latest research on long haul covid

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• Review Article
• Published: 13 January 2023

Long COVID: major findings, mechanisms and recommendations

• Hannah E. Davis   ORCID: orcid.org/0000-0002-1245-2034 1 ,
• Lisa McCorkell   ORCID: orcid.org/0000-0002-3261-6737 2 ,
• Julia Moore Vogel   ORCID: orcid.org/0000-0002-4902-3540 3 &
• Eric J. Topol   ORCID: orcid.org/0000-0002-1478-4729 3  

Nature Reviews Microbiology volume  21 ,  pages 133–146 ( 2023 ) Cite this article

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An Author Correction to this article was published on 17 April 2023

This article has been updated

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.

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Introduction

Long COVID (sometimes referred to as ‘post-acute sequelae of COVID-19’) is a multisystemic condition comprising often severe symptoms that follow a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. 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 1 ; 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 2 , 3 and 10–12% of vaccinated cases 4 , 5 . Long COVID is associated with all ages and acute phase disease severities, 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 6 , as this population represents the majority of overall COVID-19 cases. There are many research challenges, as outlined in this Review, and many open questions, particularly relating to pathophysiology, effective treatments and risk factors.

Hundreds of biomedical findings have been documented, with many patients experiencing dozens of symptoms across multiple organ systems 7 (Fig.  1 ). Long COVID encompasses multiple adverse outcomes, with common new-onset conditions including cardiovascular, thrombotic and cerebrovascular disease 8 , type 2 diabetes 9 , myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) 10 , 11 and dysautonomia, especially postural orthostatic tachycardia syndrome (POTS) 12 (Fig.  2 ). Symptoms can last for years 13 , and particularly in cases of new-onset ME/CFS and dysautonomia are expected to be lifelong 14 . With significant proportions of individuals with long COVID unable to return to work 7 , the scale of newly disabled individuals is contributing to labour shortages 15 . There are currently no validated effective treatments.

The impacts of long COVID on numerous organs with a wide variety of pathology are shown. The presentation of pathologies is often overlapping, which can exacerbate management challenges. MCAS, mast cell activation syndrome; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; POTS, postural orthostatic tachycardia syndrome.

Because diagnosis-specific data on large populations with long COVID are sparse, outcomes from general infections are included and a large proportion of medical conditions are expected to result from long COVID, although the precise proportion cannot be determined. One year after the initial infection, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections increased the risk of cardiac arrest, death, diabetes, heart failure, pulmonary embolism and stroke, as studied with use of US Department of Veterans Affairs databases. Additionally, there is clear increased risk of developing myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia. Six months after breakthrough infection, increased risks were observed for cardiovascular conditions, coagulation and haematological conditions, death, fatigue, neurological conditions and pulmonary conditions in the same cohort. The hazard ratio is the ratio of how often an event occurs in one group relative to another; in this case people who have had COVID-19 compared with those who have not. Data sources are as follows: diabetes 9 , cardiovascular outcomes 8 , dysautonomia 12 , 201 , ME/CFS 10 , 202 and breakthrough infections 4 .

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 16 , 17 ; immune dysregulation 17 , 18 , 19 , 20 with or without reactivation of underlying pathogens, including herpesviruses such as Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) among others 17 , 18 , 21 , 22 ; impacts of SARS-CoV-2 on the microbiota, including the virome 17 , 23 , 24 , 25 ; autoimmunity 17 , 26 , 27 , 28 and priming of the immune system from molecular mimicry 17 ; microvascular blood clotting with endothelial dysfunction 17 , 29 , 30 , 31 ; and dysfunctional signalling in the brainstem and/or vagus nerve 17 , 32 (Fig.  3 ). Mechanistic studies are generally at an early stage, and although work that builds on existing research from postviral illnesses such as ME/CFS has advanced some theories, many questions remain and are a priority to address. Risk factors potentially include female sex, type 2 diabetes, EBV reactivation, the presence of specific autoantibodies 27 , connective tissue disorders 33 , attention deficit hyperactivity disorder, chronic urticaria and allergic rhinitis 34 , although a third of people with long COVID have no identified pre-existing conditions 6 . A higher prevalence of long Covid has been reported in certain ethnicities, including people with Hispanic or Latino heritage 35 . Socio-economic risk factors include lower income and an inability to adequately rest in the early weeks after developing COVID-19 (refs. 36 , 37 ). Before the emergence of SARS-CoV-2, multiple viral and bacterial infections were known to cause postinfectious illnesses such as ME/CFS 17 , 38 , and there are indications that long COVID shares their mechanistic and phenotypic characteristics 17 , 39 . Further, dysautonomia has been observed in other postviral illnesses and is frequently observed in long COVID 7 .

There are several hypothesized mechanisms for long COVID pathogenesis, including immune dysregulation, microbiota disruption, autoimmunity, clotting and endothelial abnormality, and dysfunctional neurological signalling. EBV, Epstein–Barr virus; HHV-6, human herpesvirus 6; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

In this Review, we explore the current knowledge base of long COVID as well as misconceptions surrounding long COVID and areas where additional research is needed. Because most patients with long COVID were not hospitalized for their initial SARS-CoV-2 infection 6 , we focus on research that includes patients with mild acute COVID-19 (meaning not hospitalized and without evidence of respiratory disease). Most of the studies we discuss refer to adults, except for those in Box  1 .

Box 1 Long COVID in children

Long COVID impacts children of all ages. One study found that fatigue, headache, dizziness, dyspnoea, chest pain, dysosmia, dysgeusia, reduced appetite, concentration difficulties, memory issues, mental exhaustion, physical exhaustion and sleep issues were more common in individuals with long COVID aged 15–19 years compared with controls of the same age 203 . A nationwide study in Denmark comparing children with a positive PCR test result with control individuals found that the former had a higher chance of reporting at least one symptom lasting more than 2 months 204 . Similarly to adults with long COVID, children with long COVID experience fatigue, postexertional malaise, cognitive dysfunction, memory loss, headaches, orthostatic intolerance, sleep difficulty and shortness of breath 204 , 205 . Liver injury has been recorded in children who were not hospitalized during acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections 206 , and although rare, children who had COVID-19 have increased risks of acute pulmonary embolism, myocarditis and cardiomyopathy, venous thromboembolic events, acute and unspecified renal failure, and type 1 diabetes 207 . Infants born to women who had COVID-19 during pregnancy were more likely to receive a neurodevelopmental diagnosis in the first year after delivery 208 . A paediatric long COVID centre’s experience treating patients suggests that adolescents with a moderate to severe form of long COVID have features consistent with myalgic encephalomyelitis/chronic fatigue syndrome 205 . Children experiencing long COVID have hypometabolism in the brain similar to the patterns found in adults with long COVID 209 . Long-term pulmonary dysfunction is found in children with long COVID and those who have recovered from COVID-19 (ref. 210 ). Children with long COVID were more likely to have had attention deficit hyperactivity disorder, chronic urticaria and allergic rhinitis before being infected 34 .

More research on long COVID in children is needed, although there are difficulties in ensuring a proper control group due to testing issues. Several studies have found that children infected with SARS-CoV-2 are considerably less likely to have a positive PCR test result than adults despite seroconverting weeks later, with up to 90% of cases being missed 189 , 190 . Additionally, children are much less likely to seroconvert and, if they develop antibodies, are more likely to have a waning response months after infection compared with adults 193 .

Major findings

Immunology and virology.

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 18 , reduced CD4 + and CD8 + effector memory cell numbers 18 , 19 and elevated PD1 expression on central memory cells, persisting for at least 13 months 19 . 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 20 . 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 18 . The expansion of cytotoxic T cells has been found to be associated with the gastrointestinal presentation of long COVID 27 . Additional studies have found elevated levels of cytokines, particularly IL-1β, IL-6, TNF and IP10 (refs. 40 , 41 ), and a recent preprint has reported persistent elevation of the level of CCL11, which is associated with cognitive dysfunction 42 . It remains to be seen whether the pattern of cytokines in ME/CFS, where the levels of certain cytokines are elevated in the first 2–3 years of illness but decrease over time without a corresponding decrease in symptoms 43 , is similar in long COVID.

Multiple studies have found elevated levels of autoantibodies in long COVID 27 , including autoantibodies to ACE2 (ref. 28 ) (the receptor for SARS-CoV-2 entry), β 2 -adrenoceptor, muscarinic M2 receptor, angiotensin II AT 1 receptor and the angiotensin 1–7 MAS receptor 26 . 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) 44 . A major comprehensive study, however, did not find autoantibodies to be a major component of long COVID 18 .

Reactivated viruses, including EBV and HHV-6, have been found in patients with long COVID 18 , 21 , 22 , 27 (and have been identified in ME/CFS 45 ), and lead to mitochondrial fragmentation and severely affect energy metabolism 46 . A recent preprint has reported that EBV reactivation is associated with fatigue and neurocognitive dysfunction in patients with long COVID 22 .

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 47 , 48 . These insufficient immune responses include a low baseline level of IgG 48 , low levels of receptor-binding domain and spike-specific memory B cells, low levels of nucleocapsid IgG 49 and low peaks of spike-specific IgG 47 . In a recent preprint, low or absent CD4 + T cell and CD8 + T cell responses were noted in patients with severe long COVID 49 , 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 50 . 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 27 . SARS-CoV-2 viral rebound in the gut, possibly resulting from viral persistence, has also been associated with lower levels and slower production of receptor-binding domain IgA and IgG antibodies 51 . There are major differences in antibody creation, seroreversion and antibody titre levels across the sexes, with women being less likely to seroconvert, being more likely to serorevert and having lower antibody levels overall 52 , 53 , even affecting antibody waning after vaccination 54 .

Several reports have pointed towards possible viral persistence as a 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 55 , 56 , 57 , 58 , 59 , 60 . 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, likely implying a reservoir of active virus or components of the virus 16 . Indeed, multiple reports following gastrointestinal biopsies have indicated the presence of virus, suggestive of a persistent reservoir in some patients 58 , 61 .

Vascular issues and organ damage

Although COVID-19 was initially recognized as a respiratory illness, SARS-CoV-2 has capability to damage many organ systems. 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 29 , 30 , 62 . Microclots detected in both acute COVID-19 and long COVID contribute to thrombosis 63 and are an attractive diagnostic and therapeutic target. 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 64 . 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 65 . 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 66 .

An analysis of the US Department of Veterans Affairs databases (VA data) including more than 150,000 individuals 1 year after SARS-CoV-2 infection indicated a significantly increased risk of a variety of cardiovascular diseases, including heart failure, dysrhythmias and stroke, independent of the severity of initial COVID-19 presentation 8 (Fig.  2 ). 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 67 ) and in 58% of participants with long COVID (studied 12 months after infection 68 ), reinforcing the durability of cardiac abnormalities.

Multiple studies have revealed multi-organ damage associated with COVID-19. 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 69 . In a 1-year follow-up study, conducted by the same research group with 536 participants, the study authors found that 59% had single-organ damage and 27% multi-organ damage 70 . A dedicated kidney study of VA data including more than 89,000 individuals who had COVID-19 noted an increased risk of numerous adverse kidney outcomes 71 . Another VA data analysis, including more than 181,000 individuals who had COVID-19, found that infection also increases the risk of type 2 diabetes 9 (Fig.  2 ). The organ damage experienced by patients with long COVID appears durable, and long-term effects remain unknown.

Neurological and cognitive systems

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 7 , 32 . Audiovestibular manifestations of long COVID include tinnitus, hearing loss and vertigo 7 , 72 .

In a meta-analysis, fatigue was found in 32% and cognitive impairment was found in 22% of patients with COVID-19 at 12 weeks after infection 3 . Cognitive impairments in long COVID are debilitating, at the same magnitude as intoxication at the UK drink driving limit or 10 years of cognitive ageing 73 , 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 74 . Activation of the kynurenine pathway, particularly the presence of the metabolites quinolinic acid, 3-hydroxyanthranilic acid and kynurenine, has been identified in long COVID, and is associated with cognitive impairment 74 . Cognitive impairment has also been found in individuals who recovered from COVID-19 (ref.  75 ), and at higher rates when objective versus subjective measures were used 3 , suggesting that a subset of those with cognitive impairment may not recognize and/or report their impairment. Cognitive impairment is a feature that manifests itself independently of mental health conditions such as anxiety and depression 74 , 76 , and occurs at similar rates in hospitalized and non-hospitalized patients 74 , 76 . A report of more than 1.3 million people who had COVID-19 showed mental health conditions such as anxiety and depression returned to normal over time, but increased risks of cognitive impairment (brain fog), seizures, dementia, psychosis and other neurocognitive conditions persisted for at least 2 years 77 .

Possible mechanisms for these neuropathologies include neuroinflammation, damage to blood vessels by coagulopathy and endothelial dysfunction, and injury to neurons 32 . Studies have found Alzheimer disease-like signalling in patients with long COVID 78 , peptides that self-assemble into amyloid clumps which are toxic to neurons 79 , widespread neuroinflammation 80 , brain and brainstem hypometabolism correlated with specific symptoms 81 , 82 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 83 . 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’ 42 . A study from the UK Biobank, including brain imaging in the same patients before and after COVID-19 as well as control individuals, showed a reduction in grey matter thickness in the orbitofrontal cortex and parahippocampal 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 compared with controls, even in non-hospitalized patients. Although that study looked at individuals with COVID-19 compared with controls, not specifically long COVID, it may have an implication for the cognitive component of long COVID 84 . Abnormal levels of mitochondrial proteins as well as SARS-CoV-2 spike and nucleocapsid proteins have been found in the central nervous system 85 . Tetrahydrobiopterin deficiencies and oxidative stress are found in long COVID as well 86 .

In the eyes, corneal small nerve fibre loss and increased dendritic cell density have been found in long COVID 87 , 88 , as well as significantly altered pupillary light responses 89 and impaired retinal microcirculation 90 . SARS-CoV-2 can infect and replicate in retinal 59 and brain 91 organoids. Other manifestations of long COVID include retinal haemorrhages, cotton wool spots and retinal vein occlusion 92 .

Mouse models of mild SARS-CoV-2 infection demonstrated microglial reactivity and elevated levels of CCL11, which is associated with cognitive dysfunction and impaired neurogenesis 42 . Hamster models exhibited an ongoing inflammatory state, involving T cell and myeloid activation, production of pro-inflammatory cytokines and an interferon response that was correlated with anxiety and depression-like behaviours in the hamsters, with similar transcriptional signatures found in the tissue of humans who had recovered from COVID-19 (ref. 93 ). Infected non-human primates with mild illness showed neuroinflammation, neuronal injury and apoptosis, brain microhaemorrhages, and chronic hypoxaemia and brain hypoxia 94 .

Recent reports indicate low blood cortisol levels in patients with long COVID as compared with control individuals, more than 1 year into symptom duration 18 , 27 . 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 18 . This may also reflect an underlying neuroinflammatory process. Low cortisol levels have previously been documented in individuals with ME/CFS.

ME/CFS, dysautonomia and related conditions

ME/CFS is a multisystem neuroimmune illness with onset often following a viral or bacterial infection. Criteria include a “substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities” for at least 6 months, accompanied by a profound fatigue that is not alleviated by rest, along with postexertional malaise, unrefreshing sleep and cognitive impairment or orthostatic intolerance (or both) 95 . 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 96 . There is a vast collection of biomedical findings in ME/CFS 97 , 98 , although these are not well known to researchers and clinicians in other fields.

Many researchers have commented on the similarity between ME/CFS and long COVID 99 ; around half of individuals with long COVID are estimated to meet the criteria for ME/CFS 10 , 11 , 29 , 100 , and in studies where the cardinal ME/CFS symptom of postexertional malaise is measured, a majority of individuals with long COVID report experiencing postexertional malaise 7 , 100 . A study of orthostatic stress in individuals with long COVID and individuals with ME/CFS found similar haemodynamic, symptomatic and cognitive abnormalities in both groups compared with healthy individuals 101 . Importantly, it is not surprising that ME/CFS should stem from SARS-CoV-2 infection as 27.1% of SARS-CoV infection survivors in one study met the criteria for ME/CFS diagnosis 4 years after onset 102 . A wide range of pathogens cause ME/CFS onset, including EBV, Coxiella burnetii (which causes Q fever), Ross River virus and West Nile virus 38 .

