INTRODUCTION

Coronavirus disease 2019 (COVID-19) is transmitted through aerosols and droplets and can cause respiratory symptoms of varying severity. Since the beginning of 2020, when the COVID-19 pandemic was declared by the World Health Organization (WHO), several variants of the new coronavirus have been identified, with different transmission and mortality potentials. Moreover, there have been considerable numbers of cases and deaths worldwide.^1-2 After three years of pandemic, on May 5, 2023, the WHO declared the end of the Public Health Emergency of International Concern associated with COVID-19, due to the downward trend in deaths associated with the disease.³

Symptoms caused by coronavirus infection may require hospitalization and, in some cases, intensive care.⁴ During the peaks caused by COVID-19, there was evidence of saturation of the Brazilian healthcare system associated with an increase in hospital admissions as well as Intensive Care Unit (ICU) beds.⁵

Healthcare-associated infections (HAIs) are directly associated with intensive care, due to the greater propensity of critically ill patients to develop them. During the COVID-19 pandemic, an increase in HAI rates was observed.⁶ The occurrence of these infections causes numerous complications for patients, such as prolonged recovery time and, consequently, hospital stay, in addition to worsening clinical condition and death.^6-7 In intensive care, ventilator-associated pneumonia (VAP) is the most common nosocomial infection. It is associated with the use of invasive ventilatory support and is characterized when patients present pneumonia after the use of this device from the second day of intubation.^6-7 VAP has a considerable mortality rate, with more than 30% of patients dying.⁷

VAP and COVID-19 became mandatory notification conditions for the Brazilian healthcare system in 2017 and 2022, respectively.^7-8 Epidemiological notification to regional and federal agencies of diseases, such as highly transmissible respiratory infections and nosocomial infections, is of utmost importance to identify rates, patterns and outbreaks, enabling the creation of prevention and control measures.

Given the pandemic scenario that occurred between 2020 and 2023, associated with the increase in ICU admissions and HAIs, the research question was developed: what is the epidemiological profile of patients hospitalized for COVID-19 in an ICU located in Porto Alegre, RS, who developed VAP? Based on this question, the objective was to understand the epidemiological profile of patients hospitalized for COVID-19 in an ICU who developed VAP.

METHOD

This is a retrospective cross-sectional study. This study design is indicated to assess the frequency of variables that are the objects of research investigation.⁹

The sample participants were selected intentionally and non-probably. Those admitted to an ICU in a hospital complex located in Porto Alegre, RS, which exclusively treated adult patients with COVID-19 between July 2020 and June 2021, were included.

Patients admitted to the ICU due to complications from COVID-19 and who received a microbiological diagnosis of VAP were included. Patients with a clinical diagnosis of VAP, i.e., without microbial proof, and those who did not present all the information regarding the variables collected in their medical records were excluded.

Data were collected through research in electronic medical records in the institution’s management system, with the researcher’s own access, and tabulated in a spreadsheet using Microsoft Excel^®. The variables collected were: sex; date of birth and age at the time of admission to the ICU (in years); weight (in kilograms), height (in meters) and Body Mass Index (BMI); presence of comorbidities, such as smoking, diabetes mellitus (DM), hypertension (HT) and history or current condition of malignant neoplasia, heart, kidney, liver, lung and/or immunosuppressive disease; outcome (hospital discharge or death); length of hospital stay (days); length of ICU stay (days); readmission to the ICU after 30 days of transfer to the inpatient unit or discharge; time of invasive mechanical ventilation (IMV) (days); microorganisms identified in the sample; and whether they have microbial resistance to the main antimicrobials used in each case.

Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS^®). Data were presented as frequencies and percentages. Quantitative variables were expressed as mean and standard deviation when symmetrical, and median and interquartile range when asymmetrical. Variables were compared using the Mann-Whitney test, with statistical significance if p-value was less than 0.05.

