Innovative research programs around the world confront a health crisis in the wake of the Covid-19 pandemic.
Some 43 percent of people infected with Covid-19 develop long Covid, which means at least 200 million people have had or currently have the condition, according to the most recent meta-analysis. And that estimate may be conservative. At the higher end, up to 87 percent of people who come down with Covid-19 experience at least one long-term symptom consistent with long Covid .
Scientists, healthcare providers, and policymakers around the globe are honing in on long Covid to figure out the mechanisms that cause it, how to treat patients with persistent and sometimes disabling symptoms, and how to manage the sheer magnitude of the crisis.
Long Covid has gone by many names, including Post-Acute Sequelae of Covid-19 (PASC), Post-Acute Covid-19 Syndrome (PACS), Chronic Covid-19 Syndrome (CCS), and Long Haul Covid-19. In October 2021, the World Health Organization defined it this way: “the condition that occurs in individuals with a history of probably or confirmed SARS-CoV-2 infection, usually 3 months from the onset of Covid-19, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis” . Some of the most commonly reported symptoms are fatigue, memory problems, shortness of breath, sleep issues, and joint pain .
In order to determine what percentage of COVID-19 patients have gone on to develop long COVID, a recent meta-analysis looked at nearly 4,500 papers and 50 studies comprising almost 1.7 million patients in 16 countries. In addition to the global prevalence of 43 percent, researchers noted a regional frequency of 51 percent, 44 percent, and 31 percent for Asia, Europe, and the US, respectively .
Importantly, some regions—including Africa, Central America, Oceania, and the Caribbean—and some populations—especially children—were missing from the literature and point to a critical gap in understanding how long Covid affects people around the world .
Understanding what causes long Covid may be key to figuring out how to treat it. There are a few ideas out there, and one of the most compelling comes from the lab of Resia Pretorius of South Africa’s Stellenbosch University.
When scanned, the lungs of Covid-19 patients reveal opaque spots that look like ground glass and persist well beyond the acute infection in follow up scans.
Normally, blood travels through vessels and capillaries to supply oxygen to body tissues, but these micro-clots of fibrin clog the tiniest capillaries, blocking the flow of blood like a clump of hair clogs a pipe. This could explain a wide range of long Covid symptoms, because tissues become damaged when their cells are starved of oxygen [2, 3]. In addition to respiratory symptoms like shortness of breath, the effects of oxygen deprivation include non-respiratory features like postural tachycardia syndrome (PoTS), kidney dysfunction, and muscle pain .
These micro-clots are amyloid—meaning abnormally folded—and similar amyloid clotting has been associated with inflammatory diseases like Alzheimer’s, Parkinson’s, type 2 diabetes, and rheumatoid arthritis .
Plus, blood vessels are lined with a layer of endothelial cells that moves it through the system. This endothelial layer also acts as a gateway that connects the cardiovascular and immune systems, so it’s critical for maintaining blood flow and regulating inflammation. Micro-clots may kill individual endothelial cells—and breaches in that gateway dysregulates its functions [2, 3].
Digging deeper, Pretorius’ team notes that some patients with long Covid make autoantibodies—blood proteins that recognize substances from the body as foreign and target them for destruction—including one to an abnormal form of fibrin. It’s plausible that autoantibodies could play a role in long Covid like they do in other chronic inflammatory diseases [2, 3]. Right now, Pretorius’ team is developing a lab test to diagnose micro-clots in long Covid patients.
Fibrin micro-clots could also play a role in one of the most troubling aspects of long Covid: neurological features like brain fog, dysautonomia, and problems with taste and smell. Remember the layer of endothelial cells that line blood vessels? Those cells also separate the circulating blood from the central nervous system. This is the bulk of what’s meant by the “blood brain barrier” as these cells serve as sentries, regulating what can move into and out of the brain [4, 5].
