Risk factors for the in‑hospital and 1‑year mortality of elderly patients hospitalized due to COVID‑19‑related pneumonia
- Authors:
- Published online on: November 20, 2023 https://doi.org/10.3892/etm.2023.12310
- Article Number: 22
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Copyright: © Georgakopoulou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
On March 11, 2020, the World Health Organization (WHO) characterized the coronavirus disease 2019 (COVID-19), an infection caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), as a pandemic (1). As of May 24, 2023, 766,895,075 confirmed cases of COVID-19 and 6,935,889 related deaths were recorded worldwide, according to the WHO (2). With the progress of the vaccination campaign and the succession of SARS-CoV-2 mutations, the proportion of patients with COVID-19 requiring hospitalization and the mortality associated with COVID-19 have markedly changed during the pandemic, and the incidence of confirmed cases and deaths continues to decline worldwide (2).
Patients with COVID-19 present with a wide range of respiratory manifestations, ranging from mild clinical course to severe and potentially life-threatening pneumonia (3). In addition, some patients experience gastrointestinal symptoms, such as vomiting, diarrhea, abdominal pain and nausea in addition to the respiratory symptoms (4,5), as well as cardiovascular and neurological symptoms (6).
Multiple risk factors for severe COVID-19 infection have been identified since the beginning of the pandemic, such as diabetes mellitus, arterial hypertension, cardiovascular disease and malignancies (7). COVID-19 is characterized by poor outcomes and high mortality rates, particularly among elderly patients. Since the beginning of the pandemic, an older age has been recognized as a critical risk factor for disease severity, with increasing mortality rates in each decade of life (8). This phenomenon may be a consequence of a poor previous health status, with a higher prevalence of pre-existing comorbidities and a higher degree of frailty. It is unclear whether the poorer quality of service provided in health care systems collapsed worldwide by the unprecedented pandemic contributes to the observed poor prognosis of the elderly (9).
The majority of studies on the outcomes and risk factors of elderly patients refer to the first waves of the pandemic and predictors of in-hospital mortality in these patients. A previous systematic review of these studies reported that an increasing age, body mass index, male sex, dementia, reduced functionality or dependence for daily activities, the presence of infiltrates on chest X-ray, hypoxemic respiratory failure and a lower saturation of oxygen upon admission were risk factors for mortality due to COVID-19(10). High levels of D-dimers, 25-hydroxyvitamin D deficiency, high levels of C-reactive protein (CRP) plus any other lymphocyte abnormalities, higher blood urea or lactate dehydrogenase (LDH) levels, and higher platelet count (PLTs) have been established as predictors of poor outcomes in the elderly (10). It has been reported that prior treatment with renin-angiotensin-aldosterone system inhibitors, pharmacological treatments for respiratory diseases and other medications, such as antibiotics, corticosteroids, vitamin K antagonists and antihistamines in combination with other antivirals reduces the likelihood of severe COVID-19 infection and mortality. Seasonal influenza vaccination may also reduce mortality from COVID-19, according to that previous systematic review.
As elderly patients represent a vulnerable population even in the era of omicron mutation prevalence and as the infection becomes endemic, data are required to improve healthcare pathways in the context of COVID-19(11). The aim of the present study was to provide a detailed description of the clinical characteristics and management of a cohort of elderly patients (≥65 years of age) who were hospitalized with COVID-19-related pneumonia in all phases of the pandemic, to present their outcomes, and to investigate predictors of in-hospital and 1-year mortality rates in this particularly vulnerable population.
Patients and methods
Study design
For the purposes of the present study, a retrospective recording of data was carried out on consecutive elderly patients aged ≥65 years who were hospitalized with COVID-19-related pneumonia at the Infectious Diseases Unit of Laiko General Hospital during the period October 1, 2020 to July 15, 2022, including patients who were infected from the initial strain and from the Alpha, Delta, and Omicron variants. The study was conducted in line with the Declaration of Helsinki and obtained approval by the Institutional Review Board of Laiko General Hospital, Athens, Greece (protocol no. 7950/08.06.2023). Written informed was obtained from all the included the patients.
Data collection
The demographic characteristics (sex, age), clinical symptoms, the extent of pneumonia on the chest X-ray with the chest X-ray score (12), the vaccination status against SARS-CoV-2, any comorbidities and the Charlson Comorbidity Index (CCI) were recorded. The following admission laboratory findings were also recorded: Hemoglobin (Hb) and hematocrit (Hct) levels; white blood cells (WBC); neutrophils (Neu); lymphocytes (Lym); PLTs and immature granulocytes (IGs); CRP; serum albumin and LDH levels; D-dimer levels; fibrinogen (FIB); creatinine; ferritin; the levels of liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT); and cholestatic enzymes gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP). The patients were treated according to the WHO recommendations which represent the standard clinical practice (13) and these treatments received by the patients for the treatment of COVID-19 pneumonia were recorded.
