The age-related increase in the risk of severe disease and death from COVID-19 mirrors earlier patterns seen with infections. Such trends may help understand the mechanisms underlying the clinical feature. A recent study published in the preprint server medRxiv* in August 2020 shows the effect of age and sex on COVID-19 hospitalization rates in the USA and helps understand how immune function is involved in this pandemic.
Phases of COVID-19
COVID-19 is now known to occur in three phases, firstly, mild symptoms of dry cough and fever, following which most patients recover. Secondly, some patients develop viral pneumonia and need hospitalization. Thirdly, some of these inpatients develop critical respiratory difficulty, stroke-like events, and lymph node destruction, about three weeks from symptom onset, requiring intensive care unit (ICU) admission.
Many COVID-19 patients show lymphopenia early in the disease course, which serves as a marker of disease progression and mortality. Clinical trials are ongoing to assess immunotherapies and vaccines based on T cell immunity since these are being proved to be of greater efficacy than humoral immunity alone in this condition. Indeed, asymptomatic COVID-19 patients have a strong T cell response without or before any antibodies being detected.
Age-Related COVID-19 Severity Risk
Numerous studies have found that severe COVID-19 risk increases with age and is lowest for those under 20 years. Whether infection risk is also low in younger patients is controversial at present, but disease progression is much less common in this age group.
The current study explores the link between the age-related increase in the risk of COVID-19 and thymic involution as well as T cell production.
Simple Inverse Relationship
In infections like Methicillin-resistant Staphylococcus aureus (MRSA) and pneumococcal, West Nile virus, and chronic myeloid leukemia (CML), as well as heart and brain cancers, the risk is known to double every 16 years of increasing age or increase by 4.5% a year. This is precisely the rate at which thymic volume and T cell production shrink to half every 16 years.
This, therefore, shows a simple inverse relationship between disease risk and T cell production. The well-known bias towards disease in men also fits this model, since men have about 1.5 times increased risk of cancer and infectious disease, and 1.5 times lower T cell production, compared to women.
The male bias in COVID-19 risk is evident, with 33% increased hospitalization risk and 90% increased mortality risk in men and is very similar to the higher cancer risk in men. This may indicate two steps of increased risk in men, one preceding and one subsequent to hospitalization, the latter being mediated by the activation of IL-6 and the resulting dysregulated cytokine abundance – the so-called ‘cytokine storm’ – again possibly the result of T cell dysfunction.
The researchers comment, “As such, fundamental patterns in disease incidence with respect to both age and gender can be directly linked to differences in the adaptive immune system. We, therefore, tested to see if COVID-19 follows the same trend.”
Exploring Hospitalization Data
The researchers elected to use hospitalization data as more reliable than the number of cases, which depends on testing strategies. They found that the incidence of hospitalizations for this disease in many countries doubles with every 16 years of age. The incidence of cases, however, is not very different across age groups after 20 years. This could be because all adults have reliably uniform exposure to the virus while following exposure, the hospitalization risk doubles with every additional 16 years of age.
The researchers used ‘severe infection’ as an index of hospitalization, with all other cases being classified as ‘mild.’ Using a Susceptible-Infected-Removed (SIR) model, and assuming that the risk of severe disease following infection is 0.044 per year of age, they also included other factors such as age-dependent social engagement, contact with mild or severe infection, and environmental transmission without direct case contact. In this manner, they predicted the age distribution of hospitalizations in France. This country had a beautifully comprehensive dataset of confirmed cases by age.
They found that as expected, the risk of severe disease increases exponentially with age, paralleling the fall of thymic function with age above 20 years. The age group below 20 years had additional immune protection of 53-77% from severe COVID-19, perhaps due to cross-reactive antibodies against other coronaviruses or other respiratory viruses, which occur more frequently in this age group. About 40% to 60% of individuals without an exposure history do have CD4 T cells reactive to SARS-CoV-2. Confounding factors such as differences in exposure and infectivity of contacts were found to play no role in the age-dependent hospitalization rate.
The mechanism behind this association is not clear, but one good candidate is T cell exhaustion due to a high antigenic load. This is associated with the depletion of specific clones and low effector function. This has been found to occur in cancers and in infections and to predict mortality. With low T cell production over age, exhaustion becomes more likely and has been observed in a mouse cancer model.
‘Effective COVID-19 Age’
The mortality curve in COVID-19 is exponentially higher with age compared to the hospitalization curve. This could be combined with BMI and other risk factors, including cardiovascular disease, which also has an exponential rate of increase with age, to arrive at a COVID-19 age for each individual.
Combining the increase in the risk of cardiovascular disease and T cell decline with age, they obtained the observed increase in the risk of COVID-19 mortality with increasing age. The researchers say that in terms of risk, “For both hospital incidence and mortality, men are effectively ~6 years older than women.”
In other words, the risk of dying of COVID-19 is proportional to the risk of cardiovascular disease and inversely proportional to T cell production. Thus, they point out, “Cardiovascular disease is unlikely to be a risk factor for hospitalization but could be for subsequent disease progression.”
Lowest Risk in the 5-17 Years Age Group
The risk of COVID-19 is higher in children below 4 years but then decreases to the lowest observed levels up to the age of 17 years in the USA, as also seen with bacterial infections. This could be due to the effects of age on exposure, on the progression of the disease, and on infection rates following exposure, and the infectivity of the individual.
The researchers sum up that while there is apparently no difference in infection risk or transmissibility, “The simple inverse relationship between risk and thymus size we report here suggests that therapies based on T-cell mechanisms may be a promising target.” These findings could also help to understand how COVID-19 progresses to severe disease and to mitigate its severity.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.