Sign up

The Complex Challenge of Studying COVID-19’s Resilience and Uncertainties

Marcel Olde Rikkert, Professor in Geriatric Medicine and Chair of the Geriatric Department at Radboud University Medical Center, Netherlands, discusses the vulnerabilities around COVID-19 and the elderly.

According to a statement from the World Health Organization, older persons have the highest risk of developing a severe illness by COVID-19 [1]. The prevalence of COVID-19 in the community is still uncertain as it appears that several persons including elderly may not show symptoms while being infected and infectious [2]. Data indicate that the overall mortality rate is around 0.6% or slightly higher, however elderly are at much higher risk (around 15%) than children and younger adults, while frail elderly and those subject to comorbidity (especially hypertension, diabetes, cardiac pathologies) are at even greater risk [1,2]. Hence, as the COVID-19 pandemic spreads, a great variety of heath care professionals at intensive care units, specifically developed COVID-19 wards, nursing homes and in the community are working hard to deliver care as good as they can for these vulnerable persons, in a domain with many clinical uncertainties [1].

First pathophysiology of COVID-19 is uncertain in a number of ways: 1) It is only partly known why severity varies from patient to patient, and why elderly patients are most vulnerable; 2) How can large segments of the population be infected and transmissive but asymptomatic or low in symptoms (e.g. increase of low basal temperature of 35 degrees with two degrees, instead of classic fever); 3) It is largely unknown why the net outcome is so highly variable across regions and countries. 4) Currently there is uncertainty on the effectiveness of all antiviral drugs used against the SARS-CoV-2 virus, and it is unclear whether and when an effective vaccine may be available. These uncertainties and the high variability in clinical outcomes underline that COVID-19 cannot be understood and treated as a simple, direct consequence of the SARS-Cov-2 virus infection, but rather should be understood by studying the complex interaction between the virus and the unique characteristics of each host and its environment [2,3].

The primary aspect of the host likely to play a role is the immune system. The importance of the immune system as the key factor distinguishing clinical impacts in different individuals is supported by the role of inflammation in the development of complications and advances stages of disease, notably the cytokine storms that trigger Acute Respiratory Distress Syndromes (ARDS). Moreover, it may be the inflamm-aging and immunosenescence rather than the virus per se that puts people at higher risk. More broadly, there is reason to believe that understanding the interplay between aging, the immune system, comorbidity and COVID-19 will provide the key to improve understanding of the heterogeneous COVID-19 phenotypes.

Another area of great uncertainty is how to manage COVID-19 patients best. Though many protocols to harmonize quality of care for COVID-19 are written with admirable speed, and research is carried out with enormous efforts, it is still hard to validly assess effectiveness of COVID-19 health care.  Jeffrey Braithwaite convincingly describes  that 60% of health care on average is in line with evidence- or consensus-based guidelines, 30% is some form of waste or of low value, and 10% is causing net harm [4]. In a review of literature ranging from paediatrics to cardiology and psychiatry he concludes  that this 60-30-10 outcome challenge has persisted for three decades [4,5]. It would be highly interesting and valuable when the research community would also assess COVID-19 health care against similar quality of care criteria. Some domains such as the technical quality of artificial ventilation support may clearly lie in the 60% domain. Others such as the quality of palliative care, with many people dying in solitude due to strict social isolation, however may also fall in the 30% or even the 10% area. This could guide quality improvement and also international exchange of best practices.

Similarly social distancing policies should be scientifically evaluated, especially for vulnerable populations. It is an alarming paradox that while it’s an age old adage that older people should be kept mentally, socially and physically active, the major policy to protect this vulnerable group is to strictly limit all these activities [6-8]. Loss of physical and mental resilience, also by decline in immune function due to loneliness, may be highly relevant adverse reactions [9-11]. Moreover, the beneficial effects of isolation and activity restriction for COVID-19 prevention in frail older persons should stay in balance with their loss of wellbeing and welfare. In high, middle and lower income this balance also has its relevant societal and socio-economic interactions, which should be taken into account.

