Research

Long Covid and ME/CFS are devastating diseases. Here’s what the world leading researchers have unraveled and why they argue that a sharp increase in long-term funding for biomedical research accompanied by biomedical clinical trials are desperately needed now:

Long Covid: Major Findings

What We Know About Covid’s Impact on Your Brain

"Many of Covid’s earliest and most alarming effects involve the brain, including a lost sense of smell, sluggish thinking, headaches, delirium and strokes. More than four years after the pandemic began, researchers are recognizing the profound impacts Covid can have on brain health, as millions of survivors suffer from persistent issues such as brain fog, depression and cognitive slowing, all of which hinder their ability to work and otherwise function. Scientists now worry that these symptoms may be early indicators of a coming surge in dementia and other mental conditions, prolonging the pandemic’s societal, economic and health burden.

In 2021, UK researchers reported early results from a study comparing brain scans taken before and after the pandemic began. They discovered signs of damage and accelerated aging in the brain, particularly in the region responsible for smell, even in patients who had experienced mostly mild cases of Covid months earlier."

Long Covid: Major Findings

Patients With Long-COVID Show Abnormal Lung Perfusion Despite Normal CT Scans

"VIENNA — Some patients who had mild COVID-19 infection during the first wave of the pandemic and continued to experience postinfection symptoms for at least 12 months after infection present abnormal perfusion despite showing normal CT scans. Researchers at the European Respiratory Society (ERS) 2024 International Congress called for more research to be done in this space to understand the underlying mechanism of the abnormalities observed and to find possible treatment options for this cohort of patients.

Laura Price, MD, PhD, a consultant respiratory physician at Royal Brompton Hospital and an honorary clinical senior lecturer at Imperial College London, London, told Medscape Medical News that this cohort of patients shows symptoms that seem to correlate with a pulmonary microangiopathy phenotype.

"Our clinics in the UK and around the world are full of people with long-COVID, persisting breathlessness, and fatigue. But it has been hard for people to put the finger on why patients experience these symptoms still," Timothy Hinks, associate professor and Wellcome Trust Career Development fellow at the Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre senior research fellow, and honorary consultant at Oxford Special Airway Service at Oxford University Hospitals, England, who was not involved in the study, told Medscape Medical News."

Long Covid: Major Findings

COVID-19, cancer post-pandemic risk, and the radiation oncology physicist

"The COVID-19 pandemic has had a profound impact on the health-care industry in the United States and worldwide. Nearly every aspect of healthcare was impacted, including but not limited to research and development, purchasing and inventory management, health-care delivery, human resource management, and standard operating procedures. In almost every care setting, artifacts of the COVID-19 pandemic linger in the form of changes in policies and procedures, redistribution of staff and resources, shortages and oversupplies of key resources, and a shared desire to capture consistency and normalcy following a 24-month storm. In the United States, the sustainability of health-care systems following this major disruption remains an important challenge as revenue from profitable elective outpatient procedures shrunk and the demand for critical care soared. Furthermore, multiple surges in the pandemic required a shift in resources and staff to less profitable intensive care units, whereas regions impacted most triggered a national redistribution of resources, nurses, and other health-care workers.

The health-care industry in the United States is complicated. Although some market forces like competition and quality impact health-care delivery in a similar manner to other private sector industries, health systems also coordinate and collaborate to provide population health services, deliver individual care, participate in the advancement of knowledge, and establish processes and standards of care based on data. The advancement and implementation of knowledge and best practices is a shared experience based on the evidence, debate, and consensus. Given the specialized care provided by radiation oncology physicists, participation in the health-care market has been characterized more as collaborative than competitive. Despite market forces and disruptions, these physicists have remained focused and responsible for designing, delivering, and reporting the outcome of the treatment planning and delivery process.

