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Sideratou, C.; Papaneophytou, C. Potential Therapies for Long COVID-19 Syndrome. Encyclopedia. Available online: https://encyclopedia.pub/entry/52968 (accessed on 23 June 2024).
Sideratou C, Papaneophytou C. Potential Therapies for Long COVID-19 Syndrome. Encyclopedia. Available at: https://encyclopedia.pub/entry/52968. Accessed June 23, 2024.
Sideratou, Christina-Michailia, Christos Papaneophytou. "Potential Therapies for Long COVID-19 Syndrome" Encyclopedia, https://encyclopedia.pub/entry/52968 (accessed June 23, 2024).
Sideratou, C., & Papaneophytou, C. (2023, December 20). Potential Therapies for Long COVID-19 Syndrome. In Encyclopedia. https://encyclopedia.pub/entry/52968
Sideratou, Christina-Michailia and Christos Papaneophytou. "Potential Therapies for Long COVID-19 Syndrome." Encyclopedia. Web. 20 December, 2023.
Potential Therapies for Long COVID-19 Syndrome
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The coronavirus disease 2019 (COVID-19), instigated by the zoonotic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), rapidly transformed from an outbreak in Wuhan, China, into a widespread global pandemic. A significant post-infection condition, known as ‘long- COVID-19′ (or simply ‘long- COVID’), emerges in a substantial subset of patients, manifesting with a constellation of over 200 reported symptoms that span multiple organ systems. This condition, also known as ‘post-acute sequelae of SARS-CoV-2 infection’ (PASC), presents a perplexing clinical picture with far-reaching implications, often persisting long after the acute phase.

SARS-CoV-2 COVID-19 long-COVID post-COVID cytokine storm ACE-2

1. Introduction

Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) leads to an acute multisystem illness known as coronavirus disease 2019 (COVID-19) [1]. This infection has resulted in a significant global pandemic with considerable mortality and morbidity [2]. While about 80% of affected individuals experience mild to moderate disease, 5% develop critical illness [3]. The common signs of COVID-19, including shortness of breath, high body temperature, coughing, and tiredness, can lead to serious health issues like lung infection, heart inflammation, and kidney damage [4].
SARS-CoV-2, an airborne zoonotic virus, primarily employs the angiotensin-converting enzyme 2 (ACE2) receptor for cell entry by binding its spike protein to the receptor; however, other receptors might also be involved [5]. ACE2, crucial in COVID-19 pathogenesis, is abundantly found in various tissues, including the lungs, heart, liver, kidneys, gastrointestinal tract [6], and nervous system [7]. As a result, COVID-19 often manifests multi-organ damage, leading to conditions like acute myocardial injury, acute kidney injury, and acute respiratory distress syndrome (ARDS) [8][9].
The genome of SARS-CoV-2 is approximately 79% homologous to severe acute respiratory syndrome 1 (SARS-CoV-1) and 50% homologous to the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) genome [10]. As per the findings from the International Committee on Taxonomy of Viruses (ICTV) and the European Center for Disease Control (ECDC), SARS-CoV-2 is classified within the Coronaviridae family, the Orthocoronavirinae subfamily, and lineage B of the genus Coronaviruses [11]. The viral particles have a diameter ranging from 60 to 140 nm [12]. While the predominant shape of these particles is spherical or ellipsoidal, oval shapes have also been reported. The virus possesses an envelope and a helically symmetrical nucleocapsid [13].