Our societies will be facing the challenges posed by Corona for a considerable time and there is a high chance of similar viral epidemics in the future. This foreshadows the need for preparedness and sufficient resources to most efficiently deliver high-quality and sustainable care.

Specifically, older patients and other frail patient groups with chronic health conditions are particularly vulnerable and have highest morbidity, mortality and loss of wellbeing, because of impaired physical resilience. Being cognizant of their high phenotypical heterogeneity, we urgently need to gain more knowledge about their physical, mental and social resilience, as well as on resilience of our health care systems and societies. Let’s join forces internationally as this scientific challenge is too large for single centres or countries, and we can learn a lot from our shared quests through COVID-19 uncertainties.

Marcel Olde Rikkert is head of the Centre of Excellence for Geriatrics (Dept Geriatrics) and coordinator of the Radboudumc Alzheimer Centre Nijmegen Alzheimer Centre. He conducts research into: resilience and frailty in older adults; complex dementia care interventions; complexity science and systems dynamics.For further information:

Photo by Cristina Gottardi on Unsplash


1. Lithander et al.   COVID-19 in Older People: A Rapid Clinical Review. Age & Ageing. Afaa93 2020:
2. Liu K, Chen Y, Lin R, Han K. Clinical feature of COVID-19 in elderly patients: a comparison with young and middle-aged patients. J Infect. 2020 Mar 11. pii: S0163-4453(20)30116-X. doi: 10.1016/j.jinf.2020.03.005

3. Olde Rikkert M, Vingerhoets R, Geldorp N, de Jong E, Maas H. Atypisch beeld van COVID-19 bij oudere patiënten Ned Tijdschr Geneeskd. 2020;164:D5004 [In Dutch]

4. Braithwaite J, Glasziou P, WestbrookJ. The three numbers you need to know about healthcare: the 60-30-10 Challenge. BMC Medicine 2020;18:102.

5. Braithwaite J. Changing how we think about healthcare improvement. BMJ.2018;361:k2014. 

6. Silver JK. Prehabilitation May Help Mitigate an Increase in COVID-19 Peri-Pandemic Surgical Morbidity and Mortality. Am J Phys Med Rehabil. 2020 Apr 21. doi: 10.1097/PHM.0000000000001452

7. Scheffer M, Bolhuis JE, Borsboom D, et al Olde Rikkert M. Quantifying resilience of humans and other animals. Proc Natl Acad Sci U S A. 2018;115(47):11883-11890. DOI: 10.1073/pnas.1810630115

8. Gijzel SMW, Rector J, van Meulen FB, et al. Measurement of Dynamical Resilience Indicators Improves the Prediction of Recovery Following Hospitalization in Older Adults. J Am Med Dir Assoc. 2019. DOI: 10.1016/j.jamda.2019.10.0116.

9. Leschak CJ, Eisenberger NI. Two Distinct Immune Pathways Linking Social Relationships With Health: Inflammatory and Antiviral Processes. Psychosom Med. 2019 Oct;81(8):711-719. doi: 10.1097/PSY.0000000000000685.

10. Snyder-Mackler N, Sanz J, Kohn JN, Brinkworth JF, Morrow S, Shaver AO, Grenier JC, Pique-Regi R, Johnson ZP, Wilson ME, Barreiro LB, Tung J Social status alters immune regulation and response to infection in macaques. Science. 2016 Nov 25;354(6315):1041-1045. doi: 10.1126/science.aah3580.
11. Sanz J, Maurizio PL, Snyder-Mackler N, Simons ND, Voyles T, Kohn J, Michopoulos V, Wilson M, Tung J, Barreiro LB.

Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques. Proc Natl Acad Sci U S A. 2019 Oct 14. pii: 201820846. doi: 10.1073/pnas.1820846116

Skip to content