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. Other abnormalities include exercise intolerance, impaired oxygen consumption and a reduced anaerobic threshold, and abnormal metabolic profiles, including altered usage of fatty acids and amino acids. Altered neurological functions have also been observed, including neuroinflammation, reduced cerebral blood flow, brainstem abnormalities and elevated ventricular lactate level, as well as abnormal eye and vision findings. Reactivated herpesviruses (including EBV, HHV-6, HHV-7 and human cytomegalovirus) are also associated with ME/CFS 97 , 98 , 103 , 104 .

Many of these findings have been observed in long COVID studies in both adults and children (Box  1 ). Long COVID research has found mitochondrial dysfunction including loss of mitochondrial membrane potential 105 and possible dysfunctional mitochondrial metabolism 106 , altered fatty acid metabolism and dysfunctional mitochondrion-dependent lipid catabolism consistent with mitochondrial dysfunction in exercise intolerance 107 , redox imbalance 108 , and exercise intolerance and impaired oxygen extraction 100 , 109 , 110 . Studies have also found endothelial dysfunction 29 , cerebral blood flow abnormalities and metabolic changes 81 , 111 , 112 , 113 (even in individuals with long COVID whose POTS symptoms abate 114 ), extensive neuroinflammation 42 , 80 , reactivated herpesviruses 18 , 21 , 27 , deformed red blood cells 64 and many findings discussed elsewhere. Microclots and hyperactivated platelets are found not only in individuals with long COVID but also in individuals with ME/CFS 115 .

Dysautonomia, particularly POTS, is commonly comorbid with ME/CFS 116 and also often has a viral onset 117 . POTS is associated with G protein-coupled adrenergic receptor and muscarinic acetylcholine receptor autoantibodies, platelet storage pool deficiency, small fibre neuropathy and other neuropathologies 118 . Both POTS and small fibre neuropathy are commonly found in long COVID 111 , 119 , with one study finding POTS in 67% of a cohort with long COVID 120 .

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 121 , with histamine receptor antagonists resulting in improvements in the majority of patients 19 .

Other conditions that are commonly comorbid with ME/CFS include connective tissue disorders including Ehlers–Danlos syndrome and hypermobility, neuro-orthopaedic spinal and skull conditions, and endometriosis 33 , 122 , 123 . Evidence is indicating these conditions may be comorbid with long COVID as well. The overlap of postviral conditions with these conditions should be explored further.

Reproductive system

Impacts on the reproductive system are often reported in long COVID, although little research has been done to document the extent of the impact and sex-specific pathophysiology. Menstrual alterations are more likely to occur in women and people who menstruate with long COVID than in women and people who menstruate with no history of COVID and those who had COVID-19 but not long COVID 124 . Menstruation and the week before menstruation have been identified by patients as triggers for relapses of long COVID symptoms 7 . Declined ovarian reserve and reproductive endocrine disorder have been observed in people with COVID-19 (ref. 125 ), and initial theories suggest that SARS-CoV-2 infection affects ovary hormone production and/or the endometrial response due to the abundance of ACE2 receptors on ovarian and endometrial tissue 126 . Individuals with both COVID-19 and menstrual changes were more likely to experience fatigue, headache, body ache and pain, and shortness of breath than those who did not have menstrual changes, and the most common menstrual changes were irregular menstruation, increased premenstrual symptoms and infrequent menstruation 127 .

Research on ME/CFS shows associations between ME/CFS and premenstrual dysphoric disorder, polycystic ovarian syndrome, menstrual cycle abnormalities, ovarian cysts, early menopause and endometriosis 128 , 129 , 130 . Pregnancy, postpartum changes, perimenopause and menstrual cycle fluctuations affect ME/CFS and influence metabolic and immune system changes 129 . Long COVID research should focus on these relationships to better understand the pathophysiology.

Viral persistence in the penile tissue has been documented, as has an increased risk of erectile dysfunction, likely resulting from endothelial dysfunction 131 . In one study, impairments to sperm count, semen volume, motility, sperm morphology and sperm concentration were reported in individuals with long COVID compared with control individuals, and were correlated with elevated levels of cytokines and the presence of caspase 8, caspase 9 and caspase 3 in seminal fluid 132 .

Respiratory system

Respiratory conditions are a common phenotype in long COVID, and in one study occurred twice as often in COVID-19 survivors as in the general population 2 . 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 7 . Several imaging studies that included non-hospitalized individuals with long COVID demonstrated pulmonary abnormalities including in air trapping and lung perfusion 133 , 134 . 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 135 . Further immunological characterization comparing individuals with long COVID with individuals who had recovered from COVID-19 noted a correlation between decreased lung function, systemic inflammation and SARS-CoV-2-specific T cells 136 .

Gastrointestinal system

Long COVID gastrointestinal symptoms include nausea, abdominal pain, loss of appetite, heartburn and constipation 137 . The gut microbiota composition is significantly altered in patients with COVID-19 (ref. 23 ), and gut microbiota dysbiosis is also a key component of ME/CFS 138 . Higher levels of Ruminococcus gnavus and Bacteroides vulgatus and lower levels of Faecalibacterium prausnitzii have been found in people with long COVID compared with non-COVID-19 controls (from before the pandemic), with gut dysbiosis lasting at least 14 months; low levels of butyrate-producing bacteria are strongly correlated with long COVID at 6 months 24 . Persisting respiratory and neurological symptoms are each associated with specific gut pathogens 24 . Additionally, SARS-CoV-2 RNA is present in stool samples of patients with COVID-19 (ref. 139 ), with one study indicating persistence in the faeces of 12.7% of participants 4 months after diagnosis of COVID-19 and in 3.8% of participants at 7 months after diagnosis 61 . Most patients with long COVID symptoms and inflammatory bowel disease 7 months after infection had antigen persistence in the gut mucosa 140 . Higher levels of fungal translocation, from the gut and/or lung epithelium, have been found in the plasma of patients with long COVID compared with those without long COVID or SARS-CoV-2-negative controls, possibly inducing cytokine production 141 . Transferring gut bacteria from patients with long COVID to healthy mice resulted in lost cognitive functioning and impaired lung defences in the mice, who were partially treated with the commensal probiotic bacterium Bifidobacterium longum 25 .

The onset and time course of symptoms differ across individuals and by symptom type. Neurological symptoms often have a delayed onset of weeks to months: among participants with cognitive symptoms, 43% reported a delayed onset of cognitive symptoms at least 1 month after COVID-19, with the delay associated with younger age 83 . Several neurocognitive symptoms worsen over time and tend to persist longer, whereas gastrointestinal and respiratory symptoms are more likely to resolve 7 , 74 , 142 . Additionally, pain in joints, bones, ears, neck and back are more common at 1 year than at 2 months, as is paresthesia, hair loss, blurry vision and swelling of the legs, hands and feet 143 . Parosmia has an average onset of 3 months after the initial infection 144 ; unlike other neurocognitive symptoms, it often decreases over time 143 .

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 143 . Future prognosis is uncertain, although diagnoses of ME/CFS and dysautonomia are generally lifelong.

Diagnostic tools and treatments

Although diagnostic tools exist for some components of long COVID (for example, tilt table tests for POTS 145 and MRI scans to detect cardiovascular impairment 68 ), diagnostic tools for long COVID are mostly in development, including imaging to detect microclots 63 , corneal microscopy to identify small fibre neuropathy 87 , new fragmentation of QRS complex on electrocardiograms as indicative of cardiac injury 146 and use of hyperpolarized MRI to detect pulmonary gas exchange abnormalities 147 . On the basis of the tests that are offered as standard care, the results for patients with long COVID are often normal; many providers are unaware of the symptom-specific testing and diagnostic recommendations from the ME/CFS community 148 . Early research into biomarkers suggests that levels of extracellular vesicles 85 and/or immune markers indicating high cytotoxicity 149 could be indicative of long COVID. Intriguingly, dogs can identify individuals with long COVID on the basis of sweat samples 150 . Biomarker research in ME/CFS may also be applicable to long COVID, including electrical impedance blood tests, saliva tests, erythrocyte deformation, sex-specific plasma lipid profiles and variables related to isocapnic buffering 151 , 152 , 153 , 154 . The importance of developing and validating biomarkers that can be used for the diagnosis of long COVID cannot be adequately emphasized — they will not only be helpful in establishing the diagnosis but will also be helpful for objectively defining treatment responses.

Although there are currently no broadly effective treatments for long COVID, treatments for certain components have been effective for subsets of populations (Table  1 ). Many strategies for ME/CFS are effective for individuals with long COVID, including pacing 7 , 37 and symptom-specific pharmacological options (for example, β-blockers for POTS, low-dose naltrexone for neuroinflammation 155 and intravenous immunoglobulin for immune dysfunction) and non-pharmacological options (including increasing salt intake for POTS, cognitive pacing for cognitive dysfunction and elimination diets for gastrointestinal symptoms) 96 . Low-dose naltrexone has been used in many diseases, including ME/CFS 155 , and has also shown promise in treating long COVID 156 . H 1 and H 2 antihistamines, often following protocols for mast cell activation syndrome and particularly involving famotidine, are used to alleviate a wide range of symptoms 19 , 157 , although they are not a cure. Another drug, BC007, potentially addresses autoimmunity by neutralizing G protein-coupled receptor autoantibody levels 158 . Anticoagulant regimens are a promising way to address abnormal clotting 159 ; in one study, resolution of symptoms was seen in all 24 patients receiving triple anticoagulant therapy 31 . Apheresis has also shown promise to alleviate long COVID symptoms; it has been theorized to help remove microclots 160 and has been shown to reduce autoantibodies in ME/CFS 161 . However, it is quite expensive, and its benefits are uncertain. Some supplements have shown promise in treating both long COVID and ME/CFS, including coenzyme Q 10 and d -ribose 162 , and may deserve further study.

Of note, exercise is harmful for patients with long COVID who have ME/CFS or postexertional malaise 110 , 163 and should not be used as a treatment 164 , 165 , 166 ; one study of people with long COVID noted that physical activity worsened the condition of 75% of patients, and less than 1% saw improvement 109 .

Pilot studies and case reports have revealed additional treatment options worth exploring. A case report noted resolution of long COVID following treatment with the antiviral Paxlovid 167 , and a study investigating the treatment of acute COVID-19 with Paxlovid showed a 25% reduction in the incidence of long COVID 168 ; Paxlovid should be investigated further for prevention and treatment of long COVID. A small trial of sulodexide in individuals with endothelial dysfunction saw a reduction in symptom severity 169 . Pilot studies of probiotics indicated potential in alleviating gastrointestinal and non-gastrointestinal symptoms 170 , 171 . Two patients with long COVID experienced substantial alleviation of dysautonomia symptoms following stellate ganglion block 172 . An early study noted that Pycnogenol statistically significantly improved physiological measurements (for example, reduction in oxidative stress) and quality of life (indicated by higher Karnofsky Performance Scale Index scores) 173 , 174 , as hypothesized on the basis of success in other clinical studies.

Taken together, the current treatment options are based on small-scale pilot studies in long COVID or what has been effective in other diseases; several additional trials are in progress 175 . There is a wide range of possible treatment options from ME/CFS covering various mechanisms, including improving natural killer cell function, removing autoantibodies, immunosuppressants, antivirals for reactivated herpesviruses, antioxidants, mitochondrial support and mitochondrial energy generation 176 , 177 ; most need to be clinically trialled, which should happen urgently. Many newer treatment options remain underexplored, including anticoagulants and SARS-CoV-2-specific antivirals, and a lack of funding is a significant limitation to robust trials.

Impact of vaccines, variants and reinfections

The impact of vaccination on the incidence of long COVID differs across studies, in part because of differing study methods, time since vaccination and definitions of long COVID. One study indicated no significant difference in the development of long COVID between vaccinated individuals and unvaccinated individuals 178 ; other studies indicate that vaccines provide partial protection, with a reduced risk of long COVID between 15% and 41% 4 , 5 , with long COVID continuing to impact 9% of people with COVID-19.

The different SARS-CoV-2 variants and level of (and time since) vaccination may impact the development of long COVID. The UK’s Office for National Statistics found that long COVID was 50% less common in double-vaccinated participants with Omicron BA.1 than in double-vaccinated participants Delta, but that there was no significant difference between triple-vaccinated participants; it also found long COVID was more common after Omicron BA.2 infection than after BA.1 infection in triple-vaccinated participants, with 9.3% developing long COVID from infection with the BA.2 variant 179 .

The impact of vaccination on long COVID symptoms in people who had already developed long COVID differs among patients, with 16.7% of patients experiencing a relief of symptoms, 21.4% experiencing a worsening of symptoms and the remainder experiencing unchanged symptoms 180 .

Reinfections are increasingly common 181 . The impact of multiple instances of COVID-19, including the rate of long COVID in those who recovered from a first infection but developed long COVID following reinfection, and the impact of reinfection on those with pre-existing long COVID is crucial to understand to inform future policy decisions. Early research shows an increasing risk of long COVID sequelae after the second and third infection, even in double-vaccinated and triple-vaccinated people 182 . Existing literature suggests multiple infections may cause additional harm or susceptibility to the ME/CFS-type presentation 33 , 183 .

There is also early evidence that certain immune responses in people with long COVID, including low levels of protective antibodies and elevated levels of autoantibodies, may suggest an increased susceptibility to reinfection 27 .

Challenges and recommendations

Issues with PCR and antibody testing throughout the pandemic, inaccurate pandemic narratives and widespread lack of postviral knowledge have caused downstream issues and biases in long COVID research and care.

Testing issues

Most patients with COVID-19 from the first waves did not have laboratory-confirmed infection, with PCR tests being difficult to access unless individuals were hospitalized. Only 1–3% of cases to March 2020 were likely detected 184 , and the CDC estimates that only 25% of cases in the USA were reported from February 2020 to September 2021 (ref. 185 ); that percentage has likely decreased with the rise in use of at-home rapid tests.

Although PCR tests are our best tool for detecting SARS-CoV-2 infections, their false negative rates are still high 186 . Further bias is caused by false negative rates being higher in women and adults younger than 40 years 187 , those with a low viral load 188 and children (Box  1 ), with several studies showing 52–90% of cases in children missed by PCR tests 189 , 190 . The high false negative PCR rate results in symptomatic patients with COVID-19, who seek a COVID-19 test but receive a false negative result, being included as a control in many studies. Those who have a positive PCR test result (who are more likely to be included in research) are more likely to be male or have a higher viral load. Additionally, the lack of test accessibility as well as the false negative rates has created a significant barrier to care, as many long COVID clinics require PCR tests for admission.

Similarly, there is a broad misconception that everyone makes and retains SARS-CoV-2 antibodies, and many clinicians and researchers are unaware of the limited utility of antibody tests to determine prior infection. Between 22% and 36% of people infected with SARS-CoV-2 do not seroconvert, and many others lose their antibodies over the first few months, with both non-seroconversion and seroreversion being more likely in women, children and individuals with mild infections 52 , 53 , 191 , 192 , 193 . At 4 and 8 months after infection, 19% and 61% of patients, respectively, who had mild infections and developed antibodies were found to have seroreverted, compared with 2% and 29% of patients, respectively who had severe infections 191 . Still, many clinicians and researchers use antibody tests to include or exclude patients with COVID-19 from control groups.

Furthermore, during periods of test inaccessibility, tests were given on the basis of patients having COVID-19-specific symptoms such as loss of smell and taste, fever, and respiratory symptoms, resulting in a bias towards people with those symptoms.

Misinformation on PCR and antibody tests has resulted in the categorization of patients with long COVID into non-COVID-19 control groups, biasing the research output. Because low or no antibody levels and viral load may be related to long COVID pathophysiology, including a clinically diagnosed cohort will strengthen the research.

Important miscues

The narrative that COVID-19 had only respiratory sequelae led to a delayed realization of the neurological, cardiovascular and other multisystem impacts of COVID-19. Many long COVID clinics and providers still disproportionately focus on respiratory rehabilitation, which results in skewed electronic health record data. Electronic health record data are also more comprehensive for those who were hospitalized with COVID-19 than for those who were in community care, leading to a bias towards the more traditional severe respiratory presentation and less focus on non-hospitalized patients, who tend to have neurological and/or ME/CFS-type presentations.