Population health continues to intersect with health-care delivery. Prior to COVID-19, the introduction of value-based reimbursement models facilitated a shift in risk from health plans to providers. Instead of incentivizing providers to maximize the number of interactions, this shift tied reimbursement to outcomes and encouraged health systems to engage in population health. Many providers were suddenly expected to assume a larger role, including medical physicists being asked to assume the role in some care settings as biomedical scientists to defend radiation oncology outcomes.

COVID-19 has complicated both the entry and outcome of the radiation oncology intervention. Cancer screening rates dipped during the pandemic and have yet to recover. Active cancer with concomitant COVID-19 infections continues to represent a new and potentially deleterious risk for cancer patients. COVID-19 prevention methods continue to accumulate, which can be especially beneficial for high-risk patients under care. Also challenging, the implications for the future of cancer care are not well understood given the persistence of the COVID-19 pandemic continuing to cause new and recurring infections as well as the potential increased risk of cancer and other complications in patients recovering from COVID-19 infection. Finally, long COVID is greatly complicating the posttreatment evaluation, progression, and outcome of cancer patient survival and quality of life"

Long Covid: Major Findings

Characteristics and predictors of Long Covid in children: a 3-year prospective cohort study

"Summary

Background

Children can develop Long Covid, however long term outcomes and their predictors are poorly described in these patients. The primary aim is to describe characteristics and predictors of Long Covid in children assessed in-clinics up to 36 months post-SARS-CoV-2 infection, as well as investigate the role of vaccines in preventing Long Covid, risk of reinfections and development of autoimmune diseases.

Methods

Children aged 0–18 years old with confirmed SARS-CoV-2 infection were invited for a prospective follow-up assessment at a peadiatric post-covid clinic in Rome, Italy, at serial intervals (3-, 6-, 12-, 18-, 24- and 36-months post-infection onset, between 01/02/2020 and 28/02/2024). Long Covid was defined as persistence of otherwise unexplained symptoms for at least three months after initial infection.

Findings

1319 patients were initially included, 1296 reached the 3 months follow-up or more. Of the patients who underwent multiple follow-ups, 23.2% (301), 169 (13.2%), 89 (7.9%), 67 (6.1%), 47 (7.1%) were diagnosed with Long Covid at 3-6-12-18-24 months, respectively For the primary outcome of Long Covid at three months, age >12 years (P < 0.001, OR 11.33, 95% CI 4.2; 15.15), comorbidities (P = 0.008, OR 1.83, 95% CI 1.06; 2.44), being infected with original variants (P < 0.001, OR 4.77, 95% CI 2.46; 14.47), female sex (P < 0.001, OR 1.62, 95% CI 1.02; 1.89) were statistically significant risk factors. Age >12 years (P = 0.002, OR 9.37, 95% CI 1.58; 8.64), and infection with original (P = 0.012, OR 3.52, 95% CI 1.32; 8.64) and alfa (P < 0.001, OR 4.09, 95% CI 2.01; 8.3) SARS-CoV-2 variants remained statistically significant risk factors for Long Covid duration for at least 18 months. Vaccination was associated with a lower risk of long covid at 3, 6 and 12 months for older children and a lower risk of reinfections. Being infected with the original SARS-CoV-2 variant was associated with a higher risk of new-onset autoimmune diseases ((P = 0.035, 95% CI 1.12; 2.4). One patient was diagnosed with Long Covid after a re-infection.

Interpretation

This is the longest follow-up study of children with SARS-CoV-2 infection, showing a significant and long-lasting burden of Long Covid in the pediatric population. Our findings highlight the urgent need of investing in pediatric Long Covid in order to find effective diagnostic and therapeutic approaches, as well can inform preventive strategies in case of future pandemics."

Long Covid: Major Findings

UK researchers find Alzheimer’s-like brain changes in long COVID patients

"LEXINGTON, Ky (Aug. 30, 2024) — New research from the University of Kentucky’s Sanders-Brown Center on Aging shows compelling evidence that the cognitive impairments observed in long COVID patients share striking similarities with those seen in Alzheimer’s disease and related dementias.

