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P.J. Martin1, S. Billet1, Y. Landkocz1, B. Fougère2,3

1. Univ. Littoral Côte d’Opale, UR 4492, UCEIV, Unité de Chimie Environnementale et Interactions sur le Vivant, SFR Condorcet FR CNRS, F-59140 Dunkerque, France; 2. Division of Geriatric Medicine, Tours University Hospital, Tours, France; 3. Éducation, éthique, santé (EA 7505), Tours University, Tours, France.
Corresponding author: Dr. Sylvain Billet, Univ. Littoral Côte d’Opale, UR 4492, UCEIV, Maison de la Recherche en Environnement Industriel 2, 189A, Avenue Maurice Schumann, 59140 Dunkerque, France. Phone: +33-3 28 23 76 41, E-mail: sylvain.billet@univ-littoral.fr

J Frailty Aging 2021;in press
Published online March 13, 2021, http://dx.doi.org/10.14283/jfa.2021.8



The global COVID-19 pandemic has highlighted different vulnerability profiles among individuals. With the highest mortality rate, the elderly are a very sensitive group. With regard to the main symptoms, a failure of the respiratory system, associated with deregulation of the immune system, has been observed. These symptoms may also be encountered in chronic exposure of susceptible populations to air pollution, including exacerbation of the inflammatory response. Is there a relationship between age, pollution exposure and the severity of COVID-19? Although it is unclear how these parameters are related, the same pathways can be activated and appear to find a common mechanism of action in inflammation.

Key words: Inflammation, COVID-19, ageing, air pollution.




Acute inflammation is an immediate, rapid response to an attack on the body. When ­ as is usually the case ­ the inflammation is not excessive, it resolves itself after the harmful agent or pathogen has been destroyed or eliminated. Essentially, acute inflammation comprises four phases (1): homing of immune cells to the tissue; immune cell differentiation and activation in situ; a “switch» to suppressive cells; and a return to homeostasis. In contrast, chronic inflammation persists over time, does not resolve itself fully, and may damage the tissues concerned. It is known that both acute and chronic lung inflammation contributes to the harmful effects of inhaled pathogens or toxicants, and constitutes a pathogenic pathway in many lung diseases (2). Lung inflammation is characterized by two successive steps. Firstly, activated macrophages, neutrophils and T lymphocytes infiltrate into the airways. Secondly, chemokines, oxygen radicals, proteases and pro-inflammatory cytokines are produced. Cytokines include interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), and interleukin 12 (IL-12) (2, 3). The lung damage caused by excessive acute inflammation can lead to pulmonary fibrosis and can interfere with gas exchanges. Unresolved lung damage and chronic inflammation are frequently observed in acute respiratory distress syndrome, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and asthma. When inflammation cannot be resolved properly, its characteristics change as more macrophages are recruited and the adaptive system starts to respond. In the worst cases, this inflammation can evolve into an often lethal cytokine storm (also referred to as «cytokine shock» or «cytokine release syndrome»). Although the links between ageing, atmospheric pollution and COVID-19 are difficult to pinpoint, there is evidence for common pathways based on deregulation of inflammation in particular. Despite the increasing number of publications on the emerging disease COVID-19, only one author has considered the possibility of a cross impact between these different factors and focused its analysis on the treatment of inflammation and thrombotic states (4). Therefore we propose a review that considers the mechanistic aspect that would underlie this common pathway.


Inflammation and COVID-19

A cytokine storm is a massive inflammatory phenomenon in which cytokine production is both excessive and self-sustaining (5). This phenomenon has been described in a broad range of infectious and non-infectious diseases, including some human respiratory tract diseases caused by coronaviruses (6). With regard to coronaviruses that have emerged in recent years, it has been shown that infection by Severe Acute Respiratory Syndrome (SARS) coronaviruses can result in the massive production of TNFα, IL-6 and IL-8, and that infection by Middle East Respiratory Syndrome (MERS)-related coronavirus leads to the production of IL-6, IL-1β, and IL-8 (6). In severe cases of COronaVIrus Disease 2019 (COVID-19), elevated blood levels of IL-1β, IL-6, IL-8, IL-12, interferon gamma (IFN-γ), granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNFα-induced cytokines have been evidenced (7). Furthermore, lymphopenia is a universal feature in patients with COVID-19, and an analysis of T lymphocyte subsets shows a significant decrease in CD4+ and CD8+ T cells counts. Among the various cytokines involved in the cytokine storm, IL-6 and GM-CSF appear to have the most harmful effects in the exacerbation of inflammation, with (among other things) high blood pressure, tachycardia progressing to bradycardia, hypoxia, and pulmonary fibrosis. The subsequent acute respiratory distress syndrome can lead to multi-organ failure and death. Even at the beginning of the pandemic, physicians suspected that a cytokine storm was involved in the expression of the most severe forms of COVID-19.