The acute phase of COVID-19 generally lasts up to 4 weeks from the onset of the initial infection [14]. However, in a subset of patients, symptoms may continue beyond this period into a post-acute phase known as ‘long COVID-19’. Interestingly, there are instances where patients experience prolonged symptoms for weeks or even months following the initial infection, regardless of its initial severity [15]. This has captured the attention of numerous organizations and research groups, including the World Health Organization (WHO), National Institute for Health and Care Excellence (NICE), National Health Service (NHS), and Centers for Disease Control and Prevention (CDC). This lingering condition has received various names, including ‘post-acute sequelae of SARS-CoV-2 infection’, ‘post-acute COVID-19 syndrome’, ‘long-COVID-19’, ‘long-COVID,’ ‘long haulers COVID-19’, ‘long haulers,’ and ‘post-COVID syndrome’. Post-SARS-CoV-2 implications pose a public health challenge with potentially severe repercussions [16]. However, definitions vary among authorities, particularly concerning the duration of symptoms that are classified as “long-haul”. According to the CDC (https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html, accessed on 15 September 2023), long COVID is a “Wide range of new, returning, or ongoing health problems people can experience four or more weeks after first being infected with the virus that causes COVID-19”. However, the WHO defined long COVID as an “Illness that occurs in people who have a history of probable or confirmed SARS-CoV-2 infection, usually within three months from the onset of COVID-19, with symptoms and effects that last for at least two months, that cannot be explained by an alternative diagnosis” (https://www.who.int/news-room/questions-and-answers/item/coronavirus-disease-(covid-19)-post-covid-19-condition, accessed on 15 September 2023). According to the definition proposed by the NHS, long COVID is observed when “Symptoms lasting weeks or months after the infection has gone” (https://www.nhs.uk/conditions/covid-19/long-term-effects-of-covid-19-long-covid/, assessed on 15 September 2023). On the other hand, two different definitions for long COVID have been proposed by the NICE Institute for Health and Care Excellence [17]: (i) “Ongoing symptomatic COVID-19 for people who still have symptoms between 4 and 12 weeks after the start of acute symptoms”; and (ii) “post-COVID-19 syndrome for people who still have symptoms for more than 12 weeks after the start of acute symptoms”.
The variability mentioned above in definitions for long COVID-19 complicates the establishment of a unified criterion for research. To address this, the WHO recently defined long COVID-19 (Post COVID-19) as a condition appearing in individuals with a history of suspected or confirmed SARS-CoV-2 infection, typically three months post-infection, with symptoms persisting for at least two months and not explained by an alternative diagnosis (reviewed in [18]).
The scientific community has been actively conducting research since the first reported case of COVID-19, caused by the SARS-CoV-2, in early December 2019 in China [19]. With 771, 820, 937 cases and 6, 978, 175 deaths reported thus far, evidence suggests that symptoms can persist long after the acute phase of the infection (https://covid19.who.int, accessed on 1 November 2023).

2. Health Implications Related to Long COVID

COVID-19, caused by SARs-CoV-2, has systemic implications that extend beyond the respiratory system, profoundly impacting cardiovascular health and other organ systems [20]. This multifaceted virus manifests with a wide array of symptoms affecting multiple organs, ranging from ‘silent hypoxia’—characterized by low blood oxygen levels without breathlessness—to neurological symptoms such as delirium, ‘brain fog’, mood changes, and the unexpected onset of conditions like hypertension or diabetes [21][22][23]. Recent findings suggest that lung inflammation during COVID-19 infection may lead to elevated cortisol levels, a physiological response that can subsequently increase blood pressure and potentially result in vessel injury [24]. Additionally, a critical aspect of SARS-CoV-2’s pathology is its impact on microcirculation. The virus causes endothelial cell swelling and damage (endotheliitis), leading to the formation of microscopic blood clots (microthrombosis), capillary congestion, and damage to pericytes, which play an essential role in capillary integrity, tissue repair, and scar formation. These microvascular changes are integral to understanding the widespread effects of the virus, elucidating the increased risk of vessel injury and subsequent formation of microclots (reviewed in [22]).
