Long-Term COVID: Aetiology and Treatment PDF

Chapter - 3 Long-Term COVID: Aetiology and Treatment Authors Divyanshi Kaushish Student BDS Final Year, HDC, Sundernagar, Mandi, Himachal Pradesh, India Anamika Mishra Intern, HDC, Sundernagar, Mandi, H...

Chapter - 3 Long-Term COVID: Aetiology and Treatment Authors Divyanshi Kaushish Student BDS Final Year, HDC, Sundernagar, Mandi, Himachal Pradesh, India Anamika Mishra Intern, HDC, Sundernagar, Mandi, Himachal Pradesh, India Stuti Chauhan Intern, HDC, Sundernagar, Mandi, Himachal Pradesh, India Dr. Sahil Thakar Reader, Department of Public Health Dentistry, HDC Sundernagar, Mandi, Himachal Pradesh, India Dr. Samiksha Sharma Senior Lecturer, Department of Periodontology and Oral Implantology, HDC Sundernagar, Mandi, Himachal Pradesh, India Dr. Ramesh Rani Senior Lecturer, Department of Public Health Dentistry, HDC Sundernagar, Mandi, Himachal Pradesh, India Page | 37 Page | 38  Chapter - 3 Long-Term COVID: Aetiology and Treatment Divyanshi Kaushish, Anamika Mishra, Stuti Chauhan, Dr. Sahil Thakar, Dr. Samiksha Sharma and Dr. Ramesh Rani Abstract Covid-19 has expanded since its discovery in Wuhan, China and has had a significant impact on people's lives and health all around the world. Worldwide, 3.97 million deaths and more than 183 million confirmed cases of COVID-19 had been reported as of July 4, 2021. Current study has shown that a variety of persistent symptoms can linger for a long time after the initial SARS-CoV-2 infection. Reputable research institutions have now named this syndrome long covid. According to studies, extended covid can have an impact on persons with all stages of covid-19, ranging from extremely minor acute sickness to the most severe types. Similar to acute covid-19, extended covid may damage a variety of organs and systems, such as the gastrointestinal, respiratory, cardiovascular, neurological and musculoskeletal systems. Fatigue, dyspnea, heart irregularities, cognitive impairment, sleep disruptions, signs of posttraumatic stress disorder, muscle discomfort, attention issues and headache are some of the symptoms of long- term COVID. Keywords: Long covid, Covid-19, Post Covid-19 syndrome, cardiovascular, management Introduction Post-COVID circumstances are a variety of new returning, and ongoing health issues that people experience after being infected with the virus that causes COVID-19. Corona-virus belongs to the family of Coronaviridae, which has two genera: Coronavirus and Torovirus. The only two species of the genus Coronavirus capable of causing human respiratory disease are human corona-virus OC43 and human corona-virus 229E. Severe acute respiratory syndrome (SARS) is an upcoming viral infectious disease. It is an atypical pneumonia characterized by a high rate Page | 39 of transmission. In 2002 and 2012, highly contagious infective corona viruses originated from an animal reservoir and were gradually transmitted to humans, primarily Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome Corona-virus (MERS-CoV). SARS can survive after drying on plastic for 48 hours, in feces for at least 2 days, and in urine for up to 24 hours. The incubation period is 2-7 days and can extend up to 10 days. Droplets, aerosols and close contact with an infected person and infected body fluids do the transmission. WHO estimates that in India from January 3rd, 2020, to March 7th, 2023, there have been 4,46,68,368 cases confirmed of COVID-19 and 55,30,775 deaths reported. History History of emergence of coronavirus Natural philosophers first discovered the coronavirus in 1965. It is caused by acute rhinitis. In the year 2002, the SARS outbreak came with the deaths of 774 people and spread to 37 different countries of the world from Guangdong, southern China, with an economic loss of US$40 billion over the course of six months. In response to the SARS outbreak of 2002, China did not report any detection of an abnormal infection to the WHO for four months. Page | 40  Next, the second outbreak of SARS occurred in the month of March of the year 2003, when more than 8000 people were infected by the acute respiratory infections. In 2004, only four cases of SARS infection were identified the symptoms seen in the 2004 outbreak