main viral etiology (Supplementary Figures 2–4).

DISCUSSION

In this population-based study, hospitalized cases of SARI with laboratory-confirmed viral etiology were analyzed to compare the outcomes of patients with SARS-CoV-2 infection and those with seasonal viral infection during the first 3 years of the pandemic in Brazil. In the crude analysis, patients who tested positive for SARS-CoV-2, adenovirus, and RSV had a higher risk of death than those who tested positive for the other seasonal viruses. After accounting for competing events and confounders, cases that tested positive for SARS-CoV-2 and adenovirus were significantly associated with a higher risk of death. Additionally, after adjusting for competing survival risk analysis, some covariates were independently associated with fatal outcomes for all viruses: age groups (30–59, 60–79, and ≥80 years), male sex, region of hospitalization (North), presence of comorbidities, and oxygen saturation <95% on admission. Notably, Indigenous ethnicity was a risk factor for death only in patients who were SARS-CoV-2 positive, whereas a high educational level was a uniformly strong protective factor against death across all viruses.

Comparative Analysis and Interpretation

The COVID-19 pandemic has significantly affected the epidemiology of viral respiratory infections. As a result of measures taken to mitigate the pandemic, there has been a marked decrease in the circulation of other respiratory viruses, such as influenza and RSV [19, 20]. This has been observed across all age groups worldwide [21, 22]. For example, in the United States, influenza activity decreased in March 2020, was low throughout the summer of 2020, and remained low from October 2020 to May 2021 (<0.4% of respiratory specimens tested positive). The circulation of other respiratory pathogens, including RSV, common human coronaviruses, and parainfluenza viruses, also decreased in early 2020 and did not increase until spring 2021 [23]. Similarly, in our cohort, there was an absolute predominance of SARS-CoV-2, which accounted for an overall prevalence of approximately 69% of adult cases hospitalized with SARI in Brazil and 98.7% of cases with a confirmed viral etiology during the pandemic period.

Our findings revealed that in comparison with other viral infections, SARS-CoV-2 and adenovirus infections were associated with more severe outcomes, characterized by increased rates of ICU admissions, mechanical ventilation requirements, and fatalities. Notably, among all viral etiologies, SARS-CoV-2 and adenovirus infections presented a significant risk of mortality among patients with SARI. Our data indicated that individuals who tested positive for SARS-CoV-2 infection upon admission had about twice the risk of death as those who tested positive for other common viruses (HR, 1.88; 95% CI, 1.75–2.02). After accounting for potential confounders, we found that patients who tested positive for adenovirus (HR, 1.78; 95% CI, 1.22–2.60) and SARS-CoV-2 (HR, 1.60; 95% CI, 1.38–1.76) remained at a significantly higher risk of death. Although the risk rate for adenovirus-positive individuals was slightly higher than that for SARS-CoV-2, it is important to note that the burden of SARS-CoV-2 was substantially higher and accounted for 99.3% of the deaths during this period.

Several studies have compared the burden of SARS-CoV-2 infection with seasonal viruses, but most have been limited to influenza viruses [7, 8]. Findings from these studies consistently reveal that COVID-19 is associated with an elevated risk of mortality, extrapulmonary organ dysfunction, and increased health care resource utilization [9]. During the initial year of the COVID-19 pandemic, 2 studies conducted in the United States suggested that individuals hospitalized for COVID-19 had nearly 5-times greater odds of 30-day mortality than those hospitalized for seasonal flu [24, 25]. Additionally, Frohlich et al [26] reported a 2- to 3-times higher rate of mortality and ICU admissions among patients with community-acquired COVID-19 (wild type and alpha variants) than those with influenza. Nevertheless, since the start of the pandemic, the contrast in death rates between COVID-19 and influenza has tended to decrease. For example, in the United States, mortality rates among individuals hospitalized for COVID-19 were notably higher, ranging from 17% to 21% in 2020, whereas these rates decreased to 6% by 2023. In parallel, the mortality rate of individuals hospitalized due to influenza was 3.8% in 2020 and remained stable at 3.7% from 2020 to 2023 [24, 27]. Our findings are consistent with these observations. Our predictive model indicated that the risk of death from COVID-19 hospitalization decreased progressively over the first 2 years of the pandemic. After adjusting for confounding variables, hospitalization in 2022 or 2023 was a significant “protective factor” against death. This declining trend in mortality rates associated with COVID-19 hospitalizations may be attributable to factors such as SARS-CoV-2 variants, increased immunity levels due to vaccination and prior infections, and improved clinical care [27]. Note, however, that recent studies have reported a higher risk of death from SARS-CoV-2 infection. For instance, Xie et al reported that hospitalization for COVID-19 during the fall-winter period of 2022 to 2023 in the United States was associated with an HR of 1.61 when compared with hospitalization for influenza [27]. Moreover, a recent multicenter cohort study in Switzerland during the Omicron wave showed a significantly increased risk of in-hospital mortality for patients with the SARS-CoV-2 Omicron variant when compared with influenza, although the ICU admission rates were similar [9]. Taken together, these findings suggest that despite the evolving landscape of the pandemic, the risk posed by COVID-19 hospitalization still surpasses that of influenza, underscoring the unique and enduring impact of COVID-19 on patient outcomes.