Furthermore, numerous biomedical discoveries have been made, with many patients reporting a variety of persisting symptoms following SARS-CoV-2 infection, which are described as “long COVID” affecting multiple organs [25]. The term ‘long COVID’ covers a range of complications, such as cardiovascular, thrombotic, and cerebrovascular diseases [26], type 2 diabetes [26], myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) [27], and dysautonomia, notably postural orthostatic tachycardia syndrome (POTS) [28]. These symptoms can persist for extended periods, and conditions like new-onset ME/CFS and dysautonomia are often considered permanent [29]. A significant number of long COVID patients have found it challenging to rejoin the workforce [25], leading to a notable contribution to workforce deficits. As of the time of publication of this work, no treatments have been definitively confirmed as effective. Research into immune irregularities in long-term COVID patients who initially experienced mild COVID-19 symptoms reveals T cell anomalies such as T cell exhaustion, diminished CD4+ and CD8+ effector memory cells, and increased PD1 expression on central memory cells lasting at least 13 months [30]. A surge in cytotoxic T cells has been linked to the gastrointestinal symptoms of long COVID [31]. Further research indicates elevated cytokine levels, especially IL-1β, IL-6, TNF, and IP10 [32]. A recent study also highlighted prolonged high levels of CCL11 linked with cognitive issues [33].

2.1. Effect of Long COVID on the Respiratory System

The respiratory system is notably the most commonly affected by SARS-CoV-2. However, respiratory symptoms may persist beyond the acute phase of infection into what is known as the ‘long COVID-19’ phase, even after patients have ostensibly recovered. Various studies have documented abnormalities in pulmonary function tests (PFTs) and chest CT images persisting for months following hospital discharge. Dyspnea and cough have been the most frequently reported persistent respiratory symptoms [34][35][36].
It has been previously demonstrated that ACE2 is linked to acute lung injury. One proposed mechanism as far as fibrosis development resulting from the previous SARS pandemic is the direct stimulation of the Transforming Growth Factor-β (TGF-β) by the nucleocapsid protein of SARS-CoV-1. Since the nucleocapsid core of SARS-CoV-2 is almost 90% similar to that of SARS-CoV-1, it may be valid [37]. The downregulation of ACE, which further regulates Angiotensin II, may lead to the stimulation of TGF-β. In addition to TGF-β, the production of advantageous factors such as Platelet-Derived Growth Factor (PDGF) and Vascular Endothelial Growth Factor (VEGF) is also found, resulting in the activation of fibroblasts, which are the activated macrophages and neutrophils that release pro-fibrotic mediators that promote the accumulation of myofibroblasts by stimulating collagen production [38].
Pulmonary myofibroblasts can arise from various progenitors, and they typically undergo apoptosis, concluding the healing process [39]. Following their differentiation from fibroblasts, myofibroblasts stimulate collagen synthesis. However, during fibrosis, the normal cessation of extracellular matrix (ECM) production is disrupted, and increased tissue stiffness exacerbates cell injury, leading to further myofibroblast activation [40]. This creates a self-sustaining loop of activation, resulting in irreversible fibrotic changes. These cells organize into fibrotic foci within the lung tissue [41]. Growth factors, particularly those targeting tyrosine kinase pathways, persistently stimulate the formation and development of these fibrotic areas, which may regress naturally or progress to chronic pulmonary fibrosis due to excessive collagen buildup [42]. During a SARS-CoV-2 infection, the virus targets respiratory epithelial cells, triggering local innate immune responses that include the release of inflammatory cytokines and chemokines. These inflammatory mediators recruit additional immune cells such as monocytes, macrophages, neutrophils, dendritic cells (DCs), and natural killer (NK) cells and activate adaptive immune responses involving CD4+ and CD8+ T cells. The continued presence of inflammatory cytokines like IL-2, IFN-γ, and TNF-α promotes myelination and urgent granulation tissue formation, aggravating lung injury and epithelial damage [43]. These cytokines increase lung capillary permeability, leading to diffuse bilateral ground-glass opacities, hypoxemia, and, ultimately, long-term fibrotic alterations [44]. The cytokine storm induced by SARS-CoV-2 infection can result in severe respiratory complications such as ARDS. Lung autopsies from COVID-19 fatalities have shown significant macrophage infiltration in the bronchial mucosa, confirming the extent of the inflammatory response [45].
