Two years of lockdowns and restrictions have disrupted our natural immune defences

A SPIKE in infant and childhood hepatitis is causing alarm, with over 114 UK cases and 169 worldwide. Most are aged 1-5 years, with a few either side. One child – not in the UK – has died, and 7 in the UK required liver transplants.  All are negative for the viruses (A-E) that ordinarily cause the hepatitis but, among 53 UK children tested, 40 had adenovirus 41F. Additionally, 10 of 60 tested were positive for SARS-CoV2, though some appear to be late positives, with lingering virus fragments, not active infection.

Adenovirus 41F is not a usual cause of hepatitis; it is ordinarily associated with acute gastroenteritis.  I’d better add that it is remote from the adenoviruses used as vectors in COVID-19 vaccines, and the children had not been vaccinated. So please don’t make 5 from 2 plus 2; COVID vaccines are irrelevant here. Rather, to quote the UKHSA’s Technical Briefing:

“There may be a cofactor causing a normal adenovirus to produce a more severe clinical presentation in young children, such as increased susceptibility due to reduced exposure during the pandemic, prior SARS-CoV2, or other infection, or a yet undiscovered coinfection or toxin. Alternatively, there may have been emergence of a novel adenovirus strain with altered characteristics.”  

UK HSA: Investigation into acute hepatitis of unknown aetiology in children in England

My erstwhile UKHSA colleague, Meera Chand, is cited in the press on the possible link to lockdown.  I’ll come back to whether I agree at the end of this article.  But, either way, the story underscores that we dwell in a delicately balanced microbial soup.  I’m delighted to see the UKHSA acknowledging the hazard of disturbing this balance.

It’s an equilibrium that’s very well accepted in the case of bacteria.  Our guts contain more bacteria than there are people on the planet, or human cells in our bodies. Acquired shortly after birth, the ‘gut microbiome’ varies over time and among people.  A growing cohort of scientists eke a living by associating ‘unhealthy floras’ with conditions as diverse as Crohn’s disease and autism. Probiotics are sold to promote a healthy gut flora. Whilst many claims are questionable or directed towards doubling the price of yoghurt, there is no doubt that the gut flora is vital to health.  Disruption with antibiotics leaves the elderly patient vulnerable to colonisation and infection with Clostridium difficile. This causes severe recurrent diarrhoea and, at worst, may destroy the colon’s lining.  One cure, effective in over 90% of cases, is to give the patient a faecal transplant from a healthy donor, instilled through a colonoscopy or, more rarely, a nasogastric tube.

It’s harder to suggest viruses are beneficial. Nonetheless it’s curious that 5-8% of the human genome is composed of fragments of retroviruses, suggesting long co-evolution.  One theory is that they represent past ‘plague culling’ events.  Having integrated viral fragments, we maybe cease to be vulnerable to infection by the retroviruses themselves.  

At the individual level there are numerous instances of one virus retarding concurrent infection by another.  Moreover, immunity induced by a benign virus may prevent subsequent infection by its dangerous relative, as with Jenner’s classical observation that cowpox protected against smallpox.  More currently, T-cells primed by exposure to common cold coronaviruses partially cross-protect against SARS-CoV2, preventing infection and reducing severity.  Perhaps this explains why COVID-19 is so variable in severity, even among those of similar age and underlying health.

We interfere with these balances at our peril, as illustrated by polio (myelitis), a virus transmitted via faecally-contaminated water.  Although known from antiquity, polio-associated paralysis was rare until the late 19thcentury.  Thereafter there were major epidemics, peaking in the 1950s. Perversely, hygiene drove the problem.  Until the late 1800s, a new-born baby could expect its mother would have been infected in her own infancy. She consequently would deliver antibodies across the placenta and in her milk. These gave the baby protection when, in its first months, it too found itself infected. It then made its own antibodies, gaining lifelong immunity. 

Clean water terminated this happy ecology.  Infants were born to uninfected mothers, who provided no antibodies. Worse, they caught polio at older ages, when the virus enters the central nervous system, precipitating paralysis.  As a public health intervention, clean water is obviously a ‘good thing’. It ended the cholera and typhoid epidemics of early Victorian London. But it also created the conditions for polio epidemics, only ended by vaccines.

So, to the ‘non pharmaceutical interventions’ (NPIs) of these past 2 years, which aimed to suppress SARS-CoV2. Unlike clean water these were not obviously a ‘good thing’.  They caused vast harm – to education, to mental health, to non-COVID healthcare and to the social fabric.  Their cost was gargantuan.  Last, and pertinent here, they disrupted our balance with our pathogens.   Other respiratory viruses, including flu and respiratory syncytial virus (RSV) were suppressed more completely than SARS-CoV2, almost disappearing in the winter of 2020/21.  Unfortunately, just as with SARS-CoV2, there was never any possibility that these old viruses would be eradicated. 

And now, with near-normality restored, they are bouncing back, finding populations with waned immunity and an enlarged cohort of never-previously-infected children, older than when they should have first encountered common respiratory pathogens.

Since mid 2021 there have been major outbreaks of RSV in the UK, USAJapan and New Zealand. In Tokyo the 2021 peak far over-topped that of any preceding recent year (figure).  Unusually, these RSV spikes came in the summer, whereas RSV normally peaks in the autumn and winter.   Most RSV infection is trivial but a few cases are severe, making it a leading cause of hospitalisation for infants.

Influenza too will return.  And, following two winters when it was scarce, it is hard to know what variants will predominate and so how to tailor vaccines. So, maybe next winter, or the one after, expect a bad flu season.

As to whether the hepatitis outbreak is a further reflection of this disruption of natural ecology, the jury is out.  Maybe it is: most of the children are ages 1-5 years, meaning that their virologically formative years were spent in unusual isolation.  On the other hand, there is little past evidence for adenovirus 41F as an agent of hepatitis and at least one affected infant was only a month old.   If adenovirus 41F could cause hepatitis in someone so young, we should be familiar with it already. A one-month-old infant can hardly have missed out on prior ‘normal early exposure’.  So, maybe adenovirus 41F has changed, or the hepatitis aetiology is more complex.

Respiratory syncytial virus infections in children, by year and epidemiological week, Tokyo, Japan, January 2017–July 2021 (as of epidemiological week 28, 2021). Figure courtesy of Center for Disease Control and Prevention (CDC)

Irrespective, the core point, well-illustrated by RSV is that the abnormal conditions of the past two years have distorted our relationship with the life that lives on us. 

Restoring balance and establishing our equilibrium with SARS-CoV2 will take a few years. During which it is vital that we turn a deaf ear to siren calls for renewed restrictions ‘To protect the NHS’ if we have a bad flu year with SARS-CoV2 still circulating.  They will only extend and multiply the distortions. 

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David Livermore is professor of medical microbiology at the University of East Anglia. After working at the London Hospital Medical College from 1980 to 1997, he joined the Public Health Laboratory Service, and became director of its Antibiotic Resistance Monitoring and Reference Laboratory.

Photo of sleeping newborn baby by Tatiana Morozova from Adobe Stock.