key: cord-0863554-mb4ag3kp
authors: Remelli, Francesca; Volpato, Stefano; Trevisan, Caterina
title: Clinical features of SARS-CoV-2 infection in older adults
date: 2022-03-21
journal: Clin Geriatr Med
DOI: 10.1016/j.cger.2022.03.001
sha: 0486b90ce431acc4e115331af9964bc9b3bf3470
doc_id: 863554
cord_uid: mb4ag3kp

The heterogeneity of Covid-19 clinical presentation is extremely diversified, especially in older patients due to possible presence of atypical symptoms at disease onset, such as delirium, hyporexia and falls. Despite this findings, even in older people the typical clinical presentation with fever and respiratory symptoms remains the most probable. The clinical characteristic at Covid-19 onset are influenced by the presence of common health-related conditions in geriatric subjects, such as comorbidity, disability and frailty, and not simply by chronological age. Moreover, few studies investigated the tendency of Covid-19 symptoms to aggregate in cluster and the use of cluster approach might better describe the clinical complexity of the acute disease. Finally, concerning the prognostic significance of Covid-19 clinical presentation in older people, the available literature still provides discordant results: currently, patients with atypical symptoms report a higher risk to adverse outcomes, such as severity of acute illness and death.

In April 2020, SARS-CoV-2 (Covid- 19) infection was declared a pandemic emergency by the World Health Organization (WHO) 1 and after two years, in January 2022, the virus had already caused more than 357 million confirmed cases and 5.6 million deaths globally. 2 Older people have been described as extremely vulnerable to SARS-CoV-2, reporting a high probability of adverse outcomes, such as hospitalization, intensive care unit admission, and mortality. 3 In the first phases of the pandemic, in older patients the fatality rate was almost 8 times higher than in younger age groups. 4 Although advanced age has been correlated with higher mortality risk, the presence of specific health-related and clinical conditions (i.e. multimorbidity, disability, and frailty), common in older people, may explain the main age-related differences in susceptibility during SARS-CoV-2 infection. 5, 6 Moreover, these conditions could also modify the clinical presentation of Covid-19, with a higher frequency of atypical symptoms and signs in older than younger age, such as hyporexia and delirium. 7 This narrative review aims to describe the current knowledge on the clinical features of SARS-CoV-2 infection in older adults, focusing on the heterogeneity of clinical presentation and the health-related conditions that might determine a different clinical picture of this disease in advanced age. Moreover, we discuss the prognostic value of specific symptoms at Covid-19 presentation in older people.

The clinical presentation of Covid-19 disease is extremely heterogeneous (Figure 1 ): in a Cochrane systematic review published in 2020, up to 27 symptoms and signs of SARS-CoV-2 infection were described. 8 Based on the current literature, however, it is still unclear whether this high symptoms variability depends exclusively on the characteristics of the virus or, in addition to age and sex, also on the presence of the host's health-related conditions, such as comorbidities, disability, and frailty. 7 Among patients with Covid-19 infection, the most common reported symptoms were fever, cough, and dyspnoea; other frequent symptoms were headache, sore throat, fatigue, myalgia, gastrointestinal symptoms (such as nausea, vomiting, and diarrhea), anosmia, and ageusia. 9 Of note, in studies of J o u r n a l P r e -p r o o f older patients anosmia and ageusia have been described more rarely, probably because they are poorly reported by the patient, as a consequence of cognitive decline, age-related sensory's impairements, and because of the presence of the confounding effect of medications taken. 10 In addition, the prevalence of asymptomatic and paucisymptomatic patients is not irrelevant and may hamper the application of measures to contain the virus's diffusion. 2 A retrospective study on 141 individuals aged 50 years or older with SARS-CoV-2 infection confirmed that also in older people the most common clinical presentation of Covid-19 disease included typical symptoms, especially fever (79.5%), cough (61.4%), and dyspnea (31.8%) for those between 65-79 years; and fever (75.0%), cough (43.8%), dyspnea (25.5%) and fatigue (25.5%) for those aged 80 years and over. 11 Indeed, in advanced age, the variability in the clinical presentation of Covid-19 is wider due to the higher prevalence of atypical symptoms and signs, such as gastrointestinal ones (nausea, vomiting, and diarrhea), hyporexia, delirium, and falls. 12, 13 These findings confirm previous studies that focused on the clinical presentation of common diseases in geriatric patients and observed that about one-third of older individuals admitted to the Emergency Department (ED) had atypical symptoms of the underlying disease, with the absence of fever being the most common described atypia. 14

Age-related differences in the clinical presentation of Covid-19 have been widely described across the literature of the last two years. 15, 16 In a multicenter study conducted on 107 hospitalized individuals >60 years old with SARS-CoV-2 infection, the oldest group of patients (>75 years old) was more likely to present atypical symptoms, such as apyrexia and hyporexia, than the youngest one. Of note, however, the most frequent clinical presentation of Covid-19 disease was characterized by typical symptoms including fever and cough, in both age classes. 15 For example, in a study on sample of 788 Covid-19 people, of which more than 80% was middle-age adults, provided similar results and the most reported presenting symptoms on hospital admission were typical (i.e. fever and dyspnoea). 17 Consistently, several studies highlighted the presence of opposite trends in the frequency J o u r n a l P r e -p r o o f of typical and atypical symptoms across age classes: 13, 16, 18 atypical symptoms became more likely with increasing age with a parallel reduction in typical ones, although the latter remained the most frequent within the single age classes. Among atypical clinical presentations, Martín-Sánchez et al.