Inflammation and ageing

Ageing and age-related diseases share some basic mechanistic components, many of which result in inflammation. The development of a chronic, sterile, low-grade inflammatory state contributes to the pathogenesis of age-related diseases (8). Biological ageing is the result of an accumulation of genetic and epigenetic changes that lead progressively to cell damage, impaired tissue function, vulnerability to stressors, low physiological reserves, and a more limited ability to maintain homeostasis (9). Although a single mechanism for the causes and progression of biological ageing has not been established, the most frequently cited etiologies are redox stress, immune system deregulation, mitochondrial dysfunction, glycation, hormonal changes, epigenetic modifications, and telomere attrition (10). The environment may also have a role in biological ageing by disrupting the homeostatic balance (11). Even though the involvement of the afore-mentioned factors is widely accepted, the cellular and molecular details of biological ageing have yet to be determined. Some studies have suggested that chronic inflammation accelerates biological ageing (12). Although the immune response that is characteristic of acute inflammation subsides within a few days, chronic inflammation is characterized by the release of elevated levels of pro-inflammatory cytokines in response to physiological and environmental stressors. This essentially shifts the immune system into a state of low-level activation (8). The chronically active immune system activity associated with advancing age has been termed “inflammatory ageing” or “inflammaging” (13–15). Although the detailed mechanisms have yet to be characterized, the pro-inflammatory cell phenotype associated with the upregulation of the inflammatory response with age has been found to have a role in the initiation and progression of age-related diseases such as cardiovascular disease, type II diabetes, frailty, sarcopenia, Alzheimer’s disease, osteoporosis, and cancer (16, 17).


Ageing and COVID-19

The COVID-19 pandemic is having a major impact on populations worldwide. Although all age groups are at risk of contracting COVID-19, older adults are the most at risk of severe disease as a result of age-related physiological changes and possible pre-existing conditions (18–20). A very recent report showed that the mean ± Standard Deviation (SD) age of patients with severe and critical forms of COVID-19 was 59.38 ± 16.54, with more than 50% over the age of 60 and a predominance of males (64.60%) (21). Similarly, over 50% of the deceased patients are aged 60 or over (21). A study published in The Lancet Infectious Diseases estimated that the proportion of infected people likely to be hospitalized increases with age, up to a maximum of 18.4% [95% confidence interval: 11.0-37.6] among people aged 80 or over (22). In Wuhan (China), patients over 65 years of age had a greater number of co-morbidities at baseline and displayed more severe symptoms (including multisystem failure and death) than younger patients did (23). Eight out of 10 deaths reportedly occur in people with at least one co-morbidity – particularly cardiovascular disease, hypertension, and diabetes, but also a range of other pre-existing chronic conditions that often appear with age (24). One explanation for this may be that immunosenescence in the older adult is associated with greater susceptibility to infectious disease (25). Hence, “inflammaging” can accentuate the harmful effects of SARS-CoV-2 infection. Conversely, an acute SARS-CoV-2 infection may worsen any chronic, age-related, pro-inflammatory conditions. When combined with immune senescence and the age- and sex-specific distributions of angiotensin-converting enzyme II (ACE 2) in the airway epithelium, this situation may accentuate the antiviral response to inflammation (53).


Air pollution and inflammation

As mentioned above, environmental factors can have a role in the occurrence of disease. Air pollution constitutes one of the best known environmental risk factors, and is thought to cause about 3.3 million premature deaths per year worldwide (26). Air pollution is composed of particles, gases, and bio-aerosols containing pollen and airborne microorganisms (viruses, bacteria, fungi, spores, etc.). A large number of studies have shown that exposure to air pollutants is associated with cardiovascular adverse events (27). Inflammation is very frequently cited as a cause of cardiovascular disease; it is not always associated with an infection and may be triggered by other “danger signals” referred to collectively as danger-associated molecular patterns. These patterns come from damaged or altered cells (e.g. cancer cells), chemical irritants (e.g. pollutants) and even physical disturbances (e.g. mechanical forces). This sterile inflammation may be associated with oxidative conditions that are potentially triggered or exacerbated by exposure to air pollution (28, 29). Oxidative stress is generally defined as a chronic shift in the intracellular redox balance towards oxidative conditions. It is initiated by reactive oxygen species (ROS) and reactive nitrogen species, and has a central role in many adverse health effects – particularly in the respiratory tract (3). High levels of ROS may exceed the cells’ antioxidant capacity and trigger a cascade of events closely associated with inflammation and, at higher concentrations, apoptosis and genetic and epigenetic alterations. Thus, increased activation of the transcription factor nuclear factor – kappa B by oxidative stress is involved in the regulation of a large number of genes controlling the inflammatory response (30). Furthermore, environmental exposure has been shown to increase levels of pro-inflammatory cytokines (e.g. IFNγ, IL 6, IL 8, IL 12, IL-1β, and TNFα) (31). The release of these cytokines into the lung and the peripheral blood leads to systemic inflammation and immune disorders (32–35). Exposure to air pollutants also increases the numbers of immune cells (neutrophils, lymphocytes and macrophages) that infiltrate into the lungs (36). Neutrophil recruitment to the lungs increases the inflammatory response and the resulting damage. During this pollutant-induced phase of inflammation, the number of macrophages also increases via differentiation of the infiltrated monocytes into M1 macrophages (37). Chronic exposure to pollutants such as fine particles (PM2.5) can raise levels of inflammatory markers such as C-reactive protein, which is directly involved in the development of cardiovascular disease (38). This can also lead to the development of chronic inflammatory diseases, such as asthma and COPD (39).


