Age is not the only risk factor in COVID-19: the role of comorbidities and of long staying in residential care homes

The COVID 19 outbreak represents an historically unprecedented pandemic, particularly dangerous and potentially lethal for elderly population. Since the beginning of the actual SARS-CoV-2 outbreak it was evident that older people, compared to younger ones, were at higher risk to get the infection and to develop a more severe disease with unfavorable prognosis. In Italy, the National Healthcare Service, registered 418,142 total cases of COVID-19 and 39,412 deaths, as of November 3, 2020 [1]. The mean age of patients that died was 80 years, at least 20 years higher than that registered in infected people. The majority of those who are infected, that have a self-limiting infection and do recover are, in fact, younger. Conversely, those that suffer a more severe disease, that require intensive care unit admission and eventually pass away are older [2, 3].

Many reports indicate that elderly patients with COVID-19 are more likely to progress to severe disease compared to young and middle-aged ones [2]. These observations have a particular and relevant negative impact in Europe. Of the top 30 countries with the largest percentage of older people, all but one (Japan) are States in Europe and Italy is considered “a country of old people” because the life expectancy is over 80 years of age [4]. The situation is critical in the long-stay residential care homes (LSRCHs), where many elderly people and people with disabilities and severe cardiovascular and neurological diseases live all together in close contact, facilitating the dynamics of virus transmission. Residents in LSRCHs are a vulnerable population group and it has been reported that the proportion of COVID-19 cases who have died in these LSRCHs has exceeded 60% of all reported deaths [5].

In a recent report by the Organization for Economic Cooperation and Development (OECD) [6] over 75,000 deaths have been registered across 13 European countries amongst residents in long term care institutions (as of early October 2020), accounting for almost half of the total deaths caused by COVID-19. In Italy there are more than 3000 of such facilities, with 186,872 beds. That is why the Istituto Superiore di Sanità (ISS) launched a National survey on COVID-19 infection in LSRCHs, to monitor the situation and to solicit special strategies against spreading of infection [7]. The results of this Survey have been described in a final report posted on May 5th 2020 [8]. The data obtained from a total of 3292 LSRCHs in different Italian regions indicated that the mortality rate of patients, with proved infection plus those with symptoms that suggested positivity, was equal to 3.1%, but, in some regions, it reached the value of 6.5%. The main problems reported by the personnel in facing the pandemic were related to the difficulties in isolating the positive patients and in transfer the critical ones to the hospital. In addition, they complained about the scarcity of tests, adequate information and personal protective equipment.

However, despite the huge amount of data on COVID-19 worldwide, the reasons why older people are at significantly increased risk of severe disease following infection from COVID-19 are not clear. Age could not be the only risk for severe disease. It has been reported that people in their teens or twenties may develop a severe form of the disease, may require intensive care and may die as well [9]. On the other side, people who age healthily seems to be less at risk. Besides the physiological changes associated with ageing, other factors could be involved, including the decreased immune function and the occurrence of multimorbidity [10].

To date there is little information on COVID-19 in patients over 80 years of age. Therefore, in this study, we focused our attention on very elderly population (> 80 years of age) [11, 12] that referred to our University Hospital during the actual SARS-CoV-2 outbreak and we have analyzed the differences between elderly people and very elderly ones. Our aim was to try to figure out the reason why elderly and very elderly people are more prone to be infected and to develop a more severe form of the disease. We considered clinical aspects, presence of comorbidities, laboratory and radiological findings as well as their outcome, including the length of stay, mortality and viral shedding in nasal/oropharyngeal swabs.

Elderly are generally defined as having a chronological age of 65 years or older [18]. In Japan, where many elderly people live, this definition was reviewed [19]. Thanks to the advances in medical and health science the lifespan has recently increased in Japan as well as in Italy. The simple chronological age appears to be no longer appropriate to the actual situation, in both Countries, where life expectancy is of 80 years and where there is an increased number of bright and energetic elderly people. Therefore, in Japan, the term of “late elderly” was introduced to indicate a new class of people, older than 75 years of age [18]. Other factors besides the chronological age appear to play a major role in affecting the health status and the expectance of life and a careful assessment of the “elderly frailty” is required to determine the biological, functional, cognitive and clinical aspects of the elderly subjects [20]. Previous reports indicate that elderly people are particularly susceptible to Community-Acquired Pneumonia [21‐23]. When a community-acquired pneumonia is diagnosed in very elderly people, there is a significant increase in morbidity and mortality [24]. It has been observed that these patients often develop hospital-acquired complications and mortality occurs more frequently compared to younger people and to elderly ones. Moreover, the occurrence of pneumonia in elderly people is often the terminal event that complicates a long-term illness, such as dementia, cardiovascular disease, cancer, or prolonged immobilization syndrome [25]. However, it is not always easy to dissect the relative contribution of other factors, including disability, frailty, comorbidities and the health status of these patients, prior to the development of the disease. COVID-19 is a severe disease, caused by the SARS-CoV-2 virus, mostly affecting the lung where an interstitial viral pneumonia is frequently observed, with typical patchy bilateral ground glass opacities and peripheral consolidations. Elderly people appear to be more susceptible, especially to the more severe forms of the disease [26]. However, little information is available so far regarding the course of COVID 19 in very elderly people. It is well established that COVID-19 occurs more frequently among elderly people, with higher susceptibility to mortality and ICU admission [27], but a limited number of studies and of patients has focused the attention on a population over eighty years of age [3].