showed that older Covid-19 individuals presented a higher rate of confusion (5.7% vs 0.3%) and presyncope or syncope (7.9% vs 2.4%) than adults at ED admission. 13 The prevalence of confusion at Covid-19 onset reaches 11.7% in a sample of 103 older patients aged >80 years. 18 Likewise other infections, 19 the risk to develop delirium was higher in patients with SARS-CoV-2 infection aged 80 years and over than those 70-79 years old (28.4% vs 21.4%). 20 As mentioned above, when compared to older people, middle-aged adults showed atypical signs of Covid-19 disease more rarely, except for gastrointestinal symptoms. Indeed, in a prospective study performed in China in 2020 on young adults with suspected SARS-CoV-2 pneumonia, only vomiting and abdominal pain were described as atypical clinical presentations of the disease 21 , while no atypical signs were reported in other works involving adult individuals. 22 Of note, because of the young age of both samples (37 and 46.7 years old, respectively), no associated comorbidities were described. 21, 22 

Whether the peculiar clinical features of Covid-19 in older people exclusively depends on advanced age, or rather on the presence of health-related conditions, common in geriatric individuals, such as comorbidities, motor disability, and frailty, is still uncertain. Indeed, several studies showed that older people with Covid-19 can develop different clinical pictures and degrees of severity of the disease, also within the same age class (Table 1) J o u r n a l P r e -p r o o f Moreover, a widespread hypothesis supported by the scientific community is that the presence of typical geriatric syndromes (e.g. multimorbidity, disability) can influence the Covid-19 clinical presentation ( Figure 2 ). Indeed, most of the hospitalized Covid-19 patients reported more than one chronic disease (such as diabetes, hypertension, and coronary heart diseases) 27 and were more likely to develop a severe form of the disease. 24 In the study of Lian et al., older individuals showed a higher number of comorbidities than the younger group (55.15% vs 21.93%), as well as a greater risk to develop a critical Covid-19 disease. 17 These findings were confirmed also by Niu et al., 11 that reported a higher prevalence of severe Covid-19 disease in older patients and higher mortality among people >80 years old than in the 50-64 years old (18.8% vs. 1.2%, respectively). In a study on 319 Covid-19 patients aged 60 years and over, comorbidities such as chronic obstructive pulmonary disease (COPD), cardiovascular and cerebrovascular diseases, increased the probability to develop a severe disease. 28 Finally, a similar picture was observed in 586 residents of Long-Term Care facilities with suspected SARS-CoV-2 infection, within 88.8% of positive patients (n = 159) reported three or more comorbidities and this influenced the severity of Covid-19 disease (especially the presence of dementia). 25 Several studies investigated the possible link between frailty and Covid-19 clinical presentation. It is widely known that in older patients the presence of frailty, either defined according to Fried 29 or Rockwood criteria, 30 is strongly correlated with adverse outcomes. [31] [32] [33] Indeed, through the assessment of frailty, a better stratification of the individual's biological reserve and risk profile can be achieved, as compared to the simple assessment of chronological age. 34 Therefore, several studies were conducted to evaluate the role of frailty in older patients with SARS-CoV-2 infection. Although the reported results are not uniform, most of the available studies support the usefulness to assess frailty in older people with Covid-19 disease. [34] [35] [36] [37] [38] In an observational study on 165 individuals with Covid-19 admitted in a Geriatrics Unit, Marengoni et al. demonstrated that patients who were more likely to die during the hospitalization were already frail before Covid-19 onset (37.5% vs 4.1%) 36 .

In addition, every unit increment on the Clinical Frailty Scale (CFS) 39 was associated with a 30% J o u r n a l P r e -p r o o f increased risk of death, regardless of age. 36 Despite some contrasting resuts, 35 a multicenter study published in Lancet and including 1564 Covid-19 inpatients with a mean age of 74 years, frailty was associated with an 83% increased risk of death in people with a CFS of 5-6, and with more than two fold-risk in case of a CFS of 7-9, regardless of age. 34 Consistent findings emerged from a prospective study on 254 older inpatients admitted for Covid-19, where frail patients were more likely to develop in-hospital delirium (43.2% vs 8.2%) and to die compared with their non-frail counterparts. 38 Concerning clinical presentation, Bavaro et al. demonstrated that frail Covid-19 patients reported a higher risk of low oxygen saturation and extrapulmonary signs at disease onset, such as electrolytes disturbances, dehydration, and confusion. 40 In an observational study conducted on two cohorts in the hospital and community settings, delirium was reported as a very likely presenting symptom of Covid-19 in frail older individuals. 41 Considering that the presence of dementia is strictly connected with frailty, Annweiler et al. showed that older patients affected by dementia had a higher risk of developing delirium at Covid-19 onset. 20 These results were strengthened by a position paper published in 2020 by Bianchetti et al., where it was reported that 67% of older people with dementia developed delirium as a unique presenting symptom of Covid- 19. 42 In conclusion, in older people, the simple chronological age appears poorly predictive of the Covid-19 severity and health-related outcomes. For this reason, the implementation of the Comprehensive Geriatric Assessment in these patients would allow to better evaluate the presence of comorbidities, disability, and frailty, and improve prognostic estimation.

