Does Covid 19 Pandemic Challenge Decade of Healthy Ageing??

Impact of Aging on Adaptive Immunity

Adaptive immunity is important for combating viral infection, in part by generating antigen specific immunity, leading to the development of protective immunologic memory. Aging & adaptive immunity: a) Humoral immunity and aging: Somatic hypermutation (SHM) is a key process for antibody generation and diversity and ageing impacts this process at multiple levels. I) B-cell germinal centres within the spleen and tonsils of aged individual’s exhibit preserved SHM, but in the circulating B-cell pool as well as germinal centres of Peyer’s patches, SHM decreases with age. ii) E47 is a transcription factor encoded by E2A that regulates many B cell functions. iii) The activation-induced cytidine deaminase (AID) induces class switch recombination (CSR) and Ig somatic hypermutation. Expression of E47 and AID Thus, aging impairs antibody generation by B cells at several levels to reduce humoral immunity. Both the number and proportion of peripheral B-cells decrease with age. This is likely a consequence of decreased total number of IgM memory B cells. Overall, aging impacts the B-cell pool with memory B-cells exhibiting reduced numbers while naïve B-cell pool size remains preserved. All these components of humoral immunity are affected by aging as B cells isolated from peripheral blood of older human subjects have decreased. Bacterial super-infection is a complicating factor, which worsens morbidity and mortality after respiratory viral infections, including influenza and Covid 19. On a functional level, aging impairs the ability to generate protective antibodies in response to both vaccination and infections [1].

b) Aging and T-cell function: Antigen-specific B cells require interactions with CD4+ T cells for subsequent expansion and differentiation and generation of T-cell dependent antibodies. Some studies have shown that aged CD4+ T cells have a reduced ability to form functional immunological synapses upon stimulation with peptide pulsed antigen presenting cells (APC) than young T cells, leading to defective T-cell receptor activation and poorer IL-2 production with ageing. Experimental studies suggest that this restricted repertoire may impair control of influenza or herpes simplex viral infection and may be suspected in case of Covid 19 infections.

Aging and Innate Immunity

Plasmacytoid dendritic cells (pDCs) are key cellular responders of viral infection. They are the most potent type I interferon (IFN) producing cells and this action initiates several host responses. This signalling pathway induces the upregulation of several signal adaptors, including IFN regulatory factor (IRF) 3, 5 and 7. There have been several studies that have documented that aging impairs pDCs to produce type I IFNs. Initial scientific work demonstrated that this defect with aging was critical for an impaired ability to clear herpes viruses in aging mice. Other experimental studies have found that aging can impair certain components of TLR responses in macrophages and conventional dendritic cells (DCs), the production of proinflammatory cytokines and upregulation of costimulatory molecules. It is recently found that an imbalanced innate cytokine response induced lethal immune pathology during viral infection using experimental models of herpes viral infection, including HSV and CMV. If such work is translated to humans, it will suggest that specific anti-inflammatory therapies may be beneficial in older people infected with influenza viral infections and Covid 19 [1].

The virus that causes COVID-19 infects people of all ages. However, evidence to date suggests that three groups of people are at a higher risk of getting severe COVID-19 disease. These are i) older people over 60 years old ii) those with underlying medical conditions (such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer). The risk of severe disease gradually increases with age starting from around 40 years [2] and iii) Overweight and Obesity. The latest advisory from CDC Atlanta based on 2 studies in USA found that overweight patients were 40% more likely to die than healthy-weight patients, while obese patients were at 30% greater risk, compared with the healthy-weight patients [2].

There is a mix up in most of the Covid 19 worldwide data. The infection rates based on Rapid Antigen and RT-PCR tests, the symptomatic cases with different severity confirmed by RT PCR test, attack rates based on test positivity, case fatality rates among those hospitalized and post-mortally tested positive deaths. Biggest confusion is use of infection rates and case rates even though a large proportion of infections are asymptomatic, and worst is in association of deaths with comorbidity.

Globally Covid 19 mortality is to a large extent determined by access to and quality of health care. For seasonal influenza, mortality is usually well below 0.1% and for Covid it is around 1-2%. Over 95% of these deaths occurred in those older than 60 years. More than 50% of all fatalities involved people aged 80 years or older. Reports show that 8 out of 10 deaths are occurring in individuals with at least one comorbidity, those with cardiovascular disease, hypertension, and diabetes, but also with a range of other chronic underlying conditions [3].

Mortality for COVID-19 appears higher than for influenza, especially seasonal influenza. While the true mortality of COVID-19 will take some time to fully understand, the data we have so far indicate that the crude mortality ratio (CMR) or case fatality rates is between 1.5-4.5 %, globally with the exception of Mexico (10.4). The infection mortality rate (the number of reported deaths divided by the number of infections) will be lower (Figures 1-5).

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The novel Covid-19 is affecting the advanced countries disproportionately more than developing countries. Covid-19 casualty is higher in countries where there is a large ageing and overweight or Obese population. Looking at particularly the elderly dependency ratio which is the ratio of elderly population (ages 65+) per 100 people of working age (ages 15-64). source of the data for 2020 came from the CIA (Central Intelligence Agency) World Factbook--). Japan has the highest dependency ratio at 48%, Followed by Italy (36.6%), Spain (30.4%), France (33.7%), the UK (29.3%), and the US (25.6%). The developing world with higher fertility rates and lower life expectancy than developed countries have a lower elderly dependency ratio for example in India it is 8% [2]. What Does DATA Show The number of new cases per week has remained stable at 2 million for the past three weeks with the cumulative total of about 37 million cases in 235 countries. Over 1 million deaths have now been reported globally, of which the majority were reported in the Region of the Americas (55%), followed by Europe (23%). In the past week, the regions of the Americas, South-East Asia, and Europe account for 91% of new cases. India, the United States of America, Brazil, Argentina, and France reported 60% of new global cases week ended on 10th October 2020.