This study is part of a larger project entitled “Inteligência Artificial na Sistematização da Assistência de Enfermagem em pacientes com Síndrome Respiratória Aguda Grave”, which was approved by the Research Ethics Committee (REC) of the institution in question, via Opinion 4.694.150 and Certificate of Presentation of Ethical Consideration (Certificado de Apresentação para Apreciação Ética) 45203121.6.0000.5335. The researchers were included in the REC’s consolidated opinion through Opinion Amendment 5.329.313. Due to the retrospective nature of the methodology, the application of an Informed Consent Form was not necessary. Therefore, a Commitment Form for Data Use was applied, signed by the researcher. The research was conducted in compliance with the ethical standards required by Resolutions 466/2012, 510/20216 and 580/2018 of the Brazilian National Health Council.

RESULTS

Regarding the sample profile, the majority were male, with a minimum age of 30 and a maximum of 89 years, with a mean of 58.8±14.5 years. The table below presents the relationship of sociodemographic characteristics, age groups and classification according to BMI of the sample.

BMI values ranged from 21.1 to 44.5 points, with a mean of 30.2±5.7. Among the patients with obesity, five (9.3%) had grade I obesity, four had grade II obesity (7.4%) and two (3.7%) had grade III obesity.

Most patients had some comorbidity or risk factor (n=47, 87.0%). History of smoking or active smoking, obesity, hypertension, DM, previous or active diagnosis of malignant neoplasia and/or presence or history of cardiac, hepatic, immunological, pulmonary and renal diseases were considered as comorbidity or risk factor. Table 2 presents the relationship between comorbidities or risk factors identified in the portion of the sample that presented one or more cases (n=47). It was decided not to present the cases of obesity in this study, as they were already presented in Table 1.

Seven patients (14.9%) had heart disease, and one (2.1%) had two concomitant diseases (coronary artery disease and history of aneurysm). Liver disease was present in three (6.4%) patients. Conditions associated with the immune system (autoimmune diseases, infectious diseases that affect immunity and/or use of immunosuppressive medication) were present in ten (21.3%) patients, and six of these were using maintenance immunosuppressive therapy to prevent rejection of the transplanted organ, as four were kidney transplant recipients, one was liver transplant recipient and one was lung transplant recipient. Concerning lung disease, ten (21.3%) had a history or current situation of this health condition, and one (2.1%) had two concomitant lung conditions (cystic fibrosis and lung transplant). Kidney conditions were present in seven (14.9%) patients. As for malignant neoplasia, five (10.6%) had a condition already treated or under treatment at the time of hospital admission for COVID-19.

In relation to infections by microorganisms associated with VAP, 36 (66.7%) patients presented infection by a single microorganism; 16 (26.6%) presented infection by two concomitant microorganisms; and two (3.7%) presented infection by three concomitant microorganisms. Table 3 shows the relationship between the microorganisms found in the sample and the microbial resistance of each specimen.

All infections were caused by bacterial pathogens, with Staphylococcus aureus being the only gram-positive pathogen. All cases of carbapenem-resistant Klebsiella pneumoniae were K. pneumoniae carbapenemase (KPC), i.e., carbapenemase enzyme producers. Regarding S. aureus, all bacterial isolates showed sensitivity to methicillin/oxacillin.

Concerning clinical outcomes, most patients died (n=43, 79.6%). Only one (1.85%) patient was readmitted to the ICU within 30 days after discharge from the first intensive care admission. There was only one (1.9%) case of reintubation within 30 days associated with accidental extubation.

The length of hospital stay had a minimum value of 11 days and a maximum of 104 days, with a median of 33 (22;44). The length of ICU stay ranged from six to 90 days, with a median of 29 (20;41). As for the length of IMV, the data showed a minimum time of six and a maximum of 75 days, with a median of 26 (19;40). From the comparison of these data with the clinical outcomes of discharge or death, the result shown in Table 4 was obtained.

