Clinical characteristics of older patients with COVID-19: a systematic review of case reports

ABSTRACT. In the context of the current COVID-19 pandemic, higher morbidity and mortality have been reported in older adults. This age group presents physiological changes and its own clinical conditions such as frailty, dementia, among others. Objective: To describe the characteristics of COVID-19 patients, both over and under 80 years old, by conducting a systematic review of the literature describing case reports, and to summarize and critically assess these characteristics. Methods: Systematic review. The study was registered on the Registry of Health Research Projects (PRISA) of the Peruvian National Institute of Health (code EI00000631). Five electronic databases (Scopus, PubMed, PubMed Central, LILACS, and SCIELO) were systematically searched during the period between December 31, 2019 and April 16, 2020. The search focused on case reports, case studies, and case series of older people with COVID-19 infection aged over or under 80 years. When selecting the cases, priority was given to clinical and epidemiological profile, laboratory and imaging patterns, and comprehensive geriatric evaluation. Results: 1,149 articles were identified; after applying the filters, a total of 15 publications of case reports and complete records of 27 older adults were obtained. The most frequent age group was between 60 to 69 years old. There is little literature regarding case reports of older adults aged over 80 years. The most frequent parameters were hypertension, fever, cough, respiratory distress, ground-glass opacification in chest radiography and tomography. Furthermore, decrease in PaO2/FiO2 ratio and lymphocytes, and increase in C-reactive protein and Interleukin 6 were observed. Conclusions: This systematic review found little available information of patients under 80 years old, and far less for those over 80 years old, and an absence of comprehensive geriatric assessment.


INTRODUCTION
O n December 31, 2019, a cluster of new pneumonia cases (fever, dry cough, and dyspnea) was reported in the city of Wuhan, China. The outbreak of a new coronavirus (CoV), called Coronavirus Disease 2019 (COVID- 19), was thus caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The infection progressively spread throughout the world. 1 The World Health Organization (WHO) declared COVID-19 a global pandemic on March 11, 2020, by which date over 5,406,282 cases and 343,562 deaths 2 had been confirmed.
In Latin America, the first COVID-19 case was reported in Brazil on February 26, 2020, 3 whereas in Peru the first case was reported on March 6, 2020. 4 As of the date of this study, Peru has approximately 129,751 confirmed cases and 3,788 deaths. 5 COVID-19 may affect people of any age; however, with a fatality rate above 8%, people over the age of 70 years with or without comorbidities seem to be more susceptible. 6 All countries report that the highest mortality rate for severe disease is verified for those aged over 80 years. 7 One of the factors of greater virulence and severity of COVID-19 in older people are the physiological changes that occur at this age. Immunosenescence is characterized by a decreased function of innate and acquired immunity that may be conducive to an imbalance and, hence, to a chronic proinflammatory state, which make patients susceptible to infections and noncommunicable chronic diseases. 8 In addition, older people present other clinical conditions, such as frailty, sarcopenia, disability, cognitive decline, anxiety, depression, and others, which exacerbate and are conducive to a negative progression of the disease. 9 For this reason, researching and classifying these conditions are accepted as the best strategy to define the need for care and to predict the prognosis. 10,11 On the other hand, healthcare systems are not adapted to treat older adults. 12 Although an individual is considered old from the age of 60 years, various classifications based on age groups have been proposed. However, taking this into consideration, the cutoff at the age of 80 years becomes relevant and is consistent with progressive physiological changes and clinical conditions. 13 In contrast, in the general population, the current diagnosis of COVID-19 is based on epidemiology history, clinical pattern observation, auxiliary exams, such as chest X-ray and Computed Tomography, and is confirmed by molecular and/or serological tests. [14][15][16][17] According to the National Institute of Statistics and Information, older adults in Peru represented 10.14% of the total population in 2017. 18 The current COVID-19 pandemic is more lethal in older people; in Peru, reports show that 2,609 of the 3,788 deaths were of older adults. 5 It is necessary to gather information that allows to differentiate older people suffering from COVID- 19.
The purpose of this article is to describe the clinical characteristics of COVID-19 patients, aged both over and under 80 years, by conducting a systematic review.