Air pollution and COVID-19

In recent years, a large number of research groups have examined the interaction between airborne particles and viruses. For example, the risk of pneumonia caused by respiratory syncytial virus (RSV) in children is increased by the penetrate of particulate pollutants (PM2.5 and PM10) deep into the respiratory tract (40). Similar results have been reported for measles, the incidence of which was significantly amplified by an increase in PM2.5 of 10 μg/m3 (4). In Europe, the epidemiological data show that the regions known to be the most polluted by PM2.5, PM10, and NO2 (Lombardy and the Po valley in northern Italy) were also the most affected by the spread of SARS-CoV-2 (42, 43). In the United States, the results of an ecological study of 98% of the American population (currently under review) suggested a strong association between elevated particulate matter concentrations and mortality rates due to COVID-19 (44). A slight increase in long-term exposure to PM2.5 leads to a large increase in mortality associated with COVID 19. A study conducted in 120 Chinese cities determined a significant association between a 10 μg/m3 increase in PM2.5, PM10, NO2 and O3 and the number of new positive cases (2.24%, 1.76%, 6.94% and 4.76%, respectively) (45). Thus, several research groups have looked at whether or not the presence of SARS-COV-2 RNA on particulate matter in outdoor air samples is a potential early indicator of the spread of COVID-19 (43). Thus, an RT-qPCR analysis of RNA extracted from 34 PM10 samples showed the presence of the E gene (which is specific for SARS-like viruses) and RdRP genes (which are highly specific for SARS-CoV-2) (46). However, it is not known whether virus-carrying particles are contagious. There are several possible explanations for the impact of air pollution exposure on the severity of COVID-19. One of them would be that chronic exposure to air pollution has been implicated in many cardiopulmonary diseases. The oxidative stress due to exposure to pollutants leads to the production of free radicals, which damage the respiratory system and reduce resistance to viral and bacterial infections. Pollutants might both directly impair the lungs’ ability to eliminate pathogens and indirectly exacerbate any underlying cardiovascular or pulmonary diseases (47, 48). The presence of co-morbidities leads to inflammation, and pollutant-induced oxidative stress and cell damage may worsen the prognosis (49, 50). Chronic exposure to PM2.5 leads to the overexpression of alveolar ACE-2 receptors; this increase might amplify the viral load, deplete ACE-2 receptors, and weaken host defenses. Moreover, NO2 acts as a pro-oxidant by depleting the anti-oxidant pool and thus impairing tissue defenses (especially phagocytic activity) and increasing inflammation and cell damage. Exposure to NO2 causes a severe form of COVID-19 in ACE-2-depleted lungs and thus worsens the outcome (51).


Inflammation at the crossroads?

The most severe forms of COVID-19 increase in prevalence with age; as described above, the oldest people have the highest mortality rate and the greatest risk of cytokine shock. The analysis of patients with COVID-19 patients shows that younger individuals are less affected by the disease (52). This can be explained by the immature immune system in children, who are much less affected by this epidemic (53, 54). Moreover, it is now well known that the effects of air pollution are exacerbated among the elderly, with effects on the immune, respiratory and cardiovascular systems (55, 56). The cytokine storm sometimes seen in COVID-19 is particularly damaging for older adults (57); in particular, myocardial injury can be amplified by exposure to particulate pollutants. Indeed, PM2.5 exposure is known to increase the risk of heart diseases like as acute myocardial injury and infarction (58). One of SARS-CoV-2’s first targets is the respiratory tract, which is continuously exposed to external stressors. Activation of the immune system in the lungs during exposure to gaseous or particulate pollutants has already been demonstrated – especially in sensitive individuals like older adults (56). Moreover, the aggravation of chronic inflammatory respiratory diseases (e.g. asthma) by air pollution has been widely described (59, 60). Thus, COVID-19 may have more serious outcomes (e.g. cytokine shock) when the respiratory tract has already been sensitized by chronic exposure to air pollution.



In conclusion, one can legitimately hypothesize that COVID-19 is synergized by age and exposure to air pollution via an exacerbation of inflammation. Further research is needed to determine the infectious potential of SARS-CoV-2 on particulate matter and the latter’s potential role in spreading disease. Public health policies in populations such as older adults (e.g. reducing their exposure to atmospheric pollution) may now be especially important. Furthermore, disparities in socioeconomic factors and elevated prevalences of diabetes, heart disease, and chronic airway diseases (e.g. lung cancer and COPD) are likely to accentuate the mortality rate among older populations (47). The presence of common pathways (including inflammation and repeated exposure to air pollutants) may have contributed to the disproportionate impact of COVID-19 on older adults.