The study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, highlights a potential commonality in brain disorders across these conditions that could pave the way for new avenues in research and treatment.

The study was a global effort, funded by a multitude of grants from the U.S. National Institutes of Health, the Alzheimer’s Association and international organizations. The project also brought together experts from various fields of neuroscience.

Researchers at the UK College of Medicine led the study, including Yang Jiang, Ph.D., professor in the Department of Behavioral Science; Chris Norris, Ph.D., professor in the Department of Pharmacology and Nutritional Sciences; and Bob Sompol, Ph.D., assistant professor in the Department of Pharmacology and Nutritional Sciences. Their work focuses on electrophysiology, neuroinflammation, astrocytes and synaptic functions.

“This project benefited greatly from interdisciplinary collaboration,” Jiang said. “We had input from experts, associated with the Alzheimer’s Association International Society to Advance Alzheimer's Research and Treatment (ISTAART), across six countries, including the U.S., Turkey, Ireland, Italy, Argentina and Chile.”

Jiang and the collaborative team focused their work on understanding the “brain fog” that many COVID-19 survivors experience, even months after recovering from the virus. This fog includes memory problems, confusion and difficulty concentrating. According to Jiang, “the slowing and abnormality of intrinsic brain activity in COVID-19 patients resemble those seen in Alzheimer’s and related dementias.”

This research sheds light on the connection between the two conditions, suggesting that they may share underlying biological mechanisms. Both long COVID and Alzheimer’s disease involve neuroinflammation, the activation of brain support cells known as astrocytes and abnormal brain activity. These factors can lead to significant cognitive impairments, making it difficult for patients to think clearly or remember information.

The idea that COVID-19 could lead to Alzheimer’s-like brain changes is a significant development.

“People don’t usually connect COVID-19 with Alzheimer’s disease,” Jiang said, “but our review of emerging evidence suggests otherwise.”

The publication in Alzheimer’s & Dementia reveals that the cognitive issues caused by COVID-19 reflect similar underlying brain changes as those in dementia.

The study’s insights emphasize the importance of regular brain function check-ups for these populations, particularly through the use of affordable and accessible tools like electroencephalography (EEG).

The study not only highlights the shared traits between long COVID and Alzheimer’s, but also points to the importance of further research.

“The new insight opens avenues for future research and clinical practice, particularly in studying brain oscillations related to neural biomarkers of mild cognitive impairment in people with long COVID,” said Jiang.

One of the key findings is the role of astrocytes — support cells in the brain that have not been as thoroughly studied as neurons. The research suggests that damage or activation of these cells by COVID-19 can cause synaptic dysfunctions, leading to the abnormal brain activity observed in both conditions. This discovery is significant because it may help explain why EEG patterns in COVID-19 patients resemble those seen in the early stages of neurodegenerative diseases like Alzheimer’s.

Researchers believe this work could have a direct impact on patient care. They are advocating for routine EEG exams to detect early brain changes in both COVID-19 survivors and those at risk for cognitive decline.

“EEG patterns in COVID-19 patients resemble those seen in early neurodegenerative diseases,” said Norris.

“These similarities may be due to shared issues such as brain inflammation, astrocyte activity, low oxygen levels and blood vessel damage,” said Sompol.

By detecting these changes early, health care providers could potentially identify at-risk individuals sooner and implement interventions to prevent or slow the progression of cognitive decline.

As research continues, the team is particularly interested in how EEG monitoring can predict long-term outcomes in COVID-19 patients and assess the effectiveness of treatments aimed at preventing cognitive decline."

