Data from a UK healthcare worker cohort published in 2024 examined how signs and symptoms of COVID-19 changed after 1, 2, or 3 SARS-CoV-2 lab-confirmed infections. Those with no symptoms through to those whose symptoms persisted for >12 weeks recalled their experience, and the cohort included vaccinated and unvaccinated people and spanned the presence of different virus variants.

Humans not modelling

The SARS-CoV-2 Immunity and Reinfection EvaluatioN (SIREN) study is a large cohort study of UK healthcare workers. The participants were tested each fortnight by SARS-CoV-2 PCR and regular antibody testing (serology).

The cohort described in this 2024 report was sampled and tested between 01 March 2020 and 31 September 2022. Eligible members (n=5,053) were sent a survey to fill out on 12 September 2022.

To my mind, the big issue with the study is expecting people to accurately recall the constellation of 35 symptoms from their earlier infections. The first SIREN study indicated that symptom diaries were completed after infection detection, but the current paper from this cohort suggests that cohort members had to recall events that might have occurred months earlier.

They were also being expected to recall symptoms from weeks or perhaps months previously which increases the likelihood of recall bias.

Capturing that information for 12+ weeks after each positive PCR would have yielded higher-quality results.

There is also concern that fewer than half (6,677 of 16,599, or 40%) of the cohort responded to the invitation to complete the survey, and so those with symptoms may have been over-represented.

Nonetheless, let’s look at the study before us.

Three infections

5,053 of the 6,677 who responded remained eligible. Of them, 4,767 described their first infection, 991 their second and 74 their third.

No symptoms at all

The proportion of those reporting they had no symptoms at all (acute or persistent) after each infection increased from 8.9% to 13.2% to 29.7%. The majority did report symptoms after each infection, but that group shrank each time.

This pattern of increasing asymptomatic COVID-19 outcomes aligns with my recent post on modelling asymptomatic COVID-19 over time. Increased immunity correlates with milder outcomes. At least according to a person’s recall.

Most acute symptoms aren’t as common after the first infection

Five of six symptom categories showed a decrease in the proportion of the cohort affected by acute (lasting ≤12 weeks) symptoms after each infection. But the proportion of those experiencing any acute symptoms increased after the second infection, driven by an increase in respiratory symptoms (reflecting the transmission route and validating its designation as a ‘respiratory virus’). In particular, sneezing, runny nose and sore throat were remembered as worse among 4.1% to 8.9% more cohort members after their second infection than after their first. This decrease reached statistical significance between the first and second infections for two of the six broad symptom categories – systemic/inflammatory and neurological symptoms – but not for any categories between the second and third infections.

Table 1 confused me for a while as I worked through whether the ‘No symptoms’ (have a look for yourself if interested) referred to the number (sometimes abbreviated as ‘No.’) of people with symptoms or actually no symptoms. I got there in the end. But the authors didn’t graph this, and I think it’s also interesting. So here are two graphs.

Any, Typical and Acute symptoms categorised into groups

Even during a third infection, a wide range of acute symptoms were recalled by the 48.6% of the SIREN cohort who reported experiencing symptoms, although most diminished after each infection. The exception, Respiratory symptoms rose during the second infection before diminishing.

Persistent symptoms aren’t as common after the first infection

The study focused on symptoms lasting longer than 12 weeks.

From the study report’s Figure 2, we see that after each infection, most horizontal bars are smaller, indicating a decrease in the number of those experiencing the symptoms. Sometimes the drop is not much; other times, the symptom doesn’t recur by the third infection.

This implies immunity is becoming better at shutting down a persistent infection or the human response to it, after a second and third infection. We’ll look at the contribution of vaccination to this maturing immunity later on.

Persistent symptoms aren’t as common after the first SARS-CoV-2 variant infection

Next, the authors broke down the symptoms by the SARS-CoV-2 variant likely to have caused the infection: “wild-type” (the original Wuhan-originating virus) or Alpha, Delta, or Omicron.

Whether grouped into 6 categories, left as 35 individual symptoms, or noted as ‘any persistent symptoms’, the findings made it clear that there was an overall reduction in persistent symptoms among the cohort as each new variant supplanted the one before. Which also occurred in a stepwise order over time.

I’ve tried to show the most to fewest symptoms among the cohort, attributed to the infecting variant at the time of a person’s infection:

Because the emergence of each variant also correlates with elapsed time, it can appear as if the variant caused this decrease, when it may simply have been the growing SARS-CoV-2 immunity accruing among individuals in the cohort and the population in general, regardless of variant.

I make that last point as it is something to bear in mind whenever you hear about “less severe” variants. It’s a very different population in 2022 or ’23 or ’24, etc., in terms of immunity than it was in 2019.

Persistent symptoms are more common before vaccination

What we’ve seen above is that, over time, persistent symptoms affected fewer and fewer of the cohort. This is likely due to increased immunity within the cohort.

Another way to produce immunity is vaccination. So the authors looked at the difference in persistent symptoms between vaccinated and unvaccinated members of the cohort.

Unsurprisingly, vaccination prior to infection was associated with fewer symptoms in the cohort. Again, lending weight to immunity providing some protection from persistent COVID-19.

But persistent symptoms did remain in 33% of first infections and 22% of second and third infections. And a quarter of those with persistent symptoms reported that their day-to-day activities were “impacted a lot”. Persistent symptoms are a feature of COVID-19.

Final words

Vaccination is the safest, lowest-risk way to gain immunity, reducing the likelihood of COVID-19 symptoms and persistent illness after SARS-CoV-2 infection, regardless of variant.

Infection is also a way to gain immunity, but you will, much more often than not, risk symptoms from those infections. And you’ll have more symptoms – you’ll be sicker – than if you weren’t vaccinated before infection.

This study didn’t examine boosting; however, I feel confident in saying that an annual COVID-19 vaccine/booster remains useful for preventing serious illness and death.

Even after three distinct confirmed infections, nearly half (48.6%) of the cohort recalled having signs and symptoms of disease. And as we just said, a big portion go on to maintain some symptoms for more than three months. COVID-19 vaccines are a much safer way to avoid symptomatic illness and long-term health harms, but they aren’t miracle workers. Risk remains, just less of it.

You also have additional individual controls to help prevent infection. Wear a tight-fitting (elastic around the back of your head) N95 or P2 respirator (or a higher-quality respirator). Limit your time in shared indoor air spaces. And you can help others out by staying away from gatherings and work when you’re sick. Being realistic and honest, none of the actions in this paragraph will guarantee you stay infection-free, but they will each help increase your chances of preventing a SARS-CoV-2 infection. I stick by a statement I wrote back in 2014…

We live in a hyper-connected world. It’s nigh on impossible to stop respiratory viruses from spreading. This case highlights that even when we’re ill, we still feel the pressure to continue on with our jobs, our daily routine or our holiday. After all, we’ve all been a bit crook before and it has mostly been nothing much to speak of. Why should this time be any different?

Sources

1. Prevalence and impact of persistent symptoms following SARS-CoV-2 infection among healthcare workers: A cross-sectional survey in the SIREN cohort.
   https://www.journalofinfection.com/article/S0163-4453(24)00193-2/fulltext
2. Impact of prior SARS-CoV-2 infection and COVID-19 vaccination on the subsequent incidence of COVID-19: a multicentre prospective cohort study among UK healthcare workers – the SIREN (Sarscov2 Immunity & REinfection EvaluatioN) study protocol.
   https://bmjopen.bmj.com/content/12/6/e054336