The Possible Role of Plant Derived Essential Oils Against Fatigue in Post Acute Sequele Covid-19: A Literature Review Based on Evidence of Essential Oils on Fatigue

Symptoms of COVID-19 were found to be persistent after acute onset in some survivors. One of the Post Acute Sequele Covid-19 (PASC) problems is fatigue. Until now, the treatment options for fatigue in PASC are limited. Plant derived essential oils (EO) have been shown to reduce fatigue in several patient populations. The aim of this review is to present all the evidence regarding the benefits of plant derived EO for fatigue, whether they can be used as a therapy for fatigue associated PASC. Method: Literature search was conducted on the PubMed, Science Direct, Google Schoolar


Introduction
The Covid-19 pandemic is still ongoing and has caused a global health crisis with an increase in morbidity and mortality on a large scale (1,2).Several studies have reported that most of the patients who survived the acute phase of Covid-19 experienced a persistent effect even though they had recovered from mild to severe symptoms (2).This condition was reported in a previous study as Post Acute Sequele of Covid-19 (PASC) (3).
One study in Europe that followed up for 60 days from acute onset of post acute Covid-19 outpatient, as many as 87.4% of 143 patients reported persistent symptoms and most complained of fatigue (53.1%) (4).A prospective cohort study in Wuhan, China evaluated 1,733 patients 6 months from acute onset, 63% complaining of fatigue (5).As many as 63.5% of 463 patients in Indonesia experienced persistent symptoms of Covid-19 and most of them complained of fatigue (30.2%).Survivors feel that the body has not recovered as usual and these persistent and prolonged symptoms can reduce the quality of life and work productivity (6,7).
Until now, the treatment options for fatigue in PASC are limited because understanding of the mechanism of the condition is not yet fully understood (1,9).
Approaches to the management of fatigue can be pharmacologically and nonpharmacologically (12).Non-pharmacologically methods are included in the category of complementary medicine, this treatment is considered to be simpler, cost effective and safe than drug methods and has fewer side effects (15,16).Complementary and alternative medicine (CAM) in recent years has been in great demand (13).The use of herbal products is increasing worldwide, and World Health Organization studies show that 80% of the world's population depends on plants for medical aspects (17).
Plant derived EO has long been used on an as-needed basis for general health and wellness and is known to have antiviral, anti-inflammatory, immunomodulatory, antiseptic, antibacterial, analgesic, antispasmolytic, antitoxic, and relaxing effects for the management of the respiratory diseases, symptoms of cancer, migraine, hypertension, arthritis, and muscle-related pain (13,14,18,19).The antiviral properties of EOs against SARS CoV-2 have been proposed due to their lipophilic characteristic, suggesting that EOs penetrate viral membranes and cause viral lysis.In addition, EO contains many active phytochemicals that can act synergistically at various stages of viral replication.Some essential oils are also often used as aromatherapy for antispasmodic, relaxation or sedation (12,13).This aromatherapy effect is reported to reduce fatigue levels and increase stamina (12).Based on existing knowledge, combined chemo-herbal (EO) could be a better and more effective approach against Covid-19 pandemic (19).
The aim of this review is to present all the evidence regarding the benefits of plantderived EO for fatigue, whether they can be used as a therapy for fatigue associated with PASC.It is hoped that this review can help build thinking as a basis for conducting clinical trial research in the near future.

Methods
Literatur search was conducted on the PubMed, Science Direct, Google Schoolar, and Springer Link databases on October 15-20th, 2021, focusing on the last ten years of randomized clinical trial (RCT) research on the topic of the effect of EO on fatigue with the keywords 'Essential Oils', 'Fatigue' and 'Long Covid-19'.The evidence and other information obtained is then analyzed using PICO synthesis and presented in tabular and narrative form.The analysis is based on previous studies that have investigated the effect of EO on fatigue in several patient populations

Results
The literature search carried out resulted in 11 articles that matched the topic of the review.
The results of the analysis can be seen in table 1.