Long Covid: Major Findings

Early biological markers of post-acute sequelae of SARS-CoV-2 infection

"To understand the roles of acute-phase viral dynamics and host immune responses in post-acute sequelae of SARS-CoV-2 infection (PASC), we enrolled 136 participants within 5 days of their first positive SARS-CoV-2 real-time PCR test. Participants self-collected up to 21 nasal specimens within the first 28 days post-symptom onset; interviewer-administered questionnaires and blood samples were collected at enrollment, days 9, 14, 21, 28, and month 4 and 8 post-symptom onset. Defining PASC as the presence of any COVID-associated symptom at their 4-month visit, we compared viral markers (quantity and duration of nasal viral RNA load, infectious viral load, and plasma N-antigen level) and host immune markers (IL-6, IL-10, TNF-α, IFN-α, IFN-γ, MCP, IP-10, and Spike IgG) over the acute period. Compared to those who fully recovered, those reporting PASC demonstrated significantly higher maximum levels of SARS-CoV-2 RNA and N-antigen, burden of RNA and infectious viral shedding, and lower Spike-specific IgG levels within 9 days post-illness onset. No significant differences were identified among a panel of host immune markers. Our results suggest early viral dynamics and the associated host immune responses play a role in the pathogenesis of PASC, highlighting the importance of understanding early biological markers in the natural history of PASC."

Long Covid: Major Findings

Fibrin drives thromboinflammation and neuropathology in COVID-19

"Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1,2,3,4. Despite the clinical evidence1,5,6,7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8,9,10. Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID."

Long Covid: Major Findings

Antibodies from Long Covid patients prompt symptoms in mice

"In the quest to explain the symptoms of Long Covid, one suspect—antibodies in the blood that target a patient’s own tissues—is getting extra scrutiny from two teams of scientists an ocean apart. Both groups injected mice with antibodies from the blood of people with Long Covid, the constellation of symptoms that sometimes persist for months or years after a SARS-CoV-2 infection. And in certain cases, they say, the rodents developed symptoms seemingly mirroring those of their human donors, in particular a heightened sensitivity to pain.

Some scientists say these studies, one posted earlier this week, bolster the case for a dysfunctional immune system, triggered by a coronavirus infection, directly fueling Long Covid symptoms—and open the door to potential new treatment trials. “This is strong evidence” for Long Covid being an immune-mediated disorder, and likely applies to other postviral syndromes, too, says Danilo Buonsenso, a pediatric infectious disease doctor who studies and treats Long Covid in children at Gemelli University Hospital and was not involved in the work.

But although other researchers said the studies were elegantly done, and may offer novel mouse models of Long Covid, they are less certain about the bottom line. “There’s no uniform autoantibodies” in these groups of patients, says Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke. This makes it tricky to say certain autoantibodies are causing certain symptoms—in mice or in people."

Long Covid: Major Findings

Vascular Inflammation in Neuropsychiatric Long Covid

"Background: Neuropsychiatric symptoms are prominent and can have a substantial functional impact in many people with Long COVID (LC). The underlying pathophysiology of neuropsychiatric LC (N-LC) is unknown.

Methods: 28 individuals with acute COVID-19 (AC), 50 N-LC (new or worsening neuropsychiatric symptoms >3 months after COVID-19), and 29 post-COVID-19 controls with no LC (>3 months prior) were enrolled. Participants underwent cross-sectional blood testing, and the N-LC and control groups underwent neuropsychiatric testing, including verbal learning and memory, fluency, processing speed, and mental health assessments. Fourteen soluble biomarkers of vascular health were measured in plasma. ANCOVA testing with a Benjamini-Hochberg procedure was used to compare biomarkers between groups adjusting for co-morbidities.

Findings: Participants with N-LC and controls were similar demographically, while the AC group had higher rates of obesity and hypertension. Biomarkers of leukocyte adhesion to the endothelium and endothelial inflammation were elevated in N-LC compared to controls, including L-selectin, ADAMTS13, sP-selectin, and sICAM-1, whereas coagulopathy measures (D-dimer, fibrinogen) did not differ. Most biomarkers were highest in AC and lower in N-LC (AGP, CRP, haptoglobin, SAA, ADAMTS13, PF4, sP-selectin, sVCAM-1, and D-dimer). However, three biomarkers were highest in N-LC compared to AC: Fetuin (vascular calcification), L-selectin (leukocyte adhesion), and α-2 macroglobulin (endothelial adhesion). In N-LC, higher sP-selectin was strongly associated with lower fluency and verbal learning. Lower AGP was strongly associated with lower verbal memory, verbal learning, fluency, mood, and anxiety.