Recording of outcomes
In-hospital mortality rates were recorded, as well as mortality rates within 1 year of admission. Predictors of mortality were also investigated. Patients without a reliable follow-up at 1 year were excluded from the study.
Statistical analysis
Statistical analysis was performed using IBM SPSS-Statistics version 29.0 (IBM Corp.). The Kolmogorov-Smirnov test was used to examine the normal distribution of parameters. Continuous parameters with a normal distribution are shown as the mean (standard deviation), and those with a non-normal distribution are shown as the median (range). For the analysis of categorical variables, the Chi-squared or the Fisher's exact tests were used. To detect predictors of events (event=in-hospital mortality or mortality at 1 year), statistically significant variables were assessed using univariate and multivariate Cox proportional hazards regression analysis. Values of P<0.05 were considered to indicate statistically significant differences.
Results
A total of 1,124 elderly patients (603 males, 53.7%) with a mean age of 78.51±7.42 years and a median CCI of 5 were included in the study. Of these patients, 104 (9.3%) were hospitalized during the period of prevalence of the original Wuhan strain, 385 (34.3%) were hospitalized during the period of prevalence of the Alpha variant, 221 (19.7%) were hospitalized during the period of prevalence of the Delta variant, and 414 (36.8%) were hospitalized during the period of prevalence of the Omicron variant. Overall, the in-hospital mortality rate was 33.4% (375 patients) and the 1-year mortality was 44.7% (502 patients). The majority of patients had not been vaccinated or had not completed full vaccination against SARS-CoV-2 (843 patients, 75%), given the time period of infection. The demographics of the total study population are summarized in Table I.
The most common symptom upon admission was fever (755 patients, 67.2%), followed by dyspnea (619 patients, 55.1%) and cough (312 patients, 27.8%) (Table II). The most common comorbidity was arterial hypertension (558 patients, 49.6%), followed by cardiovascular disease, which included stroke, coronary artery disease, valvular diseases, arrhythmias and cardiomyopathy (433 patients, 38.5%), and diabetes mellitus (305 patients, 27.1%) (Table III).
The majority of the patients were treated with anticoagulants, dexamethasone and remdesivir; 83 (7.4%) patients received tocilizumab; 12 (1.1%) patients received baricitinib; and 9 (0.8%) patients received anakinra. In 138 (12.3%) patients, oxygen therapy with a high-flow nasal cannula was applied; in 18 (1.6%) patients, non-invasive mechanical ventilation was applied; and 134 (11.9%) patients were intubated (received invasive mechanical ventilation) (Table IV).
 | Table IVMedication that was administrated to the study population during the hospitalization period. |
In total, 3 (0.2%) patients had received prophylactic intravenous remdesivir; 4 (0.4%) patients had received the combination of monoclonal antibodies casirivimab/imdevimab; and 24 (2.1%) patients had received the combination of antiviral agents nirmatrelvir/ritonavir (Table V).
| Table VProphylactic therapy that patients received for COVID-19 prior to their admission to the hospital. |
The univariate analysis of categorical variables for the outcome of in-hospital mortality revealed that patients who succumbed to the disease in the hospital were significantly more likely to be in the Delta variant prevalence period (in-hospital mortality rate: 92/129 patients, 41.6%); these patients also had a statistically higher proportion of cardiovascular disease, heart failure, renal disease and a history of nursing home residency. In addition, the lack of complete vaccination, dyspnea and an altered mental status were significantly associated with the in-hospital mortality rate, and fever, cough, sore throat, disruptions in taste/smell and fatigue were significantly associated with the in-hospital survival rate (P<0.05; Table VI).
The univariate analysis of continuous variables for the outcome, in-hospital mortality, revealed that the patients who succumbed in hospital had a significantly older age, lower Hb and lower Hct levels, higher CCI, higher WBC, higher Neu count, higher IG count, higher value of D-dimers, higher value of creatinine, higher values of AST, ALP, GGT, LDH, CRP, ferritin and chest X-ray score, and a lower value of Lym count compared to the survivors (P<0.05; Table VII).
From the multivariate analysis for the outcome of in-hospital mortality, it emerged that age, IGs, LDH, ferritin, chest X-ray score, as well as the absence of full vaccination, cough and fatigue, were significantly and independently associated with the in-hospital mortality rate (P<0.05; Table VIII).