Pathophysiology of Fatigue in PASC
Fatigue that occurs after infection of SARS ( 2003 Although this hypothesis requires confirmation of brain-focused studies in search of a brain-signature for fatigue in PASC (10).
Hyperinflammation in acute Covid-19 causes multiorgan damage.Long-term symptoms in PASC can be caused by this.Most of the evaluations performed on PASC patients after discharge from the hospital had abnormalities in the lung parenchyma, small airway disease and acute kidney injury.These biologic factors are likely to play a role in some patients.SARS Cov-2 also demonstrated the ability to persist on certain tissues after acute infection.Some infected patients were reported not to be completely clear of the virus over a long period, with the discovery of inert RNA that should have been successfully eliminated by the body's immune system.Inert RNA deposited in certain tissues is suggested to trigger the reactivation of SARS CoV-2 (24).
A cohort study in Wuhan, China showed that over a period of 6 months from acute onset, 23% of COVID-19 survivors also complained of anxiety and depression (5).This psychological stress is generally caused by self-isolation, broken routines, loneliness, lack of family support (maintaining distance to prevent virus transmission), job loss, and due to lockdown.Psychological stress then becomes a circle that triggers fatigue (6,25).

Plant Derived-Essential Oils as Antivirus
Essential oils (EO) consist of a complex mixture of volatile phytochemicals from a diverse class including monoterpenes, phenylpropanoids and sesquiterpenes.EO is active against various viruses, such as human herpesvirus (HSV), influenza virus (IFV), yellow fever virus, human immunodeficiency virus (HIV), and bird flu.Viruses with envelopes generally respond sensitively to EO because of their lipophilic characteristic, so they can penetrate the lipid bilayer membrane and cause viral lysis.The EO obtained from Citrus bergamia, Eucalyptus globulus, with its active compounds such as eugenol and citronellol are capable against IFV.Carvacrol and its thymol isomer contained in oregano can suppress viral host cell fusion through by depletion of HIV-1 envelope membrane cholesterol, thereby blocking viral entry into the host system (19).In addition, carvacrol was able to reduce alveolar enlargement, trigger macrophage recruitment, and production of IL-1β, IL-6, IL-8, and IL-17 in bronchoalveolar lavage fluid.In addition, carvacrol has also been reported to have antiviral activity against human respiratory virus (HRSV), human rotavirus (HRV), and HSV-1 (26).
The active component 1,8-cineole from various plants has been proposed to have the ability to inactivate free influenza A viruses and disrupt the structure of the viral envelope.1,8-cineole has also been shown to protect mice from the HSV-2 virus.
Eugenol has been shown to have antiviral activity against HSV-1 and HSV-2.also found to inhibit leukocyte recruitment into the lung and downregulate the expression of pro-inflammatory cytokines (IL-6 and TNF-).EO have long been known to have antiviral activities and proposed to be able to fight SARC-CoV-2.In general, the antiviral activity of EO is by direct mechanism of action on free virus, interfere various phases including attachment, penetration, intracellular replication, and release from host cells (19).

