The health issues that may appear after recovery from coronavirus infection are referred to as Long COVID, or Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). They include fatigue, breathing difficulties, headaches, sleep disturbances, cognitive dysfunction, changed smell and taste sensation, and post-exertional malaise.
According to the CDC and WHO, post-COVID conditions represent a field of ongoing medical research in which the scientific community should find an answer to why some patients recover while others suffer from persistent symptoms. At the moment, scientific efforts focus on the mechanisms and causes of Long COVID. However, one needs to remember that Long COVID is a complex condition, and a universal cause cannot be identified yet.
Long COVID refers to ongoing or new health problems that develop afteran initialCOVID-19 infection. Researchers continue to study its causes, symptoms, risk factors, and long-term effects.
Long COVID describes symptoms that persist, return, or develop after the acute phase of COVID-19. Symptoms can vary widely and may affect multiple areas of health.
PASC stands for Post-Acute Sequelae of SARS-CoV-2. It is a medical term commonly used to describe health conditions or symptoms that continue or emerge after the initial SARS-CoV-2 infection.
The estimated prevalence of Long COVID varies between studies because researchers use different definitions, populations, and follow-up periods. Ongoing research is helping clarify how frequently it occurs.
Long COVID can affect people after COVID-19, including those who experienced mild or severe initial illness. Researchers are investigating why some people develop persistent symptoms while others recover fully.
Research into Long COVID is continuing to develop, and scientists are investigating several possible biological and physiological mechanisms. Current evidence supports the existence of persistent and sometimes fluctuating symptoms after SARS-CoV-2 infection, but the underlying causes are complex and may differ between individuals.
Researchers are studying multiple pathways, including immune responses, inflammation, vascular changes, nervous-system dysfunction, metabolic changes and possible persistence of viral material. Some findings are supported by growing evidence, while others remain hypotheses requiring further investigation.
1. Established Clinical Observations
Clinical research has consistently documented that Long COVID can involve persistent, recurring or newly developed symptoms following SARS-CoV-2 infection. Symptoms may fluctuate over time and can affect multiple body systems.
Commonly reported clinical manifestations include:
The CDC notes that Long COVID symptoms can emerge, persist, resolve and reemerge over varying periods of time. More than 200 symptoms have been reported, although symptoms and their severity vary considerably between individuals.
Post-exertional malaise is also an important clinical feature for some people with Long COVID. The CDC describes PEM as worsening of symptoms following physical or mental exertion, which may occur hours after the activity and can persist for days or longer.
2. Biological Mechanisms Under Investigation
Researchers are investigating several biological processes that may contribute to Long COVID. These mechanisms may overlap, and no single mechanism has been established as the explanation for every case.
Immune Dysregulation and Inflammation
Studies have reported changes in immune responses following SARS-CoV-2 infection. Researchers are investigating whether persistent immune activation, altered immune regulation or autoimmune processes may contribute to some Long COVID symptoms.
Inflammatory and immune-related pathways are therefore an important area of ongoing research, but their precise role and relationship to individual symptoms remain under investigation.
Endothelial and Vascular Dysfunction
The endothelium is the layer of cells lining blood vessels. Researchers are investigating whether changes in endothelial function and the vascular system may contribute to some Long COVID manifestations.
Vascular abnormalities and microvascular dysfunction have been reported in research studies, but their significance for individual patients and their role in causing specific Long COVID symptoms require further study.
Autonomic and Neurological Dysfunction
Dizziness, changes in heart rate, exercise intolerance and symptoms that occur when standing have led researchers to investigate autonomic nervous-system dysfunction and related conditions.
Researchers are also examining neurological mechanisms that could contribute to cognitive difficulties, headaches, sleep problems and other neurological symptoms.
Metabolic and Cellular Changes
Changes in metabolism, energy production and cellular function are also being investigated as potential contributors to Long COVID.
These findings may help researchers understand why some individuals experience persistent fatigue, exercise intolerance or other systemic symptoms. However, these mechanisms remain active areas of research and should not be interpreted as established causes in every patient.
Viral Persistence
One important research area concerns whether SARS-CoV-2 or viral components can persist in certain tissues after the initial infection.
Evidence of possible viral persistence has been reported, and researchers are investigating whether persistent viral material could contribute to immune or inflammatory responses in some individuals. However, the presence of viral material does not by itself establish that it is responsible for a person's Long COVID symptoms.
3. Emerging Research Hypotheses
Some mechanisms have attracted significant scientific interest but remain under active investigation.
Microclots and Microthrombi
Researchers are investigating abnormalities involving blood clotting, microvascular function and small blood clots in people with Long COVID.
