Trying to Make Sense of Long COVID Syndrome

 More than 500,000 Americans have now lost their lives to COVID-19. But thousands of others who’ve gotten sick and survived COVID-19 are finding that a full recovery can be surprisingly elusive. Weeks and months after seemingly recovering from even mild cases of COVID-19, many battle a wide range of health problems.

Indeed, new results from the largest global study of this emerging “Long COVID syndrome” highlight just how real and pressing this public health concern really is. The study, reported recently as a pre-print on medRxiv, is based on survey results from more than 3,700 self-described COVID “Long Haulers” in 56 countries [1]. They show nearly half couldn’t work full time six months after unexpectedly developing prolonged symptoms of COVID-19. A small percentage of respondents, thankfully, seemed to have bounced back from brief bouts of Long COVID, though time will tell whether they have fully recovered.

These findings are the second installment from the online Body Politic COVID-19 Support Group and its Patient-Led Research for COVID-19, which consists of citizen scientists with a wide range of expertise in the arts and sciences who are struggling with the prolonged effects of COVID-19 themselves. In an earlier survey, this group provided a first-draft description of Long COVID syndrome, based on the self-reported experiences of 640 respondents.

In the new survey-based study led by Athena Akrami, with Patient-Led Research for COVID-19 and University College London, England, the goal was to characterize the experiences of many more people with Long COVID syndrome. They now define the syndrome as a collection of symptoms lasting for more than 28 days.

This second survey emphasizes the course and severity of more than 200 symptoms over time, including those affecting the heart, lungs, gastrointestinal system, muscles, and joints. It took a particularly in-depth look at neurological and neuropsychiatric symptoms, along with the ability of COVID-19 survivors to return to work and participate in other aspects of everyday life.

The 3,762 individuals who responded to the survey were predominately white females, between the ages of 30 and 60, who lived in the United States. As in the previous survey, the study included adults with symptoms consistent with COVID-19, whether or not the infection had been confirmed by a viral or antibody test. That is a potential weakness of the study, as some of these individuals may have had some other inciting illness. But many of the study’s participants developed symptoms early on in the pandemic, when testing was much more limited than it is now.

More than half never sought hospital care. Only 8 percent said that they’d been admitted to the hospital for COVID-19. And yet, 2,464 respondents reported COVID-19 symptoms lasting six months or longer. Most of the remaining respondents also continued to have symptoms, although they had not yet reached the six-month mark.

Among the most common symptoms were fatigue, worsening of symptoms after physical or mental activity, shortness of breath, trouble sleeping, and “brain fog,” or difficulty thinking clearly. The majority—88 percent—said they coped with some form of cognitive dysfunction or memory loss that to varying degrees affected their everyday lives. That includes the ability to make decisions, have conversations, follow instructions, and drive.

Those who had prolonged symptoms of COVID-19 for more than six months reported contending with about 14 symptoms on average. Most also reported that they’d had a relapse of symptoms, seemingly triggered by exercise, mental activity, or just everyday stress. When surveyed, nearly half of respondents said they’d had to reduce their hours at work due to the severity of their symptoms. Another 22 percent weren’t working at all due to their Long COVID.

The findings show that—even in those people who don’t require hospitalization for severe COVID-19—the condition’s prolonged symptoms are having a major impact on lives and livelihoods, both here and around the world. While the number of people affected isn’t yet known, if even a small proportion of the vast numbers of people infected with COVID-19 develop Long COVID syndrome, it represents a significant public health concern.

Another recent study from China further documents the tendency of COVID-19-related symptoms to linger past the usual recovery time for a respiratory virus [2]. The study, published in Lancet, showed that six months after the onset of illness, more than 75 percent of people hospitalized with COVID-19 in Wuhan between January and May 2020 continued to report at least one symptom. Fatigue, muscle weakness, sleep difficulties, anxiety, and depression all were common. More than half of individuals also had significant persistent lung abnormalities, which were more common in those who’d been more severely ill.

It’s essential for us to learn all we can about how SARS-CoV-2, which is the coronavirus that causes COVID-19, leads to such widespread symptoms. It’s also essential that we develop ways to better treat or prevent these symptoms. The NIH held a workshop last month to summarize what is known and fill in key gaps in our knowledge about Long COVID syndrome, which is clinically known as post-acute sequelae of COVID-19 (PASC). In December, Congress authorized funding for continued research on PASC, including an appropriation of funds for NIH to support continued study of these prolonged health consequences.

