I have been writing a blog series about the post-acute sequelae of COVID-19. My plans were to cover the many systems and organs of the body and what we have learned as to the Long-term health consequences some people may suffer following infection and why. I started with the nervous system.
However, while I have been working on this, a fabulous review of Long COVID was published and it does much of what I intended to provide for you. Therefore, I am going to use this blog piece to wrap up my blog series by highlighting some of the information for you that is contained within this report.
- Long COVID (sometimes referred to as ‘post-acute sequelae of COVID-19’ or PASC) is a multisystemic condition comprising often severe symptoms that follow a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but can occur following even mild COVID-19.
- At least 65 million individuals around the world have Long COVID, based on a conservative estimated incidence of 10% of infected people and more than 651 million documented COVID-19 cases worldwide; the number is likely much higher due to many undocumented cases.
- The incidence is estimated at 10–30% of non-hospitalized cases, 50–70% of hospitalized cases and 10–12% of vaccinated cases. Thus, vaccination is important in reducing the chances of developing Long COVID and avoiding severe COVID-19 (which increases the chances for Long COVID), but even those who are vaccinated who develop breakthrough infections can develop Long COVID.
- Long COVID is associated with all ages and acute disease severities (mild, moderate, and severe) with the highest percentage of diagnoses between the ages of 36 and 50 years, and most Long COVID cases are in non-hospitalized patients with a mild acute illness.
- Hundreds of laboratory and clinical findings have been documented, with many patients experiencing dozens of symptoms across multiple organ systems. Long COVID encompasses multiple adverse outcomes, with common new-onset conditions including cardiovascular, thrombotic and cerebrovascular disease, type 2 diabetes, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia, especially postural orthostatic tachycardia syndrome (POTS).
- Symptoms can last for years, and cases of new-onset ME/CFS and dysautonomia are expected to be lifelong.
- There are currently no proven, effective treatments, though this is an area of active research.
- There are likely multiple, potentially overlapping, causes of Long COVID. Several hypotheses for its pathogenesis have been suggested, including persisting reservoirs of SARS-CoV-2 in tissues; immune dysregulation with or without reactivation of underlying pathogens, including herpesviruses such as Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) among others; impacts of SARS-CoV-2 on the microbiota, including the virome; autoimmunity and priming of the immune system from molecular mimicry; microvascular blood clotting with endothelial dysfunction; and dysfunctional signaling in the brainstem and/or vagus nerve.
- Risk factors potentially include female sex, type 2 diabetes, EBV reactivation, the presence of specific autoantibodies, connective tissue disorders, attention deficit hyperactivity disorder, chronic urticaria and allergic rhinitis, although a third of people with Long COVID have no identified pre-existing conditions.
- Higher prevalence has been reported among persons with Hispanic or Latino heritage.
- Socio-economic risk factors include lower income and an inability to adequately rest in the early weeks after developing COVID-19. This may be an important finding. I often hear from those with COVID, especially young, active adults, that after being sick for so long, they are anxious to resume their normal activities and exercise. However, we are increasingly seeing evidence that suggests overdoing it and not getting enough rest in the weeks following infection may pose increased risk for developing Long COVID.
- Long COVID impacts children of all ages. One study found that fatigue, headache, dizziness, shortness of breath, chest pain, abnormal smells, abnormal sense of taste, reduced appetite, concentration difficulties, memory issues, mental exhaustion, physical exhaustion and sleep issues were between 2 and 36 times more likely in individuals with Long COVID aged 15–19 years compared with controls of the same age. This has been another surprising feature in many patients I have spoken with following their infection. Many describe that their sleep cycle is disrupted (e.g., perhaps their normal bedtime was 10 p.m., but now they can’t fall asleep until 2 a.m.) or that they have days on end that they can’t sleep at all, followed by days in which all they do is sleep.
- Similarly to adults with Long COVID, children with long COVID experience fatigue, post-exertional exhaustion or feeling unwell, cognitive dysfunction, memory loss, headaches, orthostatic intolerance, sleep difficulty and shortness of breath.
- Although rare, children who had COVID-19 have increased risks of liver injury, acute pulmonary embolism, myocarditis and cardiomyopathy, venous thromboembolic events, acute and unspecified kidneyl failure, and type 1 diabetes.
- Infants born to women who had COVID-19 during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first year after delivery.
- Children experiencing Long COVID have hypometabolism in the brain similar to the patterns found in adults with Long COVID.
- Long-term pulmonary dysfunction is found in children with Long COVID and those who have recovered from COVID-19.