As aforementioned, the lung is the primary target organ of SARS-CoV-2 infection [46]. In the intricate landscape of COVID-19’s impact on the respiratory system, a critical distinction emerges between upper airway inflammation, typically associated with milder cases and quicker recovery, and alveolar inflammation, often indicative of more severe infections and a precursor to extensive lung fibrosis [47]. Pandolfi et al. [48] examined the correlation of broncho-alveolar inflammation in COVID-19 patients with disease severity. Their study analyzed 33 adults admitted to either the intensive care unit (ICU) or the intermediate medicine ward (IMW) using bronchoalveolar lavage (BAL). Results indicated higher neutrophil counts and lower lymphocyte and macrophage levels in ICU patients compared to IMW patients, with elevated levels of pro-inflammatory cytokines IL6 and IL8 in non-survivors. Interestingly, IL10 levels showed no significant variation between groups. Treatment with steroids resulted in lower BAL concentrations of IL6 compared to tocilizumab or antivirals, suggesting that innate immune responses primarily drive alveolitis in COVID-19.
Barilli et al. [49] demonstrated that exposure of alveolar A549 cells to supernatants from S1 spike-activated macrophages significantly increased the release of inflammatory mediators, primarily IL-8. This indicates the involvement of the NF-kB pathway in IP-10 and RANTES transcription, with STATs regulating most cytokines/chemokines. The cytokines/chemokines from activated macrophages disrupted the barrier integrity of Human Alveolar Epithelial Lentivirus-immortalized cells (hAELVi), evident through increased permeability and disorganized claudin-7. This suggests that A549 cells contribute to lung inflammation and alveolar damage, which is crucial in ARDS pathology in COVID-19. In another study, Lazar et al. [50] compared 100 patients with severe pneumonia to a control group of 61 non-COVID patients, finding that 69% of COVID-19 patients showed persistent interstitial changes indicative of fibrotic alterations. The risk of developing fibrosis correlated with higher levels of ESR, CRP, LDH, and length of hospital stay. Imaging analysis revealed an increased risk of interstitial fibrosis with a more significant number of affected pulmonary lobes and a higher percentage of interstitial pulmonary fibrosis. These results indicate that the main risk factors for post-COVID-19 pulmonary fibrosis include elevated ESR, CRP, LDH, prolonged hospitalization, and the severity of the initial pneumonia. Furthermore, pulmonary fibrosis is a recognized sequela of ARDS [51]. While the majority of patients with COVID-19 pneumonia survive the acute phase, the timing for diagnosing irreversible pulmonary fibrosis post-COVID-19 remains unclear [52]. It is still uncertain whether survivors of severe COVID-19 will develop long-term lung complications or whether COVID-19-related pulmonary fibrosis will resolve, persist long-term, or become progressive as observed in human Idiopathic Pulmonary Fibrosis (IPF) [53].

2.2. Effect of Long COVID on the Cardiovascular System

SARS-CoV-2 infection impacts the CV system during the acute phase [54]; however, cardiac complications can persist even after recovery from the acute phase of the infection [54][55]. Given the high prevalence of such complications during this stage, it is crucial to pay attention to the potential long-term cardiac implications of the disease. Emerging evidence demonstrates a significant burden on the CV system during the long COVID period (reviewed in [56]). Symptoms specific to the CV system involvement of long COVID include palpitations, chest pain, breathlessness, and postural dizziness with or without syncope [57]. Palpitations and chest pain are the most common findings of the long COVID period [58]; seemingly healthy individuals may experience dizziness and an increased heart rate while resting [59].
