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Table of Contents
Year : 2023  |  Volume : 6  |  Issue : 1  |  Page : 3-11

Long COVID: The long-term consequences of COVID-19 and the proposed pathophysiological mechanisms

1 Department of Critical Care, Care Hospital, Hyderabad, Telangana, India
2 The University Sleep Disorders Center, College of Medicine, King Saud University; National Plan for Science and Technology, Research Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission26-Sep-2022
Date of Decision30-Oct-2022
Date of Acceptance22-Nov-2022
Date of Web Publication3-Jan-2023

Correspondence Address:
Ahmed S BaHammam
Department of Medicine, University Sleep Disorders Center, College of Medicine, King Saud University, Riyadh 11324
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jnsm.jnsm_133_22

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The new devastating pandemic coronavirus disease 2019 (COVID-19) caused by the novel coronavirus severe acute respiratory syndrome (SARS-CoV-2) has been related to approximately 600 million cases and more than six million deaths till now. After recovery from COVID-19, some patients develop long-term sequelae called long COVID (LC). LC cases have been reported with multi-system involvement, with the most common being neuro-psychiatric, cardiorespiratory, hematological, and gastrointestinal systems highlighting the need for multidisciplinary team involvement and treatment. Since we are more than two and half years into this pandemic, we have more understanding of the pathophysiology and successful treatment of acute COVID-19, and we see more survivors and, subsequently, individuals with LC. However, the pathogenic mechanisms leading to LC are not clear till now. This review describes the potential pathogenic mechanisms leading to LC and common clinical manifestations reported from current evidence.

Keywords: Coronavirus disease 2019, immune response, postacute coronavirus disease 2019 syndrome, postacute sequelae of coronavirus disease 2019, postcoronavirus disease 2019 condition, severe acute respiratory syndrome coronavirus 2

How to cite this article:
Masood M, Chodisetti SS, BaHammam AS. Long COVID: The long-term consequences of COVID-19 and the proposed pathophysiological mechanisms. J Nat Sci Med 2023;6:3-11

How to cite this URL:
Masood M, Chodisetti SS, BaHammam AS. Long COVID: The long-term consequences of COVID-19 and the proposed pathophysiological mechanisms. J Nat Sci Med [serial online] 2023 [cited 2023 Jan 30];6:3-11. Available from: https://www.jnsmonline.org/text.asp?2023/6/1/3/366995

  Introduction Top

On January 30, 2020, the World Health Organization (WHO) formally proclaimed coronavirus disease 2019 (COVID-19) caused by a new unique severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Coronavirus as a Public Health Emergency of International Concern, and on March 11, 2020, it was classified as a worldwide pandemic.[1] A large percentage of SARS-CoV-2 infected people (80%) have mild symptoms, and a small percentage need acute medical care, including hospitalization and even Intensive care unit, having a cumulative case fatality rate of 2.3%.[2],[3] As of September 25, 2022, about 612 million confirmed cases of COVID-19 and 6.5 million deaths were reported to WHO globally.[4]

Acute COVID-19 symptoms may last from a few days to weeks, possibly due to the virus and body's initial immune response to infection.[5] However, in around 10%–35% of patients who suffered acute COVID-19, symptoms persist after recovery for weeks to months following a relapsing and remitting course, which is labeled by several names, including postacute sequelae of COVID-19, post-COVID-19 condition, long COVID (LC) and postacute COVID-19 syndrome, (postacute sequelae of SARS COV-2 [PASC]).[5],[6],[7],[8],[9],[10],[11] In addition, the UK National Institute for Health and Care Excellence renders a difference between continuing COVID-19 with symptoms and postacute COVID-19 syndrome, which was defined as a disease happening from 4 to 12 weeks postacquiring-infection (continuing COVID-19 with symptoms) and symptoms persisting beyond 12 weeks (postacute COVID-19 syndrome).[8]

The WHO recommends describing this condition as a "post-COVID-19 condition," and defines it as "a disorder distinguished by symptoms affecting daily activities, such as fatigue, dyspnea, and cognitive impairment, which arise after a history of likely or documented SARS-CoV-2 infection," and is given specific ICD-10 (U09) and ICD-11 (RA02) codes to identify it.[7],[12] This brief review aims to present the current knowledge on LC-19 symptoms and the underlying pathophysiology of various organ involvement.

  Search Methods Top

We searched PubMed and Google Scholar, as well as the internet, for preprint publications until mid-October 2022. We used the following keywords, "COVID-19," "LC-19," "post-COVID-19 syndrome," "post-COVID conditions," "LC," "long-haul COVID-19," "long-term effects of COVID-19," and "PASC." We retrieved original articles and systematic reviews; case reports and editorials were not included. Additionally, we searched the references of retrieved articles for relevant studies. We only searched for articles in the English language.

