Could tiny blood clots cause long COVID’s puzzling symptoms?

Scientists debate evidence for a micro-clot hypothesis that has some people pursuing potentially risky treatments

Authors: Cassandra Willyard Nature 608, 662-664 (2022)doi: https://doi.org/10.1038/d41586-022-02286-7

When Lara Hawthorne, an illustrator in Bristol, UK, began developing strange symptoms after having COVID-19, she hoped that they weren’t due to the virus. Her initial illness had been mild. “I’ve been triple vaccinated. I felt quite protected,” she says. But months later, she was still sick with a variety of often debilitating symptoms: earaches, tinnitus, congestion, headaches, vertigo, heart palpitations, muscle pain and more. On some days, Hawthorne felt so weak that she could not get out of bed. When she finally saw her physician, the diagnosis was what she had been dreading: long COVID.

Unable to find relief, she became increasingly desperate. After reading an opinion piece in The Guardian newspaper about how blood clots might be to blame for long COVID symptoms, Hawthorne contacted a physician in Germany who is treating people with blood thinners and a procedure to filter the blood. She hasn’t heard back yet — rumour has it that people stay on the waiting list for months — but if she has the opportunity to head there for these unproven treatments, she probably will. “I don’t want to wait on my health when I’m feeling so dreadful,” she says.

Researchers are baffled by long COVID: hundreds of studies have tried to unpick its mechanism, without much success. Now some scientists, and an increasing number of people with the condition, have been lining up behind the as-yet-unproven hypothesis that tiny, persistent clots might be constricting blood flow to vital organs, resulting in the bizarre constellation of symptoms that people experience.

Heart disease after COVID: what the data say

Proponents of the idea (#teamclots, as they sometimes refer to themselves on Twitter) include Etheresia Pretorius, a physiologist at Stellenbosch University in South Africa, and Douglas Kell, a systems biologist at the University of Liverpool, UK, who led the first team to visualize micro-clots in the blood of people with long COVID. They say that the evidence implicating micro-clots is undeniable, and they want trials of the kinds of anticoagulant treatment that Hawthorne is considering. Pretorius penned the Guardian article that caught Hawthorne’s attention.

But many haematologists and COVID-19 researchers worry that enthusiasm for the clot hypothesis has outpaced the data. They want to see larger studies and stronger causal evidence. And they are concerned about people seeking out unproven, potentially risky treatments.

When it comes to long COVID, “we’ve now got little scattered of bits of evidence”, says Danny Altmann, an immunologist at Imperial College London. “We’re all scuttling to try and put it together in some kind of consensus. We’re so far away from that. It’s very unsatisfying.”

Cascade of clots

Pretorius and Kell met about a decade ago. Pretorius had been studying the role of iron in clotting and neglected to cite some of Kell’s research. When he reached out, they began chatting. “We had a Skype meeting and then we decided to work together,” Pretorius says. They observed odd, dense clots that resist breaking down for years in people with a variety of diseases. The research led them to develop the theory that some molecules — including iron, proteins or bits of bacterial cell wall — might trigger these abnormal clots.

Blood clotting is a complex process, but one of the key players is a cigar-shaped, soluble protein called fibrinogen, which flows freely in the bloodstream. When an injury occurs, cells release the enzyme thrombin, which cuts fibrinogen into an insoluble protein called fibrin. Strands of fibrin loop and criss-cross, creating a web that helps to form a clot and stop the bleeding.

Under a microscope, this web typically resembles “a nice plate of spaghetti”, Kell says. But the clots that the team has identified in many inflammatory conditions look different. They’re “horrible, gunky, dark”, Kell says, “such as you might get if you half-boiled the spaghetti and let it all stick together.” Research by Kell, Pretorius and their colleagues suggests that the fibrin has misfolded1, creating a gluey, ‘amyloid’ version of itself. It doesn’t take much misfolding to seed disaster, says Kell. “If the first one changes its conformation, all the others have to follow suit”, much like prions, the infectious misfolded proteins that cause conditions such as Creutzfeldt–Jakob disease.

Long-COVID treatments: why the world is still waiting

Pretorius first saw these strange, densely matted clots in the blood of people with a clotting disorder2, but she and Kell have since observed the phenomenon in a range of conditions1 — diabetes, Alzheimer’s disease and Parkinson’s disease, to name a few. But the idea never gained much traction, until now.

When the pandemic hit in 2020, Kell and Pretorius applied their methods almost immediately to people who had been infected with SARS-CoV-2. “We thought to look at clotting in COVID, because that is what we do,” Pretorius says. Their assay uses a special dye that fluoresces when it binds to amyloid proteins, including misfolded fibrin. Researchers can then visualize the glow under a microscope. The team compared plasma samples from 13 healthy volunteers, 15 people with COVID-19, 10 people with diabetes and 11 people with long COVID3. For both long COVID and acute COVID-19, Pretorius says, the clotting “was much more than we have previously found in diabetes or any other inflammatory disease”. In another study4, they looked at the blood of 80 people with long COVID and found micro-clots in all of the samples.

So far, Pretorius, Kell and their colleagues are the only group that has published results on micro-clots in people with long COVID.

But in unpublished work, Caroline Dalton, a neuroscientist at Sheffield Hallam University’s Biomolecular Sciences Research Centre, UK, has replicated the results. She and her colleagues used a slightly different method, involving an automated microscopy imaging scanner, to count the number of clots in blood. The team compared 3 groups of about 25 individuals: people who had never knowingly had COVID-19, those who had had COVID-19 and recovered, and people with long COVID. All three groups had micro-clots, but those who had never had COVID-19 tended to have fewer, smaller clots, and people with long COVID had a greater number of larger clots. The previously infected group fell in the middle. The team’s hypothesis is that SARS-CoV-2 infection creates a burst of micro-clots that go away over time. In individuals with long COVID, however, they seem to persist.