Interestingly, in 2020, when long COVID was not yet widely recognized, Puntmann et al. [60] stressed the importance of ongoing monitoring for the long-term CV impacts of COVID-19. They found that among 100 individuals who had recovered from COVID-19, 78 showed abnormal results in cardiovascular magnetic resonance (CMR) imaging. These abnormalities included elevated myocardial native T1 (found in 73 participants), increased myocardial native T2 (in 60 participants), myocardial late gadolinium enhancement (in 32 participants), and pericardial enhancement (in 22 participants). Furthermore, ongoing myocardial inflammation was noted in 60% of the participants, irrespective of their preexisting health conditions, the severity and progress of the acute phase of their illness, or the time since their initial COVID-19 diagnosis. Subsequent studies, like the one by Huang et al. [61] with 26 recovered COVID-19 patients, also found significant cardiac involvement. In this cohort, 58% (15 patients) exhibited abnormal CMR results: 54% (14 patients) showed myocardial edema, and 31% (8 patients) had late gadolinium enhancement (LGE). Patients with abnormal CMR had diminished right ventricular function, including lower ejection fraction, cardiac index, and stroke volume relative to body surface area. These findings suggest cardiac issues, including myocardial edema, fibrosis, and right ventricular dysfunction, are prevalent in some COVID-19 recoverees.
Although the exact pathophysiological connection between long COVID-19 and CV system issues remains inconclusive, conditions like myocarditis and pericarditis may play a role. The studies mentioned above have uncovered a surprisingly high frequency of imaging abnormalities, suggesting widespread myocardial damage and inflammation in these patients. This finding is crucial for comprehending and managing the cardiac symptoms that persist in the extended recovery phase of COVID-19 [59].
The myocardium maintains a critical balance between the classical and non-classical pathways of the renin–angiotensin–aldosterone system (RAAS). An upsurge in the activity of the classical RAAS pathway, coupled with a suppression of the non-classical pathway, is correlated with adverse cardiovascular outcomes [62]. The enzyme ACE2 plays a crucial role in cardiac physiology and pathology. Specifically, the binding of SARS-CoV-2 to the ACE2 receptors on myocardial and endothelial cells results in diminished ACE2 activity, thereby impairing the conversion of angiotensin II (Ang II) to angiotensin-(1-7) [Ang 1-7] [62]. This reduction in ACE2-mediated conversion exacerbates the effects of the classical RAAS pathway, which are mediated by Ang II, leading to harmful cardiovascular effects [63].
The heightened activity of Ang II, which is characteristic of the classical RAAS pathway dominance, is associated with a decrease in collagenase activity within the cardiac tissue. This enzyme reduction can contribute to pathological remodeling of both atrial and ventricular myocardium, potentially resulting in detrimental structural and functional changes to the heart [64].
Enhanced binding of angiotensin II (Ang II) to the Ang II Type 1 Receptor (AT1R) initiates a signaling cascade that leads to phosphorylation and increased catalytic activity of a Disintegrin and Metalloproteinase 17’ (ADAM-17). Activation of ADAM-17 promotes the shedding of ACE2 from the cell surface, further decreasing Ang II clearance. The result is an amplification of Ang II-induced inflammatory responses, creating a self-perpetuating cycle of inflammation [64]. Moreover, the reduction in ACE2 activity can contribute to myocardial fibrosis, potentially leading to symptoms such as fatigue and dyspnea, characteristic of post-acute sequelae of SARS-CoV-2 infection [25].
Myocardial injury in COVID-19 may result from indirect effects mediated by the systemic inflammatory response [65], primarily through the “cytokine storm” phenomenon [66]. In the context of a SARS-CoV-2 infection, cytokine storms can activate bone marrow-derived endothelial cells, resulting in pericardial inflammation [67]. The adverse inotropic effects of pro-inflammatory cytokines can impair cardiac contractility. Persistent activation of inflammatory signaling, mainly via tumor necrosis factor-alpha (TNFα) and interleukin-1 beta (IL-1β), can lead to widespread cardiomyocyte apoptosis and subsequent abnormal left ventricular remodeling, predisposing to acute heart failure. Furthermore, cytokine storms stimulate monocytes/macrophages to release matrix metalloproteinases, accelerating the growth and rupture of atherosclerotic plaques, promoting the release of procoagulant factors, and causing hemodynamic changes, thus elevating the risk of Acute Myocardial Infarction (AMI) [68].