Interpretation: Alterations in biomarkers of vascular inflammation strongly associate with the presence of N-LC. Biomarkers of endothelial adhesion and vascular calcification are only elevated in N-LC compared to both groups, suggesting a pathophysiology distinct from the resolving effects of AC. Biomarkers related to endothelial adhesion and systemic inflammation associate with specific cognitive domains, linking vascular inflammation with brain function. Identifying abnormalities in vascular endothelial function, calcification, and remodeling may lead to therapeutic targets for N-LC."

Long Covid: Major Findings

Long COVID: major findings, mechanisms and recommendations | Nature Reviews Microbiology

"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."

Where are the Long Covid trials?

Where are the long COVID trials?

"ClinicalTrials.gov currently lists 386 trials under the search term Long COVID. However, only 94 of those studies are classed as interventional and are currently recruiting, and even more disturbing, only 12 trials are testing pharmacological interventions. The rest comprise follow-up of trials in acute infection, rehabilitation, food supplements, telehealth, psychological support, physiotherapy, acupuncture, light therapy, Chinese herbal medicine etc. While the list ranges from “nice to have additional support” to questionable alternative cures or even potentially harmful treatments, we are clearly lacking tested pharmacological interventions that treat the underlying pathophysiology."

Understanding the pathophysiology of Long Covid

Why we need a deeper understanding of the pathophysiology of Long COVID

As avoiding COVID-19 becomes increasingly difficult, we argue that deep biological analyses will identify biomarkers for long COVID and possibly identify distinct endotypes driven by different root causes so that the risk of contracting long COVID is better defined. Biomarker identification will not only be crucial for identifying predisposing factors but also allow us to implement safer, evidence-based policies. Similarly, molecular, cellular, and physiological analyses will inform precision interventions that target the root causes of each long COVID endotype. For example, persistent viral infection could be targeted by antivirals; long COVID driven by autoimmune disease could be treated using monoclonal antibodies that target lymphocytes or drugs that block cytokines and cytokine signalling; and, if the reactivation of herpesviruses contributes to disease, targeting such viruses using antivirals or vaccines could be considered. Diagnostic criteria considering the root causes to prevent and treat long COVID will require large longitudinal studies. If therapeutic targeting of root causes is not feasible, the downstream pathological changes of long COVID could still be treated.

Muscle abnormalities worsen after post-exertional malaise in long COVID

A subgroup of patients infected with SARS-CoV-2 remain symptomatic over three months after infection. A distinctive symptom of patients with long COVID is post-exertional malaise, which is associated with a worsening of fatigue- and pain-related symptoms after acute mental or physical exercise, but its underlying pathophysiology is unclear. With this longitudinal case-control study (NCT05225688), we provide new insights into the pathophysiology of post-exertional malaise in patients with long COVID. We show that skeletal muscle structure is associated with a lower exercise capacity in patients, and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID worsen after induction of post-exertional malaise. This study highlights novel pathways that help to understand the pathophysiology of post-exertional malaise in patients suffering from long COVID and other post-infectious diseases.

Distinguishing features of long COVID

Distinguishing features of long COVID identified through immune profiling

The Immunology of Long Covid

The immunology of long COVID | Nature Reviews Immunology

"Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing–remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein–Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform" therapeutic pathways.

Vaccine Injury

"Collection of peer reviewed case reports and studies citing adverse effects post COVID vaccination.