The narrative that initially mild COVID-19 cases, generally defined as not requiring hospitalization in the acute phase, would not have long-term consequences has also had downstream effects on research. These so-called mild cases that result in long COVID often have an underlying biology different from acute severe cases, but the same types of tests are being used to evaluate patients. This is despite basic tests such as D-dimer, C-reactive protein (CRP) and antinuclear antibody tests and complete blood count being known to often return normal results in patients with long COVID. Tests that return abnormal results in patients with ME/CFS and dysautonomia, such as total immunoglobulin tests, natural killer cell function tests, the tilt table or NASA lean test, the four-point salivary cortisol test, reactivated herpesvirus panels, small fibre neuropathy biopsy, and tests looking for abnormal brain perfusion 96 , should instead be prioritized. Other recurring issues include studies failing to include the full range of symptoms, particularly neurological and reproductive system symptoms, and not asking patients about symptom frequency, severity and disability. Cardinal symptoms such as postexertional malaise are not widely known, and therefore are rarely included in study designs.

Widespread lack of postviral knowledge and misinformation

The widespread lack of knowledge of viral-onset illnesses, especially ME/CFS and dysautonomia, as well as often imperfect coding, prevents these conditions from being identified and documented by clinicians; this means that they are frequently absent from electronic health record data. Further, because ME/CFS and dysautonomia research is not widely known or comprehensively taught in medical schools 194 , long COVID research is often not built on past findings, and tends to repeat old hypotheses. Additionally, long COVID research studies and medical histories tend to document only the risk factors for severe acute COVID-19, which are different from the risk factors for conditions that overlap with long COVID such as ME/CFS and dysautonomia (for example, connective tissue disorders such as Ehlers–Danlos syndrome, prior illnesses such as infectious mononucleosis and mast cell involvement) 33 , 195 , 196 .

Clinicians who are not familiar with ME/CFS and dysautonomia often misdiagnose mental health disorders in patients; four in five patients with POTS receive a diagnosis with a psychiatric or psychological condition before receiving a POTS diagnosis, with only 37% continuing to have the psychiatric or psychological diagnosis once they have received their POTS diagnosis 117 . Researchers who are unfamiliar with ME/CFS and dysautonomia often do not know to use specific validated tools when conducting mental health testing, as anxiety scales often include autonomic symptoms such as tachycardia, and depression scales often include symptoms such as fatigue, both of which overestimate mental health disorder prevalence in these conditions 197 , 198 .

Recommendations

Although research into long COVID has been expansive and has accelerated, the existing research is not enough to improve outcomes for people with long COVID. To ensure an adequate response to the long COVID crisis, we need research that builds on existing knowledge and is inclusive of the patient experience, training and education for the health-care and research workforce, a public communication campaign, and robust policies and funding to support research and care in long COVID.

We need a comprehensive long COVID research agenda that builds on the existing knowledge from ME/CFS, dysautonomia and other viral-onset conditions, including but not limited to brain and brainstem inflammation, appropriate neuroimaging techniques, neuroimmunology, metabolic profiling, impaired endothelial function, mitochondrial fragmentation, antiviral and metabolic phenotypes, hypoperfusion/cerebral blood flow, nanoneedle diagnostic testing, overlaps with connective tissue disorders, autoimmunity and autoantibodies, viral/microbial persistence, intracranial hypertension, hypermobility, craniocervical obstructions, altered T and B cells, metabolomics and proteomics, elevated blood lactate level, herpesvirus reactivations, immune changes in the early versus late postviral years, and changes to the gut microbiota. The mechanisms of and overlaps between long COVID and connective tissue involvement, mast cells and inflammatory conditions such as endometriosis are particularly understudied and should be focused on. Because of the high prevalence of ME/CFS, POTS and other postinfectious illnesses in patients with long COVID, long COVID research should include people who developed ME/CFS and other postinfectious illnesses from a trigger other than SARS-CoV-2 in comparator groups to improve understanding of the onset and pathophysiology of these illnesses 113 . Additionally, there is a known immune exhaustion process that occurs between the second and third year of illness in ME/CFS, with test results for cytokines being different between patients who have been sick for shorter durations (less than 2 years) than for those who have been sick for longer durations 43 . Because of this, studies should implement subanalyses based on the length of time participants have been ill. Because ME/CFS and dysautonomia research is not widely known across the biomedical field, long COVID research should be led by experts from these areas to build on existing research and create new diagnostic and imaging tools.

Robust clinical trials must be a priority moving forward as patients currently have few treatment options. In the absence of validated treatment options, patients and physicians conduct individual experiments, which result in the duplication of efforts without generalizable knowledge and pose undue risks to patients. Robust study design and knowledge sharing must be prioritized by both funding institutions and clinician-researchers.

It is critical that research on long COVID be representative of (or oversample) the populations who had COVID-19 and are developing long COVID at high rates, which is disproportionately people of colour 35 . Medical research has historically under-represented these populations, and over-representation of white and socio-economically privileged patients has been common in long COVID research. Researchers must work within communities of colour, LGBTQ+ communities and low-income communities to build trust and conduct culturally competent studies that will provide insights and treatments for long COVID for marginalized populations.

As a subset of patients will improve over time, and others will have episodic symptoms, care should be taken to incorporate the possibility of alleviation of symptoms into the study design, and care should be taken not to ascribe improvement to a particular cause without proper modelling.

Finally, it is critical that communities of patients with long COVID and associated conditions are meaningfully engaged in long COVID research and clinical trials. The knowledge of those who experience an illness is crucial in identifying proper study design and key research questions and solutions, improving the speed and direction of research.

Training and education of the health-care and research workforce

To prepare the next generation of health-care providers and researchers, medical schools must improve their education on pandemics, viruses and infection-initiated illnesses such as long COVID and ME/CFS, and competency evaluations should include these illnesses. As of 2013, only 6% of medical schools fully cover ME/CFS across the domains of treatment, research and curricula, which has created obstacles to care, accurate diagnosis, research and treatment 194 . To ensure people with long COVID and associated conditions can receive adequate care now, professional societies and government agencies must educate the health-care and research workforce on these illnesses, including the history of and current best practices for ME/CFS to not repeat mistakes of the past, which have worsened patients’ prognoses. The research community has made a misstep in its efforts to treat ME/CFS 199 , and some physicians, poorly educated in the aetiology and pathophysiology of the disorder, still advise patients to pursue harmful interventions such as graded exercise therapy and cognitive behavioural therapy, despite the injury that these interventions cause 200 and the fact that they are explicitly not advised as treatments 163 , 164 , 166 .

Public communications campaign

In addition to providing education on long COVID to the biomedical community, we need a public communications campaign that informs the public about the risks and outcomes of long COVID.

Policies and funding

Finally, we need policies and funding that will sustain long COVID research and enable people with long COVID to receive adequate care and support. For instance, in the USA, the creation of a national institute for complex chronic conditions within the NIH would go a long way in providing a durable funding mechanism and a robust research agenda. Further, we need to create and fund centres of excellence, which would provide inclusive, historically informed and culturally competent care, as well as conduct research and provide medical education to primary care providers. Additionally, research and clinical care do not exist in silos. It is critical to push forward policies that address both the social determinants of health and the social support that is needed for disabled people.

Conclusions

Long COVID is a multisystemic illness encompassing ME/CFS, dysautonomia, impacts on multiple organ systems, and vascular and clotting abnormalities. It has already debilitated millions of individuals worldwide, and that number is continuing to grow. On the basis of more than 2 years of research on long COVID and decades of research on conditions such as ME/CFS, a significant proportion of individuals with long COVID may have lifelong disabilities if no action is taken. Diagnostic and treatment options are currently insufficient, and many clinical trials are urgently needed to rigorously test treatments that address hypothesized underlying biological mechanisms, including viral persistence, neuroinflammation, excessive blood clotting and autoimmunity.

Acknowledgements

We would like to thank the long COVID and associated conditions patient and research community and the entire team at Patient-Led Research Collaborative. E.J.T. was supported by National Center for Advancing Translational Sciences (NCATS) grant UL1TR002550.

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Davis, H.E., McCorkell, L., Vogel, J.M. et al. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol 21 , 133–146 (2023). https://doi.org/10.1038/s41579-022-00846-2

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March 1, 2023

17 min read

Long COVID Now Looks like a Neurological Disease, Helping Doctors to Focus Treatments

The causes of long COVID, which disables millions, may come together in the brain and nervous system

By Stephani Sutherland

Stephanie Shafer

T ara Ghormley has always been an overachiever. She finished at the top of her class in high school, graduated summa cum laude from college and earned top honors in veterinary school. She went on to complete a rigorous training program and build a successful career as a veterinary internal medicine specialist. But in March 2020 she got infected with the SARS-CoV-2 virus—just the 24th case in the small, coastal central California town she lived in at the time, near the site of an early outbreak in the COVID pandemic. “I could have done without being first at this,” she says.

Almost three years after apparently clearing the virus from her body, Ghormley is still suffering. She gets exhausted quickly, her heartbeat suddenly races, and she goes through periods where she can't concentrate or think clearly. Ghormley and her husband, who have relocated to a Los Angeles suburb, once spent their free time visiting their “happiest place on Earth”—Disneyland—but her health prevented that for more than a year. She still spends most of her days off resting in the dark or going to her many doctors' appointments. Her early infection and ongoing symptoms make her one of the first people in the country with “long COVID,” a condition where symptoms persist for at least three months after the infection and can last for years. The syndrome is known by medical professionals as postacute sequelae of COVID-19, or PASC.

People with long COVID have symptoms such as pain, extreme fatigue and “brain fog,” or difficulty concentrating or remembering things. As of March 2023, the syndrome was estimated to affect more than 15 million adults in the U.S., and a 2022 report found that it had forced between two million and four million Americans out of the workforce. Long COVID often arises in otherwise healthy young people, and it can follow even a mild initial infection. The risk appears at least slightly higher in people who were hospitalized for COVID and in older adults (who end up in the hospital more often). Women and those at socioeconomic disadvantage also face higher risk, as do people who smoke, are obese, or have any of an array of health conditions, particularly autoimmune disease. Vaccination appears to reduce the danger but does not entirely prevent long COVID.

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The most common, persistent and disabling symptoms of long COVID are neurological. Some are easily recognized as brain- or nerve-related: many people experience cognitive dysfunction in the form of difficulty with memory, attention, sleep and mood. Others may seem rooted more in the body than the brain, such as pain and postexertional malaise (PEM), a kind of “energy crash” that people experience after even mild exercise. But those, too, result from nerve dysfunction, often in the autonomic nervous system, which directs our bodies to breathe and digest food and generally runs our organs on autopilot. This so-called dysautonomia can lead to dizziness, a racing heart, high or low blood pressure, and gut disturbances, sometimes leaving people unable to work or even function independently.

The SARS-CoV-2 virus is new, but postviral syndromes are not. Research on other viruses, and on neurological damage from the human immunodeficiency virus (HIV) in particular, is guiding work on long COVID. And the recognition that the syndrome may cause its many effects through the brain and the nervous system is beginning to shape approaches to medical treatment. “I now think of COVID as a neurological disease as much as I think of it as a pulmonary disease, and that's definitely true in long COVID,” says William Pittman, a physician at UCLA Health in Los Angeles, who treats Ghormley and many similar patients.

Although 15 million current U.S. sufferers is a reasonable estimate of the condition's toll, there are other, more dire assessments. A meta-analysis of 41 studies conducted in 2021 concluded that worldwide, 43 percent of people infected with SARS-CoV-2 may develop long COVID, with about 30 percent—translating to approximately 30 million people—affected in the U.S. Some studies have offered more conservative numbers. A June 2022 survey reported by the U.S. National Center for Health Statistics found that among adults who had had COVID, one in five was experiencing long COVID three months later; the U.K. Office for National Statistics put the estimate at one in 10. Even if only a small share of infections result in long COVID, experts say, they will add up to millions more people affected—and potentially disabled.

Most of the first recognized cases of long COVID were in patients who needed extended respiratory therapy or who had obvious organ damage that caused lasting symptoms. People reporting neurological symptoms were often overlooked or dismissed as traumatized by their initial illness and hospitalization. But as 2020 came to an end, says Helen Lavretsky, a psychiatrist at the University of California, Los Angeles, “we started getting to a place of sorting through what was really going on ... and it became very evident at that time that neuropsychiatric symptoms were quite prevalent,” most commonly fatigue, malaise, brain fog, smell loss and post-traumatic stress disorder, as well as cognitive problems and even psychosis.

Ghormley was in her late 30s and relatively healthy when she caught the virus, but she had underlying conditions—including rheumatoid arthritis and asthma—that put her at risk for severe COVID. She spent several days at home, struggling to breathe, and then she went to the hospital, where her blood pressure soared and her blood glucose dropped precipitously. She mostly recovered from this acute phase within a few weeks, but, she says, “I never really got better.”

Soon after coming home from the hospital, Ghormley developed what her husband called “goldfish brain.” “I'd put something down and have no idea where I put it,” she recalls. “It kept happening over and over. I was thinking, ‘This is getting weird.' My husband said I was not remembering anything. I'd try to talk, and I knew what I wanted to say, but I couldn't think of the word.”

“Everything fell apart for me,” says Tara Ghormley, who has been struggling with long COVID since 2020. Credit: Ewan Burns

She also experienced tremors, dramatic mood swings and painful hypersensitivity to sounds. “My husband opening a paper bag felt like knives stabbing me in the ear,” she recounts. Any exertion—physical or mental—left her exhausted and in pain. The changes were jarring to Ghormley, who prided herself on her sharp mind. “The thing that bothered me the most was that I was really having trouble thinking, speaking, remembering—trying to complete a task and having no idea what it was. Suddenly I had quite profound neurological deficits. Everything fell apart for me at that time. That was horribly traumatic ... it kind of broke me. I didn't feel like me.”

Roots of Dysfunction

As a veterinary internist, Ghormley says, it's her job to problem solve when mysterious symptoms arise, including her own. “I was actively trying to find reasons and find what I could do.” She theorized that some of her neurological symptoms might be the result of thrombotic events, blood clots that can cause ministrokes. Several early studies showed that COVID attacks endothelial cells, which line blood vessels. That can lead to clotting and oxygen deprivation in multiple organs, including the brain. Even subtle disruption of endothelial cells in the brain could contribute to cognitive dysfunction.

One study found that in people with neurological COVID symptoms, the immune system seems to be activated specifically in the central nervous system, creating inflammation. But brain inflammation is probably not caused by the virus infecting that organ directly. Avindra Nath, who has long studied postviral neurological syndromes at the National Institutes of Health, found something similar in an autopsy study of people who died of COVID. “When you look at the COVID brain, you don't actually find [huge amounts of virus, but] we found a lot of immune activation,” he says, particularly around blood vessels. The examinations suggested that immune cells called macrophages had been stirred up. “Macrophages are not that precise in their attack,” Nath says. “They come and start chewing things up; they produce all kinds of free radicals, cytokines. It's almost like blanket bombing—it ends up causing a lot of damage. And they're very hard to shut down, so they persist for a long time. These are the unwelcome guests” that may be causing persistent inflammation in the brain.

Determining which patients have ongoing inflammation could help inform treatments. Early research identified markers that often are elevated in people with the condition, says Troy Torgerson, an immunologist at the Allen Institute in Seattle. Three cell-signaling molecules—tumor necrosis factor alpha, interleukin 6 and interferon beta—stood out in long COVID patients. But this pattern wasn't found in absolutely everyone. “We're trying to sort through long COVID patients and say, ‘This would be a good group to take to trials of an anti-inflammatory drug, whereas this group may need to focus more on rehabilitation,'” Torgerson says. He led a study (currently released as a preprint, without formal scientific review by a journal) in which his team measured proteins from the blood of 55 patients. The researchers found that a subset had persistent inflammation. Among those people, they saw a distinct immune pathway linked to a lasting response to infection. “One subset of patients does appear to have an ongoing response to some virus,” Torgerson says.

Isolated pockets of SARS-CoV-2 or even pieces of viral proteins may remain in the body well after the initial infection and continue to elicit an immune attack. The first solid evidence for “viral persistence” outside the lungs came in 2021 from researchers in Singapore who found viral proteins throughout the gut in five patients who had recovered from COVID as much as six months earlier. A study conducted at the University of California, San Francisco, found evidence for viral particles in the brains of people with long COVID. Scientists collected exosomes, or tiny packets of cellular material, released specifically from cells of the central nervous system. The exosomes contained pieces of viral proteins as well as mitochondrial proteins, which may indicate an immune attack on those vital cellular organelles. Amounts of such suspicious proteins were higher in patients with neuropsychiatric symptoms than in those without them.

