Virus World

Background

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC) in ~ 30% of all infected individuals. Here, we present a case of PASC in a patient with rheumatoid arthritis characterized by viral persistence in the nasopharynx for 6 months after acute infection. We demonstrate transient disappearance of antigen persistence and decreased antiviral and autoimmune T cell responses after nirmatrelvir/ritonavir and tocilizumab treatment.

Case Presentation

A 37-year-old female with a 7-year history of rheumatoid arthritis enrolled in a COVID-19 research study was found to continuously test SARS-CoV-2 antigen positive in the nasopharynx for 6 months after acute infection. She simultaneously presented with new-onset PASC symptoms including chronic occipital headache and periods of intense fatigue 8 weeks after acute infection. The patient was prescribed nirmatrelvir/ritonavir to treat SARS-CoV-2 persistence at 3.5 months post-acute infection and observed a reduction in PASC symptoms 3 weeks after completing antiviral treatment. After resurgence of PASC symptoms, she stopped treatment with tocilizumab for rheumatoid arthritis to attempt complete SARS-CoV-2 viral clearance. The severity of the patient’s PASC symptoms subsequently increased, and she developed new-onset brain fog in addition to previous symptoms, which resolved after resumption of tocilizumab treatment. Assessment of adaptive immune responses demonstrated that nirmatrelvir/ritonavir and tocilizumab treatment decreased antiviral and autoreactive T cell activation. After resuming tocilizumab treatment, the patient’s PASC symptoms were significantly reduced, but nasopharyngeal antigen positivity remained.

Conclusions

These data suggest that nirmatrelvir/ritonavir should be considered in the treatment of PASC in patients who have SARS-CoV-2 antigen persistence, though care must be taken to monitor the patient for symptom resurgence or viral reactivation. In addition, the IL-6 inhibitor tocilizumab may ameliorate PASC symptoms in patients with persistent headache, fatigue, and brain fog.

Preprint available ( July 22, 2022):

https://www.researchsquare.com/article/rs-1879380/v1 

After a slow start, researchers are beginning to test ways to combat the lasting symptoms of the disease.  Bhasha Mewar has had it with doctors. Over the past two years, Mewar has spent nearly all of her life savings seeing heart and respiratory specialists, haematologists, urologists, dermatologists and more, in a desperate bid to tame her long-COVID symptoms. She has taken a slew of drugs: beta blockers to calm her racing heart, steroid inhalers to ease her laboured breathing and an antimalarial drug prescribed to her for reasons she never fully understood. And when Mewar — a curator at an art museum in Ahmedabad, India, who has been sick since what was probably a bout of COVID-19 in March 2020 — would visit her lung doctor twice a month, he always told her the same thing: you need to exercise. “I can’t even walk to the bathroom,” she would reply. It’s an unwelcome odyssey undertaken by millions of people living with long COVID, a complex and sometimes debilitating syndrome that can linger for months or years after an acute SARS-CoV-2 infection. There is no proven treatment, leaving physicians and people with the condition to play whack-a-mole with its many symptoms. And sometimes, people with the syndrome turn to untested, self-prescribed therapies. Although at least 26 randomized clinical trials of long-COVID therapies are under way (see ‘Trials take off’), many are too small or lack the necessary control groups to give clear results. “If you look at long COVID at this moment in time, I’d paint a slightly ‘Wild West’ and desperate picture really,” says immunologist Danny Altmann at Imperial College London. Even so, researchers are narrowing in on the pathology that underlies long COVID. In the next year, key trials could yield results for drugs that target the immune system, blood clots or lurking fragments of the coronavirus itself. “I’m still optimistic,” Altmann says. “The right stuff is going on, and there’s a fair amount of funding out there. Something is going to give.”