Our study adds to the current literature by comparing the burden of SARS-CoV-2 with other common seasonal viruses. Indeed, we did not find studies that included other seasonal viruses of interest, such as RSV and adenovirus [28]. Unexpectedly, we found that the relative hazard of death from adenovirus was even higher than that from SARS-CoV-2 but with a much smaller public health impact due to the low prevalence of the virus in the pandemic period. However, we must point out that although the literature shows that most adenovirus cases have a mild and self-limited infection, the clinical spectrum is broad and pneumonia can be fatal, as highlighted in our findings [29–31].

Risk Factors of Death

In the second step of our analysis, we assessed the risk factors associated with in-hospital mortality according to viral etiology among patients hospitalized with SARI during the first 3 years of the pandemic in Brazil. Notably, after accounting for potential confounding variables, the following factors were significantly associated with death in all models: age (30–59, 60–79, and ≥80 years), male sex, oxygen saturation <95% at admission, hospitalization in the vulnerable regions of the country (North), and presence of comorbidities. Our findings are in line with previous findings regarding factors associated with in-hospital mortality in patients with SARI. Age is one of the strongest risk factors for death from COVID-19, and our analysis showed that it is similar to that of other seasonal viruses. The reasons for the increased risk of death from COVID-19 in older adults are not fully understood but may include age-related immune system remodeling, immunosenescence, increased susceptibility to respiratory infections, impaired immune responses to vaccination, and a higher prevalence of comorbidities [32–34].

Interestingly, a common risk factor for all viruses was the presence of any underlying chronic medical condition, consistent with previous COVID-19 and influenza studies [35, 36]. Our data also showed a higher risk of death among males for all the viruses. For COVID-19, this is a global trend, with studies from all over the world reporting higher mortality rates among men [37]. However, the sex-specific effects of influenza infection are still rather limited, and findings from epidemiologic studies are contradictory [38]. Furthermore, our data revealed that patients hospitalized in the less developed regions of Brazil had a higher risk of death than those hospitalized in the wealthiest regions. Several studies suggest that social vulnerability is a major factor in the disproportionate impact of COVID-19 on certain populations [39]. Brazil is a middle-income country with a long history of health care disparities among its regions. These disparities are driven by several factors, including socioeconomic inequality, geographic barriers, and uneven distribution of health care resources. Despite a resilient public health system (Sistema Único de Saúde [SUS]), the poorest regions of Brazil—the North and Northeast—still have the least access to health care facilities and professionals [40–43].

Limitations

Two major limitations must be considered in our analysis. First, the availability of viral respiratory panels and testing strategies during the pandemic is an issue that needs to be addressed. Early in the pandemic, diagnostic testing for COVID-19 was the primary focus in Brazil, as in other regions around the world. The concentration of resources on COVID-19 has resulted in a reduction in the scope of viral respiratory panels that cover common seasonal pathogens, such as influenza and RSV. As the pandemic progressed and additional resources became available, testing procedures were expanded to include other viruses. However, the full viral respiratory panel only returned later during the pandemic. Additionally, owing to the economic disparities mentioned earlier, this expansion was not consistent across all regions or across the entire study period in Brazil. This strategy may have unintentionally influenced the spectrum of the viruses captured in our analysis. This underdetection could have led to an underestimation of the circulation of seasonal viruses and the impact of coinfection with other respiratory viruses with SARS-CoV-2, especially during the initial phase or peak periods of the pandemic. Another limitation, perhaps related to the previous issue, is that we had to exclude approximately one-third of the patients hospitalized with SARI because of the lack of information regarding viral respiratory tests in the database. To address this crucial point, we conducted sensitivity analysis of the excluded cases. The results of the analysis showed that the excluded patients generally exhibited a milder form of the disease, even though they still experienced a considerable proportion of severe outcomes. When compared with the included cohort, the excluded cases had proportionally fewer requirements for ICU admission, invasive ventilatory support, and in-hospital mortality rate. These characteristics may partially explain the absence of information on the viral test results in the database. Thus, it is possible that these patients had not undergone extensive investigation or were discharged earlier and the system was not updated accordingly. Therefore, we must consider that, to some extent, it may have introduced a kind of spectrum bias when the most severe cases were more comprehensively investigated regarding the viral etiology. While acknowledging the limitations of our analysis, we note that multiple studies have reported substantial evidence of decreased activity of seasonal respiratory viruses on a global scale, following the implementation of community mitigation measures to curb the transmission of SARS-CoV-2 [19, 22]. In addition, it is important to consider that most cases (64%) of our cohort were documented after 2020, when the health care system was comparatively less burdened and the issue of viral respiratory panels had been partially addressed. Finally, other limitations of this study are related to the administrative nature of the SIVEP-Gripe database [44]. Yet, we have been working with these data sets since 2021 using various statistical and data analysis techniques to address these issues [45, 46].