DISCUSSION

The profile of patients admitted to the ICU due to COVID-19 and developed VAP included males, aged between 60 and 69 years, overweight, and preexisting comorbidities, with the majority dying during hospitalization. Accordingly, a review conducted in 2023 showed that advanced age, males, and the presence of preexisting comorbidities were risk factors for worsening COVID-19 infection, consistent with the findings of this study.¹⁰

The mean age found in the sample was 58.8 years, with more than 50% of patients being 60 years or older. Similarly, an observational study carried out in 2021 showed a mean age of 64 years in patients with COVID-19 who developed VAP.¹¹ The predominance of patients over 60 years of age may be associated with the immunological vulnerability found in this population, increasing susceptibility to infections and more serious complications.^10-11

A considerable portion of the sample had a BMI equal to or greater than 30 kg/m², which, in the Ministry of Health (MoH) classification for adults (age group composed of people between 18 and 59 years old), is defined as obesity.¹²However, the MoH classification differs for people aged 60 or over, where rates in this range are not classified as obesity, but as overweight.¹² When applying this distinction to the sample, composed mainly of older adults, a predominance of overweight was observed, despite the majority having a BMI equal to or greater than 30 kg/m². The literature has identified a relationship between overweight and, especially, obesity, and an increase in severity and mortality in cases of infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A meta-analysis carried out in 2020, based on 16 studies that presented a population with more than 100,000 patients with COVID-19, identified a direct relationship between BMI and the severity and mortality of the infection by the disease.¹³ No studies were found that relate excess weight in patients who developed VAP after hospitalization for complications associated with COVID-19. However, from the analysis, it can be inferred that the results found regarding BMI are consistent with those found in the literature, since patients in the sample were admitted to intensive care due to complications associated with the virus infection.

Among the comorbidities observed in the sample, there was a predominance of hypertension and DM, respectively. Hypertension is the most prevalent comorbidity in cases of severe COVID-19, linking the complications associated with SARS-CoV-2 infection to the binding of the virus to angiotensin-converting enzyme (ACE) receptors.¹⁴ A study carried out in 2021 shows that, when using angiotensin-converting enzyme inhibitors (ACEIs), which inhibit the expression of ACE1 and promote the expression of ACE2, there is an excess of this protein in the body, allowing for an increase in susceptibility to coronavirus infection, severity and mortality from the disease.¹⁴ In line with this study, a review carried out in 2022 addresses that hypertension, in isolation, does not present an aggravating factor in cases of COVID-19, and ceasing the use of antihypertensives from the ACE inhibitor class is not a protective factor for complications associated with SARS-CoV-2 infection, recommending maintaining the use of drug therapy in order to also avoid target organ damage associated with uncontrolled hypertension.¹⁵

Studies have shown an influence on the occurrence of severe cases of COVID-19 in patients with DM. Based on the literature, it can be inferred that hyperglycemia negatively influences the action of the immune system, as well as promoting a state of chronic systemic inflammation, providing greater susceptibility to the severe form of COVID-19. The influence of the binding of SARS-CoV-2 to ACE2 produced by the pancreas in severe cases of the disease in diabetic patients is also highlighted.¹⁶

During the course of this research, a considerable number of patients who received solid organ transplants prior to hospitalization due to COVID-19 stood out. It is inferred that this result is associated with the use of immunosuppressive medications to maintain the transplant, which causes a reduction in the immune response to antigens, such as the coronavirus. Another study presented data that are in line with the findings of research.¹⁷A retrospective cohort study evaluating 600 patients who underwent solid organ transplants and were diagnosed with COVID-19 revealed higher rates of hospitalization, ICU admission, and mortality in transplant patients with the disease. Patients infected with SARS-CoV-2 were compared with those who had never received organ transplants, with a predominantly older adults with other comorbidities standing out in the transplant group.¹⁷ A systematic review that assessed the impact of COVID-19 on patients who received solid organ transplants concluded that mortality was not associated with immunosuppression, but rather with the advanced age of these patients.¹⁸Therefore, there is a need for new studies to analyze the relationship between mortality from COVID-19 and immunosuppression caused by maintenance medications for late transplants. No evidence was found indicating a relationship between VAP, COVID-19, and solid organ transplant recipients.