  Pathophysiology Top

It is not uncommon to see postinfectious sequelae in other infections like other coronaviruses (SARS-CoV and Middle East respiratory syndrome-CoV), Epstein-Barr virus, Borrelia burgdorferi, Giardia lamblia, Coxiella burnetii, and the Ross River virus apart from SARS-CoV-2. As the percentage of survivors and LC individuals grows, it is crucial to understand the mechanisms of postacute sequelae manifestations. Newell and Waickman have recently explained the possible mechanisms for dysregulated antigen-specific immune responses to be induced and maintained.[13] [Figure 1] illustrates a proposed algorithm for the potential pathophysiological mechanisms of LC.
Figure 1: A proposed algorithm for the potential pathophysiological mechanisms of LC. LC: Long COVID

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Postinfectious sequelae from SARS-Cov-2 infection are mainly due to three mechanisms: Firstly, "immunological misfiring, inflammatory storms, and persistent inflammation." As was described by Phetsouphanh et al. that even after 8 months, higher appearance of both types, I and III interferons (IFN); in addition to chemokine 9 (CXCL9), chemokine 10 (CXCL10), interleukin-8 (IL-8), and soluble T cell immunoglobulin mucin domain 3 (sTIM-3) was noticed, postulating that activated cluster differentiation 8+ T cells (CD8+ T cells) were responsible for the generation of pro-inflammatory cytokines that led to vascular damage.[14] Furthermore, this lymphocyte-activation type of LC was supported by a machine-learning method to estimate the time required for SARS-CoV-2 infection symptoms to resolve and predicted LC chronicity by increased IFN-and IL-2 levels, indicating that LC following viral clearance is due to untampered immune activation.[15]

The second mechanism includes "persistent antigen production by noninfectious viral ribonucleic acid (RNA)," which was supported by the detection of SARS-CoV-2 RNA in the lungs and a variety of nonrespiratory tissues up to 230 days after infection in autopsies, which were unrelated to cytopathic-tissue injury or significant inflammation.[16],[17] Though this theory has been disputed, Antonelli's group reported a 49% decrease in LC danger in Individuals who had been vaccinated prior to infection compared to controls who did not get vaccinated.[18] Supporting this, there is some evidence that the antigen-specific adaptive immune response is persistent but not very potent and is associated with the symptom duration in acute SARS-CoV-2 infection.[19],[20] And lastly, by "antigen perseverance in the absence of viral persistence." Following resolving an acute-infectious injury, the mechanisms listed below exist to keep antigens for immunological memory. It has been found that memory B lymphocytes that were obtained from convalescent COVID-19 patients have shown SARS-CoV-2 antigen retained in germinal cells for a long time.[21],[22] Aged convalescent patients' lavage of the alveolar fluid (bronchoalveolar lavage) showed higher quantities of activated resident memory-like CD27+ CD69+ B lymphocytes, and quite a few studies have shown an association between peripheral autoantibody concentrations and LC.[23] Moreover, increased CD69+ CD103 CD8+ T RM cells in convalescent people, which were multifunctional for producing cytotoxic cytokines, showed dysregulation of CD8+ T-cell response.[23] [Figure 2] depicts the possible clinical courses after acquiring COVID-19 and the possible long-term effects on body organs.
Figure 2: This illustration depicts the possible clinical courses after acquiring COVID-19 and the possible long-term effects on body organs "Created with BioRender.com." COVID-19: Coronavirus disease 2019, (LC: long COVID)

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  Clinical Manifestations Top

Regardless of the patient's age or the severity of the acute infection, LC is a multi-system, heterogeneous, relapsing, and remitting sickness that can appear in SARS-CoV-2 infected individuals.[24] Several studies, including systematic reviews, revealed that LC has multi-system health effects, comprising not only vague general symptoms but the involvement of almost all body systems leading to poor quality of life.[25],[26]

A recent large, longitudinal, questionnaire-based cohort study among confirmed cases of COVID-19 followed the participants at 6, 12, and 18-mon and reported that prior symptomatic infection was linked to lower quality of life, deterioration in all everyday activities, and 24 persisting complaints, including palpitations (odds ratio [OR] 2.51), chest discomfort (OR 2.09), dyspnea (OR 3.43), and confusion (OR 2.09).[27] Hospitalization, age, female sex, deprivation, pulmonary diseases, depression, and multi-comorbidities were all related to poor recovery.[27] In contrast, receiving the COVID-19 vaccine reduced the chance of developing some symptoms.

