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One of the first questions that could be answered regarding long COVID quite quickly is why it’s happening. Why did one person not recover when so many others did? That question has bedeviled many people with chronic fatigue syndrome (ME/CFS), post-infectious fibromyalgia, post-treatment Lyme Disease.

Who has not searched their past looking for some clue to help explain what happened? In my case, did a concussion or a Giardia infection, a tendency towards messy bowel movements, or my mother’s Sjogren’s Syndrome render me more susceptible, and if so, why did my twin never succumb?

Answers to those questions have rarely been forthcoming but they may be soon – at least for long COVID. Color me optimistic but it seems to me that the question of what happened may be one of the easiest and quickest to resolve in long COVID.

The reason is that in contrast to ME/CFS and other post-infectious diseases, the coronavirus – thanks to its incredible persistence is going to be spectacularly easy to catch in the act. Plus, thanks to the congressionally funded NIH and other studies, researchers will already have ample biological data on some people as they come down with long COVID.

Long COVID studies

It’s simple. Test the heck out of people who come down with COVID-19 and then again when they come down with long COVID.

The course seems clear: test the heck out of people as they come down with COVID-19, and then follow them and see how they change biologically. This kind of study doesn’t require a genius or some grand hypothesis to be successful. It needs lots of money and access to cutting-edge tools – both of which appear to be amply available. That’s why I hope and believe that over the next year or so we’ll get some real insights into how long COVID starts and why it occurs.

We’ve already seen one study suggest that the seeds of long COVID show up very early in the infection. Now comes another study suggesting the same.

The Study

The Immunoglobulin signature predicts the risk of post-acute COVID-19 syndrome study demonstrates how long COVID has galvanized the research community in ways ME/CFS and fibromyalgia never have. This undoubtedly quite expensive 600-plus person hailed from a country – Switzerland – which I don’t remember funding any ME/CFS studies. It received funding from nine different Swiss agencies and groups. Given the time needed to analyze the results, write them up and get them published, it’s clear that this study, which had a year’s worth of data, began quite early in the long-COVID “era”.

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The study began with 134 people with PCR-confirmed COVID-19 – about 2/3rds of whom experienced mild COVID.

Fifty percent still experienced at least one symptom after 4 weeks, with those with severe COVID-19 being more likely to experience prolonged symptoms. Conversely, people with high IgG3 levels prior to coming down with COVID-19 had a decreased risk of coming down with long COVID.

Immunoglobulin

Low levels of IgG3 were associated with an increased risk of coming down with long COVID.

People who came down with long COVID or PACS (post-acute-coronavirus syndrome) were characterized by decreased IgM3 levels – both during the initial coronavirus infection and apparently six months and even a year later. In contrast to the increased IgG3 levels found during the initial infections in the COVID-19 patients who did not come down with long COVID, no increase in IgG levels was found in those who did come down with long COVID.  None of the other IgG test results (IgA, IgG2, and IgG4) were significantly different.

Healthy controls with low IgG3 levels prior to coming down with COVID-19 were also at increased risk of coming down with long COVID. Next, the researchers took their IgG data, added as many factors to it as they could (age, sex, number of symptoms, disease severity, comorbid illnesses, etc.), and attempted to build a prediction model that highlighted people at risk of coming down with long COVID. The findings were then validated in a cohort of almost 400 COVID-19 patients.

The model found that having low IgG levels, being older, having a history of asthma, and experiencing a lot of symptoms during the initial infection – had a nice “area under the curve” (AUC) value of 73% which indicated that the model accurately predicted who would come down with long COVID 73% of the time. (Female gender, interestingly, was not predictive in this model).

Applying the model to hospitalized patients boosted its predictiveness to a remarkable 99% – meaning that simply assessing IgG levels, the presence of asthma, being older, and having more symptoms during the initial infection – predicted virtually every hospitalized person who came down with long COVID later.

Applying the model to non-hospitalized patients dropped the model’s predictive value to 64%; i.e. it correctly predicted almost two-thirds of the people with milder COVID who would go on to develop long COVID.

The low IgG levels were particularly intriguing as IgG antibody levels are usually stable over time and are not difficult to test; i.e. they could, if this finding is validated, provide an easy snapshot that could indicate who has an increased risk of coming down with long COVID.

The authors suggested that hospitals and doctors assess patients’ PACS scores and begin to assess if preventive treatment strategies, “such as the use of inhaled corticosteroids in asthmatic and non-asthmatic patients, and intravenous Ig therapies” are able to reduce the occurrence of long COVID.

Causes

predictive model long COVID

Low levels of IgG3 were associated with an increased risk of coming down with long COVID. particularly if they’d been hospitalized. Many more sophisticated models will surely be produced over time.

The authors proposed that an inability to quickly fight off the initial coronavirus infection may lay behind the emergence of long COVID. Interferons play an outsize role in fighting off viruses and induce B-cells to produce IgG3. Given that low interferon levels have been found in people who’ve had difficulty fighting off the coronavirus the low Ig3 levels made sense.

Having asthma turned out to be a big risk factor for long COVID. While that might not seem surprising in a condition that impairs lung functioning, other possibilities could explain the link. People with asthma tend to produce increased levels of L-4 – which blocks IgG3 production and indeed low IgG3 levels have been found in asthma.

Demonstrating that the body is nothing if not complex, several studies have suggested that having asthma may be protective to some degree and lessens the chance of having severe COVID-19. One paper attempting to explain this phenomenon noted that the same mechanism (Th2 dominance, eosinophilic upregulation) that may make asthma protective in COVID-19 might make one more susceptible to long COVID.

Given the apparently low recognition given ME/CFS in much of Europe, it was good to see these Swiss authors note that low IgG levels have been found in ME/CFS – a disease they called “debilitating”. Indeed, several studies have found IgG3 deficiencies to be the most common immunoglobulin deficiencies found in ME/CFS.

The authors’ suggestion that IVIG and similar therapies might turn out to be useful brought up the question of whether IVIG might work in ME/CFS as well. While IVIG studies have not, on the face of them, seemed to argue for the widespread use of IVIG in ME/CFS, Brownlie and Speight recently argued that interpreted properly, the studies indicate the ME/CFS patients who benefit often do so quite significantly, and that research should continue to tease out the subgroups of patients that benefit. They also assert that the evidence thus far suggests that PACS or long COVID-patients may benefit as well. They are not the first to suggest that, and many studies have been assessing IVIG effectiveness in COVID-19.

The Case for IVIG Treatment in Chronic Fatigue Syndrome (ME/CFS), Fibromyalgia, Small Fiber Neuropathy, and POTS : IVIG#3

Conclusion

This study – one of the first to employ predictive modeling – produced some interesting possibilities including that an immune deficiency found in a subgroup of ME/CFS patients (IgG3 deficiency) might open the door to long COVID as well. That finding, if validated, could provide a relatively easy-to-access test that could assess the risk of coming down with long COVID. It could also open the door to immune enhancement strategies such as IVIG that have shown to be helpful in a subset of people with ME/CFS.

We’ll see many more predictive modeling long COVID studies that assess biological factors at the time of infection and then during the emergence of long COVID to try and figure out how this mysterious condition got started and how it’s being maintained.

 

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