- Difficulties in studying Long COVID in children include that many children were never tested or have a documented + test, and children are much less likely to seroconvert (develop detectable antibodies in the blood) and, if they develop antibodies, are more likely to have a waning response months after infection compared with adults.
- Studies looking at immune dysregulation in individuals with Long COVID who had mild acute COVID-19 have found T cell alterations, including exhausted T cells, reduced CD4+ and CD8+ effector memory cell numbers and elevated PD1 expression on central memory cells, persisting for at least 13 months. Studies have also reported highly activated innate immune cells, a lack of naive T and B cells and elevated expression of type I and type III interferons (interferon-β (IFNβ) and IFNλ1), persisting for at least 8 months. A comprehensive study comparing patients with Long COVID with uninfected individuals and infected individuals without Long COVID found increases in the numbers of non-classical monocytes, activated B cells, double-negative B cells, and IL-4- and IL-6-secreting CD4+ T cells and decreases in the numbers of conventional dendritic cells and exhausted T cells and low cortisol levels in individuals with Long COVID at a median of 14 months after infection.
- The expansion of cytotoxic T cells has been found to be associated with the gastrointestinal presentation of Long COVID. Additional studies have found elevated levels of cytokines, particularly IL-1β, IL-6, TNF and IP10, and a recent preprint has reported persistent elevation of the level of CCL11, which is associated with cognitive dysfunction.
- The role of autoantibodies in Long COVID remains unclear. Multiple studies have found elevated levels of autoantibodies in Long COVID, including autoantibodies to the ACE-2 receptor, β2-adrenoceptor, muscarinic M2 receptor, angiotensin II AT1 receptor and the angiotensin 1–7 MAS receptor. High levels of other autoantibodies have been found in some patients with COVID-19 more generally, including autoantibodies that target the tissue (such as connective tissue, extracellular matrix components, vascular endothelium, coagulation factors and platelets), organ systems (including the lung, central nervous system, skin and gastrointestinal tract), immunomodulatory proteins (cytokines, chemokines, complement components and cell-surface proteins). A major comprehensive study, however, did not find autoantibodies to be a major component of Long COVID. High levels of autoantibodies in Long COVID have been found to be inversely correlated with protective COVID-19 antibodies, suggesting that patients with high autoantibody levels may be more likely to have breakthrough infections.
- Reactivated viruses, including EBV and HHV-6, have been found in patients with Long COVID (and have been identified in ME/CFS), and lead to mitochondrial fragmentation and severely affect energy metabolism. EBV reactivation has been associated with fatigue and neurocognitive dysfunction in patients with Long COVID.
- Several studies have shown low or no SARS-CoV-2 antibody production and other insufficient immune responses in the acute stage of COVID-19 to be predictive of Long COVID at 6–7 months, in both hospitalized patients and non-hospitalized patients.
- One study has reported low or absent CD4+ T cell and CD8+ T cell responses in patients with severe Long COVID, and a separate study found lower levels of CD8+ T cells expressing CD107a and a decline in nucleocapsid-specific interferon-γ-producing CD8+ T cells in patients with Long COVID compared with infected controls without Long COVID.
- SARS-CoV-2 viral rebound in the gut, possibly resulting from viral persistence, has been associated with lower levels and slower production of receptor-binding domain IgA and IgG antibodies.
- One hypothesis for why women are more likely to develop Long COVID than men is the fact that women are less likely to seroconvert, more likely to sero-revert (initially test + for antibodies in the blood, but later test -) and have lower antibody levels overall, including more antibody waning after vaccination.
- Viral persistence is also thought to be a possible driver of Long COVID symptoms; viral proteins and/or RNA has been found in the reproductive system, cardiovascular system, brain, muscles, eyes, lymph nodes, appendix, breast tissue, hepatic tissue, lung tissue, plasma, stool and urine.
- In one study, circulating SARS-CoV-2 spike antigen was found in 60% of a cohort of 37 patients with Long COVID up to 12 months after diagnosis compared with 0% of 26 SARS-CoV-2-infected individuals without PASC, likely implying a reservoir of active virus or components of the virus. Indeed, multiple reports following gastrointestinal biopsies have indicated the presence of virus, suggestive of a persistent reservoir in some patients.
- The damage that has been demonstrated across diverse tissues has predominantly been attributed to immune-mediated response and inflammation, rather than direct infection of cells by the virus. Circulatory system disruption includes endothelial dysfunction and subsequent downstream effects, and increased risks of deep vein thrombosis, pulmonary embolism and bleeding events.
- Micro-clots detected in both acute COVID-19 and Long COVID contribute to thrombosis.
- Long-term changes to the size and stiffness of blood cells have also been found in Long COVID, with the potential to affect oxygen delivery.