Furthermore, the study included four patients who were undergoing oncological treatment during their hospitalization due to complications associated with the coronavirus and who developed pneumonia due to the use of IMV. This data is consistent with that found in a study that assessed the impacts of the pandemic on oncological patients, identifying a higher prevalence of nosocomial infections in these patients, with VAP being the most common in patients with COVID-19.¹⁹ It can be inferred that, similarly to what was previously mentioned in the cases of transplant recipients, patients undergoing cancer treatment are more susceptible to infections and complications associated with them, due to the immunosuppression associated with drug therapy.¹⁹

Among the comorbidities, the prevalence of patients with lung diseases also stood out, totaling ten cases of history or active disease of these. Accordingly, the study identified that patients diagnosed with diseases such as asthma, chronic obstructive pulmonary disease, obstructive sleep apnea and hypopnea syndrome, emphysema and lung carcinoma presented greater complications associated with COVID-19 when compared to patients infected by the virus, but who did not present any respiratory tract comorbidity.²⁰ This result is associated with the nature of the disease, since COVID-19 is considered an acute respiratory infection, which can cause, in patients with previous pulmonary comorbidities, an exacerbation of the chronic condition, with worsening of respiratory function and development of serious complications, such as acute respiratory failure and acute respiratory distress syndrome.¹⁰

In the present study, only pathogens causing VAP of bacterial etiology were identified. Among these, a greater number of infections caused by gram-negative bacteria were observed, with the three main causes of infection being, respectively, A. baumannii, P. aeruginosa and K. pneumoniae. The first presented 100% microbial resistance, which is consistent with what was found in the literature. As presented by the Brazilian National Health Regulatory Agency, an increase in the rates of microbial resistance associated with A. baumannii strains was observed.²¹ Furthermore, a literature review indicates that more than 20% of nosocomial infections in ICUs are caused by this gram-negative bacterium, which is the main causative agent of VAP, with a considerable increase in cases of infection associated with A. baumannii in recent years.²² According to the findings in the study, P. aeruginosa and K. pneumoniae were also predominant in the narrative review.²³ As for gram-positive microorganisms, the only one present in the sample was S. aureus. A cohort study carried out in 2023 showed that this is the most predominant gram-positive bacteria in pneumonias associated with the use of IMV, as evidenced.²⁴ No studies were found that presented the survey of VAP associated with one or more causative microorganisms.

The study showed that, regardless of the outcome, the median length of hospital stay was over 30 days. Concerning the length of ICU stay, the median was 29 days. In line with this, another study presented values higher than those found in this study, with a median of 39.5 days of hospital stay and 43 days of ICU stay in cases of patients admitted to the ICU due to complications from COVID-19 and diagnosed with VAP.²⁴ Due to the unavailability of these data, this study did not analyze the number of days on IMV until the diagnosis of VAP, but rather the total number of days on IMV until patients’ outcome. Therefore, no studies were found that analyzed the total number of days on mechanical ventilation of patients with COVID-19 and VAP until the time of hospital discharge or death.

From the analysis of the associations between the variables of length of hospital stay, ICU stay and IMV and clinical outcomes, fewer days were observed in the cases of patients who died during hospitalization compared to those who were discharged from hospital. It is inferred that this result is related to the severity of sample participants, since, due to instability, patients presented worsening of their general condition and death shortly after transfer to the ICU.

Most patients died during hospitalization, due to the predominance of comorbidities, advanced age, and the absence or small number of people vaccinated against COVID-19 during the study period, as well as infection by microorganisms that cause VAP, allowing the occurrence of cases of acute respiratory failure, acute respiratory distress syndrome, sepsis, septic shock, and death. Although vaccination against COVID-19 began in the country during the study period, only a small percentage of Brazilians had received one or more doses of the vaccine, which explains the high mortality rate in the sample as well as due to the multiple comorbidities observed during the research.

