Long COVID is a condition characterized by persistent and continuous health issues caused by COVID-19 after the patient has recovered from the initial infections. Up to 15% of those who survive their infections has been reported to have symptoms like fatigue, shortness of breath, joint pain, chest pain, loss of smell and/or taste, as well as constipation or diarrhea and abdominal pain. Long COVID has been reported to last for months to more than a year. These symptoms can happen to anyone who has had COVID-19, even if the illness was mild, or if they had no initial symptoms. Besides these symptoms, patients who suffered severe illness with COVID-19 can experience multiorgan effects including nervous system, lung, heart, digestive tract and musculoskeletal system.
Nervous System Dysfunction
Chronic viral infections of the nervous system can be caused by many different types of viruses including the Ebstein Bar Virus (EBV), enterovirus, herpes virus, and SARS-CoV-2 (COVID-19). The symptoms of a chronic nervous system infection caused by these viruses can vary and include chronic fatigue, fibromyalgia, muscle weakness and tightness, feeling of body coldness, numbness or pain, anxiety, depression, and loss of smell or taste. Studies have shown that SARS-CoV-2 causes potentially damaging neurological problems in about one in seven people infected.3
Neurological disorders from COVID-19 are one of the most common complications among long COVID symptoms. SARS-CoV-2 is known to infect the peripheral nervous system or CNS and cause damage to the nervous system. Such damage may be caused by cytokine secretions, or direct invasion of the olfactory epithelium. Although a number of viruses including influenza also gain entry through the olfactory bulb, olfactory or gustatory dysfunction is particularly common in patients infected with SARS-CoV-2. Loss of smell without the stuffy nose is a unique symptom of COVID-19 infection. In most cases, the smell loss lasts only a few weeks, some patients may take very long time to recover from it, and more than 12% of people with COVID-19, olfactory dysfunction persists in the form of ongoing reduction in the ability to smell (hyposmia) or changes in how a person perceives the same smell (parosmia).4
A significant portion of COVID-19 patients are suffering from prolonged post-COVID-19 fatigue syndrome which may be linked to the post-COVID central nervous system dysfunction. SARS-CoV-2 may function as a physiologically severe stressor, which could be targeting a stress-integrator within the brain particularly in the hypothalamic paraventricular nucleus (PVN).5 Inflammatory mediators that are released at the site of COVID-19 infection would be transmitted as stress-signals via humoral and neural pathways. In genetically susceptible people, such stress signal might be too strong and exceed their intrinsic stress-threshold and therefore overwhelm this stress-center causing ongoing dysfunction of the hypothalamic PVN's complex neurological circuitry.5 In such a compromised state, the hypothalamic PVN might become hyper-sensitive to a wide range of life's ongoing physiological stressors. This could result in the post-exertional malaise episodes and more severe relapses, in common with chronic fatigue syndrome. When a certain stress-tolerance-level is exceeded, the hypothalamic PVN can become an epicenter for microglia-induced activation and neuroinflammation, affecting the hypothalamus and its proximal limbic system, which would account for the range of reported chronic fatigue symptoms.5
Another very common symptom of COVID as well as post-COVID infections is chronic pain that is caused by direct invasion of the nervous system or through post-viral immune reactions. The chronic pain most commonly includes headache, joint pain, and muscle pain. Although neuropathic pain has been reported in some of hospitalized patients with COVID-19, but its prevalence is probably underestimated because it is well established that chronic neuropathic pain may also develop in months after injury to the nervous system.6
SARS-CoV-2 can also have effects on the vagus nerve. The vagus nerve runs from the brain into the torso, heart, lungs, intestines, and several muscles, including those involved in swallowing. It has a role in heart rate, speech, the gag reflex, the transfer of food from the mouth to stomach, transporting food through the intestines, perspiration, and other bodily functions. SARS-COV-2 mediated vagus nerve dysfunction could be responsible for many of the symptoms of long COVID, including persistent voice problems, difficulty swallowing, dizziness, abnormally high heart rate, low blood pressure, and digestive issues.
Immune System Dysregulation and Rheumatic Autoimmunity
There is growing evidence that COVID-19 can lead to a dysregulation of the immune system with the development of autoimmune phenomena. The consequence of this immune dysregulation ranges from the production of autoantibodies to the onset of rheumatic autoimmune disease. The immune system becomes overwhelmed from fighting off the virus while concurrently fighting the autoimmune condition.
It was reported that rheumatic like symptoms such as joint pain, swelling and stiffness as well as fatigue persist months after the COVID-19 infections. The newly brought on autoimmune conditions can lead to heart, lung, and GI symptoms. The main diseases reported were vasculitis and arthritis.1 Idiopathic inflammatory myopathies, systemic lupus erythematosus, and sarcoidosis were also reported in a limited number of patients, as well as isolated cases of systemic sclerosis and adult-onset Still's disease.1 These findings highlight the potential spectrum of systemic and rheumatic autoimmune diseases that could be precipitated by SARS-CoV-2 infection.
