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Evaluating the magnitude and durability of the vaccine-induced SARS-CoV-2 immune response in people with and without HIV infection. UCSF/Gladstone Center for AIDS Research Jul 1, 2021 - Jun 30, 2022. Role: Principal Investigator. Symptoms and biomarkers of long COVID in people living with HIV.
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- Michael Peluso, MD, MHS | Department of Medicine
Peluso MJ, Antar AAR. Long COVID in people living with HIV....
- What’s New in the Search for a Long COVID Cure?
By George Spencer UCSF Magazine Summer 2023. UCSF infectious...
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- Overview
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- Six priorities
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COVID-19 offers researchers their best chance yet to understand, and find treatments for, a chronic illness associated with an infectious disease.
Infection-associated chronic conditions are not widely understood. Partly because of this, people who develop such conditions often face scepticism and stigma; health-care systems are ill-equipped to deal with them; and cases are likely to be under-reported. When it comes to COVID-19, millions of previously healthy people were infected with SARS-CoV-2 at the same time, and many of those infections were confirmed through testing. Patient-advocacy groups and the media highlighted that symptoms persisted1 in some of these people, and governments globally started to invest in programmes to tackle what, by late 2020, was understood to be a widespread infection-associated chronic condition — long COVID.
Since the earliest days of the pandemic, we have been on the front lines of care, research and advocacy concerning long COVID — defined here as symptoms, such as cognitive dysfunction, fatigue, breathlessness and pain, that persist for months or years after SARS-CoV-2 infection. On many fronts, progress in the past three years has been impressive. But we are increasingly worried that the momentum will not hold.
Research on long COVID continues to be uncoordinated, with many researchers and clinicians communicating only with other experts from their own field, be they pulmonologists, neurologists or cardiologists, for example. Few clinical trials are testing interventions that address the root causes of the condition. And the lack of infrastructure for the rapid implementation of long COVID trials, as well as the absence of long-term resourcing for the field, means that many scientists and companies with potential therapeutics are hesitating to engage. Meanwhile, the world is desperate to move on from COVID-19 — even as there is another global uptick in the spread of SARS-CoV-2.
We call for a moonshot for long COVID, a commitment — from the US government — to invest at least US$1 billion annually over the next ten years to address the problem. Such an investment would inspire governments around the globe to respond in kind to this health challenge, which exists on every continent.
Infection-associated chronic conditions, in which infections cause debilitating symptoms that persist for months, years or indefinitely5, are under-studied. There are no well-accepted measures or biomarkers for diagnosing them. Although shared biological mechanisms almost certainly underlie these conditions, none has yet been identified. And no treatments targeting root causes, rather than symptoms, have been approved by regulators.
Yet even before long COVID, such conditions were highly prevalent. In 2020, up to 2.5 million people in the United States and 24 million globally had myalgic encephalomyelitis, also known as chronic fatigue syndrome6, which has been linked to herpesvirus and enterovirus infections. In 2020, up to 1.9 million people in the United States alone might have had post-treatment Lyme disease, in which neurological symptoms, fatigue and other effects persist even after treatment of the infection7. Meanwhile, muscle aches, fever, fatigue and other problems that persist for up to two years following infection have been reported by up to 75% of Ebola survivors8 (mainly in Sierra Leone and Liberia), and diarrhoea and fatigue that persist for up to a decade by as many as 40% of people infected with the parasitic microorganism Giardia duodenalis9.
So far, long COVID has been an outlier in terms of the amount of attention it has received compared with other infection-associated chronic conditions, which have historically garnered little attention relative to disease burden. Thanks in part to teams studying other conditions, such as HIV and Ebola, being able to redirect resources towards long COVID, various research and clinical programmes to address it were established in 2020 — including at the University of California, San Francisco, where one of us (M.J.P.) is directing a long COVID research programme10. Today, epidemiological studies are under way to better establish how many people are affected, who is affected and to what degree. Larger initiatives, such as the NIH Researching COVID to Enhance Recovery (RECOVER) programme, launched in 2021, are building on the smaller efforts that jump-started the field, including one of our own organization’s (L.M.’s) patient-led research studies. And biological mechanisms and potential therapeutic targets are beginning to emerge.
It is now known, for instance, that one of at least six mechanisms (or any combination of these) could be contributing to the persistence of symptoms long after a person has been infected with SARS-CoV-23.