Conflict of interest: The authors report no conflict of interest.
Author contributions: All the authors participated in the preparation of the manuscript, the search for publications and their analysis. The authors would like to thank David Fraser (Biotech Communication SARL) for his careful correction of the English language of the manuscript.
Sponsor’s role: This research did not receive any specific grant from funding agencies in the public, commercial, or not.


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C. Udina1, J. Ars1, A. Morandi1, J. Vilaró2, C. Cáceres1, M. Inzitari1

1. REFiT Barcelona research group, Parc Sanitari Pere Virgili and Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain; 2. Blanquerna School of Health Sciences, Global Research on Wellbeing (GRoW), Universitat Ramon Llull. Barcelona, Spain.
Corresponding author: Cristina Udina, MD, Parc Sanitari Pere Virgili, C/ Esteve Terradas, 30, 08023 Barcelona, Spain, cudina@perevirgili.cat, ORCID ID: 0000-0002-0140-669X

J Frailty Aging 2021;in press
Published online February 7, 2021, http://dx.doi.org/10.14283/jfa.2021.1



COVID-19 patients may experience disability related to Intensive Care Unit (ICU) admission or due to immobilization. We assessed pre-post impact on physical performance of multi-component therapeutic exercise for post-COVID-19 rehabilitation in a post-acute care facility. A 30-minute daily multicomponent therapeutic exercise intervention combined resistance, endurance and balance training. Outcomes: Short Physical Performance Battery; Barthel Index, ability to walk unassisted and single leg stance. Clinical, functional and cognitive variables were collected. We included 33 patients (66.2±12.8 years). All outcomes improved significantly in the global sample (p<0.01). Post-ICU patients, who were younger than No ICU ones, experienced greater improvement in SPPB (4.4±2.1 vs 2.5±1.7, p<0.01) and gait speed (0.4±0.2 vs 0.2±0.1 m/sec, p<0.01). In conclusion, adults surviving COVID-19 improved their functional status, including those who required ICU stay. Our results emphasize the need to establish innovative rehabilitative strategies to reduce the negative functional outcomes of COVID-19.

Key words: COVID-19, older adults, therapeutic exercise, rehabilitation, post-ICU rehabilitation.



COVID-19’s impact increases with age (1). Besides mortality, patients may experience relevant disability, related to serious complications requiring Intensive Care Unit (ICU) admission, which has been linked to physical impairments (2). Less severe cases might experience functional decline due to immobilization due to the disease and isolation measures to prevent transmission. Early and effective rehabilitation interventions are urgent, despite healthcare systems may be overwhelmed and rehabilitation may be disrupted. Therapeutic exercise (TE) is a physical therapy technique used to improve or maintain a person’s physical condition through resistance, endurance, flexibility and balance training. The intensity, volume, progression and type of exercise must be individualized based on the physical condition and tolerance during the execution of TE. Previous research shows the benefits of supervised TE in acutely ill patients to improve their physical condition and autonomy through exercise (3). During the early weeks of the pandemic our post-acute care facility had to adapt in order to provide care for COVID-19 patients (4). In addition to maintaining the usual physical therapy interventions for more impaired patients, we created an intensive rehabilitation pathway through TE to facilitate a quick recovery and faster discharge at home. Our aim is to describe the pre-post impact on physical performance of multi-component therapeutic exercise for post-COVID-19 rehabilitation.