These findings are an important area of research, but the relationship between these abnormalities and individual Long COVID symptoms, as well as their diagnostic and therapeutic significance, remains under investigation.
Spike Protein Persistence
Some studies have investigated whether SARS-CoV-2 spike protein or related viral components can remain detectable in tissues or circulation after acute infection.
This has led to hypotheses about possible relationships between persistent viral components, immune responses and Long COVID. However, current evidence does not establish that persistent spike protein is the universal cause of Long COVID or that removing spike protein is a proven treatment for the condition.
Other Molecular Pathways
Researchers are also studying changes involving cellular signalling, the microbiome, autoimmunity, neurological pathways and other molecular processes.
These areas may eventually help explain why Long COVID presents differently between individuals, but many of these mechanisms remain hypotheses rather than established explanations.
4. What the Evidence Does and Does Not Establish
Long COVID research is evolving, and individual findings need to be interpreted in the context of study design, population, sample size and other limitations.
Importantly:
A major review in Nature Reviews Microbiology describes multiple overlapping hypotheses for Long COVID, including viral persistence, immune dysregulation, microbiome changes, autoimmunity, microvascular clotting and endothelial dysfunction, while emphasising that mechanistic studies remain at an early stage and many questions remain unanswered.
An Important Distinction: Evidence vs. Hypothesis
Long COVID research should therefore be viewed as a developing body of evidence rather than a single established mechanism.
What is well established: Long COVID can involve persistent, recurring or newly developed symptoms and can affect multiple organ systems.
What researchers are investigating: Immune dysregulation, inflammation, vascular dysfunction, autonomic dysfunction, metabolic changes and possible viral persistence.
What remains uncertain: How these mechanisms interact, which mechanisms are responsible for particular symptoms, and whether findings identified in research studies are causal or consequential.
This distinction is important when interpreting scientific studies and evaluating claims about potential Long COVID treatments or interventions.
Researchers are looking into a number of potential causes for chronic illness. The evidence is still being assessed, and these theories may overlap.
According to certain research, inflammation could continue beyond the initial infection. Researchers are looking into if long-term inflammation may be a factor in the neurological symptoms, exhaustion, and other issues that Long COVID patients describe.
Another key field of research in Long COVID is that of immune dysregulation. Changes in inflammatory signalling, antibodies, and immune cells are being studied. Some studies suggest that persistent symptoms may be the result of an immune response following infection.
Researchers looked at changes in small blood vessel function and coagulation of blood in individuals with Long COVID. Although coagulation and microcirculation abnormalities have been reported in studies, the function of microclots is yet unknown. Before these results can be regarded as a proven cause of Long COVID, additional research is required.
Research is also being done on viral persistence. Researchers are examining whether viral proteins or genetic material from SARS-CoV-2 can persist in specific tissues following an acute infection. Scientists are still looking into the importance of viral material because its existence does not necessarily indicate that it produces symptoms.
Researchers are looking into if the SARS-CoV-2 spike protein may be detected after infection and whether this could have an impact on inflammatory or immunological processes. The evidence is still limited and inconsistent, though. Long COVID has not been proven to be generally caused by persistent spike protein.
One area of ongoing Long COVID research involves the persistence of SARS-CoV-2 or its components after the initial infection. Researchers are investigating whether viral RNA, viral proteins or other viral material may remain detectable in certain tissues or in the circulation after the acute phase of COVID-19.
Spike protein has received particular scientific attention because it is an important structural protein of SARS-CoV-2 and plays a central role in viral entry into host cells. However, detecting spike protein after infection does not by itself establish that it causes Long COVID.
Current research considers viral persistence as one of several possible mechanisms that may contribute to post-acute sequelae of SARS-CoV-2 infection (PASC). The World Health Organization's information on post-COVID-19 condition notes that researchers have found evidence involving viral persistence, altered immune responses and autoimmunity, and micro-thrombosis, while emphasising that research into the causes of the condition is ongoing.
The SARS-CoV-2 spike protein is a protein located on the surface of the virus. It helps the virus interact with and enter susceptible host cells.
Because of its role in viral infection and the immune response, spike protein has been extensively studied since the beginning of the COVID-19 pandemic.
In Long COVID research, scientists are investigating whether viral proteins or other components of SARS-CoV-2 may remain detectable after the initial infection and whether this could have biological consequences.
Some studies have reported the detection of SARS-CoV-2 proteins, including spike or S1 protein, in blood or tissues after the acute phase of infection. Researchers are investigating whether these findings may indicate persistence of viral material or possible viral reservoirs in some individuals with PASC.