Multiple studies have identified inflammation markers, both in blood11 and in tissues12. Others have found that the Epstein–Barr virus, normally dormant in adults, can be reactivated in people with long COVID3. Researchers in the United States, South Africa and the United Kingdom have shown that SARS-CoV-2 can alter clotting proteins, generating microscopic clots that might affect tissue function3. Some people experience autoimmune conditions after getting COVID-19, suggesting that a contributing factor to long COVID could be the immune system attacking the body3. SARS-CoV-2 can alter mitochondrial health3, offering a potential explanation for why many people with long COVID experience fatigue and post-exertional malaise. Even the idea that SARS-CoV-2 is a transient invader is being challenged13, with multiple studies showing that fragments of the virus can stay in the body for more than six months.
Many questions remain. Yet acquiring even this understanding in such a short time suggests that precisely defining long COVID’s biology, identifying biomarkers and designing and testing targeted treatments should be possible — so long as the funding is there.
We estimate that by this point, more than $1.5 billion globally has been dedicated to long COVID research. But most of this funding has been limited to a maximum of four years. Building on the progress made so far is going to require billions more, and for resources to be committed over at least a decade. It will also need funders, regulators, researchers, pharmaceutical companies, the patient community and other stakeholders to prioritize six goals.
Agree on what long COVID is. Studies of long COVID define the condition in different ways. Some investigators include medical comorbidities associated with COVID-19, from diabetes and cardiovascular disease to Alzheimer’s disease. In some studies, symptoms must have lasted for at least three months; in others, for just 30 days. Various attempts at standardization have been made or are still under way, including efforts by the World Health Organization and the US National Academies of Sciences, Engineering, and Medicine. But most people working on long COVID continue to use the definition that is most convenient for them. This means researchers are comparing apples to — at best — oranges. The lack of clear definitions also feeds scepticism over whether the condition can even be studied in the first place.
For now, research funders and publishers could encourage more consistency by requiring that, at the very least, researchers state which formal definition they are using in their funding applications and manuscripts.
The clarity of a single, formal definition might be unobtainable. Definitions developed in the coming years could require more specific patient data, and might not easily be applied to parameters captured in 2020 or 2021. Also, it’s unclear whether a single definition can be applied across cohorts, such as those who were hospitalized with COVID-19 and those who were not. The population of people with long COVID but without a positive COVID test, either because their test was inaccurate or because they weren’t able to obtain a test, is clinically important and must also be accounted for. So it could be that a set of case definitions with varying degrees of specificity will be most useful. In clinical settings, a broad definition of long COVID could ensure that people are eligible for care. In research, a narrower definition might be warranted, although investigators should strive to ensure that any definition they use is as inclusive as possible.
Bolster team science. The first major international multidisciplinary meeting focused on long COVID — the Keystone symposium on long COVID — was held in Santa Fe, New Mexico, this August. This is exactly the kind of event needed to bring together clinical scientists, infectious-disease experts, neuroscientists, cardiologists, pulmonologists and many other researchers (including patients themselves) studying the mechanisms that might be at work in people with long COVID.
Various efforts have already been made to bring together different groups working on long COVID. Foundations and patient groups, for instance, are hosting seminars and connecting people online. But the creation of publicly funded multidisciplinary centres specific to infection-associated chronic conditions, including long COVID, would help to drive much more collaboration.
Investment now in long COVID will help to ensure that when the next pandemic comes, efforts to study potential infection-associated chronic conditions are a core part of the initial response. That means investing not just in research, but also in education programmes that enable health professionals and trainees to learn about such conditions. And it means providing grant funding, training programmes and salaries specifically for early-stage investigators wanting to pursue careers in such conditions, including long COVID.
By challenging the long-held assumption that treating infectious disease is all about tackling acute infection, a moonshot initiative for long COVID could ultimately change the way all of us think about the effects of pathogens on our health.
Nature 622, 457-460 (2023)
doi: https://doi.org/10.1038/d41586-023-03225-w
Jan 11, 2024 · 11 Citations. 1764 Altmetric. Metrics. Abstract. Long COVID (LC) occurs after at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, yet its etiology remains...
Oct 13, 2023 · Background. Postacute sequelae of COVID‐19 (PASC) and HIV are both associated with reduced exercise capacity, but whether SARS‐CoV‐2 or PASC are associated with exercise capacity among people with HIV (PWH) is unknown. We hypothesized that PWH with PASC would have reduced exercise capacity from chronotropic incompetence. Methods and Results.
Michael Peluso M.D., an HIV and infectious disease specialist at UCSF, has been studying Long Covid patients since April 2020 (LIINC Study). This, along with his history of working with HIV and other viruses, has given him the knowledge and methods to make some break-throughs into Long Covid pathogenesis, effects and, potentially, treatments.