The virus could linger in the brain for months, according to research conducted at the nih and reported in Nature in December 2022. The autopsy study of 44 people who died of COVID found rampant inflammation mainly in the respiratory tract, but viral RNA was detected throughout the body, even in the brain, as long as 230 days after infection. Two other studies, both published last year in the Proceedings of the National Academy of Sciences USA , showed evidence that SARS-CoV-2 may infect astrocytes, a type of neural support cell, gaining entrance via neurons in the skin lining the nose.

Researchers are examining inflammatory signals in patients with long COVID in increasingly fine detail. A small study led by Joanna Hellmuth, a neurologist at U.C.S.F., found that patients with cognitive symptoms had immune-related abnormalities in their cerebrospinal fluid, whereas none of the patients without cognitive symptoms did. At the 2022 meeting of the Society for Neuroscience, Hellmuth reported that she had looked at more specific immune markers in people with cognitive symptoms and found that some patients had an elevated level of VEGF-C, a marker of endothelial dysfunction. Higher VEGF-C concentrations are associated with higher levels of immune cells getting into the brain, she says, and “they're not doing their normal function of maintaining the blood-brain barrier; they're distracted and perhaps activated.” Although the studies are small, Hellmuth adds, they reveal “real biological distinctions and inflammation in the brain. This is not a psychological or psychosomatic disorder; this is a neuroimmune disorder.”

What keeps the immune system in attack mode? According to Torgerson, “one option is that you've developed autoimmunity,” in which antibodies produced by the immune system to fight the virus also mark a person's own cells for immune attack. The response to the virus “turns the autoimmunity on, and that doesn't get better even when the virus goes away,” he says. Several studies have found evidence of autoimmune components called autoantibodies that interact with nerve cells in people with long COVID.

Clues about the inflammatory processes at work could point toward treatments for neurological symptoms. “If it's a macrophage-mediated inflammatory process ... intravenous immunoglobulin could make a difference [to] dampen the macrophages,” Nath says. The treatment, referred to as IVIg, contains a cocktail of proteins and antibodies that can mitigate an overactive immune response.

IVIg can also be used to block autoantibodies. And a therapy called rituximab that targets antibody-producing B cells provides “a time-tested therapy for a lot of autoantibody-mediated syndromes,” Nath says. Another strategy is to use corticosteroids to dampen immune activity altogether, although those drugs can be used for only a limited time. “That's a sledgehammer approach, and you can see if it makes a difference. At least it gives you an idea that, yes, it's an immune-mediated phenomenon, and now we need to find a better way to target it,” Nath says.

If the virus does hang around in some form, antiviral medications could potentially clear it, which might help resolve neurological symptoms. That's the hope of scientists running a clinical trial of Paxlovid, Pfizer's antiviral drug for acute COVID.

A Chronic Fatigue Connection?

Postviral syndromes have been documented for more than a century, arising after infection with viruses from HIV to the flu. Epstein-Barr virus, which causes mononucleosis, is one of several viruses linked to a condition called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is estimated to affect at least one and a half million people in the U.S. ME/CFS bears striking resemblances to long COVID, with symptoms such as immune system dysregulation, fatigue and cognitive dysfunction. “One of the patterns we see is patients who definitely meet the criteria for ME/CFS. This is something we are seeing and treating all the time” in long COVID patients, Pittman says. ME/CFS can be severe, with some people losing mobility and becoming bedbound.

Credit: Now Medical Studios; Sources: “Neurovascular Injury with Complement Activation and Inflammation in COVID-19,” by Myoung-Hwa Lee et al., in Brain , Vol. 145; July 2022 ( blood vessel reference ); “Olfactory Transmucosal SARS-CoV-2 Invasion as a Port of Central Nervous System Entry in Individuals with COVID-19,” by Jenny Meinhardt et al., in Nature Neuroscience , Vol. 24; February 2021 ( nasal passage reference )

Nath, who also studies ME/CFS, says that “we think mechanistically they are going to be related.” Researchers suspect that ME/CFS, like some cases of long COVID, could be autoimmune in nature, with autoantibodies keeping the immune system activated. ME/CFS has been difficult to study because it often arises long after a mild infection, making it hard to identify a viral trigger. But with long COVID, Nath says, “the advantage is that we know exactly what started the process, and you can catch cases early in the [development of] ME/CFS-like symptoms.” In people who have had ME/CFS for years, “it's done damage, and it's hard to reverse that.” Nath speculates that for long COVID, if doctors could study people early in the illness, they would have a better chance of reversing the process.

Torgerson hopes that researchers will ultimately come to better understand ME/CFS because of COVID. “COVID has been more carefully studied with better technology in the time we've had it than any other infectious disease ever. I think we'll learn things that will be applicable to other inflammatory diseases driven by infection followed by an autoimmune process.”

Team Treatment

Ghormley, after months of illness, sought care at UCLA Health's long COVID clinic, among the country's few comprehensive, multidisciplinary programs for people with this syndrome. Even though her symptoms are rooted in nervous system dysfunction, she needed an array of medical specialists to treat them. The clinic grew out of a program aimed at coordinating care for medically complex COVID patients, says its director Nisha Viswanathan, an internist and primary care physician. In following up with COVID patients after several months, she realized that “we had a group of patients who still had symptoms. There was no understanding around the condition; we were just trying to see what we could offer them.” Viswanathan and others convened a biweekly meeting of UCLA Health doctors in pulmonology, cardiology, neurology, psychiatry and other specialties to discuss individual cases and overall trends.

At UCLA Health, Pittman coordinates Ghormley's treatment. He says the interdisciplinary team is crucial to getting patients the best possible care. “Oftentimes there are so many symptoms,” and some patients have seen multiple specialists before arriving, but not necessarily the right ones. As long COVID primary care providers, he says, “we do the initial testing and get them to the right person.” For Ghormley, that list of providers includes Pittman, along with a neurologist, a pulmonologist, a cardiologist, a psychiatrist, a trauma counselor, a rheumatologist and a gynecologist.

The team approach has also been critical for doctors trying to understand a brand-new disease, Pittman says. “It's been a very interesting journey from knowing almost nothing to knowing a little bit now, and we're learning more every day, every week, every month,” he says. The term “long COVID” “is an umbrella, and I think there are multiple diseases under that umbrella.” Although each long COVID patient is unique, Pittman says, “we start to see patterns developing. And with Ghormley, we saw a pattern of dysautonomia, which we see frequently.”

Dysautonomia impairs the autonomic nervous system, a network of nerves that branch out from the brain or spinal cord and extend through the body, controlling unconscious functions such as heartbeat, breathing, sweating and blood vessel dilation. For Ghormley, like many people with long COVID, dysautonomia takes the form of postural orthostatic tachycardia syndrome, or POTS. The syndrome encompasses a collection of symptoms that include a racing heart rate—particularly on standing—and fatigue, and it can cause bowel and bladder irregularities. POTS can also be a component of the exhaustion that comes with PEM. Although the symptoms may seem to affect the body, they stem from nervous system dysfunction.

Ghormley's dysautonomia led her to see cardiologist Megha Agarwal at a UCLA clinic near her home. Many physicians are not familiar with POTS, but Agarwal is particularly attuned to it, having seen it in some of her patients before COVID hit. “There's dysregulation of the nervous system, and so many things can cause it: some cancer therapies, viruses, autoimmune conditions.” Agarwal recognized POTS in Ghormley in the fall of 2020, when very little was known about long COVID. Now she believes “POTS is really what long-haul COVID is causing” in many patients. Luckily, Agarwal says, there are medical interventions that can help.

Tachycardia—the T in POTS—causes the heartbeat to speed up, contributing to exhaustion and fatigue in addition to stressing the heart itself. Drugs called beta-blockers (for the beta-adrenergic receptors they shut off in the heart) can lower the heart rate and improve symptoms. “When heart rate is controlled, not only does the pump improve,” Agarwal says, “[but people's] energy improves, their fatigue is gone, and sometimes there's better mental clarity.” For some patients like Ghormley, beta-blockers are not enough, so Agarwal adds a medication called ivabradine. “It's a bit off-label, but it's currently being aggressively studied” for POTS. For Ghormley, the combination led to real improvements, “so now she doesn't feel like she ran the Boston Marathon when all she did was sit down and stand up at work or take a shower,” Agarwal says.

Among Ghormley's toughest symptoms is her brain fog, a catchall term for a slew of cognitive problems that make it hard for her to function. For days when Ghormley works, her psychiatrist prescribes Adderall, a stimulant used to treat attention deficit hyperactivity disorder that helps her concentrate and stay focused. That has “helped immensely,” Ghormley says.

Ghormley credits her doctors and Agarwal in particular with doing the detective work to dig into her symptoms. “Nobody knew anything about it, but everyone listened to me,” Ghormley says. Perhaps because she was a professional from a medical field, no one “brushed me aside.”

That's unusual for people with long COVID, many of them women, who are often dismissed by physicians who doubt their complaints are real. “Patients just don't feel heard,” Viswanathan says. “I had a patient who told me everything, and after, I just said, ‘This must be so hard for you. I want you to know that everything you're feeling is real, and I've seen so many patients like you.' And she started crying. She said, ‘No one has told me that. I can't tell you the number of times I was told it was in my head.’”

Credit: Now Medical Studio; Sources: “Postural Orthostatic Tachycardia Syndrome as a Sequela of COVID-19,” by Cameron K. Ormiston et al., in Heart Rhythm , Vol. 19; November 2022; “Long COVID-19 and Postural Orthostatic Tachycardia Syndrome—Is Dysautonomia to Be Blamed?” by Karan R. Chadda et al., in Frontiers in Cardiovascular Medicine ; March 2022 ( references )

In addition to drugs, other types of therapies, including physical therapy, can help improve some symptoms. But people who experience PEM face a particular challenge when using movement therapies. Pittman says the exertion can make these patients feel worse. “We don't want patients to go to not moving at all, but sometimes the type of movement they're doing may be flaring their symptoms.” He notes that often PEM strikes young, previously healthy people who will say, “‘I need to push myself,' and then they go way too far and get worse. Our job is to try to find that middle ground and then make that consistent over time, so they're not getting further deconditioned but they don't have the PEM, which has been shown to set them back.”

The Long Haul

Some patients, Pittman says, “have the expectation that they're going to come in, and within a month they're going to be back to normal. And resetting those expectations can be really challenging. You have to be really empathetic because people's lives have completely changed.” But sometimes patients' quality of life can improve noticeably when they are able to adjust to a new normal. Still, he says, “patients have so many questions, and I can't lead them down a physiological pathway. I can tell them there's neuroinflammation, maybe there's autoimmunity, but we still don't have the answers. Sometimes it's really tough for us to accept and for the patient to accept that we just have to try our best.”

A number of people, Viswanathan says, benefit from reducing various treatments they have accumulated. Some people become so desperate that they will try anything from supplements to off-label medications to untested potions from the Internet. Stopping those sometimes leads to improved symptoms, she says.

Psychological care and support groups can help. Lavretsky adds that “lifestyle choices can play a huge role in improvement,” particularly better sleep habits and the use of breathing exercises to control anxiety. She tells people their bodies can heal themselves if the patients and clinicians find the right tools.

Whether that's true for everyone remains to be seen, Viswanathan says. “We see many patients who have gotten better with time. I have patients whose symptoms have disappeared in the course of a year, or they disappear and occasionally flare up again.” But for some, she says, “it could last many years.”

“We're going to be addressing this for probably decades,” Viswanathan says. “COVID is not going to go away so much as we're just going to get used to living with it, but part of [that] means that people will continue to develop long COVID.”

Vaccination appears to reduce the risk of long COVID. But a study published in May 2022 in Nature Medicine suggests the protection, though real, is not as good as one might hope. The survey of electronic health records from the U.S. Department of Veterans Affairs looked at the relatively small portion of vaccinated people who subsequently became infected. They developed long COVID only 15 percent less often than unvaccinated people. “These patients can have symptoms for one to two years or longer, and so every month you're racking up more patients. Even if it's 15 percent less, the total population of patients is still growing and exploding,” Pittman says. The best way to avoid getting long COVID, experts all agree, is to avoid getting COVID at all.

The syndrome is still mired in a lot of medical uncertainty. Patients might have one or a combination of the problems investigated so far: Long COVID might be caused by viral particles that persist in the brain or other parts of the nervous system. Or it might be an autoimmune disorder that lasts long after the virus has disappeared. Maybe overactive immune cells continue to perturb the nervous system and nearby blood vessels. Fortunately, the increasing ability to recognize specific problems is helping clinicians hone treatments that give patients the best chance of recovery.

Although Ghormley says her care has dramatically improved her symptoms and allowed her to “do some normal things again,” she continues to experience flare-ups that make it impossible for her to work for weeks at a time. One day last year she skipped a dose of her heart medication and made a Target run in the southern California heat. “I got home and basically collapsed in the hallway,” she says, and even months later things were “out of whack. If I try to move around, my legs give out.” Most frustrating—and scary—to Ghormley is the unpredictability of her symptoms. “They have changed so much; some are manageable, some debilitating. One thing will get better, and another thing comes back. I'm always hopeful that it's going to get better, but I just don't know.”

Stephani Sutherland is a neuroscientist and science journalist based in southern California. She wrote about the causes of autoimmune diseases in our September 2021 issue. Follow her on Twitter @SutherlandPhD

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Study identifies risk factors for long-haul COVID disease in adults

Lynda De Widt

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Mayo Clinic researchers have identified risk factors that can cause adult COVID-19 patients to suffer symptoms that linger for months or years. The condition is often referred to as long-haul COVID . The findings are reported in the Journal of Investigative Medicine .

Researchers surveyed more than 3,000 adults over the age of 18 who were treated via Mayo Clinic's virtual COVID-19 clinics in Florida, Arizona and Minnesota between March 2020 and March 2021. They reviewed the patients' symptoms, the incidence of long-haul COVID in the group and how many were hospitalized due to COVID-19. The patients were also asked to rate their perception of the severity of their symptoms, whether they received a diagnosis of long-haul COVID, how long it took for them to resume their usual activities, and how much time they missed from work.

Study Findings

"We found that patients with severe COVID-19 symptoms were more likely to have long-haul COVID than those who had mild symptoms," says Bala Munipalli, M.D., an internist at Mayo Clinic in Florida and co-senior author of the study. "A majority of these were women who had been hospitalized, suffered from psychological impacts from COVID-19 such as anxiety and depression, and required more than one month to return to their normal activities after the illness."

The average age of the respondents in the study was 54 and most were women, including 57% of the patients surveyed who reported severe symptoms; 60% with mild symptoms; and 65% with moderate symptoms. Most patients (92%) with mild symptoms were able to resume their usual schedules within four weeks after COVID-19 infection, but 23% of these patients with mild acute infection developed long-haul COVID. Significantly more (37.4%) patients with severe symptoms were hospitalized than those with mild (0.9%) or moderate symptoms (4.8%). Hospitalized patients also reported having persistent symptoms of long-haul COVID (67%), needing a month or more to resume their usual activities, missing work for at least three weeks, and having negative psychological side effects.

Most respondents in the study reported long-haul COVID symptoms that lasted three to six months, with those symptoms ranging in severity. The most common symptoms in the study group were fatigue, loss of smell, altered taste, shortness of breath and poor sleep.

More to learn

"The inability to resume normal activities within one month after acute COVID-19 may be a predictive factor for long-haul COVID. As we continue to study this disease, we hope to gain a better understanding of who is susceptible to it, the symptoms that remain persistent, and how to best manage these patients in the early course of their illness," says Dr. Munipalli. "Additional studies may help guide the standardization of future assessment tools to evaluate impairment and also provide valuable information to employers, educators, policymakers and patients."

The researchers note that a multidisciplinary approach to long-haul COVID is needed and that healthcare personnel should recognize key symptoms, obtain a careful medical history and physical examination, as well as pay close attention to comorbid medical conditions in patients with persistent symptoms.

Dr. Munipalli says her team plans additional research focusing on treatments for long-haul COVID.

Other Mayo Clinic researchers on this paper include Abd Moain Abu Dabrh, M.B., B.Ch., M.S. ; Dacre Knight, M.D. ; Ilana Logvinov, M.D.; Stefan Paul; Troy Delaney, Yaohua Ma; Zhuo Li; and Ravindra Ganesh, M.B.B.S., M.D.

• Mayo Clinic in Florida opens downtown Jacksonville site focused on education, research Mayo Clinic expert answers questions about the new COVID-19 vaccine

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A blood test for long Covid is possible, a study suggests

More than three years into the pandemic, the millions of people who have suffered from long Covid finally have scientific proof that their condition is real.