The univariate analysis of continuous variables for the outcome of 1-year mortality revealed that patients who succumbed within 1 year were significantly more likely to have been ill in the period of prevalence of the Alpha variant (mortality within 1 year, 52%); these patients also had a significantly greater proportion of arterial hypertension, cardiovascular disease, heart failure, renal disease, dementia, Parkinson's disease, hematological malignancy, solid organ malignancy and a history of nursing home residency. Furthermore, dyspnea and an altered mental status were statistically significantly associated with mortality, and fever, cough, sore throat, disruptions in taste/smell and fatigue were statistically significantly associated with the 1-year survival (P<0.05; Table IX).
The univariate analysis of categorical variables for the outcome of 1-year mortality revealed that patients who succumbed within 1 year had a significantly older age, lower Hb and lower Hct levels, higher CCI, higher WBC value, higher Neu value, higher value of IGs, higher value of D-dimers, higher value of creatinine, higher value of ALP, LDH, CRP, ferritin and chest X-ray score, and a lower value of Lym, ALT and GGT compared to the survivors (P<0.05; Table X).
From the multivariate analysis for the outcome of 1-year mortality, it was found that age, LDH, ferritin, ALT, CCI, chest X-ray score, the absence of cough and fatigue, and a history of dementia were significantly and independently associated with mortality within 1 year (P<0.05; Table XI).
As shown in Table I, an additional 127 elderly patients succumbed within 1 year of admission. As regards the causes of death, the majority of patients succumbed due to cardiac events, including acute myocardial infarction, arrhythmia, cardiogenic shock, or pulmonary edema. The second cause of death was septic shock (36 patients, 28.3%); in 13 patients, the cause of death was not specified, while it is noteworthy that 3 patients (2.4%) succumbed due to a new SARS-CoV-2 infection (Table XII).
Discussion
According to the present study, the in-hospital and out-of-hospital mortality of elderly patients with COVID-19 was high. Overall, the in-hospital mortality rate was 33.4% (375 patients), and the 1-year mortality rate was 44.7% (502 patients). As regards in-hospital mortality, the findings of the present study are in agreement with those of previous studies (14-18), reporting on the in-hospital mortality of elderly patients from the first waves of the pandemic. The present study is one of the few studies reporting on in-hospital mortality of elderly patients over a long period of the pandemic, including the period of prevalence of the Omicron variant. It is also the first study, to the best of our knowledge, to present the 1-year mortality for elderly patients who were hospitalized during all periods of the pandemic.
The majority of the patients who succumbed within 1 year did not survive mainly due to cardiac events. It has been documented that after COVID-19, there is an increased risk of cardiovascular events such as arrhythmias, ischemic and non-ischemic heart disease, pericarditis, myocarditis, acute heart failure and thromboembolic events. Mechanisms underlying the association between COVID-19 and the development of cardiac complications include the prolonged damage from direct viral invasion of myocardial cells and cell death, endothelial cell infection and subsequent endothelitis, the activation of the complement and complement-mediated coagulation and microangiopathy, transcriptional alteration of multiple cell types in cardiac tissue, ACE2 downregulation and renin-angiotensin-aldosterone system dysfunction, autonomic nervous system dysfunction, increased levels of pro-inflammatory cytokines, and activation of TGF-β signaling through the Smad pathway leading to fibrosis and scarring of cardiac tissue. In addition, a possible factor explaining cardiac complications is an abnormal, persistent hyperactivated immune response, either autoimmune or in the context of the persistence of the virus in immunologically privileged sites. The integration of their SARS-CoV-2 genome into the DNA of infected human cells, which can then express some transcripts containing viral and cellular human sequences, has also been reported as a putative mechanism for the sustained activation of the immune-inflammatory procoagulant cascade (19,20).
The second cause of death within 1 year was septic shock. No association was observed with the administration of immunosuppressive agents, such as corticosteroids and tocilizumab. It is likely that the emergence of new infections and septic shock after COVID-19 are due to the dysfunction of the immune system combined with the impaired immune response of the elderly following COVID-19 infection (21,22).
Of note, 3 patients succumbed due to a new SARS-CoV-2 infection, and 2 of these patients were hospitalized during the time period of the prevalence of the Omicron variant. Protection against reinfection by the original strain and the Alpha and Delta variants was found to decrease over time, but remained at 78.6% (49.8-93.6) at 40 weeks. Protection against reinfection by the Omicron BA.1 subvariant declined more rapidly and was estimated at 36.1% (24.4-51.3) at 40 weeks. However, protection against severe disease has been reported to remain high for all variants, with 90.2% (69.7-97.5) for the original strain and the Alpha and Delta variants and 88.9% (84.7-90.9) for the Omicron BA.1 subvariant at 40 weeks (23).