were fever, headache, respiratory problems, cough and shortness of breath. In 2012, MERS the Middle East Respiratory Syndrome, was first identified in Saudi Arabia. It is a viral respiratory disease caused by the Middle East Respiratory Syndrome Corona virus (MERS-CoV). Spread by dromedary camels. It spread across 27 countries on various continents and reported about 858 deaths, which is approximately 35% of the reported cases of MERS. A typical hallmark of the MERS infection is fever, cough, shortness of breath and pneumonia. Another gastrointestinal symptom associated with the infections is diarrhea. Human-to-human transmission is possible and occurs among people with close contact and healthcare workers. MERS are less contagious than SARS, but they are more fatal. In the year 2019, infectious disease caused by the SARS-CoV-2 caused outbreak of COVID-19. The first case in a small cluster was seen in China in November 2019, and the second large cluster case of COVID-19 was also seen in Wuhan, China in December 2019. As the viral infection was spreading rapidly, the situation made the WHO declare a public health emergency of international concern on January 30, 2020. The outbreak was characterized as a pandemic on March 11, 2020. Long COVID The phrase “Long COVID” gained popularity as soon as a lady named Elisa Perego from Lombardy used the hash tag Long COVID on May 20, 2020, to summarize her experience of disease as repetitive, progressive and multiphasic. The phrase "long hauler" was used by Watson and Yong. “Long-term COVID” is a term that enforces the existence of numerous symptoms even weeks or months after being infected by SARS-CoV-2 infection, disregarding the viral status. It is also called "Post-COVID syndrome". It can be continuous or may recur after some time. There could be one symptom remaining or more than one symptom present at the same time in the patient who has initially recovered from the COVID-19 infections. Most of the cases of long-term COVID have their RT- PCR test reported as negative, which stipulates the microbial recovery of the patient. Page | 41  The long haul of COVID is the delay in the clinical recovery of the patient. Based on the duration of symptoms, long COVID has been classified into 3 phases: 1) Short COVID. 2) Post-acute COVID. 3) Chronic COVID. If the duration of symptoms is restricted to less than 3 weeks, it is termed "short COVID". Similarly, if the symptoms persist for more than 3 weeks but less than 12 weeks, it is considered "post-acute COVID”. If the symptoms prolong beyond 12 weeks duration, it is considered "chronic COVID". COVID-19: Depending upon the duration of symptoms Pathophysiology of long-term COVID SARS-CoV-2 causes an acute viral infection in the body, leading to phase I of acute infection. In all the patients, there are various kinds of changes that are simultaneously occurring in the body. After the incubation period of 2-7 days, the amount of viral count in the body increases, which leads to a condition of viraemia that ultimately stimulates the febrile response in the body by T-cell lymphocyte dysfunction, also known as bystander activation or auto-immune disorder. Long Covid phase II-inflammation phase. The increase in viral load and release of various toxins leads to the “cytokine storm”, which is the hyper- activation of the immune system and the uncontrolled release of cytokines in the pulmonary system. Causing the inflammation of various organs and altering the immune status of an individual. This altered immune response by the action of interleukin-1,6,c-reactive protein, and ferritin are the pro-inflammatory markers that an individual possesses and leads to the susceptibility of acquiring more infections and Page | 42 multiple organ damage. All these multiple factors lead to the prolonged symptoms of COVID-19. Another factor associated with the pathophysiology of long COVID is in the recovery phase, which also contributes to phase III of the pathophysiology, which includes COVID -19 treatment where there is drug interaction/side effects, prolonged hospitalization leads to the sequelae of critical illness, nonspecific effects of hospitalization and deconditioning, psychological stress, COVID-19 infection associated with comorbidities such as COPD (Chronic Obstructive Pulmonary Disease), Diabetes, Hypertension, HIV. Symptoms of long COVID The symptoms of COVID-19 have been divided into two stages : 1. Acute stage of illness 2. After the acute stage of illness 1. Acute stage of illness: It leads to the short COVID, in which the symptoms of COVID-19, such as fever, cough, sore throat, and shortness of breath, last for less than three weeks. 