Dalton has also found that fatigue scores seem to correlate with micro-clot counts, at least in a few people. That, says Dalton, “increases confidence that we are measuring something that is mechanistically linked to the condition”.

In many ways, long COVID resembles another disease that has defied explanation: chronic fatigue syndrome, also known as myalgic encephalomyelitis (ME/CFS). Maureen Hanson, who directs the US National Institutes of Health (NIH) ME/CFS Collaborative Research Center at Cornell University in Ithaca, New York, says that Pretorius and Kell’s research has renewed interest in a 1980s-era hypothesis about abnormal clots contributing to symptoms. Pretorius, Kell and colleagues found amyloid clots in the blood of people with ME/CFS, but the amount was much lower than what they’ve found in people with long COVID5. So clotting is probably only a partial explanation for ME/CFS, Pretorius says.

Micro-clot mysteries

Where these micro-clots come from isn’t entirely clear. But Pretorius and Kell think that the spike protein, which SARS-CoV-2 uses to enter cells, might be the trigger in people with long COVID. When they added the spike protein to plasma from healthy volunteers in the laboratory, that alone was enough to prompt formation of these abnormal clots6.

Bits of evidence hint that the protein might be involved. In a preprint7 posted in June, researchers from Harvard University in Boston, Massachusetts, reported finding the spike protein in the blood of people with long COVID. Another paper8 from a Swedish group showed that certain peptides in the spike can form amyloid strands on their own, at least in a test tube. It’s possible that these misfolded strands provide a kind of template, says Sofie Nyström, a protein chemist at Linköping University in Sweden and an author of the paper.

Micrographs of platelet poor plasma of a healthy volunteer showing few microclots,and post-COVID-19 infection showing microclots
Micro-clots (green) in a study participant before SARS-CoV-2 infection (left four panels) and in the same person after they developed long COVID (right four panels).Credit: E. Pretorius et al./Cardiovasc. Diabetol. (CC BY 4.0)

A California-based group found that fibrin can actually bind to the spike. In a 2021 preprint9, it reported that when the two proteins bind, fibrin ramps up inflammation and forms clots that are harder to degrade. But how all these puzzle pieces fit together isn’t yet clear.

If the spike protein is the trigger for abnormal clots, that raises the question of whether COVID-19 vaccines, which contain the spike or instructions for making it, can induce them as well. There’s currently no direct evidence implicating spike from vaccines in forming clots, but Pretorius and Kell have received a grant from the South African Medical Research Council to study the issue. (Rare clotting events associated with the Oxford–AstraZeneca vaccine are thought to happen through a different mechanism (Nature 596, 479–481; 2021).)

Raising safety concerns about the vaccines can be uncomfortable, says Per Hammarström, a protein chemist at Linköping University and Nyström’s co-author. “We don’t want to be over-alarmist, but at the same time, if this is a medical issue, at least in certain people, we have to address that.” Gregory Poland, director of the Mayo Clinic’s vaccine research group in Rochester, Minnesota, agrees that it’s an important discussion. “My guess is that spike and the virus will turn out to have a pretty impressive list of pathophysiologies,” he says. “How much of that may or may not be true for the vaccine, I don’t know.”

Dearth of data

Many researchers find it plausible and intriguing that micro-clots could be contributing to long COVID. And the hypothesis does seem to fit with other data that have emerged on clotting. Researchers already know that people with COVID-19, especially severe disease, are more likely to develop clots. The virus can infect cells lining the body’s 100,000 kilometres of blood vessels, causing inflammation and damage that triggers clotting.

Those clots can have physiological effects. Danny Jonigk, a pathologist at Hanover Medical School in Germany, and his colleagues looked at tissue samples from people who died of COVID-19. They found micro-clots and saw that the capillaries had split, forming new branches to try to keep oxygen-rich blood flowing10. The downside was that the branching introduces turbulence into the flow that can give rise to fresh clots.

How common is long COVID? Why studies give different answers

Several other labs have found signs that, in some people, this tendency towards clotting persists months after the initial infection. James O’Donnell, a haematologist and clotting specialist at Trinity College Dublin, and his colleagues found11 that about 25% of people who are recovering from COVID-19 have signs of increased clotting that are “quite marked and unusual”, he says.

What is less clear is whether this abnormal clotting response is actually to blame for any of the symptoms of long COVID, “or is it just, you know, another unusual phenomenon associated with COVID?” O’Donnell says.

Alex Spyropoulos, a haematologist at the Feinstein Institutes for Medical Research in New York City, says the micro-clot hypothesis presents “a very elegant mechanism”. But he argues that much more work is needed to tie the lab markers to clinical symptoms. “What’s a little bit disturbing is that these authors and others make huge leaps of faith,” Spyropoulos says.

Jeffrey Weitz, a haematologist and clotting specialist at McMaster University in Hamilton, Canada, points out that the method Pretorius’s team is using to identify micro-clots “isn’t a standard technique at all”. He adds: “I’d like to see confirmation from other investigators.” Micro-clots are difficult to detect. Pathologists can spot them in tissue samples, but haematologists tend to look for markers of abnormal clotting rather than the clots themselves.

Other, larger studies of long COVID have failed to find signs of clotting. Michael Sneller, an infectious-disease specialist, and his colleagues at the NIH in Bethesda, Maryland, thoroughly examined 189 people who had been infected with SARS-CoV-2, some with lingering symptoms and some without, and 120 controls12. They did not specifically look for micro-clots. But if micro-clots had been clogging the capillaries, Sneller says, they should have seen some evidence — tissue damage in capillary-rich organs such as the lungs and kidneys, for example. Micro-clots might also damage red blood cells, leading to anaemia. But Sneller and his colleagues found no signs of this in any of the lab tests.