METHODS
This is an observational, cross-sectional, and systematic review study.
The ethical aspects of the study observed at all times included beneficence, non-maleficence, confidentiality, and justice principles. The study was registered on the Registry of Health Research Projects (PRISA) of the Peruvian National Institute of Health (Instituto Nacional de Salud -INS) with code EI00000631.
• Contrasting of selected studies, and resolution of divergences through discussion and consensus. • Extensive reading of the clinical case reports. • Confirmation of clinical case reports after contrasting with the inclusion criteria.
Extraction of objective information and data management: information was independently extracted by seven reviewers; an ad hoc data collection form was used. The forms were compared and resolutions were reached through discussion and consensus.
Data presentation: descriptive tables were prepared considering the four fundamental items of the study. Absolute and relative frequencies, mean and standard deviation, median and interquartile range are presented, as appropriate. The Statistical Package for the Social Sciences (SPSS) software, version 25, was used. Table 1 shows the used keywords and the strategies implemented for the systematic search in the selected databases.

RESULTS
The systematic review of the databases yielded a total of 1,149 results. After applying the filters, a total of 15 publications dealing with clinical case reports were obtained, and the review process is shown in Figure 1.

Epidemiological characteristics
During the COVID-19 pandemic, older people have disproportionately been severely affected by the disease, and indeed have required hospitalization and accounted for high death rates, particularly those aged over 80 years. 19 Considering this new virus, it is undoubtedly necessary to collect new data and develop evidence-based strategies concerning prevention and management of people affected by the virus. 20 This research only found 27 reported cases of older adults with COVID -19 that met the inclusion criteria; their median age was approximately 65 years and only one case was of an individual aged over 80 years. 21 Despite this group being the most affected by this pandemic, there are no significant studies on epidemiology or clinical manifestations of COVID-19 in older adults.
Likewise, the relatively low median age reported by this investigation would explain the verified evolution: only one death, 3.7% of the total. Wu et al., 22 in a cohort of patients, found that aging over 65 years alone is an independent risk factor for developing acute respiratory distress syndrome (ARDS) and for death probably due to less rigorous immune response. These results have been corroborated by various publications worldwide. 23,24 On the other hand, some research in older people with COVID-19 have indicated that the contributing factors for poor health outcomes include the physiological changes of aging, 25 but mainly the multiple comorbidities related to age, 26 such as heart and lung diseases, diabetes, dementia, and polypharmacy. However, a preprint has found that, in older adults from Mexico, comorbidities or inequalities in accessing healthcare systems (difficulty in accessing a healthcare service or not having health insurance) are predictors of severity for COVID-19, regardless age. 27 Hence, it should be noted that some literature has reported that a significant      proportion of older people living in nursing homes failed to be hospitalized and died, drawing attention to their limited access to healthcare services such as an adequate management with a comprehensive geriatric approach, including palliative care. 19,[28][29][30] Moreover, health profiles, stress response, and functional ability of older adults significantly vary. While some of them have low intrinsic capacity -i.e., they are care-dependent -, others have high functional capacities and actively participate in and contribute to their communities. 31 Geriatric medicine has shown that efficient health interventions in older adults should be determined by the conditions of frailty, functional ability, and care dependence of older adults. [32][33][34][35] In addition, reporting and generating information on some specific variables, such as polypharmacy, living in long-term care facilities, multiple comorbidities, and physical dependence, would enrich the literature on COVID-19 and older people available to date. 20,36 However, in this investigation, no case report referred to the evaluation of functionality, frailty condition, functional, cognitive and emotional state, or to polypharmacy or regular residence in long-term institutions. All of these aspects are considered important for the prognosis of older people.
Regarding the epidemiological characteristics of older adults with COVID-19, this study, like reports from other countries, 5,20,[31][32][33][34][35][36][37][38] found that men aged 60 to 69 years were the most affected and that more than half of older people with COVID-19 had some comorbidity, and this proportion is much higher when compared with young patients with underlying conditions. 39 For Liu et al., 38 these findings would indicate weaker immune functions in male older adults, thus increasing the risk of infection by SARS-CoV-2.  (2) Hemoglobin (g/dl) 13-17.

Clinical manifestations
Furthermore, a large percentage of older adult patients with COVID-19 included in this review had fever when admitted to the hospital, a fact that has also been reported by other investigations 40,41 in middle-aged groups. Likewise, Zhou et al. 42 report an average of 11 days lapsing from the onset of symptoms to admission in patients aged 46 to 67 years and an average of seven days from the onset of the first symptom to the appearance of dyspnea. In contrast, this study found that, in this population, an average of six days lapsed from the onset of the first symptom to hospitalization, and an average of seven days until the onset of dyspnea.
An important result of this investigation suggests that dyspnea is not a frequent symptom at hospital admission in adults and older patients with COVID-19, but is rather developed later. This is consistent with the severity of the disease. Previous studies have shown that the duration from symptom onset to dyspnea was 7-8 days in patients with COVID-19, 41,42 one day after hospital admission. Those studies have also shown that only 18.7% of patients have dyspnea at the time of admission, 19,40-43 but it was usually more frequent in patients admitted to the ICU, who required mechanical ventilation, or who died. 43,44 Although these investigations focused their study on the adult population, these  results are similar to those found in the present review, considering the low median age of older people already discussed. In contrast, the absence of dyspnea at the time of the medical consultation can be explained by Gattinoni et al.,45 who indicate that patients infected with SARS-CoV-2 would initially have severe hypoxemia due to vasoplegia, which, on account of low lung compliance, can increase ventilation and compensate it. This phenomenon is called silent hypoxemia.