2. After the acute stage of illness: It is known as the long COVID stage. Long-term COVID can be further distinguished as having old symptoms and new symptoms. Old symptoms include symptoms that are improving or not improving. Improving symptoms are the sequelae of infection and the sequelae of critical illness, whereas the symptoms that are not improving are the symptoms associated with the various kinds of infections, such as viral, bacterial, and fungal infections which could be due to persistence reinfection, or relapse of infection. Other non-improving symptoms are associated with the ongoing inflammation. New symptoms can be associated with various factors 1) Complications of COVID. 2) Complications related to the comorbidities. 3) Complication related to the treatment. 4) Nonspecific effects of hospitalization, psychological issues and conditioning. Page | 43  The most frequent symptoms in each ethnic group were fatigue, difficulty breathing, hoarseness, chest pain, irregular heartbeats, headache, chronic stiffness, cramping, frailty, sleeping problems, indigestion, rash, baldness, loss of balance and gait, and impaired judgment, to name just a few of the "long-term symptoms" revealed. The classical patterns seen in long COVID can be classified into two broad categories 1) Fatigue, headache, and upper respiratory complaints like breathlessness, loss of taste and smell, sore throat, cough, and other flu-like symptoms. 2) Multi system problems like fever and gastroenterological symptoms. Females have a higher prevalence of depression and anxiety, and those females who have a constant complaint of fatigue are more susceptible to such conditions. Complicated conditions caused by the SARS-CoV-2 infections lead to chronic cough, fibrotic lungs, bronchiectasis, and pulmonary vascular disease. Page | 44 Symptoms of long-term COVID in various vital organs Cardiovascular system A considerably higher risk of mortality is associated with cardiac damage and elevated cardiac troponin levels in individuals admitted to hospitals with acute infection of Covid-19. Pulmonary system The symptoms associated with the pulmonary system are dyspnea, coughing and sore throat. Page | 45 Central nervous system Congestive impairments, fatigue, headache, depression, anxiety, insomnia, altered smell and taste and brain fog are all symptoms of CNS. Immune system Mast cell activation syndrome (MCAS) of the immune system. Gastrointestinal system Pancreatic injury, pancreatitis, increased levels of aspartate aminotransferase and alkaline aminotransferase, diarrhea, nausea, decreased levels of T and B lymphocytes, atrophy of lymphoid follicles. Renal system Renal impairment, acute kidney injury. Reproductive system Erectile dysfunction; increased severity and number of premenstrual symptoms; irregular menstruation and reduced sperm count. Blood vessels Inflammation, vessel damage, coagulopathy, microangiopathy. Mechanisms associated with frequent symptoms 1. Headache It is defined as any discomfort or pressure in the head and neck region. It is also known as cephalalgia or pain in the head and neck region. The nerve endings that are pain-sensitive are known as nociceptors. There are mainly two mechanisms associated with the trigger of nociceptors. The first is the increased level of cytokines in the serum tumor narcotizing factors: Interleukin-2 (IL-2), granulocyte and macrophages. These different cytokines are released by T-lymphocytes and lymphocyte cells of the body in response to the SARSCoV-2 infection. The other mechanism associated with the headache is difficulty breathing due to the short breath of the patient and an impairment of parenchymal cells in the lungs. There is difficulty in ventilation and hypoxia in brain cells and the accumulation of acid metabolites that leads to dilation and obstruction in blood flow, ischemia and congestion causes headache. Page | 46 2. Sore throat The SARS-CoV-2 virus gets spread through the respiratory tract through close contact and inhalation of droplet molecules and exhibits similar symptoms to those of the influenza virus. The pro-inflammatory mediators released in the airway by immune cells of the body, which are prostaglandins and bradykinin, affect the sensory nerves causing sore throat. 