Neurological and neuropsychiatric systems

Neurological manifestations, such as anosmia, dysgeusia, headache, cognitive dysfunction, fatigue, chronic fatigue syndrome, neuropathic pain, peripheral nervous system symptoms, and paresthesia, and neuropsychiatric features, such as anxiety, depression, sleep disturbances/insomnia, and posttraumatic stress disorder are common components of LC.[28]

A recent study used the "US Department of Veterans Affairs' national healthcare" records to create a cohort of approximately 1545,06800 COVID-19 patients, approximately 6,000,000 current controls, and around 6,000,000 historical controls to calculate the risks and costs of neurologic diseases that may occur 12 months after acute SARS-CoV-2 disease.[29] The study revealed an increased risk of a variety of incident neurologic sequelae during the postacute phase of COVID-19, including ischemic and hemorrhagic stroke, cognition and memory problems, peripheral nervous system problems, episodic disorders (such as migraines and seizures), extrapyramidal and movement issues, mental health conditions, musculoskeletal disorders, sensory problems, Guillain–Barré syndrome, and encephalitis or encephalopathy.[29] At 12 months, the calculated hazard ratio (HR) for any neurologic sequela was 1.4, and the burden was 71/1000 individuals at 12 months. Even in patients who did not require hospitalization during acute COVID-19, the risks and costs were increased.[29]

Over 10,000 participants from 18 published trials were included in a meta-analysis that assessed how frequently people with acute-COVID-19 onset experience neurological and neuropsychiatric complaints conveyed ≥3 months following the acute infection, fatigue, cognitive dysfunction, and sleep problems were the most prevalent features; all identified in almost one-third of patients.[30] It was found in a number of papers that the risk of depression and anxiety was higher amongst individuals who recovered from COVID-19 after admission to a hospital or critical care unit than individuals who were managed at home or in a clinic setting.[31],[32],[33],[34] Nevertheless, in a prospective observational study, Van den Borst et al. could not notice any correlations between the COVID-19 severity grades (mild, moderate, and severe) and differences in mental and cognitive status.[35] It was interesting that hospitalization did not increase these symptoms; on the contrary, a retrospective analysis of 57,000 patients found that nonhospitalized individuals under 65-years-old had an increased prevalence of these symptoms than all other patients combined.[36] Accordingly, a recent meta-analysis of eighteen studies, including around 10,500 patients, discovered that when compared to patients who were not hospitalized, these neuropsychiatric symptoms did not worsen in hospitalized patients; however, stratification by ICU status demonstrated that these symptoms were linked to the disease's initial severity.[30] In addition, most of the symptoms increased in frequency during follow-up from mid-to-long-term, showing that they are more likely to change and develop after infection than to stay the same.[30]

Though the reason for the above conflicting results is unknown, it could be due to (1) a lack of standard definitions for cognitive dysfunction; and (2) an overestimation of symptoms in the community.

In a later article, our team studied a cohort of healthcare workers at two different time points: the initial months of the pandemic in April 2020 (T1) and 2 years into the pandemic in February 2022 (T2). The study found poor sleep quality and perceived stress were common for healthcare workers during T1, whereas at T2, although perceived stress decreased, sleep quality declined.[37]

A recent international survey study of approximately 14,000 adults from 16 countries across the globe (the ICOSS-II study) demonstrated that COVID-19 patients needing hospitalization for COVID-19 had a higher prevalence of postacute sequelae of COVID-19 symptoms.[38] The investigators reported that in contrast to COVID-negative cases, COVID-19 patients had long-lasting sleep complaints, which correlated with the severity of COVID-19. Particularly, among responders reporting persistent symptoms during hospitalization for COVID-19, tiredness (61%), insomnia symptoms (50%), and excessive daytime sleepiness (36%) were extremely frequent.[38] Therefore, when assessing individuals with long-COVID, it is highly advised to routinely assess sleep symptoms, such as daytime drowsiness and insomnia symptoms.

It was demonstrated in an autopsy study that it is not the virus itself, but several immune-mediated mechanisms are responsible for the neuropsychiatric changes.[39] These mechanisms involve platelet activation and aggregation, complement activation, immune complex deposition, activation of microglial cells, and neuronal injury, which are demonstrated by the presence of large proteins (fibrinogen, C1q, Immunoglobulin G, and Immunoglobulin M) in the perivascular space. Normally, these proteins do not cross the blood-brain barrier.[39]

In summary, the above findings together highlight the need for further research into the long-term neurologic effects of SARS-CoV-2 infection. Even while the effects of COVID-19 on physical-health have garnered much attention, mental health has unfortunately received less attention. In order to assure transdisciplinary and reliable research and to give attention and healthcare at an early stage to those most susceptible to mental health problems, it is necessary to provide equal importance to both mental and physical health from the very beginning.