We performed a cohort study of post-acute care patients that overcame COVID-19 and were included in a rehabilitation protocol based on multi-component therapeutic exercise. The inclusion criteria were: 1) ability to walk unassisted pre-COVID-19 (use of cane or walker was allowed); 2) able to stand after the resolution of acute COVID-19; 3) social situation allowed discharge in 10 days. We collected demographics, COVID-19 related variables, comorbidities (sum of hypertension, diabetes, arrhythmia, myocardial infarction, Chronic Obstructive Pulmonary Disease/Asthma, mild cognitive impairment, dementia, other neurodegenerative diseases, stroke, depression, osteoarthritis and low back pain) and prevalence of polypharmacy (5 or more drugs) at admission. Our comprehensive assessment included: pre-COVID functional status with the Barthel Index and Lawton Index and frailty status with the Clinical Frailty Scale (CFS); cognitive function at post-acute admission with the Montreal Cognitive Assessment (MoCA) for global cognition and the Symbol Digit Modalities Test (SDMT) for attention and processing speed. SDMT scores are age-adjusted (5), considering a score of 7 or higher as normal range. The Confusion Assessment Method (CAM) was used to screen for Delirium. These covariates were collected based on clinical and functional aspects that might impact physical function as well as the response to physical exercise. We assessed physical function at day 1 and 10 of the intervention. Those patients who were discharged before day 10 were evaluated at discharge. We performed the Short Physical Performance Battery (SPPB) as a measure of gait performance (time to walk 4 meters), balance (stand for 10 seconds with feet side-by-side and in semi-tandem and tandem positions) and lower limb strength (time required to stand up and sit down 5 times from a chair without using the arms). Furthermore, we assessed independence for the basic activities of daily living with the Barthel Index, need of assistance to walk with the Functional Ambulation Category (FAC) (6) and the single leg stance test (7). We evaluated exercise capacity with the 6-minute walk test (6MWT) in a sub-sample (for logistical reasons).
The 30-minute 7 days/week multi-component therapeutic exercise intervention (summarized in Figure 1) was led by an expert physical therapist and combined: a) resistance training [1-2 sets with 8-10 repetitions each (intensity between 30-80% of the Repetition Maximum (8) )]; b) endurance training (up to 15-minutes aerobic training with a cycle ergometer, steps or walking) and c) balance training (walking with obstacles, changing directions or on unstable surfaces). Additionally, recommendations were provided to decrease daily sedentary behavior. Each session was individualized to each patient’s physical condition.
Outcome measures included: SPPB global score, gait speed (m/s), balance score and chair-stand time (seconds), Barthel Index score, ability to walk unassisted (FAC score 4 or higher) and maintain single leg stance for 10 seconds and distance walked during the 6MWT (meters). We used descriptive statistics with mean and Standard Deviation (SD) or frequencies as required. We assessed differences between the initial and final values in the outcome variables with Wilcoxon signed rank test and McNemar test for continuous and categorical variables, respectively. We calculated the mean pre-post change for each continuous outcome variable: Variable POST – VARIABLE PRE. We used Mann-Whitney U test to compare the mean change in the outcomes between patients treated or not in the ICU as well as to compare baseline characteristics in both groups. All statistical analysis was performed with statistical software: IBM SPSS Statistics for Windows, Version 21.0. (Armonk, NY: IBM Corp).



We included 33 patients (66.2±12.8 years, 57.6% women), of whom 90.9% (n=30) presented with pneumonia and 60.6% (n=20) were admitted to the ICU, all (n=20) requiring mechanical ventilation, with a mean ICU stay of 10.3±9.9 days. The sample consisted of pre-COVID-19 well-functioning adults (Barthel Index 98.5±5.8 and Lawton Index 6.7±2.1) with low frailty (CFS score 2.5±1.3) and comorbidity (sum of comorbidities 1.5±1.6) but high polypharmacy at admission (72.7% (n=24)). Post-ICU patients were younger, with lower comorbidity, better pre-COVID-19 functional status and lower frailty, compared to non-ICU patients (Table 1). Although none of the patients had delirium according to CAM scores at admission, post-COVID-19 cognitive function was mildly impaired in the whole cohort and within both groups. After the intervention (mean duration=8.2±1.7 days), all physical performance measures showed a statistically significant improvement when comparing the initial and final values in the global sample and among post-ICU patients, while non-ICU patients did not improve in balance-related variables. Furthermore, post-ICU patients experienced a greater improvement in SPPB and gait speed mean change compared to non-ICU (4.4±2.1 vs 2.5±1.7, p<0.01 and 0.4±0.2 vs 0.2±0.1, p<0.01, respectively). None of the patients died during the intervention and all were discharged home. In a subsample of 22 participants (61.9±12.1 years, 63.6% women, 81.8% admitted to the ICU and 95.5% with pneumonia), mean 6MWT walked distance improved from 158.7±154.1 to 346.3±111.5 m (p<0.001).

Table 1
Baseline characteristics and functional outcomes, in the total sample and stratified by previous ICU admission

Abbreviations: ICU: Intensive Care Unit. MoCA: Montreal Cognitive Assessment. CFS: Clinical Frailty Scale. SDMT: Symbol Digit Modalities Test. SPPB: Short Physical Performance Battery. FAC: Functional Ambulation Category. SDMT normal range ≥ 7. Legend: (*) Pre-post comparison within group with Wilcoxon rank test and McNemar test (significance at a p-level < 0.05 marked with †). (‡) Comparison of the mean change between the ICU and the non-ICU groups with Mann-Whitney U Test (significance at a p-level < 0.05 marked with †)

Figure 1
Scheme of the individualized multi-component therapeutic exercise intervention, combining 3 or more modalities daily