The four most urgent questions about long COVID

Kell and Pretorius argue that just because this study didn’t find any evidence of micro-clots doesn’t mean they aren’t there. One of the key issues with long COVID is that “every single test comes back within the normal ranges”, Pretorius says. “You have desperately ill patients with no diagnostic method.” She hopes that other researchers will read their papers and attempt to replicate their results. “Then we can have a discussion,” she says. The ultimate causal proof, she adds, would be people with long COVID feeling better after receiving anticoagulant therapies.

There is some limited evidence of this. In an early version of a preprint, posted in December 2021, Kell, Pretorius and other researchers, including physician Gert Jacobus Laubscher at Stellenbosch University, reported that 24 people who had long COVID and were treated with a combination of two antiplatelet therapies and an anticoagulant experienced some relief13. Participants reported that their main symptoms resolved and that they became less fatigued. They also had fewer micro-clots. Pretorius and Kell are working to gather more data before they try to formally publish these results. But other physicians are already using these medications to treat people with long COVID. Some are even offering a dialysis-like procedure that filters fibrinogen and other inflammatory molecules from the blood. To O’Donnell, such treatment feels premature. He accepts that some people with long COVID are prone to clots, but leaping from a single small study to treating a vast number of people is “just not going to wash in 2022 in my book”, he says. Sneller agrees. “Anticoagulating somebody is not a benign thing. You basically are interfering with the blood’s ability to clot,” he says, which could make even minor injuries life-threatening.

Kell says he’s tired of waiting for a consensus on how to treat long COVID. “These people are in terrible pain. They are desperately unwell,” he says. Altmann understands that frustration. He gets e-mails almost daily, asking: “Where are the drug trials? Why does it take so long?” But even in the midst of a pandemic, he argues, researchers have to follow the process. “I’m not rubbishing anybody’s data. I’m just saying we’re not there yet,” he says. “Let’s join up the dots and do this properly.”

References

  1. Kell, D. B., Laubscher, G. J. & Pretorius, E. Biochem. J. 479, 537–559 (2022).PubMed Article Google Scholar 
  2. Pretorius, E., Briedenhann, S., Marx, J. & Franz, R. C. Ultrastruct. Pathol. 30, 167–176 (2006).PubMed Article Google Scholar 
  3. Pretorius, E. et al. Cardiovasc. Diabetol. 20, 172 (2021).PubMed Article Google Scholar 
  4. Pretorius, E. et al. Cardiovasc. Diabetol. 21, 148 (2022).PubMed Article Google Scholar 
  5. Nunes, J. M., Kruger, A., Proal, A., Kell, D. B. & Pretorius, E. Pharmaceuticals 15, 931 (2022).Article Google Scholar 
  6. Grobbelaar, L. M. et al. Biosci. Rep. 41, BSR20210611 (2021).PubMed Article Google Scholar 
  7. Swank, Z., Senussi, Y., Alter, G. & Walt, D. R. Preprint at medRxiv https://doi.org/10.1101/2022.06.14.22276401 (2022).
  8. Nyström, S. & Hammarström, P. J. Am. Chem. Soc. 144, 8945–8950 (2022).PubMed Article Google Scholar 
  9. Ryu, J. K. et al. Preprint at bioRxiv https://doi.org/10.1101/2021.10.12.464152 (2021).
  10. Ackerman, M. et al. N. Engl. J. Med. 383, 120–128 (2020).PubMed Article Google Scholar 
  11. Townsend, L. et al. J. Thromb. Haemost. 19, 1064–1070 (2021).PubMed Article Google Scholar 
  12. Sneller, M. C. et al. Ann. Intern. Med. 175, 969–979 (2022).PubMed Article Google Scholar 
  13. Pretorius, E. et al. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-1205453/v1 (2021)

Warning to anyone who’s had Covid as scientists discover symptoms that can last for TWO YEARS

Authors: Vanessa Chalmers, Digital Health Reporter May 11 2022  May 12 2022

DOCTORS have discovered the symptoms of Covid that can last for two years or more. 

Their research has shown that half of patients admitted to hospital are still likely to have at least one persistent problem two years later.

The study, published in The Lancet Respiratory Medicine, has the longest follow-up period of patients to date. 

Researchers are only able to analyse what symptoms exist after two years given the coronavirus emerged in late 2019.

So it’s possible problems like fatigue and anxiety could stick around even longer.

Lead author Professor Bin Cao, of the China-Japan Friendship Hospital, China, said: “Our findings indicate that for a certain proportion of hospitalised Covid-19 survivors, while they may have cleared the initial infection, more than two years is needed to recover fully from Covid-19.”

The study involved almost 1,200 patients, aged 57 on average, who were infected with the bug in the early phase of the pandemic.

They had all been treated in Wuhan, China, then assessed six months, 12 months and two years after discharge.

Researchers looked at their walking abilities, mental health, quality of life and more.

Covid patients were generally found to be in poorer health than those in the general population two years after infection.

They reported:

  • Fatigue or muscle weakness (31 per cent of Covid patients compared to five per cent in the general population)
  • Sleep difficulties (51 per cent compared with 14 per cent)
  • Pain or discomfort (23 per cent compared with five per cent)
  • Anxiety or depression (12 per cent compared with five per cent)

Joint pain, palpitations, dizziness, and headaches were also more common among previously hospitalised Covid patients.

Not all of those hospitalised were affected, however.

More than half (55 per cent) of participants had at least one symptom of Covid at two years, and were therefore considered “long Covid” patients.

The researchers then compared the long Covid group with the group of participants who had endured Covid, but gotten better. 

Those with long Covid had more pain (35 per cent vs 10 per cent), and mobility issues (five per cent vs one per cent) than their fully recovered counterparts.

Some 13 per cent showed symptoms of anxiety and 11 per cent depression, compared with three per cent and one per cent in non-long Covid patients, respectively. 

The researchers said it’s not possible to say whether problems like these are specific to Covid, or whether other hospital patients experience them.

Long Covid is defined as someone who still battles symptoms beyond four weeks in the UK.