Our very elderly patients, showed a more severe disease, with higher level of serum marker of inflammation (hs-CRP and NLR) and higher severity respiratory indexes (PSI and P/F). This could be due to the increased inflammatory activity, associated with aging, reflected by increased circulating levels of TNF-alpha, IL-6, cytokine antagonists and acute phase proteins in vivo [28].

Experimental observations in mice, indicate that the SARS-CoV viral replication in aged mice is associated with clinical illness and pneumonia, demonstrating an age-related susceptibility to SARS disease in animals that parallels the human experience [29]. Moreover, they demonstrated that replication of SARS CoV is enhanced in aged mice compared to younger and enhanced viral replication is accompanied by evidence of clinical illness, alveolar damage, and interstitial pneumonitis [29].

Besides to be stroked by a more severe disease, median duration of viral shedding in our very elderly patients is higher compared to that recently reported in younger and symptomatic (14 days) or asymptomatic patients (19 days) [30] and there is a statistically significant difference between the two groups. This also affects the length of the stay (LOS) in the hospital which result higher in Very Elderly. We don’t have data regarding the immune response in terms of cytokine production and production of specific immunoglobulins in our very elderly patients. However, the increased duration of viral shedding suggests that they may have a weaker immune response to SARS-CoV-2 infection, compared to younger patients. Increasing age has been defined as a predictive factor for mortality in pneumonia patients in many studies, especially among patients aged 65 years or older [31, 32]. Several studies, suggested that age ≥ 85 years was an independent predictive factor for mortality in patients affected with community acquired pneumonia [33, 34]. Calle et al. reported that age ≥ 90 years was markedly associated with mortality [35]. Ageing is associated with a progressively weakened immune system and decreased lung performance. For patients of extreme age (≥ 85 years in our study), these changes alone are probably drastic, which independently increases the risk of death due to pneumonia [34]. In the study by Zunyou Wu et al., the overall case-fatality rate of those aged 70 to 79 years was 8.0% compared to aged 80 years and older where it was 14.8% [36]. However, in this study only 3% of the total number of cases were 80 years of age or older. In another study by Niu et al., the mortality rate in patients over 80 was equal to 18% [3]. Also Yan et al. reported that older patients (> 65 years) with comorbidities and ARDS are at increased risk of death, although even in this study patients over 80 years of age were a small number [37].

In our study the number of patients with more than 80 years of age is similar to that with 65–79. The mortality rate in Very Elderly was 37.5% and this percentage was significantly higher compared to that observed in Elderly. Our findings suggest that, similarly with other severe acute respiratory outbreaks, age is a fundamental risk factor for mortality. These results also emphasize the importance of the very advanced age (i.e. ≥ 85 years).

When we try to identify which factors other than age may influence the course and outcome of the disease in these patients, two conditions appear to play a major role. The first is represented by the pre-existing health conditions or comorbidities. Patients with pre-existing pathological diseases, and in particular those affected by multiple comorbidities die more frequently than those with no or few comorbidities. In other words, COVID-19, as other community-acquired pneumonias, acts as terminal event that complicates long-term illnesses. This is in agreement with previous studies demonstrating that the presence of any comorbidity is associated with increased risk of poorer clinical outcomes [38].

The second one consisted in the observation that patients admitted to the hospital coming from previous LSRCHs, were in worst clinical conditions and died more frequently compared to those admitted coming from their homes. There are many possible explanations to that. Patients in LSRCHs may suffer of more comorbidities and fragilities, and as previously observed they are more prone to accumulate complications, thus resulting in unfavorable outcome. Another explanation is that, staying in a close environment, makes these patients more susceptible to infections. In this regard, the results of the Italian National Survey indicated that one of the major difficulties was to obtain an adequate isolation of the positive patients. Finally, the disease could be more severe because of a delay in its recognition, that, according to this survey, was due to insufficient availability of the nasal/oropharyngeal tests. Considering all these factors and based on our observations, it is necessary to obtain a better evaluation of the frailties of elderly and very elderly people that represent a population more prone to the condition of risk and vulnerability, characterized by an unstable equilibrium, if facing negative events.

Because of the rapid evolving outbreak globally, ongoing studies with the inclusion of more patients would be needed to increase the statistical power of our results.

In conclusion, the heightened susceptibility of the elderly to COVID 19, led us to demonstrate that there were considerable differences between Elderly and Very Elderly in terms of inflammatory activity, severity of disease and adverse clinical outcomes. Although age is one of the major risk factors for mortality, a thorough assessment of comorbidities and information about the provenience from residential care homes may help establishing risk stratification of patients with COVID-19 upon hospital admission and may furnish valuable information for planning adequate programs of intervention at the sanitary-assistential levels.