Abbreviation: RM: repetition maximum



In summary, in our sample of post-COVID-19 adults and older adults, physical function improved after a relatively short therapeutic exercise intervention. This improvement seems clinically meaningful, according to previous studies (9). Compared to the non-ICU group, post-ICU patients showed higher improvements, possibly due to their younger age and better functional, clinical and frailty status pre-COVID-19. Noteworthy, our sample showed mild cognitive impairment post-COVID-19 according to a brief cognitive assessment, which we might speculate as non-preexisting, especially in the ICU group, due to their relatively young age and preserved functional status. This cognitive dysfunction could be related to delirium during COVID-19’s acute phase or even be a neurological feature of COVID-19’s infection (10). Further research is needed to support these findings and to study long-term effects of COVID-19 on cognition.
Evidence about post-COVID-19 rehabilitation is still scarce, although there is a growing body of literature highlighting the need of rehabilitation strategies. To our knowledge, this is the first study on the effects of intensive rehabilitation through a structured therapeutic exercise intervention of post-COVID-19 patients in post-acute care, a setting able to combine the acute management of these patients with rehabilitative interventions (4). Improving physical function in post-ICU patients is crucial as previous research has shown long-term negative outcomes (11). However, the type of exercise intervention previously reported in post-ICU rehabilitation so far seems not comparable to our intensive and multimodal protocol (12). Previous research shows the efficacy of similar therapeutic exercise strategies tested in acute geriatric units, demonstrating functional benefits of short-term supervised exercise during acute medical illnesses: the reported magnitude of change of 2.4 points in the total SPPB (13) is similar to the change in our non-ICU group, which is indeed older and with a slightly pre-COVID-19 worse clinical and functional profile, compared to the ICU group. According to studies performed with Acute Respiratory Distress Syndrome survivors, the improvement in exercise capacity experienced in the small subsample seems also clinically relevant (14). The cognitive impairment detected among the post-ICU patients is also in line with the findings reported in Acute Respiratory Distress Syndrome survivors (15), however in our opinion the impairment detected in non-ICU patients, deserves further research to shed some light into the potential neurological manifestations of COVID-19.
Main limitations of the study are the small sample size and the absence of a control group to assess the effect of the intervention. Among the strengths, we enrolled adults and older adults post-COVID-19 with different acute care pathways during the acute phase, with a comprehensive assessment of clinical and functional variables.
In conclusion, adults and older adults surviving COVID-19 seem to improve their functional status, despite previous admission to ICU, through a short, individualized, multi-component therapeutic exercise intervention. Further research with controlled, larger samples and longer treatment periods might help elucidate the role of rehabilitation interventions in the reduction of negative functional outcomes of COVID-19, hence mitigating the potential increase in COVID-19-related disability and health care costs.


Funding: This research did not receive any funding from agencies in the public, commercial, or not-for-profit sectors.
Conflicts of interests: The authors (CU, JA, AM, JV, CC) state that they have no financial nor non-financial conflict of interests. MI received from Nestlé a fee for scientific advice, not related to the work or the topic of the current manuscript.
Ethics approval: The study procedures were approved by the institutional ethics committee. The authors declare that all study’s procedures are according to the 1964 Helsinki Declaration and that personal participant’s information was treated to ensure complete privacy. Furthermore, all procedures performed during the study were in the context of usual care of patients admitted to post-acute care.



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M. Tosato1, F. Varone1, A. Ciccullo1, R. Calvani1, D. Moschese1, A. Potenza1, M. Siciliano1, M. Fantoni1


1. Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy; ORCID: https://orcid.org/0000-0001-5750-9746.
Corresponding author: Matteo Tosato, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy, email: matteo.tosato@policlinicogemelli.it

J Frailty Aging 2021;10(1)70-71
Published online August 7, 2020, http://dx.doi.org/10.14283/jfa.2020.41



COVID-19, the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, showed higher severity and lethality in male older adults . There are currently no specific treatments. Studies are evaluating the efficacy of monoclonal antibodies against interleukin-6 receptor. Here we present the case of a 98-years old man admitted to our COVID-Hospital with acute respiratory failure. Comprehensive geriatric assessment showed no signs of frailty. First-line therapy with hydroxychloroquine and anticoagulants was not effective. Patient was administered intravenous monoclonal antibodies, and he showed remarkable clinical improvement. This case suggests that age alone should not preclude access to new therapeutic approaches. Comprehensive, multisciplinary, multidomain approaches are needed to develop patient-tailored treatments against COVID-19.

Key words: Frailty, covid-19, comprehensive geriatric assesment, aging.



In late 2019, a novel betacoronavirus (SARS-CoV-2), emerged in the province of Hubei, China. The disease related to SARS-CoV-2, named COVID-19, rapidly spread all over the world and was declared a global pandemic by the World Health Organization (WHO). While the majority of cases present with no or mild respiratory symptoms, about 20% of the cases could develop severe forms of the disease, with life-threatening complications such as respiratory failure and multiorgan dysfunction (1). Fatality rates vary between studies, but large cohort observational studies reported a greater disease severity in older patients (1-2).
We have recently observed a demographic shift towards older ages in COVID-19 patients admitted to our COVID Hospital. This phenomenon was partly due to newly discovered outbreaks in nursing homes and rehabilitation units. Older patients present specific characteristics, such as frailty, multimorbidity, polypharmacotherapy, and other conditions that render their management particularly difficult. Their unmet clinical needs represent the “new challenge” in COVID-19 pandemic.
Hereby we report a case of severe COVID-19 pneumonia in an old man admitted to our COVID-hospital in Rome, Italy.