3. Myalgia or arthralgia Muscles contain ACE-2 receptors that are angiotensin-converting enzyme 2. The molecules of the SARS CoV-2 virus bind to the receptors of ACE-2 , which are induced by the action of interleukin-6 and gradually increase the levels of CK (Creatine kinase) and LDH (Lactate dehydrogenase). Interleukin-6 also stimulates the production of PGE2 (Prostaglandins E2), which mediates pain via peripheral pain receptors. 4. Chest pain Also known as angina, this is an acute, sharp pain felt in the chest that radiates to the back and both limbs. The pro-inflammatory markers associated with chest pain and long-term COVID are C-reactive protein, leukocytes and pro-calcitonin. An increased level of these biomarkers damages the myocardial cells and as the cells enter the pleural space, it causes squeezing similar to that of angina. Hyper-activation of the ACE-2 receptors associated with myocardial muscles, which enter the cardiomyocyte, causes cardiac injury. Confusion, anxiety and hypotension, as well as respiratory distress, can indicate the severity of the cardiac injury. 5. Abdominal pain The ACE-2 receptors are hyperactive in the SARS-CoV-2 viral infection. Due to the hyperactivity of the receptor , the virus gets attached to the receptors in the large and small intestine that induce pain. Since long COVID has been described as potentially a typical pneumonia because it causes the enlargement of mesenteric lymph nodes that is similar to that of pneumonia, which is one of the major causes of abdominal pain. Page | 47 Risk factors The following are risk factors for long-term COVID 1) Decreased lymphocyte count in serum. 2) Initial disease severity. 3) Increased C-reactive protein levels. 4) Female sex organ. 5) Presence of more than 5 symptoms. 6) Increased D-dimer in serum. 7) Pre-existing comorbidities. 8) Old age. 9) Patients suffering from major depressive disorder. 10) Increased levels of protonin-1, interleukin-6, blood urea nitrogen, pro-calcitonin and neutrophil count. Details 1. Decrease lymphocyte count in serum Corona-virus is a single-stranded RNA virus that is enveloped and non- segmental in nature. It affects the respiratory tract of the body. The entry of SARS-CoV-2 stimulates the antibody and antigen mechanisms of the body, increases the production of B- and T-lymphocytes, and decreases the CD4 and CD8 cells of the body leading to a decrease in immunity and enabling the infected person to fight secondary diseases. It can be associated with systemic diseases like HIV, TB, and prolonged immune suppression. 2. Initial disease severity Cytokines are known for their double effect on the body, showing either a potentially pro-inflammatory response or an impaired anti-inflammatory response. 1) When IL-10 acts as a pro-inflammatory response: Elevated levels of Interleukin-10 stimulates the overproduction of CD8+ cells and mast cells. Mast cells directly stimulate systemic inflammation. Because of the overproduction of CD8+ cells, the body's T-helper 2 cells are depleted and interferon gamma is produced. Interferon gamma further activates other pro-inflammatory factors and the macrophages of systemic inflammation. Page | 48  2) Impaired inflammatory action: A reduced response of the body to the increased levels of IL-10 enhances the release of pro- inflammatory mediators into the blood stream, and with increased stimuli of LPS and macrophages there is an increase in blood glucose levels or a condition of hyperglycemia. SARSCoV-2 molecules rapidly replicated in the glycolytic flux, and as per the inflammatory effect of the IL-10, the macrophages mediate to the oxidative metabolisms, which decrease the inhibition effect of TNF. Inhibition of TNF is essential for the reduction of lung pathology involving SARS, the corona-virus and influenza. Therefore, initial disease severity also acts as a risk factor for long-term mortality. 