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The relative risk of dying from COVID-19 is higher for men than for women in almost all age groups in all countries. The overall relative risk ranged from 1.1 to 1.9. The novel Covid-19 is affecting the advanced countries in the Western Hemisphere disproportionately more than developing countries. In most countries, sex differences increased until ages 60–69 years, but decreased thereafter with the smallest sex difference at ages 80+. [4]. When researchers associated the incidence of Covid-19 and fatality rates across the globe with the elderly dependency ratio, which is a reasonable proxy for the age composition of the population they found that the correlation coefficients1 which were 0.53 and 0.44

respectively, both significant at the 1% level as seen in the figures 2 & 3.

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Covid-19 casualty is higher in those countries where we already have an ageing population, with older people requiring hospitalisation and subsequently die from infection. These correlations are strikingly different as the age profile of Covid-19 mortality is quite opposite to that of the Spanish flu (1918) pandemic where young working age adults were mostly the victims [1]. The recent advisory from CDC Atlanta based on two studies one in the UK and another in Brooklyn, US. The Brooklyn study, which observed over 500 patients hospitalised, found that overweight patients were 40% more likely to die than healthy-weight patients, while obese patients were at 30% greater risk, compared with the healthy-weight patients. The British study examined lifestyle risk factors among 760 had Covid-19 patients and found overweight people were roughly 30% more likely to be hospitalised upon infection.

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Indian Data

The unreleased case data from the Union ministry of health and family welfare, accessed by HT, shows that more than half (54%) of the people infected in India are between the ages of 18 and 44, while half (50%) the people who succumbed to the disease are above 60 years of age. Most deaths-50%-are in the age group of 60 years and above, followed by 37% deaths among people between 45 years and 60 years in age. About 11% of people who succumbed to the disease were between 26 and 44 years of age and 1% each belonged to the 18-25 years and below 17 years cohorts. The latest mortality data also shows 68% of the Covid-19 deaths in the country are among men and 32% are of women (Figures 1-7).

More than half the 56,292 Covid-19 deaths across states by August 22 were in the 50 -70 age group, with Covid-19 deaths being the highest in the 61-70-year age group among both genders. Twice as many men have died of the Covid-19 as women in India, with men accounting for 69% of all fatalities. By August 22, women accounted for 17,315 and men 38,973 of the total Covid-19 toll of 56,292. There were 301 Covid-19 deaths among people over the age of 90 years, who account for 0.5% of the total deaths. This is much lower than the global average, where people 85 years old and above account for 3.4% deaths [5].

With the results of the second round of Delhi’s SARS-CoV2 sero-prevalence survey released in the first week of October 2020 and other similar surveys in Mumbai and Ahmedabad showed the prevalence of infections was higher among women than among men, however the Pune sero-survey did not find such a gap (Tables 1-5).

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Both Pune and Bhopal surveys indicated a higher prevalence of seroprevalence of 64.5% in users of shared toilets compared to users of independent toilets (45.3%).

In May, the Indian Council for Medical Research

published its analysis of over one million diagnostic tests for covid-19 conducted between January 22 and April 30. They found that while men made up most positive cases, women were slightly more likely to test positive than they were to be tested.

Reported Cases & Deaths

Based on the cases reported fewer women in the official case counts may be due to because fewer women are being tested, or because fewer women develop serious enough symptoms to warrant testing or hospitalization, the evidence thus far suggests that all three might be true [6].

Similarly, the officially data of deaths indicate that fewer women than men have died of Covid 19 in India and worldwide [6].

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If one looks at the age specific case fatality rates, international evidence points to potential biological advantages for women that get blunted by gender disadvantages of women in India in seeking care early resulting in a higher risk of mortality in India. There are various underlying factors for such patterns in India like Men suffer from several lifestyle risk factors, a large proportion of women in India have poor nutritional status including both underweight and overweight prevalence as well as micronutrient deficiencies, the circumstances of health care access and affordability are also important issues which are shaped by contextual factors such as household socioeconomic status and gender roles and women are less likely to be accurately counted in death statistics as evidenced by women being historically undercounted in death statistics [6].

Covid 19 Vaccination in Elderly

In a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults, expanded to include 40 older adults, who were stratified according to age in two groups of 56 to 70 years and ≥71 years and given two doses of either 25 μg or 100 μg of vaccine administered 28 days apart. The 100-μg dose induced higher binding- and neutralizing-antibody titres than the 25-μg dose, which supports the use of the 100-μg dose in a phase 3 vaccine trial [7].

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Way Forwards

There is a dire need to understand the epidemiology of the Covid 19 disease fully. The analysis of gender and age specific infection rates need for hospitalization, severity, complications and causes of deaths, the attack rates, hospitalization, and case fatality rates. Other technical analysis should look at association of BMI, pre-existing comorbidities, and access to and quality of health services. Countries should also prepare near-real-time data on highly vulnerable populations and their conditions, with a special focus on infection and death rates, poverty, joblessness, mental health, violence, hunger, forced labour, and other forms of extreme deprivation and abuses of human rights.

While practicing physical distancing elderly people need to find ways socialization over phones, video-consultations, and discussions to keep the mental health & their sprits high. Practice of Yoga may one other way of tiding the crisis.

Countries must revise their strategies and plans for the Decade of Healthy Ageing and Global rededication is desired after the pandemic.

Indian leaders need to choose to capitalize public health expertise and invest in Public Health Services for long time to come while building public private partnership of not for profit nature.