In the present study, age, IGs, LDH, ferritin, chest X-ray score and the absence of full vaccination, cough and fatigue were significantly and independently associated with the in-hospital mortality of this older population. The majority of these findings are consistent with those of previous studies of the in-hospital mortality of elderly patients with COVID-19 (14,16,24-27). Among studies in the general population, age has been reported as an independent predictor of mortality within 1 year after COVID-19 (28,29). It has also been reported that in the general population, chronic obstructive pulmonary disease, chronic cardiovascular disease and active malignancy are also independent predictors of 1-year mortality following infection with SARS-CoV-2(29). However, there are no data to date, as mentioned above, on mortality within 1 year for elderly patients, and the present study is the first (at least to the best of our knowledge) to report that age, LDH, ferritin, ALT, CCI, chest X-ray score, the absence of cough and fatigue, and a history of dementia were statistically significantly and independently associated with mortality within 1 year.
Several factors accompanying aging, including the altered expression of the ACE2 receptor, the increased production of reactive oxygen species, the increased activity of senescent adipocytes, altered autophagy and mitophagy, immunosenescence, as well as vitamin D deficiency, may be involved in the pathophysiology of severe disease and poor outcomes in elderly patients with COVID-19(30). Increased IG counts detected in peripheral blood demonstrate an enhanced bone marrow activity and have been linked to poor outcomes in patients with COVID-19(31). Increased LDH levels in the circulation could reflect either the direct SARS-CoV-2 infection of cells or marked tissue damage secondary to an excessive systemic inflammatory response (32). Ferritin is known as an acute phase reactant, and its levels are increased in acute and chronic inflammation; in COVID-19, ferritin has been linked to disease severity (33). Elevated ALT levels have also been associated with poor outcomes of patients with COVID-19, reflecting liver injury (34-36).
It has been reported that initial chest X-ray scores of patients with COVID-19 are linked to clinical outcomes, such as mortality, the length of hospitalization and the duration of invasive ventilation (37). Since the beginning of the pandemic, comorbidities have been known to affect the outcomes of patients with COVID-19. In the three stages of COVID-19, from the initial viral replication phase to the inflammatory tissue injury and long-term consequences, specific comorbidities can either exacerbate these pathological mechanisms that determine health outcomes or lower the patient's tolerance for organ injury (38). One established risk factor for the mortality of patients with COVID-19 is a lack of vaccination (39). Furthermore, vaccination against COVID-19 has been proven to be highly beneficial in reducing hospitalization and mortality among the elderly (40,41).
In addition, cough has been shown to be associated with better outcomes in patients with COVID-19(42). As regards the symptom of fatigue, it has been linked to poor outcomes of patients with COVID-19(43); however, in the present study, it was associated with in-hospital and with 1-year survival.
Dementia is also a well-established risk factor for the poor outcomes of elderly patients hospitalized due to COVID-19 (43,44) and according to the present study, it was an independent risk factor for 1-year mortality.
The present study has certain limitations which should be mentioned. The present study was a single-center study without a control group. In addition, medications that patients were receiving for underlying diseases were not included in the analysis. Finally, SARS-CoV-2 variants were not identified individually for patients. Variant assignment was based on the prevalent variant at the time the patient was diagnosed with the infection, and distinction was made only based on whether patients were diagnosed before or after the appearance of the Omicron variant.
In conclusion, both the in-hospital and 1-year mortality of elderly patients hospitalized due to COVID-19 pneumonia is high. As regards the causes of death, the majority of patients succumbed due to cardiac events. Age, IGs, LDH, ferritin, chest X-ray score, as well as the absence of full vaccination, cough and fatigue were significantly and independently associated with in-hospital mortality, while age, LDH, ferritin, ALT, CCI, chest X-ray score, the absence of cough and fatigue, and a history of dementia were significantly and independently associated with 1-year mortality.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
NVS and VEG conceptualized the study. VEG, AT, DB, DAS, SM, AG, GK, PMV, IrE, SS, MT, IoE, OK, CVP, AA, IT, NT, PP, PS and NVS made a substantial contribution to data interpretation and analysis and wrote and prepared the draft of the manuscript. PS and NVS analyzed the data and provided critical revisions. VEG and NVS confirm the authenticity of all the data. All authors contributed to manuscript revision, and have read and approved the final version of the manuscript.
Ethics approval and consent to participate
The present study was conducted in line with the Declaration of Helsinki and gained approval by the regional Institutional Review Board (protocol number protocol no. 7950/08.06.2023). Written informed was obtained from all the included patients.
Patient consent for publication
Not applicable.
Competing interests
DAS is the Editor-in-Chief for the journal, but had no personal involvement in the reviewing process, or any influence in terms of adjudicating on the final decision, for this article. The other authors declare that they have no competing interests.
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