Due to the researchers’ choice to conduct the study in the ICU of the hospital complex that remained for the longest time with exclusive care for COVID-19 cases, the sample was smaller than expected, which proved to be a limitation of this study. It is suggested that new studies with a larger sample size be carried out. Furthermore, the present study cannot present a comparison of the morbidity and mortality of the disease caused by SARS-CoV-2 before and after the advent of vaccination in the country, due to lack of information in the electronic system, indicating the conduct of studies that present the relationship between the morbidity and mortality linked to COVID-19, before and after the advent of vaccination in Brazil, associated with comorbidities and the multiple pathogens that cause VAP.

It is believed that the results of this research may record part of what occurred during the pandemic and support future research that assesses the relationship between complications associated with SARS-CoV-2 infection, the presence of comorbidities and VAP.

REFERENCES

1. Fundação Oswaldo Cruz. (BR). Boletim Observatório Covid-19: Boletim Especial - Balanço de dois anos da pandemia Covid-19. Rio de Janeiro: FIOCRUZ; 2022. https://www.arca.fiocruz.br/handle/icict/55828.

2. Organização Pan-Americana da Saúde. OMS afirma que Covid-19 é agora caracterizada como pandemia. Brasília, DF: OPAS; 2020. https://www.paho.org/pt/news/11-3-2020-who-characterizes-covid-19-pandemic.

3. Organização Pan-Americana da Saúde. OMS declara fim da Emergência de Saúde Pública de Importância Internacional referente à Covid-19. Brasília, DF: OPAS; 2023. https://www.paho.org/pt/noticias/5-5-2023-oms-declara-fim-da-emergencia-saude-publica-importancia-internacional-referente.

4. Corrêa TD, Midega TD, Timenetsky KT, et al. Características clínicas e desfechos de pacientes com Covid-19 admitidos em unidade de terapia intensiva durante o primeiro ano de pandemia no Brasil: um estudo de coorte retrospectivo em centro único. Einstein. 2021; 19: eAO6739. https://doi.org/10.31744/einstein_journal/2021AO6739.

5. Fundação Oswaldo Cruz (BR). MonitoraCovid-19. Rio de Janeiro: FIOCRUZ; 2022. https://bigdata-covid19.icict.fiocruz.br/.

6. Blot S, Ruppé E, Harbarth S, et al. Healthcare-associated infections in adult intensive care unit patients: Changes in epidemiology, diagnosis, prevention and contributions of new technologies. Intensive Crit Care Nurs. 2022; 70: 1-15. https://doi.org/10.1016/j.iccn.2022.103227.

7. Agência Nacional de Vigilância Sanitária. (BR). Medidas de Prevenção de Infecção Relacionada à Assistência à Saúde. Brasília, DF: ANVISA; 2017. 122p. https://www.gov.br/anvisa/pt-br/centraisdeconteudo/publicacoes/servicosdesaude/publicacoes/caderno-4-medidas-de-prevencao-de-infeccao-relacionada-a-assistencia-a-saude.pdf.

8. Ministério da Saúde. (BR). Portaria GM/MS nº 1.102, de 13 de maio de 2022. Altera o Anexo 1 do Anexo V à Portaria de Consolidação GM/MS nº 4, de 28 de setembro de 2017, para incluir o Sars-CoV-2 [...]. Diário Oficial da República Federativa do Brasil, Brasília (DF), 2022 Mai 13; Seção 1. https://bvsms.saude.gov.br/bvs/saudelegis/gm/2022/prt1102_16_05_2022.html.

9. Martins AAB, Teixeira D, Batista BG, et al. Epidemiologia. Porto Alegre: SAGAH; 2018. 284 p. ISBN: 9786556903651.

10. Zhang J, Dong X, Liu G, et al. Risk and Protective Factors for Covid-19 Morbidity, Severity, and Mortality. Clin Rev Allergy Immunol. 2023; 64 (1): 90-107. https://doi.org/10.1007/s12016-022-08921-5.