Possible Role of EO against Post Viral Fatigue
Previous studies in EO plays a role in modifying mental stress and helping the body maintain its homeostasis (15).These findings suggest that inhalation of aromatherapy oils can be used as effective and safe treatment to reduce symptoms and improve quality of life (13).Another aromatic substance is sweet orange EO which is known to produce calm and reduce depression and stress.Inhaled aromatherapy and aromatherapy massage significantly reduce fatigue (16).
The compound of 1,8-cineole, alpha-terpineol and alpha-pinene from Lavender, Frankincense, Ravensara, Juniper and other EO-producing plants has been shown to reduce the production of proinflammatory mediators (13).Evening Primrose is also known to contain a lot of linoleic acid and γ-linolenic acid which has been shown to suppress inflammation mediators such as IL-1β, IL-6, and TNF-α (27).The effects of aromatherapy oils can also be explained by their role in correcting imbalances in the autonomic nervous system.Santalol contained in Sandalwood EO is associated with an increase in the parasympathetic nervous system for its relaxing and sedative effects.
Numerous studies have also shown that aromatherapy EO including lavender, rosemary, and sandalwood help improve sleep and reduce fatigue (13).
Inhaled aromatherapy EO distilled from the leaves of Mentha plus Piperita (Peppermint EO) has been found to reduce fatigue and increase stamina in the general population.
Peppermint EO dominates the literature on aromatherapy for fatigue, aromatherapists also use other EO, such as those from the Citrus plant and Black Pepper, as a traditional approach to reducing fatigue (14).The benefits that come from inhalation may not be immediately apparent, but require some short-term exposure over a period of time (16).

The Mechanism of Action of EO in the Management of Post Viral Fatigue
The use of EO as aromatherapy is one of the complementary therapeutic modalities that is widely used throughout the world to manage various disease symptoms.Aromatherapy is a type of therapy that utilizes EO produced by plants to provide pharmacological or physiological effects through the inhalation or skin absorption (18).
When the EO used in aromatherapy are inhaled, several different molecules contained in EO stimulate the olfactory nerve cells and are then transferred to the limbic system in the brain via the olfactory route in the nose.The limbic system is then activated and triggers the release of neurotransmitters such as endorphins, enkephalins, serotonin and noradrenaline.The amygdala and hippocampus areas of the limbic system are the most important areas for processing scent (24).Administration of EO by inhalation has a refreshing effect, this will affect mental and physical stability so that it can reduce depression, stress, and chronic fatigue (24,25).EO have also been used in massage because of their rapid absorption into the body (18).
Lavender belonging to the Lamiaceae family is considered to have the same effect as diazepam.Diazepam is known to decrease external emotional excitability by increasing inhibitory neurons containing aminobutyric acid in the amygdala.The limbic system provides sedative and relaxing effects and reduces anxiety by interacting with the cerebral cortex and influencing heart rate, breathing, blood pressure, stress, and hormone levels (11,12,26).
Citrus aurantium (C.aurantium) EO contains active terpene compounds that provide sedative and anti-anxiety effects.Its mechanism of action as an anti-anxiety agent is probably mediated by the involvement of 5-HT1A receptors after repeated oral administration.Previous research concluded that aromatherapy with C. aurantium extract was as effective as diazepam in reducing preoperative anxiety.Although more evidence is needed to come to a firm conclusion about the efficacy of aromatherapy in reducing anxiety (11).
Inhalation has an invigorating effect and improves concentration by being absorbed in the blood and lungs through the nose and affecting mental and physical stability.The sense of smell activates the limbic system and hormones, which can reduce depression, stress, and chronic fatigue by increasing emotional responses (25).The suggested mechanism of EO against Fatigue can be seen in Figure .1.
), MERS (2012), Epstein-Barr Virus (EBV), and other viral causes generally display the similar manifestations as SARS-CoV-2.Although the causative pathogen is different, each disease will cause a similar inflammatory response at the site of infection.The inflammatory response can be the same "stressors" as most causes of fatigue (such as emotional, sleep deprivation, physical or mental overexertion) using both humoral and neural routes.Angus M et al. have hypothesized that stressors, both viral and non-viral, can activate stress centers in the brain (hypothalamic paraventricular nucleus) (10).Islam et al. also reviewed various cases of post-infectious fatigue and suggested that elevated levels of cytokines (TNF-α, IL-1β, IL-6 and others) in Covid-19 patients contributed to the development of long-term fatigue symptoms (23).It has been hypothesized that proinflammatory cytokines and neurotoxic molecules in the acute condition of Covid-19 will be released in response to microglia cells and astrocytes which then cause neuroinflammation of the hypothalamic structures and limbic system.