Just When We Thought That COVID Was Over: A Systematic Review

As the globe continues to grapple and scuffle with new emerging strains of COVID every day, a set of recovered patients continue to show persistent enervating symptoms. Many patients never fully recovered after COVID and had neurological and psychiatric symptoms for weeks or months. The emphasis of our study is on these long haulers, particularly on the two critical organ systems of the body, i.e., the central nervous system and the muscular system. Depending upon the severity of the disease, many signs and symptoms continue to linger, ranging from weeks to months. A total of 29 studies are included in our review after thorough screening, application of inclusion and exclusion criteria, and quality appraisals. The total number of patients included is 6012. We found many long-term effects, but the emphasis of our study continued to remain on the two main organ systems that resulted in prolonged COVID with debilitating symptoms and thus affected the quality of life of these patients. Various factors and underlying pathophysiologic manifestations result in the predominance of these signs and symptoms. Furthermore, the patient's underlying medical conditions and other environmental factors may add to it. More focus is required on the quality of life post-COVID, and this requires a team of specialists. There are still many unanswered questions like which ethnicity is affected more, why females are more prone to the long symptoms, and the effects of various treatments on the long-term signs and symptoms.


Introduction And Background
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel RNA β-coronavirus that causes COVID-19, started in late 2019, affecting millions of lives and causing a huge burden on the economy and physical wellbeing [1,2]. The virus, which was formerly known to affect the lungs and cause respiratory illness, in actuality affects multiple organs of the human body, causing various signs and symptoms [2,3]. A staggering number of patients experienced long-standing symptoms even after they were tested negative for the disease; due to this fact, it is referred to as long-COVID [1].
The most common symptoms experienced include; fatigue, headache, cognitive impairments, weakness, myalgia, poor concentration, and sleep disturbances [3][4][5][6]. The most likely mechanism through which this virus enters the brain is the angiotensin-converting enzyme receptor, thus causing profuse cytokine syndrome resulting in damage to the cells [4]. Apart from cytokine syndrome, autoantibodies against various body cells and autonomic nervous system disruption lead to post-viral illness [4,6].
The purpose of our study is to focus on the two main long-standing symptoms, fatigue and headaches, resulting in poor work performance and difficulty in performing daily activities of life.

Methods
We obeyed the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines for conducting our systematic review ( Figure 1) [7]. We systematically searched multiple electronic databases, such as PubMed, PubMed Central (PMC), and Medline, for data collection. We explored the databases by using terms of medical topics and by Medical Subject Headings (MeSH) words. The keywords used are "migraine," "new-onset headache," "exacerbation of headache," "chronic fatigue syndrome," "post-viral syndrome," "lack of energy," "exhaustion," "fatigue," "COVID19", "COVID recovered patients" and "long term complications," separately and in combination to find relevant studies. The total number of articles found in electronic databases is 509.

Inclusion and exclusion criteria
For our research, we included all the articles in English. Full free texts from the last three years were included. Studies that we included are clinical trials, randomized control trials, meta-analyses, and systematic and traditional reviews. Studies include humans only from age 18 and above. Studies done before 2019, gray literature, books, documents, and duplicates were excluded from the study.
A total of 509 studies were obtained from the databases. Records were analyzed on the basis of title, abstract, and application of inclusion and exclusion criteria. A total of 182 studies were obtained. After the removal of duplicates, we were left with 178 studies. All the articles were further screened on the bases of title, abstract, and quality check; a total of 29 studies were left. The total number of patients included in the studies was 6012. Clinical trials were screened through the Cochrane risk bias assessment tool, observational studies by the Newcastle-Ottawa Scale, systematic and meta-analyses by PRISMA, and literature review by the scale for quality assessment of narrative review articles (SANRA) checklist.

