A mild infection changed my life. In the final year of high school, shortly before my final exams, I caught Epstein-Barr virus (EBV), and developed mononucleosis or glandular fever. The months of fatigue, a hallmark of EBV infections, took their toll on my exam performance, and I missed admission to law school by a single point.
While the effect on my vocation was arguably positive, mild EBV infections can, in some cases, have a devastating long-term impact on health. EBV was recently discovered to be the leading cause of multiple sclerosis (MS), a debilitating disease of the nervous system with symptoms from incontinence to depression to blindness.
The relationship between seemingly mild infections and chronic illness is an important part of preventive care, something that the Ministry of Health recently announced will be a new focus.
The connection between EBV and MS was made in January of this year by two astounding papers.
First, there was an epidemiological study led by Harvard University’s Neuroepidemiology Research Group; over 20 years, they followed the medical history of 10 million military staff, including 955 diagnosed with MS. The study shows that the risk of MS increased 32-fold following infection with EBV. This huge increase in risk, along with other evidence, is something close to proof that EBV is the main cause of MS.
Second, eleven days later, an immunological study of MS patients identified antibodies that bind to both an EBV viral protein and a human protein in the nervous system, so-called “auto-antibodies”. This unintentional cross-reaction indicates that the immune response to EBV can backfire on a patient, resulting in long-term nerve damage.
These findings mean that EBV now joins several other major viruses that cause a seemingly mild illness initially, but can later lead to more devastating disease. This list includes some grim pairings: childhood chicken pox followed by an excruciating rash (shingles) in old age; measles followed a decade later by a lethal form of encephalitis; and human papilloma virus causing cervical cancer.
Now, Covid-19 is also joining this ignoble club in the form of “long Covid”. Also known as “PASC” (post-acute sequelae of COVID-19), these longer-lasting symptoms are estimated by the National Centre for Infectious Diseases to impact one in ten unvaccinated Covid-19 patients. Studies from the UK indicate that PASC also affects those who were acutely asymptomatic.
Perhaps because some of the symptoms are more subtle than, say, pneumonia, and variable between patients, it has been easy to overlook this longer-term illness.
A major survey published in early March, led by groups at the University of Washington, identified four major PASC risk factors: type 2 diabetes, lingering Sars-Cov-2 viral RNA that stays in the body for months, auto-antibodies, and reactivation of EBV. The latter two warrant a little more explanation.
Echoing the EBV-MS story, the inflammation that occurs while fighting the infection appears to also damage the body, with a key role for auto-antibodies. This damage might even be long-range. For example, experiments in mice showed that even an infection that is confined to the lung can—through inter-organ inflammation—nevertheless cause damage to the brain. Indeed, the brains of Covid-19 patients appear to have some similarities to those suffering from Alzheimer’s dementia.
And as for PASC and the Epstein-Barr virus itself, in a surprising turn of events, Covid-19 appears to reactivate our old adversary EBV. Raised from its dormancy, EBV reactivation appears to be specifically connected to the fatigue affecting many long Covid patients. It also raises the possibility that PASC, through EBV reactivation, could potentially lead to long-term effects like EBV-induced cancer and MS.
All this is to say that a supposedly mild case of Covid-19 can lead to a drawn-out viral guerilla war: the virus can go underground, turn the body against itself, and even enlist another virus.
Covid-19’s inflammation and auto-antibodies could threaten longer-term consequences years from now. For ageing populations with declining cognitive function (e.g. most of the rich countries), the last thing they should want to risk is large cohorts of chronic PASC patients with brain damage. The current economic and political calculations in favour of allowing widespread infection may not have incorporated such long-term costs.
The current vaccines are excellent at dramatically reducing severe disease. However, their protection against PASC is not as clear: some studies suggest the vaccines reduce incidence and severity, while others show only modest protection. What is clear is that the vaccines do not eliminate PASC. This disappointment will only get worse as new strains evolve, and new vaccine versions struggle to catch up.
The current vaccines are also weak at blocking transmission of the new strains. This means millions of people run the risk of potential PASC. Prevention is the best medicine, so how can we prevent a potentially decades-long burden of PASC?
For the four major PASC risk factors there are currently only a few options. The risk associated with lingering Sars-Cov-2 RNA demands clinical trials to see if new antivirals like Paxlovid will help treat PASC, by helping to clear residual virus fragments. The EBV reactivation suggests that at least some PASC cases might have been prevented by an EBV vaccine, and adds urgency to the efforts by Moderna and others to develop them.
However, to develop new vaccines that can either prevent EBV reactivation or strongly block Covid-19 transmission might take years. Before new variant waves crash ashore, we need to improve the prevention of Covid-19’s airborne transmission.
For this, we need wider indoor use of comfortable N95 respirators like the Singapore-made 3M VFlex. We need cheaper, more frequent rapid testing with good isolation options while positive. Critically, we need a coordinated strategy to improve indoor air quality using ventilation, filtration, and ultraviolet purification. For example, upper-room germicidal ultraviolet light, used in hospitals for nearly a century, is a highly effective way to reduce airborne transmission that needs another look. Only a “vaccines-plus” approach will be able to cut transmission and lift the long shadow of PASC.
Back when I was a teenager with acute EBV, I had no idea how that mild infection would nevertheless redirect my life journey. Likewise, two years into the pandemic, we still don’t know the full, long-term impact of Covid-19 and, as a result, we continue to underestimate the long-term costs.