11. Giacobbe DR, Battaglini D, Enrile EM, et al. Incidence and Prognosis of Ventilator-Associated Pneumonia in Critically Ill Patients with Covid-19: A Multicenter Study. J Clin Med. 2021; 10 (4): 555. https://doi.org/10.3390/jcm10040555.

12. Ministério da Saúde. (BR). Secretaria de Atenção à Saúde. Departamento de Atenção Básica. Cadernos de Atenção Básica, nº 38: Estratégias para o cuidado da pessoa com doença crônica - Obesidade. Brasília, DF: Ministério da Saúde; 2014. 212 p. http://189.28.128.100/dab/docs/portaldab/publicacoes/caderno_38.pdf.

13. Du Y, Lv Y, Zha W, et al. Association of body mass index (BMI) with critical Covid-19 and in-hospital mortality: A dose-response meta-analysis. Metabolism. 2020; 117: 154373. https://doi.org/10.1016/j.metabol.2020.154373.

14. Gasmi A, Peana M, Pivina L, et al. Interrelations between Covid-19 and other disorders. Clin Immunol. 2021; 224: 108651. https://doi.org/10.1016/j.clim.2020.108651.

15. Gallo G, Calvez V, Savoia C. Hypertension and Covid-19: Current Evidence and Perspectives. High Blood Press Cardiovasc Prev. 2022; 29 (2): 115-123. https://doi.org/10.1007/s40292-022-00506-9 .

16. Govender N, Khaliq OP, Moodley J, et al. Insulin resistance in Covid-19 and diabetes. Prim Care Diabetes. 2021; 15 (4): 629-634. https://doi.org/10.1016/j.pcd.2021.04.004.

17. Sahota A, Tien A, Yao J, et al. Incidence, Risk Factors, and Outcomes of Covid-19 Infection in a Large Cohort of Solid Organ Transplant Recipients. Transplantation. 2022; 106 (12): 2426-2434. https://doi.org/10.1097/TP.0000000000004371.

18. Opsomer R, Kuypers D. Covid-19 and solid organ transplantation: Finding the right balance. Transplant Rev. 2022; 36 (3): 100710. https://doi.org/10.1016/j.trre.2022.100710.

19. Cornejo-Juárez P, Volkow-Fernández P, Vázquez-Marín CL, et al. Impact of coronavirus disease 2019 (Covid-19) pandemic in hospital-acquired infections and bacterial resistance at an oncology hospital. Antimicrob Steward Healthc Epidemiol. 2023; 3 (1): e70. https://doi.org/10.1017/ash.2023.148.

20. Beltramo G, Cottenet J, Mariet A, et al. Chronic respiratory diseases are predictors of severe outcome in Covid-19 hospitalised patients: a nationwide study. Eur Respir J. 2021; 58: 2004474. https://doi.org/10.1183/13993003.04474-2020.

21. Agência Nacional de Vigilância Sanitária. (BR). Microbiologia Clínica para o Controle de Infecção Relacionada à Assistência à Saúde. Brasília, DF: ANVISA; 2020 [cited 2023 Dec 28]. 162p. https://www.gov.br/anvisa/pt-br/centraisdeconteudo/publicacoes/servicosdesaude/publicacoes/modulo-10_manual-de-microbiologia.pdf.

22. Shadan A, Pathak A, Ma Y, et al. Deciphering the virulence factors, regulation, and immune response to Acinetobacter baumannii infection. Front Cell Infect Microbiol. 2023; 13: 1053968. https://doi.org/10.3389/fcimb.2023.1053968.

23. Boyd S, Nseir S, Rodriguez A, et al. Ventilator-associated pneumonia in critically ill patients with Covid-19 infection: a narrative review. ERJ Open Res. 2022; 8 (3): 00046. https://doi.org/10.1183/23120541.00046-2022.

24. Moreno J, Carvelli J, Lesaux A, et al. Ventilator Acquired Pneumonia in Covid-19 ICU Patients: A Retrospective Cohort Study during Pandemia in France. J Clin Med. 2023; 12 (2): 421. https://doi.org/10.3390/jcm12020421.