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What are the major findings of long COVID research?


In a recent review published in Nature Reviews Microbiology, researchers explored existing literature on long coronavirus disease (COVID). They highlighted key immunological findings, similarities with other diseases, symptoms, associated pathophysiological mechanisms, and diagnostic and therapeutic options, including coronavirus disease 2019 (COVID-19) vaccinations.

Study: Long COVID: major findings, mechanisms and recommendations. Image Credit: Ralf Liebhold/Shutterstock

Long COVID refers to a multisystemic disease among SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2)-positive individuals, with increasing prevalence rates by the day. Studies have reported on long COVID risk factors, symptoms, pathophysiology, diagnosis, and treatment options, with increasing similarities between long COVID and other diseases such as POTS (postural orthostatic tachycardia syndrome) and ME/CFS (myalgic encephalomyelitis/ chronic fatigue syndrome).

About the review

In the present review, researchers explored the existing data on long COVID immunology, symptoms, pathophysiology, diagnosis, and therapeutic options.

Key long COVID findings and similarities with other diseases

Studies have reported persistently reduced exhausted T lymphocytes, dendritic cells, cluster of differentiation 4+ (CD4+) lymphocyte and CD8+ lymphocyte counts, and greater PD1 (programmed cell death protein-1) expression. In addition, increase in innate cell immunological activities, non-classical monocytes, expression of interferons (IFNs)-β, λ1, and interleukins (IL)-1β, 4,6, tumor necrosis factor (TNF). Cytotoxic T lymphocyte expansion has been linked to gastrointestinal long COVID symptoms, and persistent increase in CCL11 (C-X-C motif chemokine 11) expression has been linked to cognitive dysfunction among long COVID patients.

Elevated autoantibody titers have been reported among long COVID patients, such as autoantibodies against ACE2 (angiotensin-converting enzyme 2), angiotensin II receptor type I (AT1) receptors, β2-adrenoceptors, angiotensin 1–7 Mas receptors, and muscarinic M2 receptors. Reactivation of Epstein-Barr virus (EBV) and human herpes virus-6 (HHV-6) has been reported in long COVID patients and ME/CFS. EBV reactivation has been linked to neurocognitive impairments and fatigue in long COVID.

SARS-CoV-2 persistence reportedly drives long COVID symptoms. SARS-CoV-2 proteins and/or ribonucleic acid (RNA) have been detected in cardiovascular, reproductive, cranial, ophthalmic, muscular, lymphoid, hepatic, and pulmonary tissues, and serum, breast, urine, and stool obtained from long COVID patients. Similar immunological patterns are noted between long COVID and ME/CFS, with elevated cytokine levels in the initial two to three years of disease, followed by reduction with time, without symptomatic improvements in ME/CFS. Lower cortisol levels, mitochondrial dysfunction, post-exertional malaise, dysautonomia, mast cell activation, platelet hyperactivation, hypermobility, endometriosis, menstrual alterations, and intestinal dysbiosis occur in both conditions.

Long COVID symptoms and underlying pathophysiological mechanisms

Long COVID-associated organ damage reportedly results from COVID-19-induced inflammation and associated immune responses. Cardiovascular long COVID symptoms such as chest pain and palpitations have been associated with endothelial dysfunction, micro-clotting, and lowered vascular density. Long COVID has been associated with an increased risk of renal damage and type 2 diabetes. Ophthalmic symptoms of long COVID, including altered pupillary responses to light, result from the loss of small nerve fibers in the cornea, increased dendritic cell density, and impaired retinal microvasculature. Respiratory symptoms such as persistent cough and breathlessness result from altered pulmonary perfusion, epithelial injury, and air entrapment in the airways.

Cognitive and neurological long COVID symptoms include loss of memory, cognitive decline, sleep difficulties, paresthesia, balancing difficulties, noise and light sensitivity, tinnitus, and taste and/or smell loss. Underlying pathophysiological mechanisms include kynurenine pathway activation, endothelial injury, coagulopathy, lower cortisol levels, loss of myelin, microglial reactivation, oxidative stress, hypoxia, and tetrahydrobiopterin deficiency.  Gastrointestinal symptoms such as pain in the abdomen, nausea, appetite loss, constipation, and heartburn have been associated with elevated Bacteroides vulgatus and Ruminococcus gnavus counts and lower Faecalibacterium prausnitzii counts. Neurological symptoms often have a delayed onset, worsen with time and persist longer than respiratory and gastrointestinal symptoms, and long COVID presents similarly in children and adults.

Diagnostic and therapeutic options for long COVID, including COVID-19 vaccines

The diagnosis and treatment of long COVID are largely symptom-based, including tilt tests for POTS, magnetic resonance imaging (MRI) to detect cardiovascular and pulmonary impairments, and electrocardiograms to detect QRS complex fragmentation. Salivary tests and serological tests, including red blood cell deformation, lipid profile, complete blood count, D-dimer, and C-reactive protein (CRP) evaluations, can be performed to assess immunological biomarker levels. PCR (polymerase chain reaction) analysis is used for SARS-CoV-2 RNA detection and quantification, and antibody testing is performed to assess humoral immune responses against SARS-CoV-2.

Pharmacological treatments include intravenous Ig for immune dysfunction, low-dosage naltrexone for neuronal inflammation, beta-blockers for POTS, anticoagulants for microclot formation, and stellate ganglion blockade for dysautonomia. Other options include antihistamines, paxlovid, sulodexide, and pycnogenol. Non-pharmacological options include cognitive pacing for cognitive impairments, diet limitations for gastrointestinal symptoms, and increasing salt consumption for POTS. COVID-19 vaccines have conferred minimal protection against long COVID, the development of which depends on the causative SARS-CoV-2 variant, and the number of vaccination doses received. Long COVID has been reported more commonly post-SARS-CoV-2 Omicron BA.2 subvariant infections.

Based on the review findings, long COVID is a multiorgan disease that has debilitated several lives worldwide, for which diagnostic and therapeutic options are inadequate. The findings underscored the need for future studies, clinical trials, improved education, mass communication campaigns, policies, and funding to reduce the future burden of long COVID.



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