The immune system is tightly regulated. Within it, immune cells known as B and T lymphocytes are normally able to distinguish between itself versus external targets. When the system becomes confused, B and T cells may start to target our own bodies, called autoimmunity. Viral infections can sometimes trigger this confusion, resulting in autoimmune diseases. Molecular mimicry occurs when the part of the virus and the B or T cells looks similar to a normal protein in the body.2 The B or T cell then sees both the viral and the self-protein as something to attack and eliminate.2 Viral infections can also cause organ damage and cell death directly. When the cells die and burst, they release self-proteins. These would normally stay hidden and wouldn’t trigger an immune reaction. Bystander activation occurs when B and T cells accidentally get in contact with self-proteins, confusing the immune system, which otherwise is trained to ignore self-proteins.2
It’s unclear whether patients were already predisposed to these diseases, or the infection unmasked an autoimmune process that had already begun. Or perhaps the infection triggered completely new autoimmunity. The triggers may even vary for different people. COVID-19 may also trigger new autoimmune responses and, potentially, new autoimmune diseases. This has already occurred with a condition called multi-system inflammatory syndrome in children (MIS-C).
Reactivation of Epstein–Barr virus (EBV) and Other Types of Viruses
A portion of long COVID symptoms like chronic fatigue, brain fog and rashes may be the result of COVID-19 inflammation-induced EBV reactivation. Research data has shown that among the patients who have developed long COVID symptoms, 67% of them were tested positive for EBV reactivation 21–90 days after testing positive for COVID-19.7 Such reactivation may occur soon after or concurrently with COVID-19 infection. Many long COVID symptoms may not be a direct result of the SARS-CoV-2 virus but may be the result of COVID-19 inflammation-induced EBV reactivation including after initially asymptomatic infections. The SARS-CoV-2 virus may stimulate sequalae involving other infectious agents such as EBV that contribute to many long COVID symptoms.7
Reactivation of latent herpes simplex virus (HSV) is also prevalent in COVID-19 patients. One study included 80 patients with mild-to-moderate COVID-19 infection who did not require hospitalization or steroid therapy showed that one or more HSV infections were observed in 28 patients (35%) with COVID-19 infections.8 It was proposed that COVID-19 infection can trigger reactivation of the latent HSV by upregulating the expression of lytic genes and supporting the antegrade progression of the activated viruses toward the epithelial tissues.8 COVID-19-related immune dysregulation, psychological stress, fever, and direct neuronal effects play a role in the activation of different cellular processes that result in increased HSV lytic gene expression and reactivation of the virus.
In addition to the EBV and HSV, reactivation of other viruses such as cytomegalovirus (CMV) reactivation is also reported to relevant for patients with long COVID who still have symptoms 3 months after they were infected. CMV is a very common virus that affects more than half of adults over the age of 40. Although CMV is usually harmless and typically does not cause any symptoms, it can affect individuals with weakened immune systems. Upon activation of the CMV induced by the COVID-19 infection, the immune system becomes busy keeping CMV at bay, which leads to an expansion of the T cells pool that is directed towards CMV. At cost, the naive T cell pool decreases and makes it more difficult for older CMV positive individuals to generate an adaptive immune response to combat new infections, such as the novel SARS-CoV-2 virus.9 An active CMV infection will lead to immunosuppression via direct inhibitory effects on antigen presentation, NK, B and T cells responses, via sophisticated viral immune evasion strategies.9 As a consequence, CMV associated immune senescence and immunosuppression in the elderly may increase their risk of dying from influenza, and other infectious diseases, like COVID-19.9
Organ Damage Caused by COVID-19
Although COVID-19 is seen as a disease that primarily affects the lungs, it can also damage many other organs, including the heart, liver, kidneys and the digestive tract. Organ damage may lead to health complications that linger after COVID-19 illness. In some people, lasting health effects may include long-term breathing problems, heart complications, chronic kidney impairment, stroke and Guillain-Barre syndrome — a condition that causes temporary paralysis. Some adults and children experience multisystem inflammatory syndrome after they have had COVID-19. In this condition, some organs and tissues become severely inflamed.
1) Lung Fibrosis and Interstitial Lung Disease
COVID-19 is a respiratory disease that especially reaches into the airways and air sacs. While the vast majority have mild or moderate infections, about 10% will develop severe COVID-19 pneumonia and 5% will develop acute respiratory distress syndrome (ARDS).12 The majority will stabilize or improve over time. However, some patients will progress to advanced lung fibrosis or post-COVID interstitial lung disease.
Studies has found that patients recovering from COVID-19 can have persistent symptoms and CT abnormalities of variable severity. At 3 months after acute infection, a subset of patients will have CT abnormalities that include ground-glass opacity (GGO) and subpleural bands with concomitant pulmonary function abnormalities.11 At 6 months after acute infection, some patients have persistent CT changes to include the resolution of GGOs seen in the early recovery phase and the persistence or development of changes suggestive of fibrosis, such as reticulation with or without parenchymal distortion.11 The etiology of lung disease after COVID-19 may be a sequela of prolonged mechanical ventilation, COVID-19–induced acute respiratory distress syndrome (ARDS), or direct injury from the virus.