Postural Orthestatic Tachycardia Syndrome (POTS)

Postural Orthostatic Tachycardia Syndrome (POTS): A critical assessment - PMC (nih.gov)

Although diagnostic criteria have been developed characterizing postural orthostatic tachycardia syndrome (POTS), no single set of criteria is universally accepted. Furthermore, there are gaps in the present criteria used to identify individuals who have this condition. The reproducibility of the physiological findings, the relationship of symptoms to physiological findings, the presence of symptoms alone without any physiological findings and the response to various interventions confuse rather than clarify this condition. As many disease entities can be confused with POTS, it becomes critical to identify what this syndrome is. What appears to be POTS may be an underlying condition that requires specific therapy. POTS is not simply orthostatic intolerance and symptoms or intermittent orthostatic tachycardia but the syndrome needs to be characterized over time and with reproducibility. Here we address critical issues regarding the pathophysiology and diagnosis of POTS in an attempt to arrive at a rational approach to categorize the syndrome with the hope that it may help both better identify individuals and better understand approaches to therapy.

Small Fibre Neuropathy (SFN)

Small fiber neuropathy associated with SARS-CoV-2 infection - PubMed (nih.gov)

"Introduction/aims: The development and persistence of neurological symptoms following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is referred to as "long-haul" syndrome. We aimed to determine whether small fiber neuropathy (SFN) was associated with SARS-CoV-2 infection.

Methods: We retrospectively studied the clinical features and outcomes of patients who were referred to us between May 2020 and May 2021 for painful paresthesia and numbness that developed during or after SARS-CoV-2 infection and who had nerve conduction studies showing no evidence of a large fiber polyneuropathy.

Results: We identified 13 patients, Eight women and five men with age ranging from 38-67 y. Follow-up duration ranged from 8 to 12 mo. All patients developed new-onset paresthesias within 2 mo following SARS-CoV-2 infection, with an acute onset in seven and co-existing autonomic symptoms in seven. Three patients had pre-existing but controlled neuropathy risk factors. Skin biopsy confirmed SFN in six, all of whom showed both neuropathy symptoms and signs, and two also showed autonomic dysfunction by autonomic function testing (AFT). Of the remaining seven patients who had normal skin biopsies, six showed no clinical neuropathy signs and one exhibited signs and had abnormal AFT. Two patients with markedly reduced intraepidermal nerve fiber densities and one with normal skin biopsy had severe and moderate coronavirus disease 2019 (COVID-19); the remainder experienced mild COVID-19 symptoms. Nine patients received symptomatic neuropathy treatment with paresthesias controlled in seven (77.8%).

Discussion: Our findings suggest that symptoms of SFN may develop during or shortly after COVID-19. SFN may underlie the paresthesias associated with long-haul post-COVID-19 symptoms."

Mast Cell Activation Syndrome (MCAS)

Hyper-inflammation caused by COVID-19 may be mediated by mast cell activation (MCA) which has also been hypothesized to cause Long-COVID (LC) symptoms.

We determined prevalence/severity of MCA symptoms in LC.

Methods

Adults in LC-focused Facebook support groups were recruited for online assessment of symptoms before and after COVID-19. Questions included presence and severity of known MCA and LC symptoms and validated assessments of fatigue and quality of life. General population controls and mast cell activation syndrome (MCAS) patients were recruited for comparison if they were ≥18 years of age and never had overt COVID-19 symptoms.

Results

There were 136 LC subjects (89.7% females, age 46.9 ±12.9 years), 136 controls (65.4% females, age 49.2 ±15.5), and 80 MCAS patients (85.0% females, age 47.7 ±16.4). Pre-COVID-19 LC subjects and controls had virtually identical MCA symptom and severity analysis. Post-COVID-19 LC subjects and MCAS patients prior to treatment had virtually identical MCA symptom and severity analysis.

Conclusions

MCA symptoms were increased in LC and mimicked the symptoms and severity reported by patients who have MCAS. Increased activation of aberrant mast cells induced by SARS-CoV-2 infection by various mechanisms may underlie part of the pathophysiology of LC, possibly suggesting routes to effective therapy.