Scientists have found clear differences in the blood of people with long Covid — a key first step in the development of a test to diagnose the illness.

The findings, published Monday in the journal Nature , also offer clues into what could be causing the elusive condition that has perplexed doctors worldwide and left millions with ongoing fatigue, trouble with memory and other debilitating symptoms.

The research is among the first to prove that "long Covid is, in fact, a biological illness," said David Putrino, principal investigator of the new study and a professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai in New York.

Dr. Marc Sala, co-director of the Northwestern Medicine Comprehensive Covid-19 Center in Chicago, called the findings "important." He was not involved with the new research.

"This will need to be investigated with more research, but at least it's something because, quite frankly, right now we don't have any blood tests" either to diagnose long Covid or help doctors understand why it's occurring, he said.

Putrino and his colleagues compared blood samples of 268 people. Some had Covid but had fully recovered, some had never been infected, and the rest had ongoing symptoms of long Covid at least four months after their infection.

Several differences in the blood of people with long Covid stood out from the other groups.

The activity of immune system cells called T cells and B cells — which help fight off germs — was "irregular" in long Covid patients, Putrino said. One of the strongest findings, he said, was that long Covid patients tended to have significantly lower levels of a hormone called cortisol.

A major function of the hormone is to make people feel alert and awake. Low cortisol could help explain why many people with long Covid experience profound fatigue, he said.

"It was one of the findings that most definitively separated the folks with long Covid from the people without long Covid," Putrino said.

The finding likely signals that the brain is having trouble regulating hormones. The research team plans to dig deeper into the role cortisol may play in long Covid in future studies.

Meanwhile, doctors do not recommend simply boosting a person's cortisol levels in an attempt to "fix" the problem.

"There is no evidence that replacing cortisol in someone with long Covid would be a safe or effective thing to do," Sala said.

The study also found that dormant viruses , such as the one that causes mononucleosis, Epstein-Barr, come alive again in long Covid patients. It's unclear, however, whether those old viruses are causing symptoms or flagging a problem within the immune system.

"We were looking for signals, and we found them," said Akiko Iwasaki, one of the researchers and a professor of immunobiology and molecular, cellular and developmental biology at the Yale School of Medicine. "Now what we need to do is home in on each of these signals and understand better how the disease has been driven by these signals."

The investigators did not find significant evidence that long Covid is the result of an autoimmune disorder, in which the body attacks itself.

Dr. Clinton Wright, director of the National Institute of Neurological Disorders and Stroke's division of clinical research, said additional studies will be necessary to find other ways Covid may lead to long-term symptoms. One theory is that the virus is hiding in brain tissue or other organs.

"We're really interested in whether the virus still exists in reservoirs in the body," he said. "It's really hard to do that by measuring blood." He was not involved with the new study.

Long Covid affects 1 in 13 U.S. adults , or 7.5%, according to the Centers for Disease Control and Prevention.

The findings offer hope to patients like Joshua Roman, 39, of New York City, who participated in the study.

"We're in such a mysterious swamp of symptoms," he said. "My long Covid treatment is just management of symptoms ."

Roman, a professional musician who plays the cello, takes daily medication to ease the lingering physical trembling that affects his ability to perform.

"It would be great if we could get to the thing that's causing me to shake in the first place, but we still don't know exactly what that is," he said.

Follow  NBC HEALTH  on  Twitter  &  Facebook .

Erika Edwards is a health and medical news writer and reporter for NBC News and "TODAY."

Blood Test Could Predict Risk of Long-Term COVID-19 Lung Problems

March 14, 2024 • By Josh Barney, [email protected] Josh Barney, [email protected]

• Josh Barney , [email protected]

UVA Health researchers are hopeful that new discoveries about long-term COVID’s impact on the lungs will provide doctors a useful tool to identify patients at risk for long-haul lung problems – and to help guide their recovery. (Illustration by John DiJulio, University Communications)

UVA Health researchers have discovered a potential way to predict which patients with severe COVID-19 are likely to recover well and which are likely to suffer “long-haul” lung problems, a finding that could better personalize treatments for individual patients.

UVA’s new research also eases concern that severe COVID-19 could trigger relentless, ongoing lung scarring akin to the chronic lung disease known as idiopathic pulmonary fibrosis, in which continuing lung damage eventually proves fatal.

“We are excited to find that people with long-haul COVID have an immune system that is totally different from people who have lung scarring that doesn’t stop,” said researcher Dr. Catherine A. Bonham, a pulmonary and critical care expert and scientific director of UVA Health’s Interstitial Lung Disease Program. “This offers hope that even patients with the worst COVID do not have progressive scarring of the lung that leads to death.”

Long-Haul COVID-19

Up to 30% of patients hospitalized with severe COVID-19 continue to suffer persistent symptoms months after recovering from the virus. Many of these patients develop lung scarring – some early on in their hospitalization, and others within six months of their initial illness, prior research has found.

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Bonham and her collaborators wanted to better understand why this scarring occurs, determine if it is similar to progressive pulmonary fibrosis and see if there is a way to identify patients at risk.

Researchers followed 16 UVA Health patients who survived severe COVID-19, including 14 who were hospitalized and placed on a ventilator during treatment. All had trouble breathing and suffered fatigue and abnormal lung function at their first outpatient checkup.

After six months, researchers found that the patients could be divided into two groups. One group’s lung health improved, prompting the researchers to label them “early resolvers.” The other group, dubbed “late resolvers,” continued to suffer lung problems and pulmonary fibrosis.

Looking at blood samples taken before the recovery paths diverged, the team found that late resolvers had significantly fewer immune cells known as monocytes – white blood cells that play a critical role fending off disease – circulating in their blood. The cells were abnormally depleted in patients who continued to suffer lung problems compared both to those who recovered and healthy control subjects.

Dr. Catherine A. Bonham, a pulmonary and critical care expert and scientific director of UVA Health’s Interstitial Lung Disease Program, said the discovery offers hope that COVID patients will not suffer progressive scarring of the lung. (Photo by Sanjay Suchak, University Communications)

The decrease in monocytes also correlated with the severity of the patients’ ongoing symptoms. That suggests that doctors may be able to use a simple blood test to identify patients likely to suffer long-haul COVID and to improve their care.

“About half of the patients we examined still had lingering, bothersome symptoms and abnormal tests after six months,” Bonham said. “We were able to detect differences in their blood from the first visit, with fewer blood monocytes mapping to lower lung function.”

The researchers also wanted to determine if severe COVID-19 could cause progressive lung scarring like idiopathic pulmonary fibrosis. They found the two conditions had very different effects on immune cells, suggesting that even though symptoms were similar, the underlying causes were very different. This held true in patients with the most persistent long-haul COVID-19 symptoms.

“Idiopathic pulmonary fibrosis is progressive and kills patients within three to five years,” Bonham said. “It was a relief to see that all our COVID patients, even those with long-haul symptoms, were not similar.”

Because of the small numbers of participants in UVA’s study, and because they were mostly male (for easier comparison with idiopathic pulmonary fibrosis, a disease that strikes mostly men), the researchers say larger studies with other medical centers are needed to bear out the findings.

Still, they are hopeful that their new discovery will provide doctors a useful tool to identify COVID-19 patients at risk for long-haul lung problems and help guide them to recovery.

“We are only beginning to understand the biology of how the immune system impacts pulmonary fibrosis,” Bonham said. “My team and I were humbled and grateful to work with the outstanding patients who made this study possible.”

Findings Published

The researchers have  published their findings in the scientific journal Frontiers in Immunology . The research team consisted of Grace C. Bingham, Lyndsey M. Muehling, Chaofan Li, Yong Huang, Shwu-Fan Ma, Daniel Abebayehu, Imre Noth, Jie Sun, Judith A. Woodfolk, Thomas H. Barker and Bonham. Noth disclosed that he has received personal fees from Boehringer Ingelheim, Genentech and Confo unrelated to the research project. In addition, he has a patent pending related to idiopathic pulmonary fibrosis. Bonham and all other members of the research team had no financial conflicts to disclose.

To keep up with the latest medical research news from UVA, subscribe to UVA Health’s   Making of Medicine  blog.

The UVA research was supported by the National Institutes of Health, grants R21 AI160334 and U01 AI125056; NIH’s National Heart, Lung and Blood Institute, grants 5K23HL143135-04 and UG3HL145266; UVA’s Engineering in Medicine Seed Fund; the UVA Global Infectious Diseases Institute’s COVID-19 Rapid Response; a UVA Robert R. Wagner Fellowship; and a Sture G. Olsson Fellowship in Engineering.

Media Contact

Josh Barney

[email protected] 434-906-8864

Article Information

March 16, 2024

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• New research offers possible cause for long COVID

Pieces of the COVID virus can lurk in our blood and tissue for more than a year after the initial illness has vanished, a discovery that might offer clues to the mystery of lingering post-infection disability, according to new research from UC San Francisco.

Four years after the U.S. went into lockdown, the worst of the pandemic has passed. But for people with long COVID, the illness remains a daily misery.

The new research suggests why: The virus is not always fully cleared after the initial infection, so remains embedded, even though people are no longer contagious.

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It is not yet known if these small viral proteins, called antigens, are causing long COVID. But, based on the new discovery, the UCSF team is conducting clinical trials of potential therapies that could attack the hidden pathogen.

“There is a lot more work to be done, but I feel like we are making progress in really understanding the long-term consequences of this infection,” said infectious disease expert Dr. Michael Peluso, who presented the research at last week’s Conference on Retroviruses and Opportunistic Infections.

While COVID remains much more serious than the usual seasonal flu, safe and highly effective vaccines have caused a dramatic decline in infections and deaths.

There is a desperate need for a diagnostic test and treatment for long COVID, which affects an estimated 7% of American adults. Currently, doctors are only treating the symptoms, rather than offering a cure. Experts predict that the disorder will place continuing demands on our health care system.

“Long COVID patients deserve swift, accurate diagnosis and timely, effective treatment,” said Jaime Seltzer, scientific director at the nonprofit MEAction, which advocates for patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS.

Is the clandestine virus constantly provoking the immune system, causing symptoms? That’s one leading theory. Another possibility is that COVID triggers an autoimmune response when the body mistakenly attacks itself. Or perhaps, long after it fends off infection, the immune system fails to turn off.

Using an ultrasensitive test of blood from 171 people who had been infected with COVID, the UCSF scientists found pieces of the viral “spike” protein that persisted up to 14 months after infection.

They discovered that the likelihood of detecting the protein was about twice as high in people who had been severely ill, requiring hospitalization, than those who were not. Detection was also higher in the blood of people who reported being very sick but were not hospitalized.

In tissue samples, traces of the virus were found up to two years after infection. It was hidden in connective tissue where immune cells are located.

The work was conducted at UCSF’s Long COVID Tissue Bank, the world’s first tissue bank with samples donated by patients with long COVID.

It provides some of the strongest evidence so far that COVID antigens can persist in some people, according to Peluso.

“The UCSF team includes people who helped make HIV and AIDS a treatable disease,” according to Amy Proal, president of PolyBio, a research foundation focused on long COVID. “These researchers rapidly pivoted into long COVID research at the outset of the pandemic, leveraging years of experience performing similar research with patients with HIV and AIDS.”

Persistent COVID infections — caused by actively replicating virus — were recently reported in another study based on a large community surveillance project in the United Kingdom. It found that 1% to 3% of people had persistent infections for more than 30 days and 0.1% to 0.5% had them for more than 60 days.

This is worrisome because these persistent active infections may act as viral “reservoirs” that lead to new and highly genetically divergent lineages, seeding a future outbreak.

That study found that the risk of long COVID was 55% higher in people with persistent infection.

“We’re making considerable headway on understanding what drives long COVID,” wrote Dr. Eric Topol, director of the Scripps Research Translational Institute in La Jolla.

“Clearly finding effective and safe treatments is an urgent matter and not enough is being done to pursue that yet, despite a long list of potential alluring interventions based on mechanistic insights,” he said. “Hopefully that will get going now — it cannot happen soon enough.”

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Simple blood test could predict risk of long-term COVID-19 lung problems

by University of Virginia

UVA Health researchers have discovered a potential way to predict which patients with severe COVID-19 are likely to recover well and which are likely to suffer "long-haul" lung problems. That finding could help doctors better personalize treatments for individual patients.

UVA's new research also alleviates concerns that severe COVID-19 could trigger relentless, ongoing lung scarring akin to the chronic lung disease known as idiopathic pulmonary fibrosis , the researchers report. That type of continuing lung damage would mean that patients' ability to breathe would continue to worsen over time.

"We are excited to find that people with long-haul COVID have an immune system that is totally different from people who have lung scarring that doesn't stop," said researcher Catherine A. Bonham, MD, a pulmonary and critical care expert who serves as scientific director of UVA Health's Interstitial Lung Disease Program. "This offers hope that even patients with the worst COVID do not have progressive scarring of the lung that leads to death."

Long-haul COVID-19

Up to 30% of patients hospitalized with severe COVID-19 continue to suffer persistent symptoms months after recovering from the virus. Many of these patients develop lung scarring—some early on in their hospitalization and others within six months of their initial illness, prior research has found. Bonham and her collaborators wanted to understand better why this scarring occurs, to determine if it is similar to progressive pulmonary fibrosis and to see if there is a way to identify patients at risk.

To do this, the researchers followed 16 UVA Health patients who had survived severe COVID-19. Fourteen had been hospitalized and placed on a ventilator. All continued to have trouble breathing and suffered fatigue and abnormal lung function at their first outpatient checkup.

After six months, the researchers found that the patients could be divided into two groups: One group's lung health improved, prompting the researchers to label them "early resolvers," while the other group, dubbed "late resolvers," continued to suffer lung problems and pulmonary fibrosis.

Looking at blood samples taken before the patients' recovery began to diverge, the UVA team found that the late resolvers had significantly fewer immune cells, known as monocytes, circulating in their blood. These white blood cells play a critical role in our ability to fend off disease, and the cells were abnormally depleted in patients who continued to suffer lung problems compared both to those who recovered and healthy control subjects.

Further, the decrease in monocytes correlated with the severity of the patients' ongoing symptoms. That suggests that doctors may be able to use a simple blood test to identify patients likely to become long-haulers—and to improve their care.

"About half of the patients we examined still had lingering, bothersome symptoms and abnormal tests after six months," Bonham said. "We were able to detect differences in their blood from the first visit, with fewer blood monocytes mapping to lower lung function."

The researchers also wanted to determine if severe COVID-19 could cause progressive lung scarring, as in idiopathic pulmonary fibrosis. They found that the two conditions had very different effects on immune cells, suggesting that even when the symptoms were similar, the underlying causes were very different. This held true even in patients with the most persistent long-haul COVID-19 symptoms.

"Idiopathic pulmonary fibrosis is progressive and kills patients within three to five years," Bonham said. "It was a relief to see that all our COVID patients, even those with long-haul symptoms, were not similar."

Because of the small number of participants in UVA's study and because they were mostly male (for easier comparison with IPF, a disease that strikes mostly men), the researchers say larger, multi-center studies are needed to bear out the findings. But they are hopeful that their new discovery will provide doctors a useful tool to identify COVID-19 patients at risk for long-haul lung problems and help guide them to recovery.

"We are only beginning to understand the biology of how the immune system impacts pulmonary fibrosis," Bonham said. "My team and I were humbled and grateful to work with the outstanding patients who made this study possible."

The paper is published in the journal Frontiers in Immunology .

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News releases.

News Release

Tuesday, March 12, 2024

NIH opens long COVID trials to evaluate treatments for autonomic nervous system dysfunction

Part of NIH’s RECOVER Initiative, trials will test at least three treatments for symptoms such as fast heart rate, dizziness and fatigue.

Two phase 2 clinical trials to test the safety and effectiveness of three treatments for adults with autonomic nervous system dysfunction from long COVID have begun. The autonomic nervous system acts largely unconsciously and regulates bodily functions, such as heart rate, digestion and respiratory rate. Symptoms associated with autonomic nervous system dysfunction have been among those that patients with long COVID say are most burdensome. The trials are part of the National Institutes of Health’s Researching COVID to Enhance Recovery (RECOVER) Initiative, a nationwide research program to fully understand, diagnose and treat long COVID. Other RECOVER phase 2 clinical trials testing treatments to address viral persistence and neurological symptoms, including cognitive dysfunction (like brain fog), launched in July 2023.