It may be defined as ongoing Covid (four to 12 weeks), or post-Covid syndrome (more than 12 weeks) by medics.

The symptoms may include fatigue, a cough, breathlessness, muscle or joint pain, loss of taste of smell and brain fog.

Colchicine: A Possible COVID-19 Long haul Cardiac Therapy

Last Updated: December 16, 2021

Last Updated: December 16, 2021

Colchicine is an anti-inflammatory drug that is used to treat a variety of conditions, including gout, recurrent pericarditis, and familial Mediterranean fever.1 Recently, the drug has been shown to potentially reduce the risk of cardiovascular events in those with coronary artery disease.2 Colchicine has several potential mechanisms of action, including reducing the chemotaxis of neutrophils, inhibiting inflammasome signaling, and decreasing the production of cytokines, such as interleukin-1 beta.3 When colchicine is administered early in the course of COVID-19, these mechanisms could potentially mitigate or prevent inflammation-associated manifestations of the disease. These anti-inflammatory properties coupled with the drug’s limited immunosuppressive potential, favorable safety profile, and widespread availability have prompted investigation of colchicine for the treatment of COVID-19.

Recommendations

  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of colchicine for the treatment of nonhospitalized patients with COVID-19, except in a clinical trial (BIIa).
  • The Panel recommends against the use of colchicine for the treatment of hospitalized patients with COVID-19 (AI).

Rationale

For Nonhospitalized Patients With COVID-19

COLCORONA, a large randomized placebo-controlled trial that evaluated colchicine in outpatients with COVID-19, did not reach its primary efficacy endpoint of reducing hospitalizations and death.4 However, in the subset of patients whose diagnosis was confirmed by a positive SARS-CoV-2 polymerase chain reaction (PCR) result from a nasopharyngeal (NP) swab, a slight reduction in hospitalizations was observed among those who received colchicine.

PRINCIPLE, another randomized, open-label, adaptive-platform trial that evaluated colchicine versus usual care, was stopped for futility when no significant difference in time to first self-reported recovery from COVID-19 between the colchicine and usual care recipients was found.5

The PRINCIPLE trial showed no benefit of colchicine, and the larger COLCORONA trial failed to reach its primary endpoint, found only a very modest effect of colchicine in the subgroup of patients with positive SARS-CoV-2 PCR results, and reported more gastrointestinal adverse events in those receiving colchicine. Therefore, the Panel recommends against the use of colchicine for the treatment of COVID-19 in nonhospitalized patients, except in a clinical trial (BIIa).

For Hospitalized Patients With COVID-19

In the RECOVERY trial, a large randomized trial in hospitalized patients with COVID-19, colchicine demonstrated no benefit with regard to 28-day mortality or any secondary outcomes.6 Based on the results from this large trial, the Panel recommends against the use of colchicine for the treatment of COVID-19 in hospitalized patients (AI).

Clinical Data for COVID-19

Colchicine in Nonhospitalized Patients With COVID-19

The COLCORONA Trial

The COLCORONA trial was a contactless, double-blind, placebo-controlled, randomized trial in outpatients who received a diagnosis of COVID-19 within 24 hours of enrollment. Participants were aged ≥70 years or aged ≥40 years with at least 1 of the following risk factors for COVID-19 complications: body mass index ≥30, diabetes mellitus, uncontrolled hypertension, known respiratory disease, heart failure or coronary disease, fever ≥38.4°C within the last 48 hours, dyspnea at presentation, bicytopenia, pancytopenia, or the combination of high neutrophil count and low lymphocyte count. Participants were randomized 1:1 to receive colchicine 0.5 mg twice daily for 3 days and then once daily for 27 days or placebo. The primary endpoint was a composite of death or hospitalization by Day 30; secondary endpoints included components of the primary endpoint, as well as the need for mechanical ventilation by Day 30. Participants reported by telephone the occurrence of any study endpoints at 15 and 30 days after randomization; in some cases, clinical data were confirmed or obtained by medical chart reviews.4

Results

  • The study enrolled 4,488 participants.
  • The primary endpoint occurred in 104 of 2,235 participants (4.7%) in the colchicine arm and 131 of 2,253 participants (5.8%) in the placebo arm (OR 0.79; 95% CI, 0.61–1.03; P = 0.08).
  • There were no statistically significant differences in the secondary outcomes between the arms.
  • In a prespecified analysis of 4,159 participants who had a SARS-CoV-2 diagnosis confirmed by PCR testing of an NP specimen (93% of those enrolled), those in the colchicine arm were less likely to reach the primary endpoint (96 of 2,075 participants [4.6%]) than those in the placebo arm (126 of 2,084 participants [6.0%]; OR 0.75; 95% CI, 0.57–0.99; P = 0.04). In this subgroup of patients with PCR-confirmed SARS-CoV-2 infection, there were fewer hospitalizations (a secondary outcome) in the colchicine arm (4.5% of patients) than in the placebo arm (5.9% of patients; OR 0.75; 95% CI, 0.57–0.99).
  • More participants in the colchicine arm experienced gastrointestinal adverse events, including diarrhea which occurred in 13.7% of colchicine recipients versus 7.3% of placebo recipients (P < 0.0001). Unexpectedly, more pulmonary emboli were reported in the colchicine arm than in the placebo arm (11 events [0.5% of patients] vs. 2 events [0.1% of patients]; P= 0.01).

Limitations

  • Due to logistical difficulties with staffing, the trial was stopped at approximately 75% of the target enrollment, which may have limited the study’s power to detect differences for the primary outcome.
  • There was uncertainty as to the accuracy of COVID-19 diagnoses in presumptive cases.
  • Some patient-reported clinical outcomes were potentially misclassified.