Complex condition

A key barrier to developing long-COVID treatments has been uncertainty about the condition’s root cause. Over the past two years, a number of hypotheses have emerged as frontrunners, and researchers hope that insight into which ones are correct could help them to develop therapies. Evidence is mounting that lingering SARS-CoV-2 — or fragments of it — continues to cause trouble by stimulating the immune system. There are also signs that the infection generates antibodies that mistakenly attack the body’s own proteins, causing damage long after the initial illness. Researchers have found hints that COVID-19 could cause microscopic blood clots that block oxygen flow to tissues. It is also possible that a SARS-CoV-2 infection can wreak long-term havoc on gut microorganisms. These hypotheses are not mutually exclusive: many researchers think that long COVID can have multiple causes. Each idea suggests a route to relief. Antiviral drugs might vanquish persistent reservoirs of SARS-CoV-2. Drugs that suppress the immune system could quench a misguided immune response. Powerful anti-coagulants could dissolve micro-clots. Although evidence is gradually accumulating in support of each of these possibilities, their links to long COVID are still tenuous enough to give some investigators pause before launching clinical trials. “The hypotheses are getting a bit stronger,” says Altmann. “But they’re not cast iron.” This uncertainty could dissuade researchers from launching trials, says epidemiologist Martin Landray, at the University of Oxford, UK. If long COVID has a number of causes, a promising treatment could be ruled ineffective in a clinical trial simply because it was given to the wrong group. Plus, there is no shortlist of key symptoms to help to enroll  participants or sort them into subgroups. More than 200 symptoms have been associated with the syndrome1, and many — such as fatigue and brain fog, two of the most common and debilitating — are hard to measure objectively, and can wax and wane. “I’ve had a whole list of symptoms; half of them I’ve forgotten,” says Mewar, who keeps a library of photographs of the medicines she has tried, to keep track of her treatments amid the brain fog that permeates her memory. “They would come and go, here a week, and then gone.” All of this complicates clinical-trial design, says Landray, an architect of RECOVERY, a large UK trial of treatments for acute COVID-19. That trial took just four months to find that low doses of the steroid dexamethasone reduced deaths from severe COVID-19 by one-third. Landray has received requests from people with long COVID and their families to engineer a similar effort to address long COVID. “I haven’t gotten involved in this space,” he says. “The science hasn’t seemed sufficiently mature.”

A trickle of trials

But some researchers have pushed ahead. Several trials try to tame errant immune responses. Some of these rely on familiar drugs, such as colchicine, an anti-inflammatory drug that treats gout and is often prescribed to people with long COVID. Other trials are using drugs that have shown some success in treating severe acute COVID-19, including steroids and other immunosuppressants, such as sirolimus, which is used to prevent organ rejection after a transplant. Small trials and anecdotal reports suggest that antihistamines show some promise, and they provide “a Band-Aid solution”, says Hannah Davis, who has long COVID and lives in New York City. Davis is a co-founder of the Patient-Led Research Collaborative, a research and advocacy group. “But it would be good to confirm that it’s helping.” Rheumatologist James Andrews at the University of Washington in Seattle is investigating a new approach to taming inflammation in people with long COVID: an experimental drug called RSLV-132. The drug, made by Resolve Therapeutics in St Petersburg, Florida, is designed to remove RNA circulating in the blood, where it is thought to promote inflammation, says Andrews. The company has tested its drug in small trials for other conditions and has found some success in reducing fatigue in people with Sjögren’s syndrome, an autoimmune disorder. Other approaches aim to manage symptoms, such as extreme fatigue, muscle weakness and memory and concentration difficulties. Roger McIntyre, who studies psychiatry and pharmacology at the University of Toronto, Canada, is enrolling participants in a trial of vortioxetine, an antidepressant that has been shown to boost cognition, to find out whether it alleviates the brain fog associated with long COVID. Another set of trials aims to tackle COVID-19’s lingering impact on the cardiovascular system. Some studies have found evidence of inflammation in the lining of blood vessels and suggest that, in some people, this could trigger the formation of microclots that then clog the lung’s tiniest vessels, the capillaries2. Cardiologist Rae Duncan, at Newcastle upon Tyne Hospitals NHS Foundation Trust, UK, and her colleagues are planning to launch a clinical trial to test a cocktail of drugs targeting this clotting process. Duncan says when she presented her clinical-trial plans to a panel of people with long COVID and their advocates, two of them became emotional: “They said, ‘This is the trial we’ve been waiting for.’”...

Published in Nature (August 9, 2022):

https://doi.org/10.1038/d41586-022-02140-w 

A study has identified four predictive factors of Post Acute Sequelae of COVID-19 (PASC), often called long COVID. These 'PASC factors' can be identified at the initial point of COVID-19 diagnosis and can anticipate if a patient is likely to develop long COVID. Additionally, researchers found that mild cases of COVID-19, not just severe cases, are associated with long COVID, and that administering antivirals very early in the disease course may potentially prevent some PASC.  A significant portion of people who contract the SARS-CoV-2 virus -- some estimates suggest more than 40 percent -- suffer chronic effects known as Post Acute Sequelae of COVID-19 (PASC), commonly referred to as long COVID. PASC symptoms include fatigue, brain fog, the loss of taste and smell, shortness of breath, and more. Now, researchers have identified several factors that can be measured at the initial point of COVID-19 diagnosis that anticipate if a patient is likely to develop long COVID. These "PASC factors" are the presence of certain autoantibodies, pre-existing Type 2 diabetes, SARS-CoV-2 RNA levels in the blood, and Epstein-Barr virus DNA levels in blood.