A review published in Nature Immunology examined evidence for a possible SARS-CoV-2 reservoir in people with PASC. The authors describe studies reporting SARS-CoV-2 RNA or proteins in tissues and plasma after acute infection and discuss possible relationships with immune, coagulation, microbiome and neurological abnormalities. Importantly, the review identifies the role of such reservoirs as an area requiring further research rather than an established explanation for every case of Long COVID. Read the Nature Immunology review on SARS-CoV-2 reservoirs in PASC.
A more recent review in Nature Reviews Microbiology also examines SARS-CoV-2 persistence and its possible relationship with post-COVID conditions, while highlighting the need for further research into the biological and clinical significance of viral persistence. Read the Nature Reviews Microbiology review on SARS-CoV-2 persistence.
Research into spike protein and Long COVID includes several related questions.
Scientists are investigating whether SARS-CoV-2 proteins such as spike, S1 or nucleocapsid can remain detectable in some people after acute infection.
The Nature Immunology review discusses studies in which SARS-CoV-2 proteins were detected in subsets of people with PASC months after infection. However, viral proteins have also been detected in some people who report recovery. Therefore, detection alone does not establish that the protein is responsible for Long COVID symptoms.
Another area of research is whether SARS-CoV-2 can persist in specific tissues or anatomical sites after the initial infection.
Researchers have reported SARS-CoV-2 RNA and/or protein in different tissues in some studies. These findings have led to the hypothesis that persistent viral reservoirs could contribute to ongoing immune or inflammatory processes.
However, important questions remain, including whether detected viral material is actively replicating, whether it remains biologically active and whether its presence directly contributes to symptoms.
Researchers are also studying whether persistent viral components could interact with the immune system.
Possible areas of investigation include:
Because SARS-CoV-2 infection can affect the vascular system, researchers are investigating possible relationships between persistent viral components, endothelial dysfunction, coagulation abnormalities and microvascular changes.
The Nature Immunology review discusses possible relationships between SARS-CoV-2 reservoirs and coagulation or vascular abnormalities in PASC. These findings are relevant to ongoing research, but the exact biological relationships and their clinical significance remain under investigation.
Some research has investigated whether persistent viral material could contribute to neurological or systemic changes.
Potential mechanisms under investigation include interactions between viral components, immune responses, vascular function and nervous-system signalling.
Long COVID can affect multiple organ systems, and current evidence does not support attributing all Long COVID symptoms to one biological mechanism. WHO notes that post-COVID condition can affect systems including the heart and blood vessels, lungs, nervous system, gut and endocrine system.
Current research provides evidence that SARS-CoV-2 RNA and proteins can sometimes be detected after acute infection and that viral persistence may be relevant to some cases of PASC.
However, several important questions remain unanswered.
Research has not established that:
These distinctions are important because detecting a biological marker and demonstrating that the marker causes a disease are two different scientific questions.
An important principle when interpreting Long COVID research is the difference between association and causation.
If a study finds that spike protein or another viral component is present more frequently in a group of people with PASC, this may provide evidence for an association. It does not automatically demonstrate that the protein caused their symptoms.
Researchers must also determine:
These questions require carefully designed clinical, laboratory and longitudinal studies.
The possibility of SARS-CoV-2 persistence provides researchers with an important area for further investigation. If persistent viral material contributes to disease in a subset of people, understanding where it persists, how the immune system responds to it and whether it can be safely targeted could eventually inform future diagnostic or therapeutic approaches.
Current research, however, does not establish viral persistence as the single explanation for Long COVID. A major review in Nature Reviews Microbiology describes several potentially overlapping mechanisms, including viral persistence, immune dysregulation, microbiome changes, autoimmunity, microvascular abnormalities and dysfunctional neurological signalling. The authors also note that mechanistic studies remain at an early stage and that many questions remain unanswered. Read the full review: Long COVID: Major Findings, Mechanisms and Recommendations.
Published studies have reported evidence of SARS-CoV-2 proteins or RNA persisting in some individuals after acute infection, but the significance of these findings remains under investigation. The presence of viral material does not by itself establish causation, and current evidence does not demonstrate that removing spike protein is a proven treatment or cure for Long COVID.
Readers should therefore distinguish between published findings, proposed biological mechanisms and hypotheses that require further clinical validation.
Long COVID research has expanded considerably, but scientists are still working to understand why some people develop persistent symptoms after SARS-CoV-2 infection and why symptoms can differ substantially between individuals.