- A long-lasting reduction in vascular density, specifically affecting small capillaries, was found in patients with Long COVID compared with controls, 18 months after infection.
- A study finding elevated levels of vascular transformation blood biomarkers in Long COVID also found that the angiogenesis markers ANG1 and P-selectin both had high sensitivity and specificity for predicting Long COVID status.
- A large study found significantly increased risk of a variety of cardiovascular diseases, including heart failure, dysrhythmias and stroke, independent of the severity of initial COVID-19 presentation 1 year after SARS-CoV-2 infection.
- Cardiac MRI studies revealed cardiac impairment in 78% of 100 individuals who had a prior COVID-19 episode (investigated an average of 71 days after infection) and in 58% of participants with Long COVID (studied 12 months after infection).
- One prospective study of low-risk individuals, looking at the heart, lungs, liver, kidneys, pancreas and spleen, noted that 70% of 201 patients had damage to at least one organ and 29% had multi-organ damage.
- In a 1-year follow-up study with 536 participants, the study authors found that 59% had single-organ damage and 27% multi-organ damage.
- Neurological and cognitive symptoms are a major feature of Long COVID, including sensorimotor symptoms, memory loss, cognitive impairment, paresthesia, dizziness and balance issues, sensitivity to light and noise, loss of (or phantom) smell or taste, and autonomic dysfunction, often impacting activities of daily living.
- Audio-vestibular manifestations of Long COVID include tinnitus, hearing loss and vertigo.
- Cognitive impairments in Long COVID can be debilitating, at the same magnitude as intoxication at the UK drink driving limit or 10 years of cognitive ageing, and may increase over time, with one study finding occurrence in 16% of patients at 2 months after infection and 26% of patients at 12 months after infection.
- Possible mechanisms for neuro-pathologies in Long COVID include neuroinflammation, damage to blood vessels by coagulopathy and endothelial dysfunction, and injury to neurons. Studies have found Alzheimer disease-like signaling in patients with Long COVID, peptides that self-assemble into amyloid clumps which are toxic to neurons, widespread neuroinflammation, brain and brainstem hypometabolism correlated with specific symptoms and abnormal cerebrospinal fluid findings in non-hospitalized individuals with Long COVID along with an association between younger age and a delayed onset of neurological symptoms.
- Multilineage cellular dysregulation and myelin loss were reported in a recent preprint in patients with Long COVID who had mild infections, with microglial reactivity similar to that seen in chemotherapy, known as ‘chemo-brain’.
- A study of brain imaging and cognitive testing revealed a reduction in grey matter thickness in the orbitofrontal cortex and para-hippocampal gyrus (markers of tissue damage in areas connected to the primary olfactory cortex), an overall reduction in brain size and greater cognitive decline in patients after COVID-19 without Long COVID compared with controls, even in non-hospitalized patients.
- In the eyes, corneal small nerve fiber loss and increased dendritic cell density have been found in Long COVID, as well as abnormal pupillary light responses and impaired retinal microcirculation. Retinal hemorrhages, cotton wool spots and retinal vein occlusion have all been noted in patients with Long COVID.
- Low blood cortisol levels in patients with Long COVID as compared with control individuals have been detected more than 1 year into symptom duration. Low cortisol production by the adrenal gland should be compensated by an increase in adrenocorticotropic hormone (ACTH) production by the pituitary gland, but this was not the case, supporting hypothalamus–pituitary–adrenal axis dysfunction.
- Approximately half of patients with Long COVID meet criteria for ME/CFS. Up to 75% of people with ME/CFS cannot work full-time and 25% have severe ME/CFS, which often means they are bed-bound, have extreme sensitivity to sensory input and are dependent on others for care.
- A study of orthostatic stress in individuals with Long COVID and individuals with ME/CFS found similar hemodynamic, symptomatic and cognitive abnormalities in both groups compared with healthy individuals.
- Consistent abnormal findings in ME/CFS include diminished natural killer cell function, T cell exhaustion and other T cell abnormalities, mitochondrial dysfunction, and vascular and endothelial abnormalities, including deformed red blood cells and reduced blood volume.
- Patients with Long COVID have mitochondrial dysfunction including loss of mitochondrial membrane potential and possible dysfunctional mitochondrial metabolism, altered fatty acid metabolism and dysfunctional mitochondrion-dependent lipid catabolism consistent with mitochondrial dysfunction in exercise intolerance, redox imbalance, and exercise intolerance and impaired oxygen extraction.
- Dysautonomia, particularly POTS (postural orthostatic tachycardia syndrome), is commonly comorbid with ME/CFS.
