key: cord-0788869-hj54fq9r
authors: Dadras, Omid; SeyedAlinaghi, SeyedAhmad; Karimi, Amirali; Shamsabadi, Ahmadreza; Qaderi, Kowsar; Ramezani, Maryam; Mirghaderi, Seyed Peyman; Mahdiabadi, Sara; Vahedi, Farzin; Saeidi, Solmaz; Shojaei, Alireza; Mehrtak, Mohammad; Azar, Shiva A.; Mehraeen, Esmaeil; Voltarelli, Fabrício A.
title: COVID‐19 mortality and its predictors in the elderly: A systematic review
date: 2022-05-23
journal: Health Sci Rep
DOI: 10.1002/hsr2.657
sha: e7f38f3a2bce6cee59f1f29f83712a3998d9b4ef
doc_id: 788869
cord_uid: hj54fq9r

BACKGROUND AND AIMS: Older people have higher rates of comorbidities and may experience more severe inflammatory responses; therefore, are at higher risk of death. Herein, we aimed to systematically review the mortality in coronavirus disease 2019 (COVID‐19) patients and its predictors in this age group. METHODS: We searched PubMed, Web of Science, and Science Direct using relevant keywords. Retrieved records underwent a two‐step screening process consisting of title/abstract and full‐text screenings to identify the eligible studies. RESULTS: Summarizing findings of 35 studies demonstrated that older patients have higher mortality rates compared to the younger population. A review of articles revealed that increasing age, body mass index, a male gender, dementia, impairment or dependency in daily activities, presence of consolidations on chest X‐ray, hypoxemic respiratory failure, and lower oxygen saturation at admission were risk factors for death. High d‐dimer levels, 25‐hydroxy vitamin D serum deficiencies, high C‐reactive protein (≥5 mg/L) levels plus any other abnormalities of lymphocyte, higher blood urea nitrogen or lactate dehydrogenase, and higher platelet count were predictors of poor prognosis and mortality in the elderly. Studies have also shown that previous treatment with renin–angiotensin–aldosterone system inhibitors, pharmacological treatments of respiratory disorders, antibiotics, corticosteroids, vitamin K antagonist, antihistamines, azithromycin, Itolizumab (an anti‐CD6 monoclonal antibody) in combination with other antivirals reduces COVID‐19 worsening and mortality. Vaccination against seasonal influenza might also reduce COVID‐19 mortality. CONCLUSION: Overall, a critical consideration is necessary for the care and management of COVID‐19 in the aged population considering the drastic contrasts in manifestation and prognosis compared to other age groups. Mortality from COVID‐19 is independently associated with the patient's age. Elderly patients with COVID‐19 are more vulnerable to poor outcomes. Thus, strict preventive measures, timely diagnosis, and aggressive therapeutic/nontherapeutic care are of great importance to reduce acute respiratory distress syndrome and severe complications in older people.

In the winter of 2019, an unknown infection was reported from Wuhan, China. Further investigations demonstrated its Coronaviridae origin. 1,2 Soon, many countries around the world reported cases of coronavirus disease 2019 . 3, 4 After some months, the World Health Organization announced this outbreak as a pandemic. 5 The clinical spectrum of this disease ranges from asymptomatic infection to a severe disease turning into acute respiratory distress syndrome (ARDS) and death. 6, 7 ARDS causes lungs to become stiff and precipitates hypoxemia and subsequent death in a considerable proportion of the patients if they do not receive adequate ventilation. 8 Since then, as of February 19th, more than 416.6 million confirmed cases and more than 5.8 million deaths were reported around the world. 9, 10 There have been many efforts how to make COVID-19 diagnosis faster and more reliable; but still, real-time reverse transcription-polymerase chain reaction is the most helpful assay for COVID-19 diagnosis. 11 Severe acute respiratory syndromecoronavirus-2 (SARS-CoV-2) can affect not only the respiratory system but also many vital human organs. 12 Few options exist for COVID-19 treatment and physicians mostly rely on symptomatic treatments. 13 Aging can change the human body in many aspects and then affect the human immune system in many ways, such as a higher inflammatory response to antigens with lower efficacy to suppress infections. 14, 15 On the other hand, older patients have more chronic diseases, such as hypertension, making them more susceptible to severe forms of COVID-19 based on some earlier reports. [16] [17] [18] Therefore, older people have higher mortality rates compared to younger patients (the mortality of people over 60 years old is 4.5% in comparison to 1.4% in people under 60) 19, 20 and therapeutic interventions may be less effective among them. Therefore, it has become an important challenge how to manage elderly people infected by COVID-19 to decrease the mortality rate.