Current evidence supports several important observations about Long COVID, while other findings remain areas of active investigation. The CDC currently describes Long COVID as an infection-associated chronic condition that can affect one or more organ systems and can follow a continuous, relapsing and remitting, or progressive course. (CDC Clinical Overview of Long COVID)
Research has also identified several possible biological mechanisms, including immune changes, inflammation, vascular abnormalities and possible persistence of viral material. However, these mechanisms should not be interpreted as a single proven cause of Long COVID. (WHO: Post COVID-19 Condition)
| Research question | Current evidence |
|---|---|
| Can COVID-19 lead to persistent symptoms? |
Yes. Some people develop symptoms that persist, recur or appear after the initial infection. |
| Can Long COVID affect multiple organ systems? |
Yes. Long COVID can affect one or more body systems, including the cardiovascular, respiratory, neurological and gastrointestinal systems. |
| Is inflammation being investigated? |
Yes. Inflammatory pathways and persistent immune activation are active areas of research. |
| Are immune changes being studied? |
Yes. Studies have reported changes in immune-cell activity, antibodies and other immune responses in some people with Long COVID. |
| Are vascular and microclot abnormalities being studied? |
Yes. Researchers are investigating endothelial dysfunction, coagulation abnormalities and microvascular changes, including microclots. |
| Is viral persistence being investigated? |
Yes. SARS-CoV-2 RNA and proteins have been detected in some tissues and body compartments after acute infection, and researchers are investigating their possible significance. |
| Is spike protein persistence being investigated? |
Yes. Some studies have reported persistent SARS-CoV-2 spike or related viral proteins in subsets of people, making this an active area of research. |
| Is persistent spike protein proven to cause Long COVID? |
No. Current evidence does not establish persistent spike protein as the universal or primary cause of Long COVID. |
| Is there one proven treatment for all Long COVID patients? |
No. Long COVID is heterogeneous, and there is currently no single treatment proven to work for everyone. Clinical care generally focuses on evaluating and managing individual symptoms and conditions. |
One of the clearest findings from Long COVID research is that SARS-CoV-2 infection can be followed by persistent or recurring health problems.
The condition can involve multiple organ systems, and symptoms may include fatigue, post-exertional malaise, cognitive difficulties, sleep problems, breathlessness, pain, cardiovascular symptoms and autonomic symptoms. The CDC defines Long COVID as a condition that can affect one or more organ systems and may be continuous, relapsing and remitting, or progressive. (CDC Clinical Overview)
The World Health Organization also recognises post-COVID-19 condition as a condition that can affect multiple body systems and reports symptoms such as fatigue, breathlessness, muscle or joint pain and impaired sleep among commonly reported manifestations. (WHO: Post COVID-19 Condition)
Although the existence and clinical impact of Long COVID are well documented, the biological mechanisms behind the condition are not completely understood.
Researchers are investigating several potentially overlapping mechanisms, including:
A major review published in Nature Reviews Microbiology describes multiple hypotheses for Long COVID, including persistent SARS-CoV-2 reservoirs, immune dysregulation, autoimmunity, microbiome changes, microvascular blood clotting and endothelial dysfunction, while noting that mechanistic research remains at an early stage and many questions remain unanswered. (Nature Reviews Microbiology)
Viral persistence is one of the areas receiving significant research attention.
Studies have reported SARS-CoV-2 RNA or proteins in different body compartments after the acute infection. Researchers are investigating whether these findings represent persistent viral reservoirs or viral components and whether they contribute to immune, inflammatory or other biological changes associated with Long COVID.
Recent research reviews continue to describe this as an unresolved question. A 2025 review in Nature Reviews Microbiology notes that SARS-CoV-2 RNA and proteins have been detected in different body compartments after infection, while also stating that whether Long COVID is caused by persistent replicating SARS-CoV-2 remains controversial. (Nature Reviews Microbiology)
Spike protein is therefore an important research topic, but it should not be presented as an established universal cause of Long COVID.
An important principle when interpreting Long COVID research is the difference between association and causation.
For example, if a study finds that a particular protein, immune marker or vascular abnormality is more common in people with Long COVID, this can provide evidence of an association. It does not automatically prove that the finding caused the person's symptoms
Researchers need additional evidence to establish causation, including reproducibility, appropriate control groups, biological plausibility, longitudinal evidence and, where appropriate, evidence that changing the suspected mechanism changes clinical outcomes.
This distinction is particularly important when interpreting research into spike protein persistence, microclots, inflammation and immune changes.
The current research picture is best understood as a combination of established clinical observations and developing biological hypotheses.