“As a long COVID patient, I know firsthand how disruptive and frightening symptoms including rapid heart rate, dizziness and fatigue can be. Patient representatives across RECOVER have also shared that these symptoms are some of the most debilitating symptoms of long COVID,” said Heather Marti, co-chair of the RECOVER National Community Engagement Group. “These trials are giving me and others with long COVID hope that it will restore our health and get us back to the lives we so desire.”

The two trials, collectively known as RECOVER-AUTONOMIC, are testing three potential treatments in adults who, following COVID-19, now have postural orthostatic tachycardia syndrome (POTS). An autonomic nervous system disorder, POTS is characterized by unexpected fast heart rate, dizziness, fatigue or a combination of these symptoms when a person stands up from sitting or lying down. 

“The trials were developed with input from people living with long COVID, caregivers, community representatives, clinicians and scientists all with unique expertise in the field,” said Gary H. Gibbons, M.D., director of the National Heart, Lung, and Blood Institute at the NIH and co-chair of RECOVER. “We are grateful for their collective involvement which significantly shaped the trials and the choice of interventions.”

The trials will initially examine three potential treatments:

• Gamunex-C, a form of intravenous immunoglobulin (IVIG), contains antibodies to help the body protect itself against infection from various diseases and is given by intravenous infusion.
• Ivabradine, an oral medication that reduces heart rate.
• Coordinator-guided, non-drug care, which includes a series of activities managed through weekly phone calls with a care coordinator, such as wearing a compression belt and eating a high-salt diet, which are recommended for patients with POTS to counteract excessive loss of fluids.  

“Patients who develop POTS after having COVID-19 are often severely limited by their symptoms, and there are no proven effective treatments,” said Christopher Granger, M.D., Duke University Medical Center, who is co-leading RECOVER-AUTONOMIC. “These interventions were selected because they have shown potential benefit in treating symptoms for POTS. The theory we’re testing is that they might also help individuals with long COVID.”  

Participants will first be randomly assigned to receive either IVIG, ivabradine or a placebo. Participants will then be randomly assigned a second time to receive either coordinator-guided, non-drug care or what is considered the usual non-drug care for POTS following COVID-19, such as diet and lifestyle recommendations. RECOVER-AUTONOMIC is an adaptive clinical trial, meaning if additional potential interventions emerge, they can quickly be added and studied in the trial.

Researchers plan to enroll 380 total participants at 50 sites across the United States. Teams at the trial sites will recruit participants from their health systems and surrounding communities. The current list of sites for the trials can be found on ClinicalTrials.gov (search: NCT06305793, NCT06305806 and NCT06305780) and additional sites will be added to this list as they begin enrolling participants.

Diversity among the trial participants is a high priority for RECOVER. To support diverse and inclusive representation, study sites are chosen based on geographic location, their connections to communities, and their track records for enrolling diverse research participants.

With the launch of the RECOVER-AUTONOMIC trials, RECOVER is currently testing seven treatments across four clinical trials and continues to enroll participants. Those interested in learning more about RECOVER clinical trials should visit trials.recovercovid.org .

About RECOVER : The National Institutes of Health Researching COVID to Enhance Recovery (NIH RECOVER) Initiative brings together clinicians, scientists, caregivers, patients, and community members to understand, diagnose, and treat long COVID. RECOVER has created one of the largest and most diverse groups of long COVID study participants in the world. In addition, RECOVER clinical trials are testing potential interventions across five symptom focus areas. For more information, please visit recovercovid.org . 

HHS Long COVID Coordination: This work is a part of the National Research Action Plan , a broader government-wide effort in response to the Presidential Memorandum directing the Secretary for the Department of Health and Human Services to mount a full and effective response to long COVID. Led by Assistant Secretary for Health Admiral Rachel Levine, the Plan and its companion Services and Supports for Longer-term Impacts of COVID-19 report lay the groundwork to advance progress in the prevention, diagnosis, treatment, and provision of services for individuals experiencing long COVID.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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Scientists Offer a New Explanation for Long Covid

By Pam Belluck

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A team of scientists is proposing a new explanation for some cases of long Covid, based on their findings that serotonin levels were lower in people with the complex condition.

In their study , published on Monday in the journal Cell, researchers at the University of Pennsylvania suggest that serotonin reduction is triggered by remnants of the virus lingering in the gut. Depleted serotonin could especially explain memory problems and some neurological and cognitive symptoms of long Covid, they say.

Why It Matters: New ways to diagnose and treat long Covid.

This is one of several new studies documenting distinct biological changes in the bodies of people with long Covid — offering important discoveries for a condition that takes many forms and often does not register on standard diagnostic tools like X-rays.

The research could point the way toward possible treatments, including medications that boost serotonin. And the authors said the biological pathway that their research outlines could unite many of the major theories of what causes long Covid: lingering remnants of the virus, inflammation, increased blood clotting and dysfunction of the autonomic nervous system.

“All these different hypotheses might be connected through the serotonin pathway,” said Christoph Thaiss, a lead author of the study and an assistant professor of microbiology at the Perelman School of Medicine at the University of Pennsylvania.

“Second of all, even if not everybody experiences difficulties in the serotonin pathway, at least a subset might respond to therapies that activate this pathway,” he said.

“This is an excellent study that identifies lower levels of circulating serotonin as a mechanism for long Covid,” said Akiko Iwasaki, an immunologist at Yale University. Her team and colleagues at the Icahn School of Medicine at Mount Sinai recently published a study that identified other biological changes linked to some cases of long Covid, including levels of the hormone cortisol. These studies could point to specific subtypes of long Covid or different biological indicators at different points in the condition.

The Back Story: A series of disruptions set off by bits of virus in the gut.

Researchers analyzed the blood of 58 patients who had been experiencing long Covid for between three months and 22 months since their infection. Those results were compared to blood analysis of 30 people with no post-Covid symptoms and 60 patients who were in the early, acute stage of coronavirus infection.

Maayan Levy, a lead author and assistant professor of microbiology at the Perelman School of Medicine, said levels of serotonin and other metabolites were altered right after a coronavirus infection, something that also happens immediately after other viral infections.

But in people with long Covid, serotonin was the only significant molecule that did not recover to pre-infection levels, she said.

The team analyzed stool samples from some of the long Covid patients and found that they contained remaining viral particles. Putting the findings in patients together with research on mice and miniature models of the human gut, where most serotonin is produced, the team identified a pathway that could underlie some cases of long Covid.

Here’s the idea: Viral remnants prompt the immune system to produce infection-fighting proteins called interferons. Interferons cause inflammation that reduces the body’s ability to absorb tryptophan, an amino acid that helps produce serotonin in the gut. Blood clots that can form after a coronavirus infection may impair the body’s ability to circulate serotonin.

Depleted serotonin disrupts the vagus nerve system, which transmits signals between the body and the brain, the researchers said. Serotonin plays a role in short-term memory, and the researchers proposed that depleted serotonin could lead to memory problems and other cognitive issues that many people with long Covid experience.

“They showed that one-two-three punch to the serotonin pathway then leads to vagal nerve dysfunction and memory impairment,” Dr. Iwasaki said.

There are caveats. The study was not large, so the findings need to be confirmed with other research. Participants in some other long Covid studies, in which some patients had milder symptoms, did not always show depleted serotonin, a result that Dr. Levy said might indicate that depletion happened only in people whose long Covid involves multiple serious symptoms.

What’s Next: A clinical trial of Prozac.

Scientists want to find biomarkers for long Covid — biological changes that can be measured to help diagnose the condition. Dr. Thaiss said the new study suggested three: the presence of viral remnants in stool, low serotonin and high levels of interferons.

Most experts believe that there will not be a single biomarker for the condition, but that several indicators will emerge and might vary, based on the type of symptoms and other factors.

There is tremendous need for effective ways to treat long Covid, and clinical trials of several treatments are underway. Dr. Levy and Dr. Thaiss said they would be starting a clinical trial to test fluoxetine, a selective serotonin reuptake inhibitor often marketed as Prozac, and possibly also tryptophan.

“If we supplement serotonin or prevent the degradation of serotonin, maybe we can restore some of the vagal signals and improve memory and cognition and so on,” Dr. Levy said.

Pam Belluck is a health and science writer whose honors include sharing a Pulitzer Prize and winning the Victor Cohn Prize for Excellence in Medical Science Reporting. She is the author of “Island Practice,” a book about an unusual doctor. More about Pam Belluck

New Long COVID Findings Offer Fuller Picture of Condition

Research published this week suggests that a test for long COVID could be possible.

Study: 1 in 14 Hit With Long COVID

Seth Wenig | AP

A woman walks through a door with a sign asking shoppers to wear masks in New York on Feb. 9, 2022.

COVID-19 isn’t going away – and neither is long COVID. But new data about its prevalence as well as research into biomarkers of long COVID published this week are helping researchers understand what to look for when it comes to the condition.

Data published by the Centers for Disease Control and Prevention’s National Center for Health Statistics on Tuesday was a stark reminder that, while not widespread, some children are affected by long COVID.

Pulling from the 2022 National Health Interview Survey, the data shows that 1.3% of children ever had long COVID as of last year, according to reports from their parents.

The researchers defined long COVID as the “presence of symptoms for at least 3 months after having COVID-19 among those who received either a positive test or a doctor’s diagnosis of COVID-19.”

The rate of long COVID is significantly higher among adults than in children. The survey found that in 2022, about 7% of adults – or about 1 in 14 – reported ever having long COVID. More women reported having had long COVID than men – a trend also observed in children.

Adults ages 35-49 were most likely to have had long COVID, according to the data. Hispanic adults were more likely than Black and white adults to have it.

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The survey also found a higher prevalence of long COVID among Americans living in more rural areas compared with those living in large central metropolitan areas.

There are no approved treatments or tests for the condition. Its cause (or, more likely, causes) remains unknown, though studies have made some progress .

Research published Monday in the journal Nature found that people with long COVID have clear differences in their hormone and immune function when compared to people without the condition. The findings offer hope that a test for the condition is possible.

“These findings are important – they can inform more sensitive testing for long COVID patients and personalized treatments for long COVID that have, until now, not had a proven scientific rationale,” David Putrino, principal investigator of the study, said in a statement . “This is a decisive step forward in the development of valid and reliable blood testing protocols for long COVID.”

The study looked at survey results and blood samples from 270 individuals. It found that the blood of those experiencing long COVID had specific biomarkers, like abnormal T cell activity, reactivation of dormant viruses and low cortisol levels.

“These markers need to be validated in larger studies, but provide a first step in dissecting the disease pathogenesis of long COVID,” Akiko Iwasaki, co-principal investigator of the study, said in a statement.

Coronavirus metrics are increasing in the U.S., underscoring that COVID-19 – as well as long COVID – will be a lasting problem. Health officials have moved away from trying to prevent coronavirus infections, instead shifting their focus to preventing hospitalizations and deaths. Still, many Americans are dealing with repeat infections of COVID-19, which can come with increased risk for a myriad of health problems.

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Disclaimer: The Spanish COVID-19 site is currently undergoing significant updates which may lead to a delay in translated content. We apologize for any inconvenience.

Long COVID or Post-COVID Conditions

Some people who have been infected with the virus that causes COVID-19 can experience long-term effects from their infection, known as Long COVID or Post-COVID Conditions (PCC). Long COVID is broadly defined as signs, symptoms, and conditions that continue or develop after acute COVID-19 infection. This definition  of Long COVID was developed by the Department of Health and Human Services (HHS) in collaboration with CDC and other partners.

People call Long COVID by many names, including Post-COVID Conditions, long-haul COVID, post-acute COVID-19, long-term effects of COVID, and chronic COVID. The term post-acute sequelae of SARS CoV-2 infection (PASC) is also used to refer to a subset of Long COVID.

What You Need to Know

• Long COVID is a real illness and can result in chronic conditions that require comprehensive care. There are resources available .
• Long COVID can include a wide range of ongoing health problems; these conditions can last weeks, months, or years.
• Long COVID occurs more often in people who had severe COVID-19 illness, but anyone who has been infected with the virus that causes COVID-19 can experience it.
• People who are not vaccinated against COVID-19 and become infected may have a higher risk of developing Long COVID compared to people who have been vaccinated.
• People can be reinfected with SARS-CoV-2, the virus that causes COVID-19, multiple times. Each time a person is infected or reinfected with SARS-CoV-2, they have a risk of developing Long COVID.
• While most people with Long COVID have evidence of infection or COVID-19 illness, in some cases, a person with Long COVID may not have tested positive for the virus or known they were infected.
• CDC and partners are working to understand more about who experiences Long COVID and why, including whether groups disproportionately impacted by COVID-19 are at higher risk.

In July 2021, Long COVID was added as a recognized condition that could result in a disability under the Americans with Disabilities Act (ADA). Learn more: Guidance on “Long COVID” as a Disability Under the ADA .

About Long COVID

Long COVID is a wide range of new, returning, or ongoing health problems that people experience after being infected with the virus that causes COVID-19. Most people with COVID-19 get better within a few days to a few weeks after infection, so at least 4 weeks after infection is the start of when Long COVID could first be identified. Anyone who was infected can experience Long COVID. Most people with Long COVID experienced symptoms days after first learning they had COVID-19, but some people who later experienced Long COVID did not know when they got infected.

There is no test that determines if your symptoms or condition is due to COVID-19. Long COVID is not one illness. Your healthcare provider considers a diagnosis of Long COVID based on your health history, including if you had a diagnosis of COVID-19 either by a positive test or by symptoms or exposure, as well as based on a health examination.

Science behind Long COVID

RECOVER: Researching COVID to Enhance Recovery

People with Long COVID may experience many symptoms.

People with Long COVID can have a wide range of symptoms that can last weeks, months, or even years after infection. Sometimes the symptoms can even go away and come back again. For some people, Long COVID can last weeks, months, or years after COVID-19 illness and can sometimes result in disability.

Long COVID may not affect everyone the same way. People with Long COVID may experience health problems from different types and combinations of symptoms that may emerge, persist, resolve, and reemerge over different lengths of time. Though most patients’ symptoms slowly improve with time, speaking with your healthcare provider about the symptoms you are experiencing after having COVID-19 could help determine if you might have Long COVID.

People who experience Long COVID most commonly report:

General symptoms ( Not a Comprehensive List)

• Tiredness or fatigue that interferes with daily life
• Symptoms that get worse after physical or mental effort (also known as “ post-exertional malaise ”)

Respiratory and heart symptoms

• Difficulty breathing or shortness of breath
• Fast-beating or pounding heart (also known as heart palpitations)

Neurological symptoms

• Difficulty thinking or concentrating (sometimes referred to as “brain fog”)
• Sleep problems
• Dizziness when you stand up (lightheadedness)
• Pins-and-needles feelings
• Change in smell or taste
• Depression or anxiety

Digestive symptoms

• Stomach pain

Other symptoms

• Joint or muscle pain
• Changes in menstrual cycles

Symptoms that are hard to explain and manage

Some people with Long COVID have symptoms that are not explained by tests or easy to manage.

People with Long COVID may develop or continue to have symptoms that are hard to explain and manage. Clinical evaluations and results of routine blood tests, chest X-rays, and electrocardiograms may be normal. The symptoms are similar to those reported by people with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and other poorly understood chronic illnesses that may occur after other infections. People with these unexplained symptoms may be misunderstood by their healthcare providers, which can result in a delay in diagnosis and receiving the appropriate care or treatment.

Review these tips to help prepare for a healthcare provider appointment for Long COVID.

Health conditions

Some people experience new health conditions after COVID-19 illness.

Some people, especially those who had severe COVID-19, experience multiorgan effects or autoimmune conditions with symptoms lasting weeks, months, or even years after COVID-19 illness. Multi-organ effects can involve many body systems, including the heart, lung, kidney, skin, and brain. As a result of these effects, people who have had COVID-19 may be more likely to develop new health conditions such as diabetes, heart conditions, blood clots, or neurological conditions compared with people who have not had COVID-19.

People experiencing any severe illness may develop health problems

People experiencing any severe illness, hospitalization, or treatment may develop problems such as post-intensive care syndrome (PICS).

PICS refers to the health effects that may begin when a person is in an intensive care unit (ICU), and which may persist after a person returns home. These effects can include muscle weakness, problems with thinking and judgment, and symptoms of post-traumatic stress disorder  (PTSD), a long-term reaction to a very stressful event. While PICS is not specific to infection with SARS-CoV-2, it may occur and contribute to the person’s experience of Long COVID. For people who experience PICS following a COVID-19 diagnosis, it is difficult to determine whether these health problems are caused by a severe illness, the virus itself, or a combination of both.