3. Increased C-reactive protein levels C-reactive proteins are made by the hepatocytes of the body. Any increase in C-reactive protein indicates inflammation in the body. Inflammation caused by the increase in C-reactive protein might be acute or chronic, depending on the duration of the increased level of C-reactive protein beyond the physiologic limits. Prolonged increases in the levels indicate the increased duration of inflammation in the body, pointing towards other associated systemic diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It also increases the risk of cardiovascular disease, vasculitis and asthma. 4. Female sex organ The SARS-CoV-2 virus acts on the ACE-2 receptors of the various systems of the body. When the SARSCov-2 virus binds to the ACE-2 receptor in the ovary, it causes physiological disruption of ovarian steroid hormones. The ubiquitous estrogen and androgen receptors are disrupted, leading to early menopause, fatigue, muscle pain, sleep disturbances, menstrual irregularities and other long-term effects. 5. Presence of more than 5 symptoms The presence of more than 5 symptoms in the body increases the burden on the immune system to fight against the viral load and increases the tendency of the body to get weaker. 6. Increased D-dimer in serum An increased level of D-dimer and prolonged states of hypoxia lead to the development of thrombo-embolism; its development is often associated Page | 49 with other complications like severe endothelial dysfunction and hyper- coagulopathy, leading to an increased risk of cardiovascular diseases. 7. Pre-existing comorbidities The already exciting systemic diseases are the predisposing factors for the prolonged symptoms of COVID-19. The levels of various biomarkers are already disturbed due to associated diseases like diabetes, hyperparathyroidism, hypothyroidism, HIV, TB, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) etc.. 8. Old age In old age, the human body undergoes the neurodegenerative procedure, which tends to kill the neurons and slow the motor skills, gradually leading to the loss of functionality in every individual. As age progresses, the body loses its potential to fight infection, which acts as an indicator for risk factors. 9. Patients suffering from major depressive disorder(MDD) According to the World Health Organization, there are 280 million people in the world suffering from MDD. Fatigue, sleep deprivation, post-traumatic stress disorder, anxiety and depression are the most common symptoms seen in this neuropsychiatric disorder. Female patients with a preexisting psychiatric condition are more affected. 10. Increased levels of protonin-1, interleukin-6, blood urea nitrogen, procalcitonin and neutrophil count All the pro-inflammatory markers increase the inflammation in the body and directly and indirectly affect other body systems. By stimulating the mast cells' activation and inhibiting other pathways to control the production of cells. Page | 50 Investigations to check responses of different body system against long COVID Treatment of long COVID WHO suggests there is no specific treatment for long-term COVID and that only symptomatic relief is given to the patient. Rehabilitation therapies are provided to patients along with medicine to help manage the symptoms of various organs. 1) Respiratory system: There should be continued monitoring of the chest examination in a patient for a period of 12 weeks to avoid any condition like breathlessness and also to simultaneously monitor the blood oxygen level. While the patient associated with fibrotic lungs must be provided with anti-fibrotic therapy. 2) Cardiovascular disease: Blood pressure and heart rates are also properly monitored for a better condition and immune modulating drugs are also given as supportive treatment. 3) Treatment of fatigue and neuropsychiatric conditions: In such conditions, behavioral therapy is guided by the National Institute for Health and Care Excellence (NICE). 4) Brain fog: It is suggested to take a holistic approach in such conditions by providing chemo-brain activities and repeating the same activity again and again. Along with speech and language therapies. 