Conclusion and Policy Implications

In this large population-based retrospective cohort study, individuals with SARS-CoV-2 and adenovirus had approximately twice the risk of death as those positive for other common seasonal viruses after controlling for clinical and epidemiologic confounders. However, due to the overwhelming prevalence of SARS-CoV-2, the public health burden of COVID-19 is substantially higher. The risk factors for death varied among viruses. Yet, an increased risk of death was uniformly associated with older age, male sex, comorbidities, hospitalization in the poorest regions of Brazil, and low oxygen saturation on admission.

Our findings may have relevant implications for future public health interventions and underscore the importance of closely monitoring and understanding the viral epidemiology in the post–COVID-19 era. However, the long-term effects of the COVID-19 pandemic on the epidemiology of viral respiratory infections remain unclear. After respiratory virus pandemics have ultimately been controlled, the causative viruses have persisted in circulation for many years. Therefore, SARS-CoV-2 may eventually become an endemic seasonal pathogen. Nevertheless, the equilibrium dynamics of SARS-CoV-2 in this new environment, alongside seasonal viruses, remain largely unknown. Therefore, further studies are essential to better understand the differences in clinical outcomes between SARS-CoV-2 and other seasonal respiratory viruses and the potential implications of coinfection.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online (http://jid.oxfordjournals.org/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.

Notes

Acknowledgments. All data from the SIVEP-Gripe were systematically collected by frontline health care workers. We are profoundly grateful and in debt to all frontline health care workers for impressive efforts to address the COVID-19 pandemic in Brazil.

Author contributions. Conceptualization: E. A. O., M. C. L. O.; methodology: E. A. O., M. C. L. O., E. A. C.; investigation: E. A. O., M. C. L. O., A. C. S. S., C. S. D., L. M. D., H. M.-J., I. O. Y., S. C. G., C. C. P.; formal analysis: E. A. O., M. C. L. O., A. C. S. S., C. S. D., L. M. D., H. M.-J., I. O. Y., R. H. M., S. C. G., C. C. P., E. A. C.; writing–original draft preparation: E. A. O., C. S. D., C. C. P., S. C. G., R. H. M., A. C. S. S.; writing–review and editing: E. A. O., C. S. D., L. M. D., M. C. L. O., A. C. S. S., R. H. M.; data curation: E. A. O., M. C. L. O.; data access and verification: E. A. O., M. C. L. O., E. A. C.; supervision: E. A. O., who was responsible for the decision to submit the manuscript. The authors of this study contributed intellectual content during the drafting or revision process and accepted responsibility for the entire work by ensuring that any questions related to the accuracy or integrity of any part of the work were thoroughly investigated and resolved. The authors certify that this study has been reported honestly, accurately, and transparently. The authors are accountable for the overall work and content of this article, including its scientific accuracy and integrity. The authors accept full responsibility for any errors or omissions in the article and for the accuracy of the data presented.

Data sharing. SIVEP-Gripe data are publicly available on the following address: https://opendatasus.saude.gov.br/dataset/bd-srag-2020/resource/d89ea107-4a2b-4bd5-8b8b-fa1caaa96550. Our analysis code is available as requested for the corresponding author (Eduardo A. Oliveira, eduolive812@gmail.com).

Disclaimer. The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.

Financial support. This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); and Fundação de Apmparo a Pesquisa do Estado de Minas Gerais (FAPEMIG).

References

Author notes