Radiological findings
Regarding the imaging findings, it was evident that the most predominant radiological finding at the time of admission, during hospitalization, and in the ICU was the ground-glass opacification pattern, a result similar to that found in other studies. [46][47][48][49][50][51] However, this investigation only found a few cases with sequential radiological examinations. In this regard, it is worth considering the timing of the X-ray or CT, since there is evidence that the patterns may vary specifically depending on the timing of the natural history of the disease. 47 Thus, it is suggested that, in future radiological studies, the day of the imaging examination should be considered regarding the patients' onset of symptoms. Likewise, it was found that the locations of the lesions were mostly peripheral, which is in accordance with what has been reported in younger ages. [47][48][49][50] Conversely, Salehi et al., 48 found atypical initial imaging presentation of consolidative opacities superimposed on ground glass mainly in older populations. In this review, a basal consolidation pattern was more frequent observed in plain chest X-rays, whereas, the ground-glass pattern is more likely to be observed in CT scan. Therefore, the imaging findings in older people do not differ from that found in younger age groups, and the CT scan, due to its high sensitivity for the diagnosis of COVID-19, 51 could potentially be used as a detection technique in epidemic areas. Nevertheless, it is necessary to carry out more studies and consider a larger sample to determine this hypothesis.

Laboratory features
Moreover, alterations in laboratory tests were similar to those presented in other articles for middle-aged groups. 52,53 Concerning altered values, the PaO 2 /FiO 2 ratio was less than 150 in most of the patients, demonstrating that the infection causes a severe level of hypoxemia. 53 In the white series, leukocytosis in patients admitted to the ICU was found. In contrast, lymphopenia worsens during the ICU stay, with decrease in the CD8 lymphocyte group. These findings corroborate another study in which decreases in leukocytosis, CD8 lymphocytes, and Natural Killer cells occur, possibly associated with overexpression of the Natural-Killer receptor group 2-A (NKG2A), which is induced by SARS-CoV-2 causing functional fatigue of the lymphocytes from the initial phase of the disease. 54,55 The evaluation of troponins was normal, despite 37% of the patients having some cardiovascular history. A meta-analysis found that troponins were elevated in patients with severe COVID-19. 56 Finally, the presence of increased urea values is associated with higher hospital mortality in COVID-19 patients due to reported kidney involvement. 57 It is worth emphasizing that, according to laboratory evidence, the inflammatory process has been present in older people with COVID-19 since hospitalization. According to Zhao et al., 58 in a study that included 82.4% older people, the increase in C-reactive protein, interleukin 6, and procalcitonin was observed in more than 60% of cases. Likewise, another study indicated that increased lactate dehydrogenase and C-reactive protein are strongly associated with the presence of severe COVID-19 disease. 59 Both results are supported by Chen et al., 43 who indicate that low values of these markers are associated with patients who recovered from the disease. On the other hand, excessive increase in IL-6 after acute lung damage leads to multiple organ failure (MOF) and to a cytokine storm. 45 Additionally, increase in C-reactive protein may be partly attributed to the effects of IL-6. 60 Although the production of procalcitonin in viral infections is inhibited by interferon (INF-y), procalcitonin is elevated in severe patients. This could reflect the presence of an over-aggregated bacterial infection, which would cause increase in the concentrations of interleukin 1 beta (IL1-b), tumor necrosis factor alpha (TNF-a), and IL-6. 61