In the present article, we aimed to systematically review the mortality rates in older patients compared to young patients. We also reviewed the factors increasing the mortality rate in the elderly, such as underlying diseases.

This systematic review follows the preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines (PRISMA 2020 checklist is mentioned in Supporting Information Material 1). We conducted this systematic review by searching the online databases of PubMed, Web of Science, and Science Direct for the relevant literature using keywords and operational phrases. The studies were retrieved and the duplicate records were removed. We followed a two-step screening process to sort the eligible results. First, we examined the title and abstract of the records and the ineligible studies were removed. Then, their full texts were evaluated based on their cohesion to the inclusion/exclusion criteria and the eligible ones were included for qualitative synthesis. The screening process was performed by two researchers, and another independent researcher addressed any controversies between them. 

We included the original studies that evaluated the mortality in the elderly and/or reported the risk factors for higher mortality rates. The exclusion criteria were the following: 1) Nonoriginal studies, including reviews and non-original editorials;

2) pure laboratory or animal studies not conducted on humans;

3) case reports and case series; 4) studies not conducted on the elderly patients; 5) studies not related to the mortality of the patients; and 6) abstracts or conference abstracts, or not available full-text.

Two researchers extracted and organized it into a word 

We used the Newcastle-Ottawa scale (NOS) to analyze the risk of bias in the studies. 21 NOS provides a maximum score of 9 for each study in three categories of selection, comparability, and exposure.

We defined a score of 4 or below as "poor," and above that as "acceptable."

We used the recommendations of the Cochrane handbook of systematic reviews chapter 14.2 to assess the certainty of the evidence for this study. 22 

After removing irrelevant and duplicates, the title and abstract of the remaining 110 articles were reviewed. Applying the eligibility criteria, 23 articles were excluded, and 35 full-text articles that met the inclusion criteria were included in the final review ( Figure 1 ).

The included studies were conducted in 10 countries (China = 14, Italy = 5, Spain = 5, France = 2, South Korea = 2, Cuba = 2, and one study from Germany, Australia, Brazil, and Japan). One of the articles was also a report on multinational scientific collaborations. Table 1 shows a summary of the findings. All the studies had acceptable scores in the risk of bias assessment ( Table 2 ). Certainty of evidence analysis results is mentioned in Table 3 , demonstrating acceptable evidence certainty for most of the parameters, except for the lack of matching the control groups of several studies for confounders.

We summarized each study's main findings. Studies have revealed that increasing age, dementia, and impairment in dependency in activities of daily living were strong risk factors for inhospital death, regardless of disease severity. D-dimer level was also an independent predictor of mortality.

According to the findings, body mass index had an association with severe COVID-19. Moreover, 25-hydroxy vitamin D deficiency is associated with more severe lung involvement, longer disease duration, and risk of death in the elderly.

The review of articles showed that predicting survival factors were female sex, previous treatment with renin-angiotensin-aldosterone system inhibitors, higher oxygen saturation at admission, and a greater 

Considerable differences in the clinical course and risk predictors for COVID-19 exist between the elderly and other age groups patients. 53 Our knowledge of the COVID-19 infection implies that the elderly, in DADRAS ET AL. | 3 of 15 contrast to young-and middle-aged patients, are more susceptible to severe clinical outcomes of the disease and fatality. In fact, old age is a significant predictor of poor prognosis, suggesting that agingrelated mechanisms may be integral elements in disease severity. 51 58 Another study demonstrated a 1.55-fold increase in the mortality rate for every 5 years increase in age. 46 To date, both predictors for in-hospital mortality of the elderly and some survival factors have been identified. The mortality predictors include hypernatremia, lymphopenia, high interleukin 6 (IL-6) and CRP serum levels, elevated D-dimer, dyspnea, dementia, and so forth. 24, 39, 46, 52 Also, in a study on the elderly population, men had higher mortality than women. 34 On the other hand, survival factors such as interferon atmotherapy and reduced metabolic pathway activities were also identified. 31 Subject to advanced age and comorbidities, the elderly are considered a high-risk group for developing severe manifestations and complications, some of which are discussed as follows. They are more likely to be hospitalized or admitted to the intensive care unit.