As these efforts and others proceed in the coming months, the hope is that we’ll gain much more insight and get some answers soon. And, if you’ve had or are currently experiencing symptoms of COVID-19, there’s still time to share your data by participating in the Patient-Led Research for COVID-19’s second survey .

References:

[1] Characterizing Long COVID in an international cohort: 7 months of symptoms and their impact . David HE et al. Medrxiv. 27 December 27 2020.

[2] 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Huang C, Huang L, et al. Lancet. 2021 Jan 16;397(10270):220-232.

https://directorsblog.nih.gov/2021/01/19/trying-to-make-sense-of-long-covid-syndrome/#comments

Androgen Receptors for COVID-19

 By Derek Lowe

There’s a report of an interesting small-molecule drug effort against the coronavirus that seems to have produced rather significant results. The idea goes back to effects that were noticed last year – for example, in this population-based study from Italy. It’s been known since the early days of the pandemic that males were overall more susceptible to severe disease than females, and there have been a number of hypotheses put forward to try to explain this. But an answer might lie back in the virus’s mechanism of infection. As the world knows, the current coronavirus uses the ACE2 protein as a cellular entry point, followed by a key protein cleavage effected by the nearby TMPRSS2 transmembrane serine protease. That one’s involved in more than one viral infection route, and the idea of using serine protease inhibitors as antivirals had already been tried against type A influenza  – but, it has to be said, without any dramatic success. Favipiravir is one such molecule, but it hasn’t made much of a dent in the pandemic, either.

But there are other ways to target this mechanism. It turns out that TMPRSS2 expression is linked to the transcriptional-activating activity of the androgen receptor. The Italian work linked above found that men who were taking androgen receptor antagonists (generally as a treatment for prostate cancer) seemed to be at significantly lower COVID-19 risk, which result is especially striking considering that pre-existing cancer in general is a risk factor for severe coronavirus outcomes. Instead of trying to inhibit TMPRSS2 activity at its active site, AR antagonists keep it from being expressed in the cell membrane in the first place.

This line of thought has led to several followups. Here’s a proposal from last June that androgen antagonists be tried out in this fashion, and here’s a later study from Michigan that established that specific cell types in the airway do indeed co-express androgen receptors and TMPRSS2, which is then regulated in the lung by AR activity. In July, a Chinese company (Kintor Pharmaceutical) announced that it was providing an investigational androgen receptor antagonist (proxalutamide) for a clinical trial to be run in Brazil. And that trial (involving 588 patients) has now read out. The press release says that there were very significant reductions in disease severity, in overall mortality, and in the length of hospitalization. These look like strong results, and I’m glad to see them. Anti-androgen therapy is pretty strong stuff, so it’s good that the course of treatment is reasonably short. This is indeed the receptor through which testosterone exerts most of its effects, so the effects of long-term treatment in men can be quite noticeable (women have fewer side effects, but non-zero). But blockade of the androgen receptor in this way is generally a cleaner route than (say) blocking the synthesis of testosterone itself, because there are quite a few other pathways involved with testosterone metabolites, etc.

Now, one thing to note is that proxalutamide itself is still an investigational drug – to the best of my knowledge, it hasn’t been approved anywhere. Here’s a trial in Florida looking at a much more common AR antagonist (bicalutamide), but unfortunately it’s only 100 patients. And here’s one looking at the combination of bicalutamide and the serine protease inhibitor camostat at Johns Hopkins, but it’s only 60 patients. I think we might be in a more useful place if the Brazil trial had been run with an already-approved AR antagonist, but this is one of those situations when interests and feasibility don’t overlap as well as they should. We have in general had far too many small, underpowered trials of possible therapies during this pandemic (a topic that will get a blog post all its own!) I hope that if the effect size of this treatment is as large as it appeared in the proxalutamide trial that these others will show something as well, but we’ll see.

Back on the biological level, you may be wondering how the expression of some transmembrane serine protease gene ended up being tied to the testosterone receptor in the first place. Well, that’s gene expression, for better or for worse. It’s a tangle – all sorts of things are wired crossways to all sorts of other things, in patterns that sometimes seem reasonable and sometimes seem random. Remember, there are far more genes out there than there are transcription factors, so everything at that level is doing multiple duty and affecting the expression of a long list of things. As always, evolution’s one question is “Did you survive to produce offspring” and its one rule is “Whatever works”. It’s important to remember that the AR isn’t just a male thing: women have androgen receptors as well, and those pathways are most certainly not silent. For a recent example, here’s evidence that for estrogen-receptor-positive breast cancer, you might also want to activate the androgen receptors as well in therapy. This hypothesis has been argued about for some time, but evidence for it has been increasing, and clinical trials around it are underway.