- POTS is associated with G protein-coupled adrenergic receptor and muscarinic acetylcholine receptor autoantibodies, platelet storage pool deficiency, small fiber neuropathy and other neuro-pathologies. Both POTS and small fiber neuropathy are commonly found in Long COVID, with one study finding POTS in 67% of a cohort with Long COVID.
- Mast cell activation syndrome is also commonly comorbid with ME/CFS. The number and severity of mast cell activation syndrome symptoms substantially increased in patients with Long COVID compared with pre-COVID and control individuals, with histamine receptor antagonists resulting in improvements in the majority of patients.
- Shortness of breath and cough are the most common respiratory symptoms, and persisted for at least 7 months in 40% and 20% of patients with Long COVID, respectively.
- Several imaging studies that included non-hospitalized individuals with Long COVID demonstrated pulmonary abnormalities including in air trapping and lung perfusion.
- An immunological and proteomic study of patients 3–6 months after infection indicated apoptosis and epithelial damage in the airway but not in blood samples.
- Long COVID gastrointestinal symptoms include nausea, abdominal pain, loss of appetite, heartburn and constipation. The gut microbiota composition is significantly altered in patients with COVID-19, and gut microbiota dysbiosis is also a key component of ME/CFS.
- Gut dysbiosis lasting at least 14 months is reported in patients with PASC, and low levels of butyrate-producing bacteria are strongly correlated with Long COVID at 6 months.
- One study indicated viral persistence in the feces of 12.7% of participants 4 months after diagnosis of COVID-19 and in 3.8% of participants at 7 months after diagnosis.
- Most patients with Long COVID symptoms and inflammatory bowel disease 7 months after infection had antigen persistence in the gut mucosa.
- Several neurocognitive symptoms worsen over time and tend to persist longer, whereas gastrointestinal and respiratory symptoms are more likely to resolve.
- Pain in joints, bones, ears, neck and back are more common at 1 year than at 2 months, as is paresthesia (abnormal sensations), hair loss, blurry vision and swelling of the legs, hands and feet.
- Parosmia has an average onset of 3 months after the initial infection; unlike other neurocognitive symptoms, it often decreases over time.
- Few people with Long COVID demonstrate full recovery, with one study finding that 85% of patients who had symptoms 2 months after the initial infection reported symptoms 1 year after symptom onset. Future prognosis is uncertain, although diagnoses of ME/CFS and dysautonomia are generally lifelong.
As I wrap up this series on the post-acute sequelae of COVID-19, I am now going to shift to covering specific new insights on COVID-19 in more frequent posts, as well as returning to covering a broad range of public health, health policy, health law and health reform issues.
11 thoughts on “Long COVID”
Thank you for this information but as a person with Long Haul Covid it is hard to read and digest. I am wondering if you could put together a summary statement for folks like me.
I am so sorry to learn that you developed Long COVID. Yes, it is incredibly complicated. You may want to read some of the blog posts in the earlier part of this series where I took pains to try to make sure people could understand the concepts and terms. I will also try to write some more blog posts in the future that try to break down some of this into shorter and more understandable pieces.
Thanks for following my blog.
I appreciate your quick response, not expecting that at all. I am always interested in new information, it is just so hard for me to digest and make sense of it. Any Dummying down you can do is great for me.
Don’t worry, you are not alone. Some of it is so complicated, I have to get super-specialists to dumb it down for me! And, as I said, I am going to shift to more frequent, but also more focused blog pieces in the future and that will allow me to work more to make things clearer to everyone.
Dr David, thank you for all your research and helping us understand the severity of this virus. Scary, but at least we have some guides and encouraging progress and hopefully help us all to be a little more open-minded in following the sciences as it progresses. My wife is in the process of being evaluated once again for pulmonary issues. This summary of yours will be given to her doctor and discussed during the evaluation sessions. Thank you. DuWayne
Thank you, Dr. Pate. Your effort and diligence in keeping us informed are greatly appreciated. Many are experiencing LongCovid, but are unaware or remain silent in fear of being medically labeled by employers and insurance companies. Keep educating the public. Let’s get the word out.
You are so right. We have to be sure to educate physicians so that patient’s concerns, signs and symptoms are taken seriously. We have to make sure that more research is done and funded to make sure that we not only understand who gets Long COVID, why they get Long COVID and what can be done to treat it, but though SARS-CoV-2 appears to be a worse offender than most viruses, it is only one of many viruses that cause a host of post-viral syndromes. Learning about Long COVID, may help us to treat others and I hope, in the future, to be able to identify those who may be at increased risk for post-viral syndromes so that we can take steps to ensure preventative measures are taken and prompt treatment can be initiated if infected. We also need to make sure that patients know how to access physicians specifically focused on and experienced in treating these patients who have the most disabling symptoms and conditions so that they can be properly diagnosed, treated or enrolled in clinical trials.