People More Likely to Develop Long COVID

Some people may be more at risk for developing Long COVID.

Researchers are working to understand which people or groups of people are more likely to have Long COVID, and why. Studies have shown that some groups of people may be affected more by Long COVID. These are examples and not a comprehensive list of people or groups who might be more at risk than other groups for developing Long COVID:

• People who have experienced more severe COVID-19 illness, especially those who were hospitalized or needed intensive care.
• People who had underlying health conditions prior to COVID-19.
• People who did not get a COVID-19 vaccine.

Health Inequities May Affect Populations at Risk for Long COVID

Some people are at increased risk of getting sick from COVID-19 because of where they live or work, or because they can’t get health care. Health inequities may put some people from racial or ethnic minority groups and some people with disabilities at greater risk for developing Long COVID. Scientists are researching some of those factors that may place these communities at higher risk of getting infected or developing Long COVID.

Preventing Long COVID

The best way to prevent Long COVID is to protect yourself and others from becoming infected. For people who are eligible, CDC recommends staying up to date on COVID-19 vaccination , along with improving ventilation, getting tested for COVID-19 if needed, and seeking treatment for COVID-19 if eligible. Additional preventative measures include avoiding close contact with people who have a confirmed or suspected COVID-19 illness and washing hands  or using alcohol-based hand sanitizer.

Research suggests that people who get a COVID-19 infection after vaccination are less likely to report Long COVID, compared to people who are unvaccinated.

CDC, other federal agencies, and non-federal partners are working to identify further measures to lessen a person’s risk of developing Long COVID. Learn more about protecting yourself and others from COVID-19 .

Living with Long COVID

Living with Long COVID can be hard, especially when there are no immediate answers or solutions.

People experiencing Long COVID can seek care from a healthcare provider to come up with a personal medical management plan that can help improve their symptoms and quality of life. Review these tips  to help prepare for a healthcare provider appointment for Long COVID. In addition, there are many support groups being organized that can help patients and their caregivers.

Although Long COVID appears to be less common in children and adolescents than in adults, long-term effects after COVID-19 do occur in children and adolescents .

Talk to your doctor if you think you or your child has Long COVID. Learn more: Tips for Talking to Your Healthcare Provider about Post-COVID Conditions

Data for Long COVID

Studies are in progress to better understand Long COVID and how many people experience them.

CDC is using multiple approaches to estimate how many people experience Long COVID. Each approach can provide a piece of the puzzle to give us a better picture of who is experiencing Long COVID. For example, some studies look for the presence of Long COVID based on self-reported symptoms, while others collect symptoms and conditions recorded in medical records. Some studies focus only on people who have been hospitalized, while others include people who were not hospitalized. The estimates for how many people experience Long COVID can be quite different depending on who was included in the study, as well as how and when the study collected information.  Estimates of the proportion of people who had COVID-19 that go on to experience Long COVID can vary.

CDC posts data on Long COVID and provides analyses, the most recent of which can be found on the U.S. Census Bureau’s Household Pulse Survey .

CDC and other federal agencies, as well as academic institutions and research organizations, are working to learn more about the short- and long-term health effects associated with COVID-19 , who gets them and why.

Scientists are also learning more about how new variants could potentially affect Long COVID. We are still learning to what extent certain groups are at higher risk, and if different groups of people tend to experience different types of Long COVID. CDC has several studies that will help us better understand Long COVID and how healthcare providers can treat or support patients with these long-term effects. CDC will continue to share information with healthcare providers to help them evaluate and manage these conditions.

CDC is working to:

• Better identify the most frequent symptoms and diagnoses experienced by patients with Long COVID.
• Better understand how many people are affected by Long COVID, and how often people who are infected with COVID-19 develop Long COVID
• Better understand risk factors and protective factors, including which groups might be more at risk, and if different groups experience different symptoms.
• Help understand how Long COVID limit or restrict people’s daily activity.
• Help identify groups that have been more affected by Long COVID, lack access to care and treatment for Long COVID, or experience stigma.
• Better understand the role vaccination plays in preventing Long COVID.
• Collaborate with professional medical groups to develop and offer clinical guidance and other educational materials for healthcare providers, patients, and the public.

Related Pages

• Caring for People with Post-COVID Conditions
• Preparing for Appointments for Post-COVID Conditions
• Researching COVID to Enhance Recovery
• Guidance on “Long COVID” as a Disability Under the ADA

For Healthcare Professionals

• Post-COVID Conditions: Healthcare Providers

Search for and find historical COVID-19 pages and files. Please note the content on these pages and files is no longer being updated and may be out of date.

• Visit archive.cdc.gov for a historical snapshot of the COVID-19 website, capturing the end of the Federal Public Health Emergency on June 28, 2023.
• Visit the dynamic COVID-19 collection  to search the COVID-19 website as far back as July 30, 2021.

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• Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website.
• You will be subject to the destination website's privacy policy when you follow the link.
• CDC is not responsible for Section 508 compliance (accessibility) on other federal or private website.

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Unraveling long COVID: Here's what scientists who study the illness want to find out

Researchers looking for root causes of long COVID work in the autopsy suite inside the Clinical Center at the National Institute of Health in Bethesda, Maryland. Valerie Plesch/Bloomberg via Getty Images hide caption

Researchers looking for root causes of long COVID work in the autopsy suite inside the Clinical Center at the National Institute of Health in Bethesda, Maryland.

For people suffering from long COVID's often disabling symptoms , including intense fatigue, breathing troubles, cognitive issues and heart palpitations, the list of scientific unknowns may sound defeating. There's still no validated treatment or diagnostic test specifically for the condition , although there are many candidates.

Clinicians who treat long COVID are acutely aware of the unsettled nature of the field. "You do sort of feel like you're out in the wilderness," says Dr. Rasika Karnik , medical director of UChicago Medicine's post-COVID clinic.

Karnik first began seeing long COVID patients in the fall of 2020. There's more information to work with now, she says, but doctors' approach still comes down to treating individual symptoms, rather than the underlying cause of the illness. "It's hard to look a patient in the eyes and say 'we're not quite sure yet' and to keep repeating that," she says.

But researchers are making progress in the field, and they presented their recent findings at one of the first major gatherings dedicated to sharing emerging evidence about the possible root cause of long COVID and implications for treatment.

"I know there's been a lot of frustration that there haven't been faster answers," says Dr. Catherine Blish, a professor of medicine at Stanford University and one of the organizers of the conference, held by the nonprofit Keystone Symposia in Santa Fe, N.M., in late August.

"But in all honesty, we are so much further ahead at this relative point than for any other major disease in my lifetime as an infectious disease specialist," she says.

The meeting underscored that scientists have made headway in developing evidence of a clear biological basis for what patients have been reporting for years.

Shots - Health News

As pandemic emergencies end, some patients with long covid feel 'swept under the rug'.

" I've never doubted it — people are suffering," says Harlan Krumholz , a cardiologist at Yale University who's involved in long COVID research. "But we're now seeing imaging evidence, biopsy evidence, physiologic testing evidence of derangements in people who have long COVID."

Here are some of the new findings and promising lines of research highlighted during the three-day gathering.

Narrowing in on some key suspects behind the disease

If long COVID were a crime scene, authorities would have no shortage of leads.

They've pinpointed a handful of possible reasons why patients suffer from an array of chronic symptoms. The tricky thing is disentangling which mechanisms are bystanders and which are actually doing the damage.

Why viral reservoirs are a prime suspect for long COVID sleuths

"At this point, we have hints and correlative data," says Blish. "We can say we see this finding in a subset of people, but that doesn't mean it's the cause of their problems."

Take the theory of viral persistence: There's now strong evidence that protein and genetic material from SARS-CoV-2 persist in the blood and tissue of some long COVID patients well after their initial illness. Scientists believe these "viral reservoirs" could be driving many of the problems in long COVID patients , although it isn't yet clear exactly how this is happening — and whether the virus itself is replicating.

Dr. Michael Peluso , an infectious disease specialist at the University of California, San Francisco, told conference attendees that his team is now confident in their data showing pieces of viral antigen in the blood of people anywhere from six months to more than a year after they've had COVID-19.

They compared these blood samples to ones collected years before the pandemic to verify their conclusions. "That's a very, very important finding, showing that this is indeed real," he says.

But the story gets more messy from there because these viral reservoirs may not be the primary culprit.

While they are more likely to find viral persistence in the most symptomatic long COVID patients, not everyone with long COVID has it, Peluso notes, "And then really importantly, we're also seeing this in some people who feel totally fine — and we don't know what that means."

Finding activated T cells where they shouldn't be

Other leads have come from imaging technology that traces the activity of T cells, a type of white blood cell, which are part of the body's main antiviral immune response.

"We saw some very unexpected findings," says Dr. Timothy Henrich , an associate professor of medicine at the University of California, San Francisco.

His lab has found activated T cells in the gut wall, lung tissue, certain lymph nodes, the bone marrow, the spinal cord and the brainstem, long after someone's initial infection.

"You really shouldn't have activated T cells in the spinal cord or the brainstem," he says. "We are seeing evidence of this immune response in areas we don't typically see in the setting of an acute viral infection."

Here too the immunological detective work opens up even more questions: This T cell activity is also present in people who've recovered from an infection and have no long COVID symptoms, although Henrich notes the levels appear to be higher in certain tissues of people with long COVID.

So what does this immune response actually indicate about the underlying cause of the disease?

Henrich says T cell activity could be evidence that the immune system is trying to purge the viral reservoirs, or that the immune response has gone awry, possibly in the form of an autoimmune response, and is "doing damage to people, even if the virus has been cleared or is not replicating in those tissues," he says.

Patients and advocates for people suffering from long COVID and myalgic encephalomyelitis/chronic fatigue syndrome hosted an installation of 300 cots in front of the Washington Monument on the National Mall in Washington, D.C., in May, to represent the millions of people suffering from post-infectious disease. Andrew Harnik/AP hide caption

Patients and advocates for people suffering from long COVID and myalgic encephalomyelitis/chronic fatigue syndrome hosted an installation of 300 cots in front of the Washington Monument on the National Mall in Washington, D.C., in May, to represent the millions of people suffering from post-infectious disease.

Similar questions bedevil researchers pursuing another theory.

Research shows that people with long COVID have high levels of Epstein-Barr antibodies and that an acute COVID infection can trigger reactivation of the virus.

Akiko Iwasaki , a professor of immunobiology at Yale University, says it's well known that this herpesvirus can lead to a "long COVID-like syndrome," but whether or not the reactivation is driving long COVID symptoms — or just an indication of a dysregulated immune system — remains to be seen.

All of those involved in research stress that they don't expect just one answer to long COVID. It's likely that many of these theories about its underlying cause are interrelated. And certain mechanisms may only be causing symptoms in some patients and not others.

Microclots could point the way to treatment

Early in the pandemic, it was recognized that COVID-19 can wreak havoc on the vascular system, in particular causing inflammation and damage to the inner lining of blood vessels, known as endothelial cells.

Resia Pretorius , a medical researcher at Stellenbosch University in South Africa, says the clotting and hyperactivation of platelets in long COVID is essentially a "persistent continuation" of what happens during an acute infection within the blood vessels.

Long COVID scientists try to unravel blood clot mystery

Her research has focused on the role of tiny, harmful blood clots she's seeing in the blood of long COVID patients that appear to have "trapped inflammatory molecules that you might expect inside the blood if you have inflamed [or] damaged endothelial layers."

"It's not unique to long COVID, but long COVID has so much more of these inflammatory molecules in circulation," says Pretorius. "And what makes it so interesting is that the spike protein drives these microclots to form."

As the clots accumulate, they may choke off blood flow, preventing oxygen from reaching tissue.

In Santa Fe, Pretorius shared preliminary data from her team showing that so-called "triple therapy" — a combination of three medications — targeting clotting and platelet hyperactivation could benefit some long COVID patients. The preprint showed that this regime resolved symptoms in the majority of the 91 patients who were followed, although the results are not yet peer-reviewed and the study was not a clinical trial.

The approach is not without risk; many patients reported bruising, some had nosebleeds and one reported a gastrointestinal bleed.

Pretorius says microclots are not necessarily the root cause of long COVID, though.

It could be that viral reservoirs are actually helping trigger this vascular mayhem in the first place. These microclots, if left untreated, could also tie into other problems seen in long COVID patients, perhaps leading some to develop autoimmunity, says Pretorius. "That is a problem to solve because we know autoimmune diseases are notorious for being so, so difficult to treat."

Sex differences may play a role in long COVID risk

In general, males tend to do worse during an acute bout of COVID-19, but studies show that long COVID appears to be more prevalent among females. Yale's Iwasaki says this is also the case for other " post-acute infection syndromes ."

Goats and Soda

A new clue to the reason some people come down with long covid.

This background led Iwasaki's lab to look into sex differences in the immune profiles of long COVID patients, in hopes of finding another path to understanding what could be driving the illness. She says they've found that reactivation of Epstein-Barr virus and the activation of T cells are more prevalent among females, whereas males have different "immune signatures."

"We're already starting to see sex differences in long COVID symptoms, as well as potentially the autoimmunity more associated with female patients," she says. "This insight is critical going forward because now we can separate out long COVID into different clusters. And depending on the driver of the disease, we can start targeting it with proper medicine."

Iwasaki's lab has also zeroed in on the role of hormones.

At the conference, she shared evidence of reduced cortisol levels in long COVID patients and shared a separate, unpublished finding that female long COVID patients tend to have reduced testosterone levels and that males have reduced estradiol levels.

Those who had lower testosterone (compared to the controls who don't have long COVID symptoms) also have higher activation of T cells, whether they're males or females, says Julio Silva, a graduate student in Iwasaki's lab who presented the new findings on testosterone. And this was "associated with higher neurological symptoms and overall higher symptom burden," says Silva.

The impetus to look at testosterone was, in part, because of "anecdotes from trans individuals who were informing us that while on testosterone therapy, their symptoms had improved dramatically," says Silva. While the results are preliminary and need to be replicated, he says they at least raise the question "could hormonal therapy help?"

Taken together, Iwasaki says their data strongly suggest there could be problems in the area of the brain that's responsible for regulating these hormones.

Viral persistence offers one possible target for treating long COVID

In the absence of a clear roadmap for treating long COVID, doctors and patients have taken to trying all kinds of therapies — from antivirals to drugs approved for treating addiction .

"All of this research is so critical to understanding the underlying mechanisms of long COVID," says Lisa McCorkell, co-founder of the advocacy group Patient-Led Research Collaborative. "We need to pair that with focusing on clinical trials. We have enough evidence right now to at least try some things."

In Santa Fe, UCSF's Peluso outlined how his team had just launched a small trial using monoclonal antibodies to target the coronavirus spike protein in long COVID patients — one vehicle for testing whether viral persistence is the underlying cause of at least some patients' symptoms. Meanwhile, Iwasaki and Krumholz, both at Yale, have started a clinical trial testing whether a 15-day course of Paxlovid can help alleviate symptoms.

Stanford's Blish points out that as more clinical trials start up, their success will hinge on being deliberate about which patients should be enrolled, since long COVID is a catch-all term for what may be multiple different illnesses.

"We need to understand in detail who's most likely to benefit from those trials, because if we just take everyone, that trial will fail," she says.

Many o ther trials are in the works, too, but Dr. Jennifer Curtin says those will inevitably take time to produce evidence that trickles down to patient care.

"It's that tough sort of in-between status right now," says Curtin, co-founder of the telehealth clinic RTHM that treats long COVID and other overlapping conditions like myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS for short. "So what do you do for the people who are sick and suffering now until we get that data?"

Curtin, who has lived with ME/CFS herself, says their clinic's approach is to perform intensive workups, draw lots of blood and try to identify which symptoms they can treat.

"Treatment is very much individually tailored," she says. "Right now it's a journey that you take with your patients. You're going through this together. You're both learning on this road and it can be tough."

Always in the backdrop at the Santa Fe gathering was the question of whether there would be enough funding — be it from the U.S. Congress or the pharmaceutical industry — to advance the research agenda toward treatments.

"What we really need here is industry engagement. We need funding for clinical trials. And that, to me, is something that's missing," says McCorkell.

• viral persistence
• autoimmune diseases

New long COVID study uncovers high inflammation in patients as Senate calls for more research on 'crisis'

The study followed 113 patients at four different hospitals in Switzerland.

A new study in Science is shining a light on the continuing impact of long COVID, with research revealing further and continuing health concerns for some of the 16 million sufferers in the U.S.