5) Organ dysfunction: The goal of these guidelines is to provide specific treatment for a specific organ with regular follow-ups and diagnosis. 6) Emerging treatments for long-term COVID include hyperbaric oxygen, montelukast and deupirfenidone, along with vitamin C supplements. Conclusion Long covid is a viral infection caused by RNA virus when persistent symptoms of Covid-19 or any new symptom arises after getting cured from the infection of Covid-19. It affects multiple organ systems of the body, it mainly acts on the ACE-2 receptors of the body. The major symptoms seen in an individual are the fatigue, cough, breathlessness, dyspnea, etc. The mode of transmission of the disease is through droplet infection or due to direct contact with an infected individual. However , there is no specific treatment for the cause, patients are given only supportive treatment. Page | 51 References 1. Crook H, Raza S, Nowell J, Young M, Edison P. Long covid- mechanisms, risk factors and management. Pubmed BMJ. 2021;374:1648. Doi: 10.1136/bmj.n1648. Erratum in: BMJ. 2021 Aug 3;374:n1944. PMID: 34312178. 2. Centers for Disease Control and Prevention (CDC).Long covid or Post- covid condition. https://www.cdc.gov/coronavirus/2019-ncov/long- term-effects/index.html 3. BMJ Best Practice. Severe acute Respiratory syndrome. https://bestpractice.bmj.com/topics/en-gb/904 4. Britannica, The Editors of Encyclopaedia. “Coronavirus”. Encyclopaedia Britannica, 2023, https://www.britannica.com/science/coronavirus-virus-group. Accessed 30 March 2023. 5. World Health Organisation. https://covid19.who.int/region/searo/country/in/ 6. Nkengasong J. China’s response to a novel coronavirus stands in stark contrast to the 2002 SARS outbreak response. Nature medicine Nat Med. 2020;26:310-311. https://doi.org/10.1038s41591-020-0771-1 https://www.nature.com/articles/s41591-020-0771-1 7. Webmed. Coronavirus History. https://www.webmd.com/covid/coronavirus-history 8. World Health Organisation. Middle East Respiratory Syndrome (MERS-CoV).Fact Sheet. https://apps.who.int/mediacentre/factsheets/mers-cov/en/index.html 9. World Health Organisation. Cardiovascular Diseases (CVDs). https://www.who.int/news-room/fact-sheets/detail/cardiovascular- diseases-(cvds) 10. World Health Organisation. Coronavirus disease (Covid-19) pandemic. https://www.who.int/europe/emergencies/situations/covid-19 11. Raveendran AV, Rajeev Jayadevan, Sashidharan S. Long COVID: An overview, Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2021;15(3):869-875. ISSN 1871-4021. https://doi.org/10.1016/j.dsx.2021.04.007. (https://www.sciencedirect.com/science/article/pii/S1871402121001193 ) Page | 52 12. Ministry of Health and Family Welfare. https://www.pib.gov.in/PressReleaseIframePage.aspx?PRID=1727216 13. Richard G, Stefanacci DO. MGH, MBA, Thomas Jefferson University, Jefferson College of Population Health. Disorders in older people. MSD manual. https://www.msdmanuals.com/home/older-people’s-health- issues/the-aging-body/changes-in-the-body-with-aging 14. Montazersaheb S, Hosseiniyan Khatibi SM, Hejazi MS, et al. COVID- 19 infection: an overview on cytokine storm and related interventions. Virology Journal. Virol. J. 2022;19:92. https://doi.org/10.1186/s12985- 022-01814-1 15. Memish ZA, Perlman S, Van Kerkhove MD, Zumla A. Middle East respiratory syndrome. Pubmed Lancet. 2020;395(10229):1063-1077. Doi: 10.1016/S0140-6736(19)33221-0. Epub 2020 Mar. PMID: 32145185; PMCID: PMC7155742. https://pubmed.ncbi.nlm.nih.gov/32145185/ 16. Johns Hopkins Medicine. Coronavirus Diagnosis: What should I expect? https://www.hopkinsmedicine.org/health/conditions-and- diseases/coronavirus/diagnosed-with-covid-19-what-to- expect#:~:text=Post- COVID19%20symptoms%2C%20such%20as%20lingering%20cough% 2C%20on%20and,Persistent%20symptoms%20are%20sometimes%20k nown%20as%20long%20COVID-19. 17. Medicinal News Today. What to know about mast cell activation syndrome. Medically reviewed by Megan Soliman, MD-By Rachel Ann Tee-Melegrito-Updated on, 2021. https://www.medicalnewstoday.com/articles/mast-cell-activation- syndrome. 18. https://www.scienceabc.com/humans/post-mortemstages-of-death- different-stages-the-body-goes-through Page | 53 Page | 54