The PRINCIPLE Trial

PRINCIPLE is a randomized, open-label, platform trial that evaluated colchicine in symptomatic, nonhospitalized patients with COVID-19 who were aged ≥65 years or aged ≥18 years with comorbidities or shortness of breath, and who had symptoms for ≤14 days. Participants were randomized to receive colchicine 0.5 mg daily for 14 days or usual care. The coprimary endpoints, which included time to first self-reported recovery or hospitalization or death due to COVID-19 by Day 28, were analyzed using a Bayesian model. Participants were followed through symptom diaries that they completed online daily; those who did not complete the diaries were contacted by telephone on Days 7, 14, and 29. The investigators developed a prespecified criterion for futility, specifying a clinically meaningful benefit in time to first self-reported recovery as a hazard ratio ≥1.2, corresponding to about 1.5 days of faster recovery in the colchicine arm.

Results

  • The study enrolled 4,997 participants: 212 participants were randomized to receive colchicine; 2,081 to receive usual care alone; and 2,704 to receive other treatments.
  • The prespecified primary analysis included participants with SARS-CoV-2 positive test results (156 in the colchicine arm; 1,145 in the usual care arm; and 1,454 in the other treatments arm).
  • The trial was stopped early because the criterion for futility was met; the median time to self-reported recovery was similar in the colchicine arm and the usual care arm (HR 0.92; 95% CrI, 0.72–1.16).
  • Analyses of self-reported time to recovery and hospitalizations or death due to COVID-19 among concurrent controls also showed no significant differences between the colchicine and usual care arms.
  • There were no statistically significant differences in the secondary outcomes between the colchicine and usual care arms in both the primary analysis population and in subgroups, including subgroups based on symptom duration, baseline disease severity, age, or comorbidities.
  • The occurrence of adverse events was similar in the colchicine and usual care arms.

Limitations

  • The design of the study was open-label treatment.
  • The sample size of the colchicine arm was small.

Colchicine in Hospitalized Patients With COVID-19

The RECOVERY Trial

In the RECOVERY trial, hospitalized patients with COVID-19 were randomized to receive colchicine (1 mg loading dose, followed by 0.5 mg 12 hours later, and then 0.5 mg twice daily for 10 days or until discharge) or usual care.6

Results

  • The study enrolled 11,340 participants.
  • At randomization, 10,603 patients (94%) were receiving corticosteroids.
  • The primary endpoint of all-cause mortality at Day 28 occurred in 1,173 of 5,610 participants (21%) in the colchicine arm and 1,190 of 5,730 participants (21%) in the placebo arm (rate ratio 1.01; 95% CI, 0.93–1.10; P = 0.77).
  • There were no statistically significant differences between the arms for the secondary outcomes of median time to being discharged alive, discharge from the hospital within 28 days, and receipt of mechanical ventilation or death.
  • The incidence of new cardiac arrhythmias, bleeding events, and thrombotic events was similar in the 2 arms. Two serious adverse events were attributed to colchicine: 1 case of severe acute kidney injury and one case of rhabdomyolysis.

Limitations

  • The trial’s open-label design may have introduced bias for assessing some of the secondary endpoints.

The GRECCO-19 Trial

GRECCO-19 was a small, prospective, open-label randomized clinical trial in 105 patients hospitalized with COVID-19 across 16 hospitals in Greece. Patients were assigned 1:1 to receive standard of care with colchicine (1.5 mg loading dose, followed by 0.5 mg after 60 minutes and then 0.5 mg twice daily until hospital discharge or for up to 3 weeks) or standard of care alone.7

Results

  • Fewer patients in the colchicine arm (1 of 55 patients) than in the standard of care arm (7 of 50 patients) reached the primary clinical endpoint of deterioration in clinical status from baseline by 2 points on a 7-point clinical status scale (OR 0.11; 95% CI, 0.01–0.96).
  • Participants in the colchicine group were significantly more likely to experience diarrhea (occurred in 45.5% of participants in the colchicine arm vs. 18.0% in the standard of care arm; P = 0.003).

Limitations

  • The overall sample size and the number of clinical events reported were small.
  • The study design was open-label treatment assignment.

The results of several small randomized trials and retrospective cohort studies that have evaluated various doses and durations of colchicine in hospitalized patients with COVID-19 have been published in peer-reviewed journals or made available as preliminary, non-peer-reviewed reports.8-11 Some have shown benefits of colchicine use, including less need for supplemental oxygen, improvements in clinical status on an ordinal clinical scale, and reductions in certain inflammatory markers. In addition, some studies have reported higher discharge rates or fewer deaths among patients who received colchicine than among those who received comparator drugs or placebo. However, the findings of these studies are difficult to interpret due to significant design or methodological limitations, including small sample sizes, open-label designs, and differences in the clinical and demographic characteristics of participants and permitted use of various cotreatments (e.g., remdesivir, corticosteroids) in the treatment arms.

Adverse Effects, Monitoring, and Drug-Drug Interactions

Common adverse effects of colchicine include diarrhea, nausea, vomiting, abdominal cramping and pain, bloating, and loss of appetite. In rare cases, colchicine is associated with serious adverse events, such as neuromyotoxicity and blood dyscrasias. Use of colchicine should be avoided in patients with severe renal insufficiency, and patients with moderate renal insufficiency who receive the drug should be monitored for adverse effects. Caution should be used when colchicine is coadministered with drugs that inhibit cytochrome P450 (CYP) 3A4 and/or P-glycoprotein (P-gp) because such use may increase the risk of colchicine-induced adverse effects due to significant increases in colchicine plasma levels. The risk of myopathy may be increased with the concomitant use of certain HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin, simvastatin) due to potential competitive interactions mediated by CYP3A4 and P-gp pathways.12,13 Fatal colchicine toxicity has been reported in individuals with renal or hepatic impairment who received colchicine in conjunction with P-gp inhibitors or strong CYP3A4 inhibitors.

