Long COVID and possible preventive options

Most of the people who suffered from COVID-19 fully recovered, but approximately 10–20% of them developed a wide variety of symptoms after they recover from their initial illness. Long COVID can develop at any patient; however, several studies suggest that the development of Long Covid syndrome may be linked to severity of acute illness. Some of the risk factors are hospitalization (with mechanical ventilation), Intensive Care Unit admission, age (over 50 years), gender (female) and comorbidities. Since the precise mechanism of Long COVID has not been clarified, neither the management of Long COVID-19 syndrome has been solved yet. Promising results have been published with vaccines as they effectively reduced the risk of Long COVID; however, other data suggest that vaccination results only partial protection in the post-acute phase of the disease. Recently, the orally effective antiviral agents (Paxlovid, molnupiravir) are preferred for outpatient management, and they highly reduce the progression of mild-to-moderate COVID-19 to severe one, and consequently, might reduce the development of Long COVID. Finally, recently, several clinical trials are in progress with either dietary supplements or drugs with different mechanisms of action. Additional information on the precise mechanisms, risk factors of Long COVID may result in successful preventive and therapeutic management of Long Covid 19 syndrome.


Introduction
Long COVID or post-COVID refers to the prolonged symptoms which may be new or returning ones, that patients may develop after recovery from the initial, acute SARS-CoV-2 infection.The post-COVID symptoms are highly heterogeneous and complex, fatigue, dyspnea, sleep disorders, gastrointestinal disturbance, chronic cough, anxiety, depression, memory loss, concentration problems and a significant impairment in their quality of life have been reported; fatigue and neurocognitive complaints are the predominate ones.The symptoms can be mild to severe, may persist for months, and can fluctuate or relapses.
The Long Covid terminology is generally used for the description of the condition when the symptoms last far longer than it would be expected after recovery from SARS-CoV-2 infection.However, since both the course, the symptoms, the severity and the duration of Long COVID show great diversity, there is no consensus how to define it.

Definitions of Long COVID
Fernández- de-las-Peñas et al. (2021a, b) distinguished four stages in the course of Long COVID: a./4-5 weeks after the initial phase of the disease characterized by infectionrelated symptoms, b./from week 5 to 12 after the onset acute post-COVID symptoms, c./from week 12-24 after the initial period Long post-COVID symptom, and d./over 24 weeks after the acute infection the persistent post-COVID symptoms (Fernández-de-Las-Peñas et al. 2021a).
Another definitions by the same group distinguished two phases: acute post-COVID (from week 5 to week 12) and chronic post-COVID (lasting more than 12 weeks after symptom's onset) (Fernández-de-las-Peñas 2022).Similarly, two phases, the ongoing symptomatic COVID-19 (from 4 to 12 weeks) and the post-COVID-19 syndrome (12 weeks or more) were suggested by Datta et al. (2020).Furthermore, according to Yong (2021) when the symptoms persist for more than 3 months after the onset of the disease, it can be taken as Long COVID.
The National Institute for Health and Care Excellence guideline (United Kingdom) distinguishes Long-and post-COVID conditions: Long COVID means the ongoing symptomatic COVID-19, where symptoms last for 4 to 12 weeks and post-COVID-19 syndrome, where the symptoms persist beyond 12 weeks in the absence of an alternative diagnosis (NICE 2020).
Similarly, the World Health Organization (WHO) defines Long COVID as symptoms that persist for 3 months after the onset of COVID infection and the symptoms cannot be explained by an alternative diagnosis (Soriano et al. 2022).

Prevalence of Long-COVID syndrome after the acute SARS-CoV-2 infection
People infected with SARS-CoV-2 approximately 10-20% developed a wide variety of symptoms after they recover from their initial illness (Ballering et al. 2022); others have experienced higher prevalence, 30% of the development of Long COVID-19 in people infected with SARS-CoV-2 (Yoo et al. 2022).On the other hand, much lower (around 7%) prevalence of Post-Acute Sequelae of SARS-CoV-2 infection (PASC) was found by Xie et al. (2021), though it was consistently higher in people with poorer baseline health and in those who had more severe acute infection.

