Long COVID

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[1] 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.

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[1] https://www.nature.com/articles/s41579-022-00846-2