Considerations in Pregnancy

There are limited data on the use of colchicine in pregnancy. Fetal risk cannot be ruled out based on data from animal studies and the drug’s mechanism of action. Colchicine crosses the placenta and has antimitotic properties, which raises a theoretical concern for teratogenicity. However, a recent meta-analysis did not find that colchicine exposure during pregnancy increased the rates of miscarriage or major fetal malformations. There are no data for colchicine use in pregnant women with acute COVID-19. Risks of use should be balanced against potential benefits.12,14

Considerations in Children

Colchicine is most commonly used in children to treat periodic fever syndromes and autoinflammatory conditions. Although colchicine is generally considered safe and well tolerated in children, there are no data on the use of the drug to treat pediatric acute COVID-19 or multisystem inflammatory syndrome in children (MIS-C).

References

  1. van Echteld I, Wechalekar MD, Schlesinger N, Buchbinder R, Aletaha D. Colchicine for acute gout. Cochrane Database Syst Rev. 2014(8):CD006190. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25123076.
  2. Xia M, Yang X, Qian C. Meta-analysis evaluating the utility of colchicine in secondary prevention of coronary artery disease. Am J Cardiol. 2021;140:33-38. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33137319.
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www.covid19treatmentguidelines.nih.govAn official website of the National Institutes of Health

Long COVID Could Be Linked to the Effects of SARS-CoV-2 on the Vagus Nerve

SciTechDaily

Authors: EUROPEAN SOCIETY OF CLINICAL MICROBIOLOGY AND INFECTIOUS DISEASES FEBRUARY 11, 2022

New research to be presented at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID 2022, Lisbon, April 23-26) suggests that many of the symptoms connected to post-COVID syndrome (PCC, also known as long COVID) could be linked to the effect of the virus on the vagus nerve – one of the most important multi-functional nerves in the body. The study is by Dr. Gemma Lladós and Dr. Lourdes Mateu, University Hospital Germans Trias i Pujol, Badalona, Spain, and colleagues.

The vagus nerve extends from the brain down into the torso and into the heart, lungs, and intestines, as well as several muscles including those involved in swallowing. As such, this nerve is responsible for a wide variety of bodily functions including controlling heart rate, speech, the gag reflex, transferring food from the mouth to the stomach, moving food through the intestines, sweating, and many others.

Long COVID is a potentially disabling syndrome affecting an estimated 10-15% of subjects who survive COVID-19. The authors propose that SARS-CoV-2-mediated vagus nerve dysfunction (VND) could explain some long COVID symptoms, including dysphonia (persistent voice problems), dysphagia (difficulty in swallowing), dizziness, tachycardia (abnormally high heart rate), orthostatic hypotension (low blood pressure) and diarrhea.

The authors performed a pilot, extensive morphological and functional evaluation of the vagus nerve, using imaging and functional tests in a prospective observational cohort of long COVID subjects with symptoms suggestive of VND. In their total cohort of 348 patients, 228 (66%) had at least one symptom suggestive of VND. The current evaluation was performed in the first 22 subjects with VND symptoms (10% of the total) seen in the Long COVID Clinic of University Hospital Germans Trias i Pujol between March and June 2021. The study is ongoing and continues to recruit patients.

Of the 22 subjects analyzed, 20 (91%) were women with a median age of 44 years. The most frequent VND-related symptoms were: diarrhea (73%), tachycardia (59%), dizziness, dysphagia and dysphonia (45% each), and orthostatic hypotension (14%). Almost all (19 subjects, 86%) had at least 3 VND-related symptoms. The median prior duration of symptoms was 14 months. Six of 22 patients (27%) displayed alteration of the vagus nerve in the neck shown by ultrasound – including both thickening of the nerve and increased ‘echogenicity’ which indicates mild inflammatory reactive changes.

A thoracic ultrasound showed flattened ‘diaphragmatic curves’ in 10 out of 22 (46%) subjects (which translates a decrease in diaphragmatic mobility during breathing, or more simply abnormal breathing). A total of 10 of 16 (63%) assessed individuals showed reduced maximum inspiration pressures, showing weakness of breathing muscles.

Eating and digestive function was also affected in some patients, with 13 of 18 assessed (72%) having a positive screen for self-perceived oropharyngeal dysphagia (trouble swallowing). An assessment of gastric and bowel function performed in 19 patients revealed 8 (42%) had their ability to deliver food to the stomach (via the esophagus) impaired, with 2 of these 8 (25%) reporting difficulty in swallowing. Gastroesophageal reflux (acid reflux) was observed in 9 of 19 (47%) individuals; with 4 of these 9 (44%) again having difficulty delivering food to the stomach and 3 of these 9 (33%) with hiatal hernia – which occurs when the upper part of the stomach bulges through the diaphragm into the chest cavity.

A Voice Handicap Index 30 test (a standard way to measure voice function) was abnormal in 8/17 (47%) cases, with 7 of these 8 cases (88%) suffering dysphonia.

The authors say: “In this pilot evaluation, most long COVID subjects with vagus nerve dysfunction symptoms had a range of significant, clinically-relevant, structural and/or functional alterations in their vagus nerve, including nerve thickening, trouble swallowing, and symptoms of impaired breathing. Our findings so far thus point at vagus nerve dysfunction as a central pathophysiological feature of long COVID.”

Meeting: The European Congress of Clinical Microbiology & Infectious Diseases (ECCMID 2022)

Heart-disease risk soars after COVID — even with a mild case

Authors: Saima May Sidik 10 February 2022

Nature

Massive study shows a long-term, substantial rise in risk of cardiovascular disease, including heart attack and stroke, after a SARS-CoV-2 infection.

Even a mild case of COVID-19 can increase a person’s risk of cardiovascular problems for at least a year after diagnosis, a new study1 shows. Researchers found that rates of many conditions, such as heart failure and stroke, were substantially higher in people who had recovered from COVID-19 than in similar people who hadn’t had the disease.

What’s more, the risk was elevated even for those who were under 65 years of age and lacked risk factors, such as obesity or diabetes.