Used therapies
Regarding treatment, antivirals were the most frequently used drugs in older adults, but their efficacy for the treatment of COVID-19 is unclear. This review found that 51.9% of hospitalized older patients with COVID-19 received some antiviral; however, 64% of them ended up in the ICU. One of the most widely used antivirals was Lopinavir-Ritonavir. Nevertheless, the only clinical trial of this drug observed that hospitalized adult patients with severe COVID-19 did not show any benefits over standard care. 62 The second most widely used antiviral during hospitalization in the reviewed cases was Interferon. Recently, a clinical trial carried out by Hung et al., 63 evaluated the triple therapy of Interferon beta-1b, Ribavirin plus Lopinavir-Ritonavir, finding that this combination has better performance than the treatment with Lopinavir-Ritonavir alone in alleviating symptoms and shortening duration of virus clearance and hospital stay in patients with mild to moderate COVID-19 infection. However, this study did not have a placebo group and the triple therapy was only administered to those patients with an illness duration of seven days or less. On the other hand, Remdesivir, an experimental antiviral (GS-5734), has been subject to only one clinical trial to date; such study found that adult patients with a median age of 65 years, admitted to the hospital for severe COVID-19, and given the drug had no clinical benefits. 64 Nevertheless, the complete results of a clinical trial funded by the US National Institute of Allergy and Infectious Diseases are still being evaluated and, according to its preliminary report, such drug would have shortened the recovery time of hospitalized adults with COVID-19 (average age of 59 years). 65 Other antivirals, such as Oseltamivir, have limited activity against SARS-CoV-2, while Favipiravir and Umifenovir, the internationally available influenza antivirals, have different viral targets and require further investigation. 66 Likewise, aminoquinolines was not frequently used for the treatment of older people (two out of the 27 cases); however, the latest studies on aminoquinolines are controversial. Initially, Gautret et al., 67 found that Hydroxychloroquine treatment was significantly associated with reduced viral load in patients with COVID-19 and its effect was enhanced by Azithromycin. However, this study did not include the criterion of clinical severity of participants, the mean age was around 51.2 years, no randomization was used, and sample size was limited. Then, Tang et al., 68 found that Hydroxychloroquine treatment did not result in a significantly higher likelihood of negative conversion than standard care alone of hospitalized adult patients (mean age of 46 years) with mild to moderate COVID-19 infection. Other observational studies found that treatment with Hydroxychloroquine, Azithromycin, or both was not significantly associated with differences in hospital mortality, 69 risk of intubation, or death, 70 and it did not appear to have any effect on reducing admissions to intensive care or death. 71 Furthermore, in patients aged 60 years and older, Hydroxychloroquine for the treatment of COVID-19 has a high risk of prolongation of the corrected QT (QTc) interval, and concurrent treatment with Azithromycin is associated with greater changes in electrocardiogram. 72 To date, the clinical trial from Mehra et al., 73 conducted with 96,032 adult patients (mean age of approximately 53.8 years), the largest sample to date, failed to determine a benefit of Hydroxychloroquine or Chloroquine, when used alone or with a macrolide, in the hospital results of COVID -19; those who did not survive had a mean age of 60 years and had some comorbidity. Thus, taking into account the current evidence, the administration of aminoquinolines in older people should be done with caution and be strictly monitored, considering adverse effects and polypharmacy due to the large number of interactions with other drugs. Even in countries where Hydroxychloroquine has been indicated to treat COVID-19, such use should be reconsidered or the monitoring and care should be strengthened.
As for immunological treatments in older adults with COVID-19, scientific evidence is insufficient to support their use; however, new clinical evidence could shed light on such treatments. To date, there are no published results of clinical trials on convalescent plasma treatment, 74 except one clinical trial (NCT04345991) that will finish its study in June 2021 75 and nine others that will be completed in the following months. However, no specification has been given on whether they will assess older people and whether the results of this group will be separately presented. Similarly, there are no clinical trials to support Tocilizumab treatment. However, the relevant intervention of IL-6 in cytokine storm allows some authors to theorize that Tocilizumab may become an effective medicine for patients with severe COVID-19. 46 An important outcome of the present study was the scarce information found in the literature regarding case reports of COVID-19 infection in adults aged over 80 years.
In addition, the authors found no evidence of case reports of COVID-19 infection in older patients that considered specific conditions, such as frailty, dementia, emotional status, level of functionality, polypharmacy, and others, and how to manage them.
The age group was between 60 to 69 years, and the main clinical, laboratory, radiological, and therapy-related findings were as follows: a) more than one comorbidity; b) fever, which was the most frequently reported manifestation at hospital admission; c) dyspnea, which was the most frequently reported manifestation at hospitalization; d) imaging of ground-glass opacification, which was the main outcome at hospital admission and hospitalization; e) increased level of lactate dehydrogenase, C-reactive protein, interleukin 6, and procalcitonin were the most frequently observed features; and f) antivirals, Hydroxychloroquine, antibiotics, corticoids, monoclonal antibodies, and herbal drugs were used as treatment options.