Let’s hope that the AR blockade idea can have a positive impact in the current pandemic, then. And we can also hold this idea if we face another virus that uses the ACE2 receptor for cell entry. That was the case with SARS in 2003, and we might see it again!

https://blogs.sciencemag.org/pipeline/archives/2021/03/11/androgen-receptors-for-covid-19

EU probes low platelet safety signal with COVID-19 shots

 EU regulators are reviewing reports of low blood platelets in patients who received any of the three approved COVID-19 vaccines from Pfizer/BioNTech, AstraZeneca and Moderna.

The experts have also recommended a safety update on the label of Oxford University/AstraZeneca’s COVID-19 vaccine, which has been linked to anaphylactic reactions, in what has turned out to be a concerning week for vaccine safety.

Several cases of immune thrombocytopenia – a disorder characterised by low levels of blood platelets that can lead to bruising and bleeding – were reported in the European Medicines Agency’s safety surveillance database.

After reviewing the safety reports received so far, the Pharmacovigilance Risk Assessment Committee (PRAC) decided to request an in-depth review of all available data, including case reports, clinical trials and the published literature, from the respective marketing authorisation holders for these vaccines.

The PRAC has enhanced safety monitoring in place for the vaccines and said it is not yet clear whether there is a causal association between vaccination and the reports of immune thrombocytopenia.

But the reports do point to a ‘safety signal’ – defined as information on new or changed adverse events that may potentially be associated with a medicine and that warrants further investigation.

The PRAC will investigate and if a causal relationship is confirmed or considered likely, an update to the products’ labels will be the most likely outcome.

There has also been a signal of localised swelling related to dermal fillers with the Pfizer/BioNTech shot, which has the brand name Comirnaty in Europe, and will be investigated separately by the PRAC.

AZ vaccine safety update

The PRAC has also issued advice on anaphylactic reactions to the Oxford/AZ shot, a known side effect that can occur very rarely and is already included in its risk management plan.

The committee said appropriate medical treatment must be available in the event of an anaphylactic event with the vaccine.

A recommendation that people should be monitored for at least 15 minutes after the shot is already included in the plan.

Existing guidance says that any person developing such a reaction after the first dose of the vaccine should not be given a second dose.

The PRAC is separately reviewing all cases of thromboembolic events, and other conditions related to blood clots, reported post-vaccination with the AZ shot.

The EMA reiterated that there is currently no indication that vaccination has caused these conditions, which are not listed as side effects with this vaccine.

In an update yesterday the safety committee said the incidence of blood clots in the vaccinated population was the same as would have been expected without the shot.

This advice was echoed by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) after several European countries suspended vaccination campaigns as a precaution.

Norway and Iceland are the latest countries to put vaccination campaigns on hold, but the UK is continuing to use the AstraZeneca COVID-19 vaccine.

Dr Phil Bryan, MHRA vaccines safety lead, said: “Blood clots can occur naturally and are not uncommon. More than 11 million doses of the COVID-19 AstraZeneca vaccine have now been administered across the UK.

“Reports of blood clots received so far are not greater than the number that would have occurred naturally in the vaccinated population.”

https://pharmaphorum.com/news/eu-experts-call-for-allergic-reaction-safety-update-on-astrazeneca-covid-shot/

SARS-CoV-2 mRNA vaccines induce a robust germinal centre reaction in humans

 

Ali Ellebedy, Jackson Turner, Jane O'Halloran, Elizaveta Kalaidina, Wooseob Kim, Aaron Schmitz, Tingting Lei, Mahima Thapa, Rita Chen, James Case, Fatima Amanat, Adriana Rauseo, Alem Haile, Michael Klebert, Teresa Suessen, William Middleton, Florian Krammer, Sharlene Teefey, Michael Diamond, Rachel Presti, Xuping Xie, Pei-Yong Shi

DOI:

10.21203/rs.3.rs-310773/v1

PDF: https://www.researchsquare.com/article/rs-310773/v1.pdf

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA)-based vaccines are ~95% effective in preventing coronavirus disease 2019. However, the dynamics of antibody secreting plasmablasts (PBs) and germinal centre (GC) B cells induced by these vaccines in SARS-CoV-2 naïve and antigen-experienced humans remains unclear. Here we examined peripheral blood and/or lymph node (LN) antigen-specific B cell responses in 32 individuals who received two doses of BNT162b2, an mRNA-based vaccine encoding the full-length SARS-CoV-2 spike (S) gene. Circulating IgG- and IgA-secreting PBs targeting the S protein peaked one week after the second immunization then declined and were undetectable three weeks later. PB responses coincided with maximal levels of serum anti-S binding and neutralizing antibodies to a historical strain as well as emerging variants, especially in individuals previously infected with SARS-CoV-2, who produced the most robust serological responses. Fine needle aspirates of draining axillary LNs identified GC B cells that bind S protein in all participants sampled after primary immunization. GC responses increased after boosting and were detectable in two distinct LNs in several participants. Remarkably, high frequencies of S-binding GC B cells and PBs were maintained in draining LNs for up to seven weeks after first immunization, with a substantial fraction of the PB pool class-switched to IgA. GC B cell-derived monoclonal antibodies predominantly targeted the RBD, with fewer clones binding to the N-terminal domain or shared epitopes within the S proteins of human betacoronaviruses OC43 and HKU1. Our studies demonstrate that SARS-CoV-2 mRNA-based vaccination of humans induces a robust and persistent GC B cell response that engages pre-existing as well as new B cell clones, which enables generation of high-affinity, broad, and durable humoral immunity.

https://www.researchsquare.com/article/rs-310773/v1

Brazil's health ministry to buy 10 million doses of Russia's sputnik covid-19 vaccine

 The Brazilian Health Ministry on Friday signed a contract to buy 10 million doses of Russia’s Sputnik V vaccine to be delivered during the second quarter.

The ministry said the doses are being imported by Brazilian pharmaceutical company Uniao Quimica, which is expected to manufacture the vaccine in Brazil later this year.

https://www.reuters.com/article/us-health-coronavirus-brazil-sputnik/brazils-health-ministry-to-buy-10-million-doses-of-russias-sputnik-covid-19-vaccine-idUSKBN2B42LF

U.S. limits supply of Eli Lilly's COVID-19 antibody therapy in three states

 The U.S. Department of Health and Human Services said it will limit distribution of Eli Lilly and Co’s COVID-19 antibody therapy in three states over concerns regarding the impact of a new variant on its effectiveness.

The U.S government is evaluating recommendations for using the antibody, bamlanivimab, in regions where the variant, CAL.20C, which was found in California, is circulating in high numbers, the department said. (bit.ly/3ljEZzK)

While evaluations are ongoing, direct ordering of bamlanivimab will not be allowed in California, Arizona and Nevada, HHS said, adding that other authorized COVID-19 antibody therapies will remain available in the states.

The U.S. FDA in November granted emergency use authorization to bamlanivimab and a two-antibody cocktail developed by Regeneron Pharmaceuticals Inc. Eli Lilly also has a combination therapy of two antibodies, bamlanivimab and etesevimab, which was authorized in February.

Eli Lilly said earlier this week its combination therapy reduced the risk of hospitalization and death by 87% in high-risk COVID-19 patients in a study.

https://www.reuters.com/article/us-health-coronavirus-eli-lilly-antibody/u-s-limits-supply-of-eli-lillys-covid-19-antibody-therapy-in-three-states-idUSKBN2B42U5

Vaccines for all over-40s in UK by Easter

 People over 40 in the UK will be offered their first coronavirus vaccination by Easter on April 4 as a boost in supplies will allow rapid expansion of the inoculation programme, the Telegraph reported on Friday, citing a senior government source.

Vaccine stocks are expected to more than double, allowing the National Health Service (NHS) to offer a million doses a day in coming weeks, the newspaper said. 

People over the age of 50 are expected to receive an invitation for a vaccine dose over the next week, around three weeks ahead of the government’s target, according to the report.

A spokeswoman for the Department of Health and Social Care said that the claim that over-40s would be offered vaccine shots by Easter is “incorrect,” when contacted by Reuters. “We have set out our timelines for the vaccination programme and there is no change to this.”

“We intend to offer a first dose to all over-50s by mid-April and all adults by the end of July,” the spokeswoman said.

https://www.reuters.com/article/us-health-coronavirus-britain-vaccine/vaccines-for-all-over-40s-in-uk-by-easter-telegraph-idUSKBN2B42UP