Review The pathophysiology of coronavirus
Coronavirus is a single-stranded ribonucleic acid (RNA) virus with projections of glycoproteins on the outer surface. The main structure is composed of many proteins, with four proteins being the most important integral constituents, namely spike protein, M protein, nucleocapsid N glycoprotein, and E protein [4]. This virus gains entry into the human body through the nasal route. Once inside the body, it binds to the receptor named angiotensin-converting enzyme 2 (ACE2). As these receptors are located in the various cells of the body, this disease presents with a wide array of signs and symptoms [8].
This severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or coronavirus disease (COVID-19), depending on its persistence of signs and symptoms, is classified as post-acute, with signs and symptoms ranging from about less than a month, and chronic, with signs and symptoms lasting for more than three months [1]. It has been seen that some patients who are recovered from COVID-19 still experience varying symptoms like fatigue, long-standing headaches, impaired cognition, generalized malaise, various psychiatric conditions, and many more. Therefore, this long-standing trail of symptoms is referred to as long COVID [5].
According to a study, T-cell dysfunction may be linked to the pathophysiology of long COVID, as seen in various autoimmune diseases. One of the mechanisms behind the pathophysiology of COVID-19 affecting other organs besides the lungs is the formation of antigen-antibody complexes, activating the humoral immune response [1].  Effect on the central nervous system (CNS) The virus gains entry into the brain through the olfactory bulb. The blood-brain-barrier (BBB) has ACE-2 receptors on the endothelial cells resulting in the viral entry into the nervous system, thus causing various signs and symptoms. The virus causes inflammation of the brain through a mechanism called cytokine storm syndrome.
Cytokine storm syndrome causes the percolation of various inflammatory cells resulting in increased amounts of cytokines, thus causing inflammation of the brain [1]. Apart from direct damage caused by the virus to the brain, tissue hypoxia and edema also leads to brain damage, as these findings were seen in the autopsy of patients deceased due to COVID-19 [1]. According to one of the studies, hypoxia leads to damage to the mitochondria, thus causing brain fog, i.e., altered cognition.
Neurological signs and symptoms of COVID-19 include headache, vomiting, brain fog, fatigue, behavioral problems, vertigo, loss of sense of taste and smell, and various psychiatric conditions; all of these conditions are referred to as neuro-COVID [1,8,[9][10][11][12]. From all the studies which we have included in our review, headache is the most prevalent neurological complaint lasting from days to weeks post recovery.
The chain of reactions occurring after the virus enters the body is shown in Figure 3

Effect on the peripheral muscles and mechanism of weakness and fatigue
One of the most important complications of COVID-19 is muscle weakness and unbearable fatigue. The presence of ACE-2 receptors on the skeletal muscles is the reason why skeletal muscles are affected by COVID-19 and thus present with continuing body aches. The muscle weakness could be due to the disease itself, whereas the sedentary mode of life due to the pandemic, long bed rest, and calorie deficit diet during the illness also contributed to the development of muscle weakness [8]. According to a study, brain fog, stringent fatigue, and other long-standing complaints of long COVID mirror myalgic encephalopathy or chronic fatigue syndrome, which develops after a viral infection [13]. Some studies have found autoantibodies against various cell lines and receptors aid in the austerity of symptoms. Along with that, involvement of the autonomic nervous system also pitches in the clinical picture of long COVID [10]. All this has led to poor quality of life. COVID-19 recovered patients cannot cope with daily activities and need help in carrying out their basic tasks. Rehabilitation is required for these patients so that they can return to their pre-COVID physical fitness level. Rehab includes a multifaceted approach which includes aerobic exercises, breathing exercises, proper sleep hygiene, and help with proper meal planning [9,10]. The use of multivitamins and as-needed analgesics for minor signs and symptoms of long COVID can also be helpful.  A list of all the studies included in the review is shown in Table 1.
Author and

Limitations
As this disease is still new, we have a lot to learn. Most of the studies showed the prevalence of long COVID symptoms in people already with psychiatric disorders, and it is more prevalent in the female population; this creates bias of whether there was any association with the body physique or hormonal changes that contributed to this finding, or if the prevalence of more autoimmune diseases in females lead to these symptoms. More evidence is required to show the association between autoimmune diseases and COVID-19. In order to assess fatigue, there is a need for a standard questionnaire, which should be used to grade fatigue without bias. The role of steroid use in patients with severe COVID-19 needs attention. As corticosteroids can disrupt the cytokine storm, resulting in reduced signs and symptoms, no clear evidence was found that showed whether fatigue still persists in patients who used steroids. We still do not have enough data showing which ethnicity is more affected. We still do not have enough data showing which ethnicity is affected more and the role of antibodies in the severity of acute disease. More information is needed regarding the type of antibody that is more prevalent in causing these long COVID signs and symptoms. Information from primary care providers could be an asset in collecting statistics on long-term signs and symptoms and following up with patients. There is a need for more observational studies, case reports, and case series to answer all these questions thoroughly.

Conclusions
This virus is still a challenge as it is evolving into different variants with every coming day. Vaccines are out there, and the general population needs to be counseled on the benefits of the vaccine as it can not only prevent the need for hospitalizing but also it can help in preventing patients from going into the long sequelae requiring bed rest and thus causing muscle wasting and severe debilitating fatigue.
The toll on the body post-COVID is both mental and physical. A team of specialists, including physical therapists, nutritionists, primary care providers, nurses, and home care attendants, needs to work hand in hand to provide the best care for this group of people, especially the elderly. They need counseling, physical rehabilitation, regular physical therapy sessions, and of course, nutrient-rich diets to ensure that these groups of people can resume their daily activities of living without depending on someone and can enjoy life to the fullest.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.