This is because any infection, bacterial or viral, has the potential to cause airway epithelial injury and apoptosis and both have the capacity to modulate the host response to injury leading to the development of pulmonary fibrosis. A number of predictors have been putatively identified and they included advanced age, severe illness, prolonged ICU/hospital stay and mechanical ventilation, a history of smoking, and chronic alcoholism.
2) Post-COVID-19 Heart Syndrome
SARS-CoV-2 infection may be associated with the long-term extrapulmonary organ manifestations with cardiac involvement being one of the most prevalent. Besides lung inflammation, myocardial injury is a typical COVID-19-related phenomenon, present in 20–30% of patients and contributing to 40% of deaths.13 However, myocardial injury in the course of COVID-19 may be even more prevalent. The silent but progressive myocardial injury in the course of COVID-19 might contribute to the development of heart failure and other cardiovascular complications following virtual recovery. One study involving 100 COVID-19 convalescents showed that at 2 to 3 months following the acute phase of the disease, persistent cardiac involvement was observed in 78% patients and ongoing myocardial inflammation in 60% patients, which was independent of the severity and overall course of the acute disease and the time from the original diagnosis.13 Moreover, increased troponin concentration, an indicator of heart damage, was demonstrated in 76 (76%) of patients without any clinically overt signs and symptoms of myocardial dysfunction.13
In another study including 139 healthcare workers with confirmed past SARS-CoV-2 infection, myocarditis was observed in 37% of the participants at a median of 10 weeks after infection.13 Importantly, only half of the participants had symptoms of COVID-19, demonstrating that cardiac sequelae might be associated with an altered or delayed immune response, and that even asymptomatic patients and/or patients not aware of the infection may suffer from serious cardiovascular complication in the longer perspective.
3) Gastrointestinal Symptoms
COVID-19 frequently presents with acute gastrointestinal (GI) symptoms. Up to one-third of COVID-19 patients present with gastrointestinal complaints. Patients with severe COVID-19 are at a particularly high risk for developing gastrointestinal complications. Some of these complications include acute liver injury and elevated transaminases, acute cholecystitis, acute pancreatitis, ileus and feeding intolerance, acute colonic pseudo-obstruction, and mesenteric ischemia.15 Mesenteric ischemia is decreased or blocked blood flow to your large or small intestine and it is the most serious gastrointestinal complication reported in critically ill COVID-19 patients. It can be chronic, due to plaque buildup over time, or acute, due to a blood clot.15
The angiotensin-converting enzyme 2 (ACE2) receptor is highly expressed throughout the gastrointestinal tract. Thus, SARS-CoV-2 may enter gastrointestinal cells via ACE2 receptors to cause direct damage to the gastrointestinal organs. When COVID-19 attacks the cells in the lining of the gastrointestinal tract, it may break down these linings and cause the onset of gastrointestinal issues like gastritis, peptic ulcers and gut diseases with symptoms of abdominal pain which persist even after recovery from COVID-19. This damage can also affect the microcapillaries of the intestine which leads to blood accumulation and leaking into the intestines. Studies has shown that 40% of patients from COVID survivor groups without pre-existing GI symptoms reported new GI symptoms after 106 days after discharge following hospitalization for COVID-19.14 The most common GI symptoms were abdominal pain, constipation, diarrhea, and vomiting.
4) Liver and Kidney damage:
Hyper-inflammatory response due to SARS-CoV-2 adversely affect several internal organs. Besides lung injury, which is the main outcome of SARS-CoV-2 infection, it has been reported to adversely impact other organs including the liver and kidneys. SARS-CoV-2 can have a direct adverse impact on liver as well as kidneys due to systemic inflammatory response or drug toxicity, leading to elevated levels of liver injury markers and acute kidney injury. Clinical outcomes of SARS-CoV-2 infection could be worse in patients suffering from pre-existing liver and kidney disease.
There have been several studies to demonstrate adverse effects of SARS-CoV-2 virus on the liver, and its impairment post SARS-CoV-2 infection is also an emerging concern. Previous studies of SARS coronavirus have shown that up to 60% of patients had a liver impairment showing viral nucleic acid and damage in a liver biopsy.16 Because the liver is one of the potential entry targets for SARS-CoV-2, the liver damage caused due to infection can be attributed to several factors including direct damage by penetrating virus, inflammatory or immune response, increased risk of thrombosis and liver lesions. Elevated levels of liver injury markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase and total bilirubin levels have been reported in patients of SARS-CoV-2.16
Individuals with no underlying kidney problems also show signs of kidney damage after getting infected with SARS-CoV-2. Renal injury by SARS-CoV-2 can also be attributed to multiple factors such as direct injury due to virus infection or due to systemic effects including host immune clearance and immune response, endothelium-mediated vasculitis, thrombus formation, glucose and lipid metabolism disorder and hypoxia.16