Susceptibility to Long COVID
Long COVID can develop at any patient, also after mild-tomoderate cases and also in youngers, who were not admitted to hospital or even had asymptomatic COVID-19 (Dennis et al. 2021;Shah et al. 2021, Yong 2021).In addition, it has also been raised that neither the severity of the infection nor the intensity of the treatment the patients received, have any role in the development of Long COVID-19 (Crook et al. 2021).
In contrast, several studies suggest that the development of Long Covid symptoms may be linked to symptomatic COVID-19 infection; severity of illness, hospitalization (with mechanical ventilation), as well as sex (women) may have role in higher incidence of Long COVID (Baratta et al. 2021;Fernández-de-Las-Peñas et al. 2021b).
Others also confirmed and raised additional risk factors, for example the severity of illness (need for hospital or Intensive Care Unit /ICU/ admission), ventilatory support, age (over 50 years), gender (female) and comorbidities (asthma or previous respiratory disease, obesity and increased body mass index).On the other hand, several diseases, such as diabetes, hypertension, cancer and immunosuppression are risk factors for severity and mortality in the acute phase of COVID-19 infection, but no association has been proven with the development of post-COVID syndrome (Carod-Artal 2021).In consistence with the previous data, it has been found that patients who had to be admitted to hospital to the Intensive Care Unit (ICU) developed more frequently Long COVID, e.g., the prevalence of different post-COVID-19 symptoms were higher in patients who were treated in intensive care unit compared to ward patients, such as fatigue (72% vs. 60.3%),dyspnea (65.6% vs. 42.6%),attention and memory disorders (52% vs. 33.8%),and swallowing and language disorders (68.7% vs. 42.6%)were the most frequent symptoms (Halpin et al. 2021).Furthermore, patients (n = 119) treated in ICU, after recovery from the acute disease, 56% more likely to develop a neuropsychiatric disorder compared to non-ICU survivors (Taquet et al. 2021).Similarly, in patients who had been admitted to hospital for severe pneumonia 2 months after discharge, persistent symptoms were common, e.g., 68% had persistent fatigue, 57% sleep disorders, 39% persistent dyspnea or cough (D'Cruz et al. 2021).
In another study of 143 hospitalized patients with COVID-19, 87% of the patients had symptoms 2 months after being discharged and 40% reported a decrease in their quality of life, and fatigue persisted in over 50% for more than 60 days after the onset of symptoms (Carfì et al. 2020).Similar results have been published by Tomasoni et al (2021): patients with pneumonia due to SARS-CoV-2 infection complained about persistent physical symptoms (52%), anxiety (29%) and cognitive disorders (17%) 1-3 months after discharge (Tomasoni et al. 2021).Moreover, the health status of COVID-19 patients was evaluated at 6 and 12 months after hospital discharge.It was found that patients who needed respiratory support compared to patients who did not require, had higher probability of having symptoms at 6 and even in at 12 months.Consequently, it may be concluded that hospitalized COVID-19 patients with more severe symptoms in the acute phase may have higher risk of developing Long Covid symptoms (Lopez-Leon et al. 2021).

Vaccines
The effect of vaccines on the development of Long COVID is inconsistent in the light of literature.The third dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine has important potential benefits; beyond reducing the illness, may prevent the COVID-19 sequelae after breakthrough infections.It was found that two or three doses of vaccine reduced the odds of developing Long COVID by 75 and 85%, respectively (Labos 2022;Ledford 2021).Accordingly, others have found that two doses of a COVID-19 vaccine resulted in 50% reduction of the risk of Long COVID.The data were obtained from self-reported information of 1.2 million UK individuals (Antonelli et al. 2022).
In contrast, though vaccination decreased the risk of death and post-acute sequelae, the protection was only partial in the post-acute phase of the disease (15%) according a study on US veterans (Al-Aly et al. 2022).

Antiviral compounds
As it was discussed above, several data suggest potential correlation between the severity of the acute infection of SARS-CoV-2 and the risk of the development of Long COVID-19.Therapeutic management of non-hospitalized (hospitalized) patients may prevent the progression of mildto-moderate COVID-19 to severe one and, consequently, might reduce the risk of Long Covid.
Currently, for outpatient management, the orally effective antiviral agents are preferred such as nirmatrelvir plus ritonavir (Paxlovid) and molnupiravir.Recent findings suggest that oral treatment with nirmatrelvir plus ritonavir resulted in a 89% reduction of the risk of progression of mild-tomoderate COVID-19 to severe one (Hammond et al. 2022, Ledford 2022).Similarly, early treatment with molnupiravir (alternative therapy in non-hospitalized patients with mildto-moderate COVID-19 who are at high risk of disease progression when Paxlovid is not available) reduced the risk of hospitalization (and death) in non-hospitalized, unvaccinated adults with mild-to-moderate COVID-19 who had at least one risk factor for severe COVID-19 illness (Jayk Bernal et al. 2022).
Parenteral preparations which also may prevent the progression of mild-to-moderate SARS-CoV-2 infection to severe one are the monoclonal antibody bebtelovimab as well as remdesivir, which is recommended both for the treatment of non-hospitalized and hospitalized patients, reduced the progression to mechanical ventilation for nonventilated patients (Ali et al. 2022) (Table 1).