“It doesn’t matter if you are young or old, it doesn’t matter if you smoked, or you didn’t,” says study co-author Ziyad Al-Aly at Washington University in St. Louis, Missouri, and the chief of research and development for the Veterans Affairs (VA) St. Louis Health Care System. “The risk was there.”

Al-Aly and his colleagues based their research on an extensive health-record database curated by the United States Department of Veterans Affairs. The researchers compared more than 150,000 veterans who survived for at least 30 days after contracting COVID-19 with two groups of uninfected people: a group of more than five million people who used the VA medical system during the pandemic, and a similarly sized group that used the system in 2017, before SARS-CoV-2 was circulating.

Troubled hearts

People who had recovered from COVID-19 showed stark increases in 20 cardiovascular problems over the year after infection. For example, they were 52% more likely to have had a stroke than the contemporary control group, meaning that, out of every 1,000 people studied, there were around 4 more people in the COVID-19 group than in the control group who experienced stroke.

The risk of heart failure increased by 72%, or around 12 more people in the COVID-19 group per 1,000 studied. Hospitalization increased the likelihood of future cardiovascular complications, but even people who avoided hospitalization were at higher risk for many conditions.

“I am actually surprised by these findings that cardiovascular complications of COVID can last so long,” Hossein Ardehali, a cardiologist at Northwestern University in Chicago, Illinois, wrote in an e-mail to Nature. Because severe disease increased the risk of complications much more than mild disease, Ardehali wrote, “it is important that those who are not vaccinated get their vaccine immediately”.COVID’s cardiac connection

Ardehali cautions that the study’s observational nature comes with some limitations. For example, people in the contemporary control group weren’t tested for COVID-19, so it’s possible that some of them actually had mild infections. And because the authors considered only VA patients — a group that’s predominantly white and male — their results might not translate to all populations.

Ardehali and Al-Aly agree that health-care providers around the world should be prepared to address an increase in cardiovascular conditions. But with high COVID-19 case counts still straining medical resources, Al-Aly worries that health authorities will delay preparing for the pandemic’s aftermath for too long. “We collectively dropped the ball on COVID,” he said. “And I feel we’re about to drop the ball on long COVID.”

doi: https://doi.org/10.1038/d41586-022-00403-0

References

  1. Xie, Y., Xu, E., Bowe, B. & Al-Aly, Z. Nature Med. https://www.nature.com/articles/s41591-022-01689-3 (2022).PubMed Article Google Scholar 

Long COVID’s daunting toll seen in study of pandemic’s earliest patients

Authors: Melissa Healy   6 hrs ago

COVID-19 patients in Wuhan were among the pandemic’s first victims, and a comprehensive new study finds that a year after shaking the coronavirus, survivors were more likely than their uninfected peers to suffer from mobility problems, pain or discomfort, anxiety and depression.

detailed accounting of 1,276 people hospitalized for COVID-19 in the pandemic’s opening months reveals that a full year later, almost half continued to report at least one lingering health problem that is now considered a symptom of “long COVID.”

One out of five said they had continued fatigue and/or muscle weakness, and 17% said they were still experiencing sleep difficulties. Just over one in four said they were suffering anxiety or depression in the wake of their bout with the SARS-CoV-2 virus.

For the growing number of patients who identify themselves as COVID “long haulers,” the new accounting offers cause for optimism — and concern. The period from six to 12 months after infection brought improvement for many. But most patients struggling with symptoms at the six-month mark were not yet well six months later.

The findings, catalogued by a team of Chinese researchers, were published late Thursday in the medical journal Lancet.

“This is not good news,” said David Putrino, a rehabilitation specialist who works with COVID long haulers at Mount Sinai Hospital in New York. “If you run the numbers here, about one-third of the group that had persistent symptoms are getting better after 12 months, while two-thirds are not.”

Putrino also called the findings a “wake-up call” to public health officials that even when the pandemic is over — a distant enough prospect in the midst of a fourth wave of infections — its downstream consequences will not be.

“We’re going to need resources for many years to come to deal with these patients,” he said.

There will be a lot of them. More than 87,000 COVID-19 patients are being hospitalized each day in the United States, and 2.7 million have receiving hospital care in the past year alone.

The half who contend with persistent symptoms will show up in doctors’ offices with clusters of vague and perplexing complaints including brain fog, heart palpitations, pain and exhaustion. And despite emerging evidence that time and specialized treatment can help many to improve, few will have the wherewithal to spend months in intensive rehabilitation for their symptoms, Putrino said.

An editorial published alongside the new study noted that only 0.4% of COVID long haulers are receiving rehabilitative treatment for their symptoms.

Even as scientists puzzle over the common biological mechanisms of long COVID’s diverse symptoms, healthcare providers “must acknowledge and validate the toll of the persistent symptoms of long COVID on patients, and health systems need to be prepared to meet individualised, patient-oriented goals, with an appropriately trained workforce,” Lancet’s editors wrote.

The new research also offered some glimmers of hope.

When the study’s COVID-19 patients were examined at six months, 68% said they had at least one of 15 symptoms considered hallmarks of long COVID, which is also known as Post-Acute Sequelae of COVID, or PASC. At one year, 49% were still afflicted by at least one of those symptoms.

The proportion of patients with ongoing muscle weakness and fatigue dropped from 52% to 20% during that time. Patients experiencing loss of smell dropped from 11% to 4%, and those afflicted with sleep problems fell from 27% to 17%. The 22% who reported hair loss at six months dwindled to 11% a full year out.

At the same time, the numbers of patients reporting breathing difficulties saw a slight increase, rising from 26% at six months to 30% after a year. Likewise, patients who reported new depression or anxiety increased from 23% to 26% during that period.

Study co-author Xiaoying Gu from the China-Japan Friendship Hospital in Beijing said the slight uptick in anxiety and depression was, like all of long COVID’s symptoms, hard to explain.

The psychiatric symptoms “could be caused by a biological process linked to the virus infection itself, or the body’s immune response to it,” he said. “Or they could be linked to reduced social contact, loneliness, incomplete recovery of physical health or loss of employment associated with illness.”