Case representation

A 98-years old man was admitted to our hospital on April 15th, following a 2-day history of cough and dyspnea. The patient came from a rehab-unit where he was admitted following hip fracture. He was independent in daily activities before hospital admission and not frail (Clinical Frailty Scale score was 3) (3). Chronic obstructive pulmonary disease, hypertension, chronic lymphocytosis and benign prostatic hypertrophy were also present in his medical history. Blood tests at admission showed C-Reactive Protein 221.7 mg/L (Reference Value [RV] <5.0), D-dimer 4425 ng/mL (RV <500), ferritin 1286 ng/mL (RV 21-275), IL-6 105.8 ng/L (RV <4.4). Chest X-rays documented signs of interstitial pneumonia (Figure 1). Patient presented in severe clinical conditions, hypoxemic, requiring oxygen supplementation with a FiO2 of 0.6. Patient was treated immediately with hydroxychloroquine and anticoagulant therapy with no clinical benefits. At day 5, he was administered intravenous sarilumab (400 mg as single dose). The day after, patient started showing remarkable clinical improvement. Over the following weeks, we observed a full consciousness recovery and improvement in respiratory function, with progressive reduction of oxygen supplementation. On May 8th he was discharged from the hospital after blowing out his 99 candles.

Figure 1
Patient’s chest X-rays at hospital admission



As of 9 May 2020, the current COVID-19 pandemic has already caused over 270,000 deaths worldwide (4). Older patients are more vulnerable to COVID-19 as witnessed by their higher hospitalization and mortality rate; in particular, institutionalized older persons appear particularly at risk of experiencing negative outcomes. COVID-19 has now become the main challenge in geriatric care. Thus, geriatricians are increasingly recognized as key figures in multidisciplinary hospital teams dealing with the COVID-19 pandemic (5). There are currently no specific treatments available for COVID-19. Several studies are underway to evaluate the efficacy of monoclonal antibodies against the interleukin-6 receptor (tocilizumab and sarilumab) in mitigating the cytokine cascade and improving the clinical course of the disease. However, older adults are usually excluded from clinical trials and therefore are at risk, during this pandemic phase, of not having access to the treatments being studied. In our case, a 98-years old patient optimally responded to off-label sarilumab with marked improvement in clinical conditions and no adverse reactions reported. Although clinical trials will be necessary to assess safety and efficacy of sarilumab in the treatment of COVID-19, our finding may be promising.



This case suggests that age alone should not preclude access to new therapeutic approaches. Comprehensive, multisciplinary, multidomain approaches assessing, among others, comorbidity burden and frailty status, are needed to develop patient-tailored treatments against COVID-19.


Funding: This case report received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest: On behalf of all authors, the corresponding author states that there is no conflict of interest.
Ethical approval: Not applicable. No research study involved.
Statement of human and animal rights: All procedures performed in the study were in accordance with the ethical standards of the institutional or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and conformed to the Declaration of Helsinki on human research.
Informed consent: The patient included in the study gave written informed consent for the publication.



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S.-L. Wee1,2,3, P.L.K. Yap1,4


1. Geriatric Education and Research Institute (GERI), Singapore; 2. Health and Social Sciences Cluster, Singapore Institute of Technology (SIT), Singapore; 3. Programme in Health Services and System Research, Duke-National University of Singapore (NUS) Medical School, Singapore; 4. Geriatric Medicine, Khoo Teck Puat Hospital (KTPH), Singapore.
Corresponding author: Shiou-Liang Wee, Geriatric Education and Research Institute (GERI), Singapore, weeshiouliang@gmail.com

J Frailty Aging 2020;9(3)132-133
Published online May 22, 2020, http://dx.doi.org/10.14283/jfa.2020.28



Since the outbreak of Coronavirus Disease 2019 (COVID-19), there have been few deadlier places than in nursing homes. As such, several useful guidelines on coping with COVID-19 in nursing homes have emerged. The critical immediate term measures mentioned in the guidelines have longer term implications especially on quality of care. We discuss how these measures instituted for infection control can be synergistic with person-centered care which has been synonymous with quality of care in nursing homes.

Key words: COVID-19, person-centred care, nursing home, infection control.


Vulnerability of residents in dormitory like nursing homes to COVID-19

The first case of Coronavirus Disease 2019 (COVID-19) in Singapore was confirmed in a tourist from Wuhan on 23 January 2020. Initial numbers grew in a relatively controlled manner given the prompt and coordinated public health measures in Singapore (1), with its contact-tracing praised by epidemiologists as “gold standard of near-perfect detection” (2). The first cluster of cases at a local nursing home (NH) surfaced on 1 April 2020, and quickly progressed by 23 Apr 2020 to five out of the total of 80 nursing homes in Singapore recording positive cases (3). Therefore, on 8 May, COVID-19 testing was instituted for all the 16,000 residents and 9,000 staff of all nursing homes (4). Frail and elderly nursing home residents, who are at highest risk of morbidity and mortality from COVID-19 (5), mostly reside in dormitory-like wards in Singapore and are cared for by staff who move freely between wards. The dire consequences of COVID-19 outbreaks in nursing homes in the Europe and US prompt deliberations on how better to care for vulnerable older people in long term care facilities during a pandemic, which have implications that extend to non-pandemic times too.


