Long COVID affects millions globally, causing debilitating symptoms that can persist for months or years.
Experts are calling for urgent clinical trials to find treatments.
Key Facts:
- Long COVID can cause fatigue, brain fog, muscle weakness, sleep disturbances and other symptoms lasting weeks to years after initial infection.
- The mechanisms are unclear but may involve viral persistence, immune dysregulation, microclots, gut dysbiosis and other factors.
- Prevention with vaccination and early antiviral treatment may reduce long COVID risk.
- Proposed treatments target viral persistence, inflammation, microclots, mitochondrial function and other biological pathways.
- Small uncontrolled studies provide hints but large randomized controlled trials are needed to truly test efficacy.
- Research is urgently needed on treatments tailored to long COVID subtypes and diverse affected populations.
Source: Front Immunol. 2023
Treatments for Long COVID in Trials 2023
Below are various treatments under clinical investigation for long-COVID.
Antivirals
Antivirals like nirmatrelvir/ritonavir (Paxlovid) or molnupiravir are being studied to clear any residual SARS-CoV-2 virus.
They inhibit viral replication machinery to shorten infection.
Small trials of Paxlovid are underway.
Case reports describe long COVID patients improving after Paxlovid, but controlled data is needed.
Anti-inflammatories
Many anti-inflammatory therapies are proposed to dampen chronic inflammation in long COVID.
These include:
- Corticosteroids like dexamethasone. A small study found dexamethasone reduced long COVID risk after initial hospitalization.
- Cytokine inhibitors for targets like IL-6, using drugs like tocilizumab. Case reports describe benefit but large trials are needed.
- JAK inhibitors like baricitinib to block intracellular inflammatory signaling.
- LDN (low dose naltrexone), which may modulate glial cell neuroinflammation. Small open-label studies report symptom improvements.
Anticoagulants/Antiplatelets
Anticoagulants like apixaban and antiplatelets like aspirin are proposed to resolve microclots, based on limited evidence of hypercoagulation markers in long COVID.
But clotting changes are inconsistently found, and these drugs can increase bleeding risk.
Small uncontrolled trials report benefit, but safety and efficacy remain unproven.
Mitochondrial Supplements
Mitochondrial supplements like CoQ10 aim to improve impaired energy metabolism.
Small studies show mixed results so far.
AXC0092, a combination of amino acids to enhance mitochondrial function, showed significant improvement in fatigue in a small trial, with a larger trial now underway.
Gut Microbiome Modulators
Prebiotics, probiotics, and fermented foods are being studied to correct dysbiosis of the gut microbiome linked to inflammation in long COVID.
These non-drug approaches could provide relative low-risk options, but current data is extremely limited.
Along with drugs, non-pharmacological approaches like cognitive behavioral therapy, pacing, graded exercise, and acupuncture also show theoretical promise for long COVID and warrant further research.
What is Long COVID?
Long COVID refers to lingering symptoms after acute SARS-CoV-2 infection.
It can occur even after mild initial illness and affect nearly any organ system.
Common symptoms include profound fatigue, cognitive dysfunction (“brain fog”), headache, sleep disturbances, muscle weakness, cardiac effects like palpitations, respiratory problems like shortness of breath, gastrointestinal issues like diarrhea, and mental health effects like depression.
Long COVID prevalence is estimated around 10-30% of COVID-19 cases.
With over 650 million COVID cases globally so far, this translates to 65-200 million people with long COVID worldwide.
The impact is disabling for many, preventing return to normal activities and reducing quality of life.
Long COVID can be considered a spectrum encompassing post-acute sequelae of SARS-CoV-2 infection (PASC) and other post-viral phenomena like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
There are no standard diagnostic criteria, but symptoms persisting over 12 weeks after acute COVID-19 is one common definition.
Possible Mechanisms of Long-COVID
The biological mechanisms behind long COVID remain unclear.
Proposed contributors include:
Viral Persistence – SARS-CoV-2 genetic material and proteins have been detected months after initial infection in some patients, suggesting viral reservoirs that could drive persistent inflammation.
Immune Dysregulation – Imbalances in cytokines like interleukin-6 (IL-6) and inflammatory cell types have been found in long COVID, hinting at chronic immune activation.
Microclots – Tiny clots trapping inflammatory proteins in the microcirculation could impair tissue oxygenation and cause symptoms.
Mitochondrial Dysfunction – Impaired energy metabolism could contribute to fatigue and other symptoms.
Gut Dysbiosis – Shifts in the gut microbiome linked to increased inflammation have been reported.
Reactivation of other viruses like Epstein-Barr virus (EBV) may also play a role.
Different mechanisms could drive different long COVID subtypes.
Many pathways likely intersect – for example, viral persistence could trigger chronic inflammation.
Long COVID: A Public Health Crisis
With millions globally affected, long COVID represents an urgent public health crisis.
People experiencing lingering symptoms are desperate for solutions.
While progress is being made, the pace remains far too slow compared to the scale of the problem.
Expediting clinical trials will require coordination between patients, researchers, funders, industry and regulatory agencies.
Increased funding and improved data sharing infrastructure are needed.
Creative trial designs could accelerate learning, for example by leveraging digital health tools for decentralized participation.
The world must mobilize to find solutions through rigorous science scaled to the size of the crisis.
Only then can we stem the rising human toll of this devastating post-viral phenomenon.
References
- Study: Therapeutic trials for long COVID-19: a call to action from the interventions taskforce of the RECOVER initiative
- Authors: Hector Bonilla et al. (2023)