Due to its high clinical heterogeneity, the clustering approach has been proposed to better describe the presenting symptoms of Covid-19, increase the accuracy of clinical diagnosis, and forecast the progress towards more severe forms of the disease. Indeed, some researchers observed the tendency of some symptoms and signs to aggregate, identifying specific symptom clusters of Covid-19 disease (Table 2) Specifically, Cluster 1 was characterized by the co-presence of ageusia, anosmia, and fever; Cluster 2 by dyspnoea, cough and chest pain, Cluster 3 by asthenia, myalgia, and headache, Cluster 4 by diarrhea and vomiting, and Cluster 5 by rhinitis and pharyngodynia. Clusters 1 and 2 were the most strictly associated with SARS-CoV-2 infection. However, this study did not perform any sub-analysis on different age groups (about one-third were >60 years old), and no information on comorbidity and pre-acute physical performance was reported.

In a similar study, Trevisan et al. A third study performed using the clustering approach was conducted by Sudre et al.: 43 their purpose was to identify specific symptom clusters to predict the prognosis of Covid-19 disease, specifically the necessity of respiratory support. This work will be discussed in the next paragraph.

Regarding the prognostic significance of Covid-19 presenting symptoms in older patients, the available literature is still not uniform. In two Chinese studies performed in 2020 on older individuals with SARS-CoV-2 infection, no differences in mortality were observed based on the clinical characteristics at disease onset. 44, 45 On the other hand, in an Italian study conducted on 14 hospitalized older individuals with delirium during Covid-19 disease, the authors found that all patients who developed hypokinetic delirium died compared with the 50% of those with hyperkinetic form. These results supported the role of delirium as a negative prognostic factor in older patients with Covid-19 disease, especially the hypokinetic form. 46 These findings are consistent with those described by previous geriatric literature, 14 inasmuch delirium appeared strictly associated with a higher risk of death, regardless of clinical respiratory severity, pre-acute cognitive status, and motor disability. In a multicenter retrospective study in patients aged 80 years and over with Covid-19, mortality was 24% higher in those experiencing falls and 12% higher in those with confusion at the disease onset. 47 In addition to these symptoms, Gómez-Belda et al. found that the presence of oxygen saturation <93% at Covid-19 onset was associated with increased mortality (OR=11.65, 95%CI: 3.26-41.66) in patients >70 years old. 48 Concerning the prognostic significance of symptom clusters, to our knowledge, only one study investigated the need for respiratory support (supplemental oxygen and ventilation) in Covid-19 patients. 43 This work was conducted by Sudre et al. 43 Cluster 6 (non-specific symptoms) were associated with a higher risk of needing respiratory support during the acute disease. Of note, this study involved young individuals (mean age 44 years old) and did not investigate possible age-related differences. Currently, therefore, data on the Covid-19 symptom clusters that may be more strongly associated with higher mortality are still lacking, especially as concerns older people.

Severe health-related and social effects of the SARS-CoV-2 pandemic affect especially older people, due to the high risk of social isolation, hospitalization, disability, and death. In addition, the heterogeneity of clinical presentation in this age class has often led to a delay in diagnosis, and, consequently, of treatment. Thus, based on the available studies on Covid-19 symptoms and signs in advanced age, standardized questionnaires should be created and administrated at disease onset and, in case of hospitalization, at admission; in this context, the clustering approach may help to improve the diagnostic phase of the disease. Moreover, the prognostic value of Covid-19 presenting symptoms may be extremely useful to discriminate high-risk patients, therefore it should be deeply investigated with special attention to the older population.

The Covid-19 clinical presentation is extremely heterogenous and, in older people, it is influenced, not simply by chronological age, but also by common geriatric syndromes, such as multimorbidity, motor disability, and frailty. Consequently, although typical respiratory symptoms remain the most frequent clinical presentation of Covid-19 in all age classes, in older patients atypical symptoms (including but not limited to delirium and hyporexia) are more common than in middle-aged adults and have been associated with adverse outcomes. Moreover, some studies described the tendency of Covid-19 presenting symptoms to aggregate in clusters and this approach seems to better capture the J o u r n a l P r e -p r o o f The symptoms clusters associated with SARS-CoV-2 positivity were: 1) ageusia, anosmia, and fever; 2) dyspnea, cough, and chest pain.

Anosmia and ageusia were the key symptoms for SARS-CoV-2 positivity, especially if associated with fever. The cluster characterized by severe respiratory symptoms is also strictly related to the outcome. 

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