Growing number of nursing homes, but what kind?

As with many ageing nations, residential long term care in Singapore has become a pragmatic option for older persons who, for various reasons, cannot receive care appropriate for their needs at home. To meet this challenge, a comprehensive Healthcare Masterplan 2012-2020 has been progressively implemented in Singapore over the last decade with the endeavour to double the capacity of NHs (6). Besides accelerating the number of new and larger NHs, which grew from 64 in 2012 to 77 in 2019, there is also a desire to make a gradual transition from an institutional to a more home-like and person centric care model to better meet the needs of future cohorts of increasingly educated seniors who value greater privacy and autonomy. It is noteworthy that the recent guidelines (7-9) on coping with COVID-19 in long term care can have bearings on person centred care (10) (PCC) and the converse applies likewise.


Synergism in infection control and person centred care

For many NHs in our setting, including the one with the first COVID-19 cluster, dormitory style living with up to eight beds in a cubicle is still the norm in government subsided facilities. Single rooms are few and meant for immuno-compromised residents or isolation of those with infectious diseases. Single rooms housed within small and home-like environments, which afford greater privacy, freedom and personalisation of space, is aligned with PCC and have been evidenced to be associated with less agitation, and better mood and sleeping patterns in people with dementia (11). PCC also promotes autonomy where residents are self-caring as far as possible and encouraged to engage in higher order tasks to maintain a sense of meaning and purpose, and to optimize functional capabilities. Having more independent residents is advantageous during a pandemic given the need for isolation and safe distancing, with decreased staff-resident contact time. These measures for infection control can conceivably be continued beyond the pandemic in the form of single rooms to secure an enhanced living ambience for the residents and respects their right to individuality and self-determination.
A dormitory-like living arrangement, with frequent staff movement between shifts and wards, can promote depersonalised care as staff have less opportunities to acquaint themselves well with the residents and build relationships. These relatively more expansive living spaces with limited staffing often prioritise safety above autonomy whereby frail residents who attempt to get out of bed on their own are restrained to prevent falls. In contrast, small and home-like environments, with consistent staff caring for the same residents, help to promote closeness and nurture relationships which are fundamental to the wellbeing of both residents and staff. Moreover, having the same staff care for a smaller group of residents has the advantage of reducing the risk of cross-infection during an outbreak. The intimacy and trust developed over time also lends itself more expediently to honest conversations on which advance care plans are founded. Making advance care plans is pertinent in the face of a pandemic like COVID-19 (12) which preferentially increases mortality in frail nursing home residents. A 90 year old woman from Belgium made the decision to refuse ventilator treatment during the current pandemic, saying “Keep this for the younger patients, I have had a beautiful life” (13).


Harnessing technology application

Regular human interaction and engagement are crucial to PCC. This becomes highly challenging to fulfil with the need for physical distancing and infection control. COVID-19 has seen the application of several available technologies. Likewise, technologies can be relevant in long term care and especially useful in a pandemic. Autonomous robots have been deployed in COVID-19 isolation rooms to deliver meals and medication, monitor vital signs and act as portals of communication between staff and patients (14). If single rooms for PCC are advocated, these robots can be adopted and the residents given time to familiarise so that even those with dementia will not be averse to interacting with them. The digital interface, delivered through robots or video conferencing, can also prompt reminders for daily activities, engage residents in therapy and interactive games, and provide opportunities for conversations with staff, family and friends. Hence, pre-emptive adoption of technology in long term care can ease transition into more technology enabled care during pandemic times. Conversely, the uptake of technology during a pandemic can also facilitate more sustainable use of technology beyond the pandemic.



Recently, we completed a study on “Rethinking the design of nursing homes”. Part of the study involved several local NHs which included an early adopter of PCC which had instituted systematic enhancements in the built environment and care culture of the organisation (15). Preliminary results showed promising improvements in the residents’ overall well-being. If COVID-19 has sparked the best of human compassion, ingenuity and adaptability; we hope the exchange of learnings from PCC and COVID-19 can bring about better care to enhance well-being in residents of nursing homes.


Conflicts of Interest: The authors declare no conflict of interest.



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15. Urban Redevelopment Authority (URA) Skyline Issue 12. Rethinking the design of nursing homes. https://www.ura.gov.sg/Corporate/Resources/Publications/Skyline/Skyline-issue12/Rethinking-design-of-nursing-homes. Accessed 27 April 2020.


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