On August 9, 2024, it appeared in Nature Medicine the review Long COVID science, research and policy on the state of science and policy around post-COVID. This article builds on the January 2023 article by Davis, et al., of which C-support previously published an extensive summary. Below you can read a summary of the review written by the authors Ziyad Al-Aly, Hannah Davis, Lisa McCorkell, Letícia Soares, Sarah Wulf-Hanson, Akiko Iwasaki & Eric J. Topol.
Post-COVID: science, research and policy
Post-COVID-2 is a multisystem disease in which multiple organ systems are affected by disruptions in biological processes, including viral persistence, immune dysregulation, and mitochondrial dysfunction, according to the authors. Post-COVID-XNUMX can be highly debilitating and affects people of all ages and backgrounds. Common symptoms include cognitive dysfunction (brain fog), debilitating fatigue, post-exertional malaise (PEM), and dysautonomia (such as postural orthostatic tachycardia syndrome (POTS)). Severe SARS-CoV-XNUMX infection and re-infections increase the risk of post-COVID-XNUMX, while vaccinations and antivirals during acute infection appear to reduce the risk. The chance of recovery is very limited, with many concerns about potential long-term health problems.
The impact of post-COVID is not limited to the health of the individual or the immediate environment, but poses a lasting challenge to global health and economy. Therefore, the broader impact on global health, economy and health care is described to initiate a broad discussion and coordinated effort around the research and policy challenges of post-COVID.
The global burden and prevalence
The global burden of post-COVID is difficult to determine due to varying research methods and post-COVID definitions. Globally, the prevalence of disease in the population is estimated to be between 6% and 7% in adults, and about 1% in children. Metadata shows that about 6,2% of people with COVID symptoms experience at least one of the three common post-COVID symptoms (cognitive problems, fatigue, respiratory problems) after three months. Globally, post-COVID affects about 400 million people, with an estimated annual economic impact of $1 trillion. Actual numbers may be higher as reinfections, asymptomatic SARS-CoV-2 infections, and symptoms that develop over a longer period of time are not included in the study.
Possible mechanisms
More research is needed into the underlying mechanisms of post-COVID. It is unlikely that a single mechanism can explain the broad and diverse symptoms across multiple organ systems. It is a complex disease that most likely has multiple subtypes, each with unique risk factors, biological processes, disease course, and possibly differential responsiveness to therapy. With multiple factors, including genetic predisposition, immune response, microbiome “health,” and viral properties, influencing disease progression. Potential mechanisms include:
- Viral persistence: The virus can persist in tissues, such as the brain and coronary arteries, and cause long-term inflammation there.
- Immune dysregulation: Increased (auto)immune responses, T-cell exhaustion and sometimes reactivation of other viruses such as Epstein-Barr (Pfeiffer) play a role.
- Neuroinflammation: Changes in the brain, such as white matter abnormalities, disrupted blood-brain barriers, and persistent inflammatory responses, may contribute to symptoms such as brain fog.
- Cardiovascular problems: Inflammation in the blood vessels increases the risk of clotting problems and tissue damage, especially in the coronary arteries.
- Hormonal Disruption: An imbalance of (stress) hormones, such as low cortisol levels, can worsen fatigue and sleep disorders.
- Disrupted signal transmission in the brain: Lowered serotonin levels can cause cognitive problems and mood swings.
- Mitochondrial dysfunction: Disrupted energy production in the cell leads to metabolic problems and abnormal muscle responses to exertion.
Post-COVID shares these mechanisms with other post-acute infectious syndromes (PAIS), such as ME/CFS (Q fever, Lyme, Legionnaires' disease, sepsis). More research is needed to fully understand these mechanisms and develop targeted treatments.
Prevention, treatment and care models
Several preventive measures can contribute to reducing the risk of SARS-CoV-2 infection and the subsequent risk of post-COVID, such as non-pharmaceutical measures, vaccination and antivirals, more research, a standardized care model, and finally (re)cognition. Also non-pharmaceutical measures, such as the use of masks and improving indoor air quality. A SARS-CoV-2 vaccination reduces the risk in adults by an average of 40% and offers protection for children. Research shows that antivirals can reduce the risk of post-COVID when administered in the acute phase in people with mild to moderate SARS-CoV-2 infection. Finally, the use of metformin shortly after infection is mentioned as a possible way to reduce the risk of post-COVID.
The evidence for effective post-COVID treatments remains limited. Lack of good clinical trials to inform treatment choices, ensuring the application of methods and treatments based on similar conditions. An example of a well-conducted study on the modulation of the microbiome with a reduction in symptoms suggests that the microbiome could be a potential therapeutic target.
There is no standardized care model for post-COVID, which results in a high variability in the quality of care. Patients worldwide experience difficulties in obtaining a diagnosis and recognition by medical professionals. The development of optimal broadly applicable care models for post-COVID should be based on available resources, expertise and the specific patient population.
The social and economic impact
Post-COVID has far-reaching consequences for individuals and society. Patients experience daily limitations in their lives and well-being, such as social exclusion and mental health problems due to a lack of recognition and acknowledgement. The current healthcare system is under pressure. Post-COVID often requires complex and long-term care, partly due to chronic conditions such as cardiovascular diseases and diabetes as a result of a SARS-CoV-2 infection. In addition, post-COVID leads to loss of income and reduced productivity due to absenteeism, but also to progress in global healthcare and the reduction of healthcare inequalities. It is important to strengthen investments in healthcare, research and economic systems. Further research and international collaborations to effectively address the long-term consequences are necessary.
A roadmap for research and policy
An integrated research and policy strategy to address the complex challenges of post-COVID requires a long-term approach and is needed to improve care and quality of life for patients. Therefore, the authors developed a research and policy roadmap with recommendations, based on existing knowledge, policy gaps and collaborations with patients.
- More research into the biological mechanisms of post-COVID, with a PAIS broad vision, that contribute to the development of treatment strategies. But also integral studies into the economic impact, care models, social and societal consequences of policy interventions in relation to health outcomes and disease burden.
- Diagnostic innovations such as advanced imaging, biomarkers and data from wearable biosensors for early detection, risk assessment and better disease management.
- Large-scale (epidemiological) studies to gain insight into the number of new cases, the number of patients in the population, subtypes, identification of vulnerable groups, and the severity, course and long-term consequences of post-COVID on overall health.
- More innovative and large-scale research designs, such as platform trials. More clinical studies on repurposed medicines and new antivirals.
- Establishing universal, flexible definitions and clinical endpoints to adequately capture the complexity of post-COVID.
- Guidelines for preventive measures; a more widely implemented vaccination strategy, investment in improved indoor air quality and the development of vaccines aimed at long-term immunity.
- Broader support; such as appropriate work arrangements, more flexible disability benefits, available patient organisations and supporting social and community organisations.
- New public campaigns to reduce stigma surrounding post-COVID.
- Policy to improve accessibility and quality of care, through broader coverage of health insurance and extra attention to quality of care, especially for vulnerable target groups.
- Knowledge dissemination in the training of healthcare professionals and continuous medical education for greater recognition and treatment.
- Optimizing pandemic preparedness; developing systems to measure post-acute and chronic disease and long-term outcomes.