Glucocorticoids
COVID-19 is a multi-organ damage with substantial inflammatory component.In sever COVID-19, elevated levels of inflammatory markers have been observed.Though glucocorticoids are highly potent anti-inflammatory agents and show substantial benefits, their role in the therapy of COVID-19 has been debated.Recent study indicate that glucocorticoids (dexamethasone) have beneficial effect in hospitalized patients who are receiving respiratory support and the glucocorticoid therapy has been started after the first week, when already immunopathological elements dominate and the active viral replication (typical in the first week) have only a minor role.But no benefit (even a potential harm) was observed among patients who did not require respiratory support (oxygen or invasive mechanical ventilation) (The RECOVERY Collaborative Group 2021).
In contrast, it has not been clarified how glucocorticoids may influence the risk of the development of Long/post-COVID.Glucocorticoids as highly potent anti-inflammatory agent may reduce not only the mortality but also the progression of the disease (e.g., may prevent the need of invasive  The precise mechanism of Long COVID has not been clarified.One of the potential mechanisms of Long COVID might be that lingering SARS-CoV-2 or fragments of the virus may further stimulate the immune system.Furthermore, it has also been raised that the infection induces production of antibodies that may damage the body's own proteins, resulting in a cell/tissue damage for a longer period after the initial illness.It has also been observed that SARS-CoV-2 infection resulted in a formation of microscopic blood clots that reduce the oxygen supply of the tissues in a great extent (Ledford 2022).
Recently, several clinical trials are in progress in order to find effective, safe management of acute SARS-CoV-2 infection or Long Covid-19 syndrome.Most of the trials on Long COVID-19 analyzed the effect of either dietary supplements, e.g., mitoquinone (synthetic analogue of coenzyme Q10 with antioxidant property), vitamin K 2 , Vitamin D 3 , and N-acetyl-cysteine, or drugs, with different mechanism of action, for example, lithium, which has multiple mechanisms including anti-inflammatory actions, that may be relevant for treating Long COVID, naltrexone (opioid receptor antagonist, in lower doses has unique immune modulation activity), rintatolimod (stimulates the innate immune system by activating the TLR-3 receptors) amphetamine-dextroamphetamine (psychostimulants), vortioxetine (serotonin reuptake inhibitor, antidepressant), ipilimumab (monoclonal antibody, activates the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system), pentoxifylline and ibudilast (both are phosphodiesterase inhibitors, pentoxifylline has also anti-inflammatory and immunomodulatory properties via adenosine A2A receptor), ivabradine (funny current (I f ) inhibitor), and few antivirals, such as Paxlovid, remdesivir, favipiravir as well as vaccines (e.g., Pfizer/BioNTech BNT162b2 mRNA COVID-19 vaccine, Janssen COVID-19 Vaccine) (Table 2).
The results of completed (by 24 November, 2022) clinical trials of drugs or dietary supplements on Long COVID syndrome are summarized on Table 3. From the 12 trials, more than half was ended as "no results".The effect of dietary supplement Formula C was studied on the symptoms of Post-Acute COVID-19 Syndrome and improvement was experienced.However, limitation of the trial is the small number of participants (n = 32) and the lack of a true placebo.Leronlimab (humanized monoclonal antibody against the CCR5 receptor located on T lymphocytes) reduced several raw symptom scores in participants compared to control, but the mean symptom score changes for leronlimab vs placebo were statistically not significant.The clinical trial with Zilucoplan (complement C5 inhibitor) aimed to study the inhibition of post-COVID-19 acute lung injury, and the lung repair mechanisms.The results of the trial showed a relevant respiratory and clinical improvement in hypoxemic COVID-19 patients with systemic inflammation (Table 3).

Concluding remarks
Survivors of COVID-19 may have long-lasting symptoms.If Long COVID developed, its symptomology is very different and its management depends on which organ system has been damaged.Randomized trials are in progress to test drugs able to attenuate the different symptoms.The tested drugs have different mechanism of action, and several of them are repurposing drugs that already have approved for other conditions.
Though several mechanisms have been raised, the precise cause of Long COVID is unclear.Consequently, at present, no pharmacologic agent has been known that effectively reduces or abolishes the symptoms of Long COVID.One of the assumption has raised that the coronavirus after the acute infection is lingering in different tissues (e.g., in intestine, liver, and brain) where it causes damage.On the other hand, initial infection can induce production of antibodies and additional immunological reactions which can attack the body's own tissues after the acute infection has already passed.Vaccination against SARS-CoV-2 considerably reduces the infection rates and the severity of symptoms as well as the development of Long COVID, though data on the protective role of vaccines are inconsistent.Therefore, further studies are needed to determine the effect of SARS-CoV-2 vaccination on Long COVID.Furthermore, since correlation between the severity of the acute infection of SARS-CoV-2 and the risk of the development of Long COVID-19 has been found, the orally effective as well as the parenteral antiviral agents that prevent the progression of mild-to-moderate COVID-19 to severe one might reduce also the risk of Long COVID.Finally, the role of different factors, such as gender, age, comorbidities, and severity of initial COVID-19 disease, should also be considered and clarified in the risk of post-COVID-19 condition.

Table 2
Ongoing clinical trials on Long COVID (ClinicalTrials.govwebsite)* *In the ClinicalTrials.govdatabase, on 29.11.2022,333 hits were recived for the search term "long covid".Among the ongoing clinical trials, drug intervention was performed in 21 cases.For scope reasons, studies using drugs and dietary supplements in the experimental stage have not been included in the table In the ClinicalTrials.govdatabase, 326 results were found for the keywords Long COVID, of which 58 trials studies were completed on 24.11.2022.Out of the completed trials, 15 involved the use of a drug or dietary supplements.3 studies related to acute therapy, these were not relevant from the point of view of Long COVID *