That’s part of what Abdul Mannan Baig explores in his lab at Aga Khan University in Pakistan. It’s been clear since 2020 that Covid-19 is neuroinvasive—meaning it can get past that cellular barrier and into the brain—and perhaps even preferentially targets the nervous system [4, 5].
Baig hopes to tease out how much of this neuro-invasion comes from breaching the blood brain barrier via micro-clots, oxygen starvation, and autoantibodies versus other mechanisms like a direct passage from the nasal cavity to the brain or direct injury to brain cells [4, 5].
The UK leads on this point, thanks to a series of government-funded studies and the ease with which researchers can access information through the nationalized patient data system .
There are at least 13 ongoing trials, including one focused on children and young people (CLoCK), one targeting mechanisms like micro-clots and autoantibodies (REACT-LC), and a few exploring interventions, such as repurposing anticoagulants to deal with micro-clots and antihistamines for inflammation (HEAL-COVID, STIMULATE-ICP) .
The STIMULATE-ICP study, led by Amitava Banerjee of University College London and Melissa Heightman of University College London Hospitals NHS Foundation Trust, is the largest trial for long Covid so far. It includes more than 60 researchers, clinicians, and partners across more than 30 organizations and is actively recruiting 4,500 participants.
The study will explore multi-organ scans to aid diagnosis and investigate repurposed drugs to address micro-clots and inflammation—but that’s not all . The trial also proposes an innovative remote rehabilitation program to address inequities in accessing the more than 80 long Covid clinics that operate in the UK . Remote rehabilitation includes digital dashboards for clinicians connected to mobile apps for patients, as well as specific measures to investigate barriers to tech uptake .
Perhaps most interesting, STIMULATE-ICP features a community advisory board of people with long Covid. This will ensure a patient-centered focus and help address misconceptions about long Covid as the team works toward clear, scalable recommendations that could serve as a model around the world .
In an April 5, 2022 factsheet, US president Joe Biden directed Health and Human Services to coordinate a national, interagency response to long Covid. This includes developing a national research plan that builds on the NIH RECOVER program, which began funding US researchers in 2021, and ramping up enrollment in the CDC-funded INSPIRE study, which is recruiting long-Covid patients right now .
One of the challenges facing the US response to long Covid is the decentralized healthcare system, which makes it more difficult to access patient data compared with the UK trials.
This may drive grassroots action to address long Covid in the US, including identifying symptoms and management strategies and advocating for policies and research programs that prioritize the lived experience of people with long Covid.
A fascinating aspect of long Covid is that this is the first time the clinical description of a health condition began on social media . Starting in 2020, people with persistent symptoms after Covid-19 came together through outlets like the Long Covid Support Group on Facebook and Body Politic Covid-19 Support Group on Instagram, which launched May 2 and May 26, respectively—just over a month after the first official US case of Covid-19 .
This global, patient-led movement includes researchers and clinicians who have long Covid and strengthen the grassroots push for research and evidence-based treatment . One of the most notable grassroots efforts is the Patient-Led Research Collaborative (PLRC), which published the first all-patient survey of persistent symptoms back in May 2020. They’re working with the Council of Medical Specialties Societies to secure funding through the Patient-Centered Outcomes Research Institute, a US non-profit linked to the Affordable Care Act, to develop a patient-led model for long Covid research . On April 22, PLRC announced $3 million in funding from the direct giving fund Balvi, which will support patient-directed grants to outside researchers as well as the collaborative’s own research program.
One of the clear lessons of the Covid-19 pandemic is global interconnectedness. As long Covid numbers continue to climb, insights gleaned from research programs around the world will drive diagnosis and treatment.
Chen C. et al. 2022. Global Prevalence of Post COVID-19 Condition or Long COVID: A Meta-Analysis and Systematic Review. The Journal of Infectious Diseases jiac136.
Kell DB., GJ Laubscher, and E. Pretorius. 2022. A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications. Biochemical Journal 479: 537-559.
Pretorius E. et al. 2021. Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasm. Cardiovascular Diabetology 20: 172.
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