Cytokine storms are also linked with lymphopenia, characterized by reduced lymphocyte counts [69]—the inflammatory response results in lymphocyte depletion, impairing the body’s ability to fight the SARS-CoV-2 infection. Consequently, cytokine production is deregulated, leading to damage to healthy cells, initially in the lungs and potentially extending to other organs, including the heart [70].

2.3. Effect of Long COVID on the Nervous System

Individuals with long COVID can exhibit a broad spectrum of symptoms, including persistent neuropsychiatric issues that may arise or persist for months following the initial infection [25][71][72]. Recognized as a condition affecting multiple organs, long-term COVID-19 definitively involves both the Central Nervous System (CNS) and Peripheral Nervous System (PNS), contributing to the enduring nature of the disease [73][74]. Approximately one-third of individuals who test positive for SARS-CoV-2 experience neurological and neuropsychiatric symptoms early in the course of the disease, and these symptoms can persist long after the acute infection has resolved. Commonly reported symptoms include anosmia (loss of smell), ageusia or dysgeusia (altered taste), headache, fatigue, cognitive impairment (‘mental fog’), and memory loss, enduring for weeks or even months [75][76]. Other observed issues include impaired concentration, sensory disturbances, and depression [77]. Numerous studies conducted globally have consistently reported fatigue as the most frequent and debilitating symptom of long COVID-19, independent of the disease’s initial severity or the occurrence of respiratory distress [78][79]. Moreover, SARS-CoV-2 infection can precipitate inflammatory neurological syndromes, such as encephalitis and acute disseminated encephalomyelitis, along with ischemic and hemorrhagic strokes [80].
SARS-CoV-2 has brain tropism, and the neurological dysfunctions that have been reported may be due to the Renin–Angiotensin System (RAS) damage of the nervous system. The imbalance of the two aspects of RAS: (1) ACE/Ang II/AT1R, and (2) ACE2/Ang (1-7)/Angiotensin II Type 2 Receptor (AT2R) in the brain leads to neuroinflammation, neurotoxicity, and Blood–Brain Barrier (BBB) disruption among other things. AT1R, among others, causes inflammation and oxidative stress [81]. AT2R has an essential role in neuraxon regeneration, i.e., it protects the brain by conducting neuronal survival, and in the case of SARS-CoV2 infection, it protects one against the deleterious effects of AT1R along with MasR [82].
Various post-COVID-19 effects, such as hyposmia/anosmia and memory/cognitive impairment, have been attributed to hypometabolism in different areas of the brain. For example, hypometabolism of the brainstem is associated with hyposmia/anosmia, while hypometabolism of the cerebellum or frontal cortex is linked to memory/cognitive impairment. The Positron Emission Tomography (PET) scans of long COVID patients who express persistent complaints at least three weeks after the onset of their acute infection symptoms showed hypometabolism in their bilateral rectal/orbital helix (containing the olfactory helix) in the right temporal lobe (amygdala and hippocampus extending into the right thalamus), in the bilateral brainstem bridge/myelin and the bilateral cerebellum. These findings could indicate the involvement of the ACE2 receptor in the neurotropism of SARS-CoV-2, particularly in the olfactory bulb. This is likely due to the dissemination route from the nose to the olfactory bulb, where the ACE2 receptor has a strong presence; it has been hypothesized that the ACE2 receptor is the cause of several coronaviruses [83].
As aforementioned, cytokine storm, a systemic hyperinflammatory state characteristic of the acute phase of COVID-19, activates neuroglial cells and increases the risk of neurological complications post-infection [84]. Various viruses, including SARS-CoV-2, can infiltrate the CNS through hematogenous routes, triggering immune-induced neurological disorders [85]. SARS-CoV-2 has neurotropic properties; during severe infections, it can infect brain-resident cells such as macrophages, microglia, and astrocytes. These cells, when infected, contribute to a pro-inflammatory state within the CNS [86].
