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 suggestions. Image Credit: Ralf Liebhold/Shutterstock
Long COVID refers to a multisystemic disease amongst 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 aspects, symptoms, pathophysiology, diagnosis, and treatment options, with increasing similarities between long COVID and other diseases comparable to POTS (postural orthostatic tachycardia syndrome) and ME/CFS (myalgic encephalomyelitis/ chronic fatigue syndrome).
In regards to the review
In the current review, researchers explored the prevailing 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. As well as, 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 chronic increase in CCL11 (C-X-C motif chemokine 11) expression has been linked to cognitive dysfunction amongst long COVID patients.
Elevated autoantibody titers have been reported amongst long COVID patients, comparable to 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 within the initial two to a few 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 each 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 comparable to chest pain and palpitations have been related to endothelial dysfunction, micro-clotting, and lowered vascular density. Long COVID has been related to an increased risk of renal damage and sort 2 diabetes. Ophthalmic symptoms of long COVID, including altered pupillary responses to light, result from the lack of small nerve fibers within the cornea, increased dendritic cell density, and impaired retinal microvasculature. Respiratory symptoms comparable to persistent cough and breathlessness result from altered pulmonary perfusion, epithelial injury, and air entrapment within the airways.
Cognitive and neurological long COVID symptoms include lack of memory, cognitive decline, sleep difficulties, paresthesia, balancing difficulties, noise and lightweight sensitivity, tinnitus, and taste and/or smell loss. Underlying pathophysiological mechanisms include kynurenine pathway activation, endothelial injury, coagulopathy, lower cortisol levels, lack of myelin, microglial reactivation, oxidative stress, hypoxia, and tetrahydrobiopterin deficiency. Gastrointestinal symptoms comparable to pain within the abdomen, nausea, appetite loss, constipation, and heartburn have been related to 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, may be performed to evaluate immunological biomarker levels. PCR (polymerase chain response) evaluation is used for SARS-CoV-2 RNA detection and quantification, and antibody testing is performed to evaluate 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, weight loss plan limitations for gastrointestinal symptoms, and increasing salt consumption for POTS. COVID-19 vaccines have conferred minimal protection against long COVID, the event of which will depend on the causative SARS-CoV-2 variant, and the variety 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 necessity for future studies, clinical trials, improved education, mass communication campaigns, policies, and funding to scale back the longer term burden of long COVID.