SARS-CoV-2 infection can be followed by persistent, recurring or newly developed symptoms, and Long COVID can affect multiple organ systems.
Scientists have identified immune, inflammatory, vascular, neurological, metabolic and other biological changes in some people with Long COVID.
Researchers are still determining how these changes interact, which mechanisms contribute to specific symptoms, whether different Long COVID subtypes involve different mechanisms, and which findings are causes, consequences or associations.
There is currently no scientific basis for concluding that one mechanism, such as persistent spike protein, explains every case of Long COVID or that eliminating a particular biological component is a universally proven treatment.
Long COVID research is a rapidly developing field. New studies continue to investigate potential biomarkers, disease mechanisms, diagnostic approaches, prevention strategies and treatments.
As the evidence develops, research findings should be interpreted according to their study design, population, limitations and ability to demonstrate causation.
For this reason, the Spike Detox Research Library focuses on published research and distinguishes between established clinical observations, biological findings, emerging hypotheses and areas where evidence remains uncertain.
Long COVID research spans clinical observations, immune mechanisms, viral persistence, vascular changes and other potential biological pathways. The studies below have been selected to provide a balanced overview of important research areas. They include reviews and primary research studies and should be interpreted according to their study design, population and limitations. Where mechanisms remain uncertain, the research is presented as an area of investigation rather than established causation.
A meta-narrative review examining the prevalence, clinical manifestations, proposed pathophysiological mechanisms and management of post-acute sequelae of COVID-19 (PASC).
A major review examining the clinical features and proposed mechanisms of Long COVID, including viral persistence, immune dysregulation, autoimmunity, microbiome changes, endothelial dysfunction and microvascular abnormalities.
A review examining evidence for SARS-CoV-2 persistence or viral reactivation in PASC. The authors discuss reports of SARS-CoV-2 RNA or antigens in some organs and highlight the unresolved questions surrounding their relationship with immune responses and Long COVID symptoms.
A 2024 review examining potential immune mechanisms underlying Long COVID, including altered immune responses, immune-cell changes, autoimmunity, inflammatory pathways, viral persistence and microbiome-related mechanisms.
A mixed-method systematic review examining evidence for different biological mechanisms proposed in Long COVID. The review included 19 systematic reviews and 46 primary studies and found varying levels of evidence across proposed mechanisms.
A recent review synthesising research on potential mechanisms underlying Long COVID, including viral persistence, immune dysregulation, systemic inflammation, endothelial dysfunction and metabolic changes.
This publication examines the evidence surrounding fibrinaloid microclots in Long COVID and discusses their proposed relationships with vascular abnormalities, inflammation, immune dysfunction and other biological processes.
A prospective observational study examining the relationship between COVID-19 vaccination and post-acute sequelae among patients with systemic autoimmune rheumatic diseases.
A number of path ways being studied in Long COVID are directly related to inflammation.
Immune responses are regulated by cytokines. Researchers are investigating if certain individuals with Long COVID may have extended inflammation due to changes in cytokine activity.
Todetermineif abnormal immune signalling continues after infection, scientists are studying immune-cell function, antibody responses, and other immunological pathways.
Blood vessels have endothelial cells lining them. Changes in endothelial function may have an impact on circulation and be a factor in some symptoms associated with the heart, lungs, or exercise.
Additionallyunder research are changes in cellular metabolism and oxidative stress. Researchers are investigating the possibility that these mechanisms could combine with inflammation and lead to decreased exercise tolerance or tiredness.
Researchers are investigating several possible mechanisms behind Long COVID, including persistent inflammation, immune system changes, and the possible persistence of viral material. Spike protein has also been studied as part of these theories, but its role in Long COVID is not yet fully established.
Some research has proposed that viral proteins or remnants may persist in certain tissues after infection and contribute to ongoing biological changes. These hypotheses remain under investigation and do not establish that spike protein is the cause of Long COVID.
Studies have reported findings involving immune responses, inflammation, and viral components in some people with Long COVID. However, results vary between studies, and the presence of viral material does not necessarily prove that it causes persistent symptoms.
Researchers continue to examine potential mechanisms of Long COVID, including viral persistence, immune dysregulation, inflammation, and vascular changes. Clinical studies are also evaluating possible approaches to symptom management and recovery.
Long COVID is a complex and varied condition, making research challenging. Differences in study design, patient populations, definitions, and testing methods can produce inconsistent findings. More large, well-controlled studies are needed to clarify the role of spike protein and other proposed mechanisms.
Browse more scientific studies and review articles.
SN Comprehensive Clinical Medicine
Annals of the Rheumatic Diseases
Nature Reviews Microbiology
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