The cytokine storm can also induce cerebral perfusion anomalies, compromise the integrity of the BBB, disrupt astrocytic functions essential for synaptogenesis, and cause neurotransmitter imbalances [87]. This cascade of events can dysregulate neurogenesis and disrupt the normal functioning of neurons, oligodendrocytes, and neuroglial cells [88]. Consequently, disturbances in neuronal plasticity, synaptic function, myelination, and BBB maintenance may lead to cognitive deficits and an array of long-term neuropsychiatric symptoms associated with COVID-19 [89]. Elevated pro-inflammatory cytokine levels have been implicated in causing confusion and altered consciousness [90], and the excessive release of cytokines and chemokines can also result in brain damage through microglial activation [91]. Additionally, an imbalance between TH17 cells and regulatory T cells (Tregs) has been linked to learning and sleep disturbances [92].
Ocular muscle abnormalities, such as pain with eye movements, extraocular movement abnormalities, Adie’s pupil, diplopia, and strabismus, have been observed in both elderly and young COVID-19 patients [93]. In a case study involving five COVID-19 patients with neurological symptoms, neurological examinations revealed flaccid paresis with limb predominance and unilateral facial nerve involvement [94]. Peripheral neuropathy symptoms in COVID-19 patients, such as sudden numbness, limb pain, and weakness, have been noted, along with debates against Guillain-Barre due to the sudden onset of symptoms, lack of ascending pattern, and normal cerebrospinal fluid (CSF) [95].
Furthermore, Oaklander et al. [96] evaluated peripheral neuropathy in patients with prolonged long COVID symptoms. Their study of 17 patients without prior neuropathy history revealed significant neuropathy evidence, with 63% of skin biopsies, 17% of electrodiagnostic tests, and 50% of autonomic function tests confirming the diagnosis. Common diagnoses included small-fiber neuropathy, critical illness axonal neuropathy, and multifocal demyelinating neuropathy, typically occurring within one month of mild COVID-19 infection. Despite an average improvement of 52%, none reported complete symptom resolution, with 65% receiving immunotherapies. These findings suggest small-fiber neuropathy is a common outcome of long COVID, potentially due to immune dysregulation caused by the infection.
In more than one-third of patients with a history of severe SARS-CoV-2 infection, involvement of the central or peripheral nervous system has been observed, with a higher incidence of neurological symptoms reported in patient studies [73]. The most frequent long-COVID neurological manifestations include fatigue, ‘brain fog’, headache, cognitive impairment, sleep, mood, smell or taste disorders, myalgias, sensorimotor deficits, and dysautonomia. Current understanding of the pathophysiological mechanisms involved in long-COVID is limited, but neuroinflammatory and oxidative stress processes are believed to play a significant role in propagating these neurological sequelae [73].

3. Potential Therapies for Long COVID-19 Syndrome

Several guidelines have been developed that focus on treating and managing long COVID-19. For example, NICE has proposed comprehensive assessment, investigation, and management approaches (https://www.nice.org.uk/guidance/ng188/resources/covid19-rapid-guideline-managing-the-longterm-effects-of-covid19-pdf-51035515742; accessed on 15 October 2023). Similarly, the NIH has released treatment guidelines for COVID-19, but these offer limited guidance for managing long-term COVID-19 effects (https://www.covid19treatmentguidelines.nih.gov/, accessed on 15 October 2023).
While a significant portion of research has appropriately focused on the acute phase of COVID-19, there is a growing recognition of the need to address the long-term effects of the disease. In this context, drug repurposing is emerging as a critical area of investigation. Antihistamines are under consideration following cellular studies indicating that histamine-1 receptor antagonists might inhibit SARS-CoV-2 entry into cells expressing the ACE2 receptor, but their efficacy for treating long COVID-19 remains to be established [30][97].