Thanks for following my blog, and I continue to keep those with Long COVID in my prayers.
Dr Pate, thank you for continuing to educate the public with the science and facts. You have been a huge help in guiding us through this pandemic.
Knowing that our school districts are doing zero mitigation to stop any spread to protect our children, how would you navigate having a school aged child and the choice of in-person or virtual? It seems as though in-person school brings the inevitable risk of contracting Covid and then all the perils that may come with that, either for the child and/or the entire family.
We have been doing virtual since the start of the pandemic. Every year we consider going in-person, but we know the surge will come and we don’t want to play with those risks. We already have a couple autoimmune diseases within our family and we assume Covid would not be a good thing to add on top of it.
I know you have said before to get in touch with the schools and ask what they do or will do to help, but we all know the answer by now. Covid is over. Or just use hand sanitizer. I already know my kids would be the only ones with masks on! Or one of few…
Any advice you can share on if in-person is a safe choice for the long term physical health for children? Mentally and emotionally, my kids have been resilient with the change. They have found other great ways to socialize and stay healthy. I know everyone wants to go back like it’s 2019, but no matter how hard we pretend like this isn’t happening, Covid just keeps slapping us in the face!
Thank you, Sarah, and thank you for you very thoughtful question. This is something that I have given a great amount of thought to, because I fear that years from now we may detect long-term health consequences for some children who have been repeatedly infected.
Ultimately, I think the debate has to be about thinking about air in schools much like we think about clean water in our homes and public buildings to prevent disease. We all accept that clean water is important to prevent us from various communicable diseases. We need to think about improving air ventilation, circulation, filtration and treatment as the way to prevent children (and, in turn, their families) from various communicable diseases (i.e., not just focusing on COVID, which too many are too complacent about) like influenza, RSV, measles, rhinoviruses, human metapneumovirus, parainfluenza virus, etc.).
The advantage should be that we can make a strong case. First, we avoid making this just about COVID, which as you state, many think is no longer a problem. Second, we avoid the irreconcilable differences and emotional responses parents have about masks. Third, we can make the financial case for schools – most funds to schools are tied to student attendance. We can ask schools to just look at respiratory season absences they have historically experienced and quantify the dollars lost by student absences. Even if schools remain hesitant, then lets ask school districts to conduct an experiment. Make the changes at some of their schools and then compare student absences. If costs are prohibitive to make changes to their HVAC systems, then mobilize the school parent-teacher organizations to raise funds and buy the much less costly materials to make Corsi-Rosenthal boxes. Parents and students can assemble them for each room. And, finally, make the case to parents. How many parents face a challenge with how to care for a sick child and also meeting their requirements for work. My guess is that most parents would welcome simple steps that would reduce the number of days their child would miss school.
Thanks for your comment and thanks for following my blog!
Appreciate your response! I know you made many efforts to enlighten the districts on how we can implement solutions and it’s unfortunate it has become such a black and white issue of masks or no masks. We wish there could be a more united response in making our schools more universally safe for students and staff. I know I cannot make a change, but I did voice the discrimination this puts on many families who live with invisible diseases and/or any underlying health concerns. For any one who is immune aware, putting your health through constant illness isn’t a smart move. We always remind our kids, we can always keep learning, we can always make new friends, but you can’t do either if your quality of life is taken from you. Sadly, it seems as though society doesn’t understand the fragility that is our immune system. Once it is turned on for any autoimmune disease, there’s no turning it off.
Our districts make schools accessible for handicapped children, accommodate hearing impaired and many other disabilities. However, when it comes to invisible illnesses, somehow our districts think they’re experts in immunology and virology and give families no choice, but to stay out to stay safe. That’s the discrimination we feel at least and it doesn’t look like it will ever change. Living with chronic conditions teaches you to adapt to a new normal to persevere…so I suppose we will apply that same mindset to school as well. They won’t make any changes so we will accept our new path, but at least we have better odds at staying a little healthier!
Thank you again for your response!
Thanks, Sarah. Yes, I have tried to push back on those who have advocated for medical freedom to point out that that means those who are at high risk lose their freedoms or take greatly increased risks in their daily lives. The responses to why their freedoms should prevail over others’ freedoms is alarming. I have also tried to make the case for why it is even in their self interests to protect the immunocompromised due to the increased risk for new variants and recombinants if we allow the immunocompromised to get infected, but unsuccessfully so.
I am so sorry for the effect this has had upon you and your family and countless others out there.
Take care and be safe!