Long COVID is a syndrome, or collection of symptoms, that continue or develop after an acute COVID-19 infection and can last weeks, months or years. There is no test to confirm if symptoms are related to long COVID. Some scientists suggest that long COVID is caused by overactive immune cells, but the exact cause remains unclear.

The study followed 113 patients at four different hospitals in Switzerland with mild and severe COVID-19 and found that 40 had symptoms of long COVID at six months, 22 of whom had persistent symptoms at 12 months.

Researchers looked at blood samples from the 40 who experienced long COVID symptoms, compared them to controls who were not infected with COVID-19, and found that those who had long COVID had evidence of inflammation (increased complement activity), blood cell dysregulation (hemolysis and platelet activation) and tissue injury in their blood.

MORE: Long COVID research opens door for further exploration on post-viral illness

The specific details from the small study may help provide "a basis for new diagnostic solutions," according to the researchers, for the condition with no known cure or FDA-approved treatments.

While these results finding evidence of inflammation in patients with long COVID symptoms are not entirely surprising nor specific to long COVID, they are a step forward in identifying the cause of long COVID.

It's more than just researchers, though, looking into developments in our understanding of the syndrome. The condition received renewed attention from the federal government last week, as the U.S. Senate Committee on Health, Education, Labor and Pensions convened a group of patients and experts to testify about the impacts of long COVID before a bipartisan group of Senators.

In the Senate's first-ever hearing on this topic, Sen. Tammy Baldwin said researchers and government officials need to "increase the sense of urgency" over understanding and treating the condition.

For Sen. Bernie Sanders, chairman of the committee, more needs to be done.

"We think we haven't done anywhere near enough, and we hope to turn that around," he said.

Medical experts testified at the hearing, telling the committee that the condition can emerge in patients of all ages and backgrounds, that the risk increases with multiple infections, and rates of long COVID are higher in minority communities.

"The burden of disease and disability from long COVID is on par with the burden of cancer and heart disease," Dr. Ziyad Al-Aly, M.D., a clinical epidemiologist at Washington University, said. "We must develop sustainable solutions to prevent repeated infections with SARS-CoV-2 and long COVID that would be embraced by the public."

Patients and Caregivers

Angela Meriquez Vazquez , a long COVID patient from California, testified that she has helped over 15,000 sufferers through online advocacy.

"We are living through the largest mass destabilizing event in modern history," she told the Senators.

MORE: America's gun violence problem by the numbers

As she told her own story, Meriquez Vazquez, a former runner, said she is currently on 12 medications. Although she said she has managed to continue working, and she has health care, the condition has forced her to work from home, lying down to minimize her symptoms.

"Not since the emergence of the AIDS pandemic has there been such an imperative for large-scale change in healthcare, public health, and inequitable structures that bring exceptional risks of illness, suffering, disability, and mortality," Meriquez Vazzque said.

One of the Senators -- Republican Roger Marshall -- shared his own testimony, revealing to the committee that one of his loved ones "is one of the 16 million people" who has "suffered for two years" with the condition.

He told the committee his family member's illness is "like mono(nucleosis) that does not go away," adding that the person has seen 30 doctors in an attempt to find help.

Marshall said there needs to be more focus on treatments for long COVID at the Centers for Disease Control and Prevention.

"I'm frustrated that our CDC is more focused on vaccines than they are on treatments," he said.

Epidemiologists and Researchers weigh in

Dr. Al-Aly, while testifying, repeatedly called on our country's leaders and medical experts to come together to tackle the ongoing health crisis.

"We are the best nation on earth, and we can solve this," he said.

One of his proposed solutions is establishing a new multidisciplinary research institute to address infection-associated chronic conditions.

Research into the condition has been "slow," Dr. Charisse Madlock-Brown, Ph.D. from the University of Iowa, said at the hearing. She noted clinical trials are in the "experimental medicine" phase and pushed for more investment to identify proven treatments.

Sen. Tim Kaine said the National Institutes of Health has been provided more than $1 billion since 2020 to study long COVID, and he urged representatives from NIH to testify before the committee. In 2021, the NIH launched the Researching COVID to Enhance Recovery initiative to identify further risk factors and causes of long COVID.

"We can't take two years just to get 'geared up,'" he said.

According to the most recent information from the CDC , long COVID can cause up to 200 symptoms , including chronic fatigue, blood clots, gastrointestinal issues, brain fog and heart issues. Symptoms can last from months to years following a COVID infection. Risk factors for developing long COVID after a COVID-19 infection that have been identified include severe COVID-19 illness, underlying health conditions (such as asthma, diabetes, obesity or autoimmune diseases) and not getting the COVID-19 vaccine.

While the interest from the Senate and the new study in Science are promising, more research needs to be done to find the specific cause of why some people get long COVID from COVID-19, and others do not, and to find effective treatments.

Erin Hannon, MD, contributed to this report. Hannon is a resident physician in pediatrics from Columbia University/New York-Presbyterian Hospital, and a member of the ABC News Medical Unit.

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Many people recover fully within a few days or weeks after being infected with SARS-CoV-2, the virus that causes COVID-19. However, others have symptoms that linger for weeks, months, or even years after their initial diagnosis. Some people seem to recover from COVID-19 but then see their symptoms return, or they develop different symptoms within a few months. Even people who had no symptoms when they were infected can develop them later. Either mild or severe COVID-19 can lead to long-lasting symptoms.

Long COVID, long-haul COVID, post-COVID-19 condition, chronic COVID, and post-acute sequelae of SARS-CoV-2 (PASC) are all names for the health problems that some people experience a few months after a COVID-19 diagnosis. Symptoms of Long COVID may be the same as or different than  symptoms of COVID-19 . Long COVID can also trigger other health conditions such as diabetes or kidney disease.

For more information on Long COVID, check out these U.S. government resources:

National Institutes of Health (NIH)

• Explore Long COVID information, news , and more on the COVID-19 research website
• Learn about NIH’s  RECOVER initiative and find clinical trials on Long COVID
• Read how this NIH-funded RECOVER study developed a new symptom scoring system that will improve future Long COVID treatments
• Read this NHLBI news story about how obstructive sleep apnea increases risks for Long COVID
• Read this NHLBI news story about how lingering symptoms are common after COVID hospitalization
• Read how an NIH-funded RECOVER study identified potential long COVID disparities
• Read this NHLBI news story about how Long COVID may be less common in children
• Read how an NHLBI-funded study found that exercise lags are common after Long COVID
• Read this NIH Director’s Blog post about using artificial intelligence to advance the understanding of Long COVID
• Read this NHLBI news story about how Long COVID impacts children. 

Centers for Disease Control and Prevention (CDC)

• Find tips for talking with your healthcare provider about Long COVID
• Check out this fact sheet about caring for people living with post-COVID conditions

This White House fact sheet provides information about comprehensive government efforts to prevent, diagnose, and treat Long COVID.

What are Long Covid Symptoms?

Check out this interactive graphic from NIH to learn how Long COVID affects different parts of the human body.

RECOVER Research Review (R3) Seminar Series

The NIH RECOVER initiative’s R3 Seminar Series promotes a shared understanding of the scientific research on Long COVID. This forum speeds up discovery by allowing experts to

Opinion New landmark study offers hope to people with long covid

Long before the coronavirus pandemic brought about persistent symptoms known as long covid , an eerily similar condition was disabling thousands of Americans. Previously healthy individuals would go from living normal and active lives to being so fatigued that they could hardly get out of bed. Many had a preceding viral or bacterial infection.

The condition is called myalgic encephalitis/chronic fatigue syndrome (ME/CFS). Though more than 1 in 100 American adults suffer from it, little is known about the disease. It’s common for patients to go through years of misdiagnosis. There are no approved treatments.

A new landmark study from the National Institutes of Health sheds important light on ME/CFS and offers hope for the millions of people living with this disease and the closely related condition of long covid.

This study is notable in that it is the most in-depth and multidisciplinary study of ME/CFS to date, involving more than 75 investigators across 15 NIH institutes and taking nearly eight years to complete. The manuscript, published in Nature Communications, is 29 pages long, with more than 60 pages of supplemental information.

Patients with ME/CFS were carefully screened to ensure they don’t have other confounding health conditions and then matched to healthy volunteers. Both groups underwent extensive studies, including blood draws, brain imaging, muscle strength testing, heart- and lung-function assessments, and even spinal fluid analysis.

Three major findings stand out: First, the research provided clear evidence of physiological abnormalities in ME/CFS patients. Compared with the healthy control group, these individuals had immunologic disturbances, including higher levels of the B cells that are activated when the body encounters an infection. The ME/CFS patients also had spinal fluid with unusually low levels of substances called catecholamines, which help regulate the nervous system.

The senior author of the study, Avindra Nath , told me in an interview that “we can pretty emphatically say that deconditioning and psychological factors cannot explain their symptoms.” This is huge for many ME/CFS sufferers who have been repeatedly dismissed by medical professionals and told there was nothing physically wrong with them.

Second, researchers found functional and not structural abnormalities. For instance, there were no masses or lesions in the brain, but there was a region called the temporoparietal junction that had lower activity compared with healthy controls. It’s possible that the decreased activity disrupts how the brain tells the body to exert effort, worsening fatigue.

This finding, too, is good news, because functional abnormalities are potentially treatable and might even be reversible. Indeed, there were a few participants in the study who spontaneously recovered.

Third, investigators discovered significant differences between men and women. While this was not entirely surprising, as women are more likely than men to have ME/CFS and autoimmune diseases, the study found specific and marked differences between the two groups in immune cell populations and markers of inflammation.

For example, men had abnormal T cell activation, and women had abnormal B cell patterns. These findings can help inform future research, Nath said, because “what would work in women may not work in men.”

Overall, the results support the hypothesis that ME/CFS is due to persistent immune activation. Normally, when someone comes down with an infection, their immune system works overtime to get rid of the foreign agent and then calms down when the infection is gone. But in ME/CFS patients, pieces of the virus or bacteria may linger in the body and continue to stimulate the immune system long after the infection should have resolved.

“More and more researchers have started using the term ‘post-infectious syndromes,’” Nath told me. “It’s quite possible that all these diseases are one and the same thing, but what initiates them may be different.” The inciting agent could be the coronavirus, the Epstein-Barr virus, Lyme disease or a whole host of other pathogens, but the subsequent illness ends up wreaking havoc in a similar way.

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Nath and his colleagues decided to make every piece of their data publicly available so that scientists around the world can use the findings to jump-start their own research. Ongoing studies are attempting to pinpoint a biomarker — a finding on a blood test — so that post-infectious syndromes can be more easily diagnosed. Crucially, Nath and others have started clinical trials to test therapeutics that target specific parts of the immune system.

“These patients are very desperate, and we should give them hope,” Nath said. He wants to assure people with post-infectious syndromes that there are researchers dedicated to studying their illness and that everyone is extremely motivated. “The answers may take some time, but we will find them,” he said.

I hope he is right and that this NIH study will be the catalyst for many more. The millions of Americans newly living with long covid urgently need treatments, as do all the people who have ME/CFS, for whom medical attention and scientific resources have been long overdue.

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COVID-19: Long-term effects

Some people continue to experience health problems long after having COVID-19. Understand the possible symptoms and risk factors for post-COVID-19 syndrome.

Most people who get coronavirus disease 2019 (COVID-19) recover within a few weeks. But some people — even those who had mild versions of the disease — might have symptoms that last a long time afterward. These ongoing health problems are sometimes called post- COVID-19 syndrome, post- COVID conditions, long COVID-19 , long-haul COVID-19 , and post acute sequelae of SARS COV-2 infection (PASC).

What is post-COVID-19 syndrome and how common is it?

Post- COVID-19 syndrome involves a variety of new, returning or ongoing symptoms that people experience more than four weeks after getting COVID-19 . In some people, post- COVID-19 syndrome lasts months or years or causes disability.

Research suggests that between one month and one year after having COVID-19 , 1 in 5 people ages 18 to 64 has at least one medical condition that might be due to COVID-19 . Among people age 65 and older, 1 in 4 has at least one medical condition that might be due to COVID-19 .

What are the symptoms of post-COVID-19 syndrome?

The most commonly reported symptoms of post- COVID-19 syndrome include:

• Symptoms that get worse after physical or mental effort
• Lung (respiratory) symptoms, including difficulty breathing or shortness of breath and cough

Other possible symptoms include:

• Neurological symptoms or mental health conditions, including difficulty thinking or concentrating, headache, sleep problems, dizziness when you stand, pins-and-needles feeling, loss of smell or taste, and depression or anxiety
• Joint or muscle pain
• Heart symptoms or conditions, including chest pain and fast or pounding heartbeat
• Digestive symptoms, including diarrhea and stomach pain
• Blood clots and blood vessel (vascular) issues, including a blood clot that travels to the lungs from deep veins in the legs and blocks blood flow to the lungs (pulmonary embolism)
• Other symptoms, such as a rash and changes in the menstrual cycle

Keep in mind that it can be hard to tell if you are having symptoms due to COVID-19 or another cause, such as a preexisting medical condition.

It's also not clear if post- COVID-19 syndrome is new and unique to COVID-19 . Some symptoms are similar to those caused by chronic fatigue syndrome and other chronic illnesses that develop after infections. Chronic fatigue syndrome involves extreme fatigue that worsens with physical or mental activity, but doesn't improve with rest.

Why does COVID-19 cause ongoing health problems?

Organ damage could play a role. People who had severe illness with COVID-19 might experience organ damage affecting the heart, kidneys, skin and brain. Inflammation and problems with the immune system can also happen. It isn't clear how long these effects might last. The effects also could lead to the development of new conditions, such as diabetes or a heart or nervous system condition.

The experience of having severe COVID-19 might be another factor. People with severe symptoms of COVID-19 often need to be treated in a hospital intensive care unit. This can result in extreme weakness and post-traumatic stress disorder, a mental health condition triggered by a terrifying event.

What are the risk factors for post-COVID-19 syndrome?

You might be more likely to have post- COVID-19 syndrome if:

• You had severe illness with COVID-19 , especially if you were hospitalized or needed intensive care.
• You had certain medical conditions before getting the COVID-19 virus.
• You had a condition affecting your organs and tissues (multisystem inflammatory syndrome) while sick with COVID-19 or afterward.

Post- COVID-19 syndrome also appears to be more common in adults than in children and teens. However, anyone who gets COVID-19 can have long-term effects, including people with no symptoms or mild illness with COVID-19 .

What should you do if you have post-COVID-19 syndrome symptoms?

If you're having symptoms of post- COVID-19 syndrome, talk to your health care provider. To prepare for your appointment, write down:

• When your symptoms started
• What makes your symptoms worse
• How often you experience symptoms
• How your symptoms affect your activities

Your health care provider might do lab tests, such as a complete blood count or liver function test. You might have other tests or procedures, such as chest X-rays, based on your symptoms. The information you provide and any test results will help your health care provider come up with a treatment plan.

In addition, you might benefit from connecting with others in a support group and sharing resources.

• Long COVID or post-COVID conditions. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects.html. Accessed May 6, 2022.
• Post-COVID conditions: Overview for healthcare providers. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html. Accessed May 6, 2022.
• Mikkelsen ME, et al. COVID-19: Evaluation and management of adults following acute viral illness. https://www.uptodate.com/contents/search. Accessed May 6, 2022.
• Saeed S, et al. Coronavirus disease 2019 and cardiovascular complications: Focused clinical review. Journal of Hypertension. 2021; doi:10.1097/HJH.0000000000002819.
• AskMayoExpert. Post-COVID-19 syndrome. Mayo Clinic; 2022.
• Multisystem inflammatory syndrome (MIS). Centers for Disease Control and Prevention. https://www.cdc.gov/mis/index.html. Accessed May 24, 2022.
• Patient tips: Healthcare provider appointments for post-COVID conditions. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/post-covid-appointment/index.html. Accessed May 24, 2022.
• Bull-Otterson L, et al. Post-COVID conditions among adult COVID-19 survivors aged 18-64 and ≥ 65 years — United States, March 2020 — November 2021. MMWR Morbidity and Mortality Weekly Report. 2022; doi:10.15585/mmwr.mm7121e1.

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• How do COVID-19 antibody tests differ from diagnostic tests?
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• How to measure your respiratory rate
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• Safe outdoor activities during the COVID-19 pandemic
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• Sex and COVID-19
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• Treating COVID-19 at home
• Unusual symptoms of coronavirus
• Vaccine guidance from Mayo Clinic
• Watery eyes

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