Also, compared with younger people, they have a longer hospitalized time, and their duration of the disease has a positive correlation with age. 28 From the pulmonary aspect, they are more likely to develop critical pneumonia and ARDS. A study found more grade IV and V pneumonia, based on the pneumonia severity index, among the elderly than younger COVID patients. 53 These severe complications can be traced back to lung muscle atrophy, reduced airway clearance, lung reserve, and defense barrier function. 28 Heart failure and acute cardiac injury are other complications of COVID-19 that are more common in the elderly. The reason for their higher frequency could be underlying chronic cardiovascular diseases. 49 Moreover, fungal and bacterial infections were more prevalent among the elderly based on the increased number of white blood cells and neutrophils in their laboratory tests. 51, 53 Furthermore, gastrointestinal symptoms interfering with feeding can make the elderly more vulnerable to malnutrition. 36, 59 Acute liver and kidney injuries, septic shock, and multiple organs dysfunction syndrome are other complications quite common in this age group. 49, 51, 53 The general pattern of signs and symptoms in COVID-19 infection among the elderly is almost similar to that of young-and middle-aged patients. However, a few differences may be noticed. A study reported fever, cough, and dyspnea as the most common symptoms. 46 Also, it has been reported that symptoms in the elderly begin with fever and cough, followed by shortness of breath and admission in 2-7 days. Then, they can be developed into respiratory failure, ARDS, and death in the following days. 34 COVID-19 signs and symptoms in the elderly differ from others in some aspects. The time from onset of the infection to confirmed diagnosis has been reported longer than that nonelderly patients. A study has attributed this to the atypical manifestation of clinical symptoms. 47 Another study has found that anorexia is more common in the elderly, while younger patients are more likely to develop a fever. Also, the elderly showed a higher systolic blood pressure and slower heart rate than the younger patients. 51 Substantial risk factors for poor prognosis among the elderly include fever during hospitalization and severe initial F I G U R E 1 Preferred reporting items for systematic reviews and meta-analyses flow diagram of the selection process. cTnI, cardiac troponin-I; GNRI, geriatric nutritional risk index; GRF, glomerular filtration rate; HFNC, high-flow nasal cannula; hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; MV, mechanical ventilation; proBNP, pro-B-type natriuretic peptide; PSI, pneumonia severity index; RAAS, renin-angiotensin-aldosterone system; VKA, vitamin K antagonist.

presentations, such as dyspnea, tachypnea, hypoxia, altered mental status, and hypotension. 23, 24 Of interest, the elderly are more often asymptomatic and afebrile while having a similar viral load to the symptomatic patients; therefore, they can be a significant source of viral spread. 28 Considering that the elderly usually have different underlying comorbidities and are more susceptible to severe complications of COVID-19 infection, comprehensive care for them is of great importance. Early diagnosis and supportive care may prevent severe outcomes. 46 Also, particular attention should be paid to a thorough T A B L E 2 Newcastle-Ottawa scale quality assessment for the included studies L i Q . 27 **** ** *** 9 6 Liu K. 29 **** -*** 7 7 Liu Z. 30 **** -*** 7 8 Mei Q. 31 **** ** *** 9 9 Ménager P. 32 **** ** ** 8 10 Blanco J. I. M. 33 **** -*** 7 11 Mostaza J. 34 **** -*** 7 12 Mori H. 28 **** -*** 7 13 Annweiler G. 35 **** ** *** 9 14 Araújo, M. P. D. 36 *** -*** 6 15 Bongiovanni M. 37 *** * *** 7 16 Cocco P. 38 *** ** ** 7 17 Covino M. 39 *** ** *** 8 18 Dai S. P. 40 **** -*** 7 19 Díaz Y. 41 *** -*** 6 20 FranchiniM. 42 *** -*** 6 21 Gao, S. 43 *** -*** 6 22 Pratt N. 44 *** -*** 6 23 Ramos-Rincon J. M. 45 *** ** *** 8 24 Recinella G. 46 *** ** *** 8 25 Rui L. 47 *** -** 5 26 Saavedra D. 48 *** -** 5 27 Song J. 49 **** -*** 7 28 Sulli A. 50 **** ** *** 9 29 Tan X. 51 *** -*** 6 30 Trecarichi E. 52 *** ** *** 8 31 Wang L. 53 *** * *** 7 32 Wassenaar T. M. 54 *** -*** 6 33 Yan F. 55 **** ** *** 9 34 Zeng F. 56 **** * *** 8 35 Zhang P. 57 **** ** *** 9 DADRAS ET AL. | 11 of 15 assessment of them while they are admitted since they are more prone to severe illness. Different aspects that need to be focused on include advanced respiratory support due to more susceptibility to ARDS and cardiac monitoring due to the possibility of acute cardiac injury. 49 Other strategies for improving the health condition of the elderly include minimizing exposure to the virus as a preventive measure, implementing telemedicine methods, having multidisciplinary teams and multicomponent programs for geriatric units, maintaining good nutritional status and healthy eating habits, and influenza vaccination resulting in a reduced impact of COVID-19 epidemic waves. 36, 38, 39 Having multiple comorbidities such as diabetes mellitus (DM), hypertension, heart disease, lung disease, and so forth, are predictive factors of poor prognosis, higher mortality, and morbidity in the elderly. 40 

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