Patients who required mechanical ventilation were more likely than those with less severe illness to have measurable lung impairment and abnormal chest X-rays at both six and 12 months.

But in the tally of more subjective long COVID symptoms, the difference between the most severely ill and those who required no supplemental oxygen at all was very small.

That finding underscores the fact that even patients who are only mildly ill are at risk of developing a range of persistent symptoms.

Of the study population’s 479 patients who held jobs when the pandemic struck, 88% had returned to work a year after their illness. Most of the 57 who did not return said they either could not or were unwilling to do the tasks required of them.

The findings from the Wuhan patients also tracked with the widespread observation that persistent post-COVID infection symptoms are more common in women than in men. Women who had been hospitalized for COVID-19 were twice as likely as their male counterparts to report depression or anxiety 12 months later. In addition, they were close to three times as likely to show evidence of impaired lung function, and 43% more likely to report symptoms of fatigue and muscle weakness.

All of the study’s participants were treated at a single hospital in Wuhan, where reports of a mysterious new form of pneumonia first surfaced in December 2019. The researchers followed a large group of patients sickened in the first five months that the outbreak.

That makes the Lancet report one of the earliest and largest accounts of lingering COVID-19 symptoms to be tallied and vetted by other researchers, and the only one to compare such patients to a group of uninfected peers matched on a wide range of demographic and health attributes.

One thing is already clear, the journal editors noted: “Long COVID is a modern medical challenge of the first order.”

This story originally appeared in Los Angeles Times.

Covid-19 Vaccine Analysis: The most common adverse events reported so far

Authors: DATED: AUGUST 6, 2021 BY SHARYL ATTKISSON 

As of July 19, 2021 there were 419,513 adverse event reports associated with Covid-19 vaccination in the U.S., with a total of 1,814,326 symptoms reported. That’s according to the federal Vaccine Adverse Event Reporting System (VAERS) database.

Report an adverse event after vaccination online here.

Each symptom reported does not necessarily equal one patient. Adverse event reports often include multiple symptoms for a single patient.

Reporting of illnesses and symptoms that occur after Covid-19 vaccination does not necessarily mean they were caused by the vaccine. The system is designed to collect adverse events that occur after vaccination to uncover any patterns of illnesses that were not captured during vaccine studies.

Read CDC info on Covid-19 vaccine here.

Scientists have estimated that adverse events occur at a rate many fold higher than what is reported in VAERS, since it is assumed that most adverse events are not reported through the tracking system. Reports can be made by doctors, patients or family members and/or acquaintances, or vaccine industry representatives. 

Read: Exclusive summary: Covid-19 vaccine concerns.

Some observers claim Covid-19 vaccine adverse events are not as likely to be underreported as those associated with other medicine, due to close monitoring and widespread publicity surrounding Covid-19 vaccination.

Approximately 340 million doses of Covid-19 vaccine have been given in the U.S. Slightly less than half of the U.S. population is fully vaccinated.

According to the Centers for Disease Control (CDC) and Food and Drug Administration (FDA), the benefits of Covid-19 vaccine outweigh the risks for all groups and age categories authorized to receive it.

Watch: CDC disinformation re: studies on Covid-19 vaccine effectiveness in people who have had Covid-19.

The following is a summary of some of the most frequent adverse events reported to VAERS after Covid-19 vaccination. (It is not the entire list.)

Most common Covid-19 vaccine adverse events reported as of July 19, 2021

Yellow highlighted adverse events are subjects of investigations, warnings or stated concerns by public health officials. For details, click here.

128,370 Muscle, bone, joint pain and swelling including:

  • 39,902 Pain in extremity
  • 37,819 Myalgia, muscle pain, weakness, fatigue, spasms, disorders, related
  • 30,138 Arthralgia, joint pain or arthritis, swelling, joint disease, bone pain, spinal osteoarthritis
  • 14,682 Back pain, neck pain
  • 5,829 Muscle and skeletal pain, stiffness, weakness

119,866 Injection site pain, bleeding, hardening, bruising, etc.

105,332 Skin reddening, at injection site or elsewhere, rash, hives

100,564 Fatigue, lethargy, malaise, asthenia, abnormal weakness, loss of energy

89,302 Headache, incl. migraine, sinus

68,252 Vomiting, nausea

68,064 Fever

63,133 Chills

60,913 Pain

49,574 Dizziness

34,076 Flushing, hot flush, feeling hot, abnormally warm skin

31,785 Lung pain or abnormalities, fluid in lung, respiratory tract or lung congestion or infection, wheezing, acute respiratory failure including:

  • 23,005 Dyspnoea, difficulty breathing
  • 1,398 Pneumonia
  • 1,128 Respiratory arrest, failure, stopped or inefficient breathing, abnormal breathing
  • 563 Covid-19 pneumonia
  • 265 Mechanical ventilation
  • 217 Bronchitis

30,909 Skin swelling, pain, tightness, face swelling, swelling under skin, hives, angioedema including:

  • 7,579 Skin pain, sensitivity, burning, discoloration, tenderness

25,319 Heart failure, heart rhythm and rate abnormalities, atrial fibrillation, palpitations, flutter, murmur, pacemaker added, fluid in heart, abnormal echocardiogram including:

  • 3,105 Heart attack or cardiac arrest, sudden loss of blood flow from failure to pump to heart effectively, cardiac failure, disorder

22,085 Itchiness

29,861 Sensory disturbance including:

  • 8,236 Tinnitus, hearing noise
  • 7,951 Abnormal vision, blindness
  • 6,349 Ageusia, loss of taste, altered taste, disorders
  • 2,249 Anosmia, loss of smell, parosmia (rotten smell)
  • 2,075 Hypersensitivity
  • 1,560 Sensitivity or reaction to light 
  • 890 Hearing loss, deafness