Monoclonal antibodies like Leronlimab, which is used for HIV and has been shown to reduce viral plasma levels in acute COVID-19 patients, are being investigated for their potential to mitigate long-lasting COVID-19 symptoms [98]. Tocilizumab, which blocks interleukin-6 receptors, was tested in a small clinical trial for acute COVID-19, and research into its long-term effects is ongoing. Melatonin, noted for its antioxidant properties, is also being considered for treating long-term COVID-19 effects (reviewed in [99]).
For the cardiovascular manifestations of long COVID-19, NICE guidelines suggest beta-blockers as treatment options for conditions such as angina, cardiac arrhythmias, and acute coronary syndromes [100]. Sulodexide has been found to reduce symptom severity in patients with endothelial dysfunction [101]. The effectiveness of Cognitive Behavioral Therapy (CBT) has been questioned due to reported adverse effects [102]. The use of intravenous vitamin C to alleviate fatigue in long COVID-19 patients has been recently reviewed [103].
The persistent neurological complications post-COVID-19 have made Biofeedback (BFB) therapy an area of interest, with potential benefits for headaches, seizures, and insomnia, and Neurofeedback (NFB) has been documented for its long-term effectiveness [104]. For long-term neurological symptoms, glucocorticoids may be beneficial [105], and medications like tryptans and indomethacin could address prolonged symptoms such as headaches [106][107].
Pulmonary symptoms often persist post-acute COVID-19. Critical Care guidelines recommend chest imaging for early detection of pulmonary impairment and the use of corticosteroids to improve function [108]. Hyperpolarized MRI has been cited for its ability to detect gas exchange abnormalities [109]. According to Mayo Clinic recommendations, managing factors that worsen dyspnea, such as smoking cessation and avoiding pollutants, is crucial [110]. Treatment for pulmonary fibrosis should follow idiopathic pulmonary fibrosis guidelines, and anti-fibrotic therapies are considered promising options [111]. Clinical trials also evaluate the efficacy of hyperbaric oxygen therapy, montelukast, and pirfenidone for respiratory conditions associated with long COVID.
The role of COVID-19 vaccination in addressing long COVID is multifaceted and operates on three distinct levels. Firstly, the vaccines effectively prevent SARS-CoV-2 infection, thereby reducing the risk of developing long COVID. Secondly, for vaccinated individuals who contract COVID-19, the vaccines tend to lessen the severity of the disease, which may mitigate the development or intensity of long COVID symptoms. Finally, emerging evidence suggests that vaccination may also benefit those already suffering from long COVID, potentially alleviating some of the persistent symptoms associated with the condition [33][112].
A significant reduction in the incidence of long COVID following vaccination was reported in a systematic review by Byambasuren et al. [112]. In a study by Tran et al. [113], the first dose of the COVID-19 vaccine was associated with decreased severity of the disease and improved impacts on patients’ social, professional, and family lives. The study also found that vaccination led to a higher remission rate of long COVID symptoms and an increased proportion of patients reporting an acceptable symptom state. However, it is essential to note that a small percentage of patients experienced adverse effects, and some reported a worsening of symptoms or relapses post-vaccination [114].
Nayyerabadi et al. [115] also reported significant improvements in long COVID patients post-vaccination, including decreased symptoms and affected organ systems, and increased WHO-5 Well-Being Index Scores. This study suggested that vaccination helps in reducing systemic inflammation in long COVID patients. Despite these improvements, the persistence of SARS-CoV-2 S1 antigen in non-classical monocytes, regardless of vaccination status, indicates an ongoing inflammatory process.
Overall, vaccination before SARS-CoV-2 infection has been associated with reduced risks or odds of long COVID [116]. This is highlighted in a recent systematic review by Notarte et al. [117] which induced eleven studies involving 36,736 COVID-19 survivors to investigate changes in long-COVID symptoms after vaccination. While most studies showed improvement in symptoms post-vaccination, a few reported no change or worsening symptoms. The comprehensive impact of COVID-19 vaccination on long COVID continues to be an active research area.

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