Respiratory system

It is one of the most commonly affected systems during both acute and LC. Dyspnea, cough, and hypoxemia are common respiratory symptoms in adults, while in children, postviral cough is the most common.[40] Some COVID-19 patients may develop acute respiratory failure with extensive bilateral pneumonia. Some COVID-19 patients progress to advanced lung fibrosis, also called Post-COVID-19 interstitial lung syndrome (PCOILS). Tomassetti et al., described high-resolution computed tomography (HRCT) of 118 patients with PCOILS and found a nonspecific interstitial pattern as the common pattern.[41] In addition, pulmonary fibrosis and pulmonary arterial hypertension are other reported long-term sequelae.[42] [Figure 3]a shows a chest X-ray (CXR) of a patient with acute respiratory failure a few days post-COVID-19; the CXR shows bilateral airspace opacities with near total opacification of both lungs. [Figure 3]b shows the CXR of the same patient 2 weeks later; it shows bilateral diffuse reticular interstitial lung thickening with some air space consolidation opacities still present.
Figure 3: (a) A CXR of a patient with acute respiratory failure a few days post-COVID-19; the CXR shows bilateral airspace opacities with near total opacification of both lungs. (b) A CXR of the same patient 2 weeks later; shows bilateral diffuse reticular interstitial lung thickening with some air space consolidation opacities still present. COVID-19: Coronavirus disease 2019. CXR: Chest X-ray

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Up to 40% of COVID-19 patients develop greater severity of physiological parameters like lower forced vital capacity, total lung capacity, diffusion capacity for carbon monoxide (DLCO), and respiratory muscle weakness.[42] In addition, HRCT abnormalities are observed with severe/critical acute COVID-19 compared with mild and moderate infection, which were similar to mild/moderate disease after 8–12 months of follow-up.[42]

Persistent respiratory signs and symptoms are caused by pathophysiological pathways, including direct lung-related-tissue damage and lung-related pathological-inflammation, like viral persistence, immunological dysregulation, and autoimmune disease. On the other hand, the most typical physiological anomalies are explained by microvascular abnormalities, impaired alveolar membrane diffusion, and extrapulmonary restriction.[14]

At a 3-month follow-up, Gonzalez et al. found an aberrant DLCO in up to 80% of the patients who had survived ARDS caused by SARS-CoV-2 infection.[43] Other cohorts have confirmed these findings.[44],[45] The "UK-Interstitial-Lung-Disease-Long-COVID19-Study" with sub-studies POST COVID-19 interstitial lung Disease and Xenon MRI investigation of Alveolar dysfunction and PCOILS are some of the eagerly anticipated studies.

According to a recently released study, after hospital discharge, survivors of SARS-CoV2-driven ARDS exhibit specific whole-blood transcriptome patterns that are related to postinfection pulmonary impairment.[46] Insights into the mechanisms underlying lung damage and recovery can be gained from the transcriptional programs revealed, opening the door to developing specialized therapeutic approaches and instruments for clinical decision-making.

Cardiovascular system manifestations

The cardiovascular system is another system commonly affected by COVID-19, which could manifest as acutely, long-lasting, or persistent. Electronic medical records of >73,000 COVID-19 survivors from the US Veteran Affair revealed a high disease burden manifested by hypertension (HR-15.2), circulatory signs and symptoms (HR-6.7), coronary atherosclerosis (HR-4.4) and heart failure (HR-3.9).[32] It was observed that most nonpulmonary causes of shortness of breath are mainly due to exacerbation of heart failure, acute myocarditis, cardiomyopathy, or atypical presentation of the cardio-renal syndrome.[47] Al-Aly et al. compared more than 150,000 veterans who had acute COVID-19 infection to those who had not contracted the virus, as well as to a prepandemic control group, and discovered that those who had COVID-19 had a higher chance of developing cardiovascular disorders after the first 30 days.[48] The manifestations spanned several categories and included heart failure, thromboembolic disease, pericarditis, myocarditis, dysrhythmias, cerebrovascular diseases, and dysrhythmias. They were also present in people who were not hospitalized.[48]

Though direct invasion of the myocardium by the SARS-CoV-2 virus can lead to myocarditis, it is infrequent. However, several additional theories have been put forth to account for cardiac dysfunction., such as the downregulation of angiotensin-converting enzyme 2 (ACE2) and dysregulation of the renin-angiotensin-aldosterone system, increased levels of pro-inflammatory cytokines, complement-mediated coagulopathy and microangiopathy, autonomic dysfunction, transcriptional changes in a variety of heart tissue cell types, and activation of transforming growth factor-signaling via the Smad pathway all contribute to the fibrosis and scarring of cardiac tissue.[49],[50]

A recent investigation measured blood indicators of heart damage or dysfunction and performed magnetic resonance imaging in a chosen cohort of patients with COVID-19 who had no prior cardiac disease or significant comorbidities.[51] A follow-up after a median of 109 days (n = 346) of COVID patients with cardiac complaints such as palpitation, syncope, chest pain, or dyspnea demonstrated that comparative to symptomless persons, symptomatic patients showed greater heart rate and imaging values or contrast agent buildup, indicating cardiovascular inflammation contribution. In addition, structural heart disease or significant cardiac damage or dysfunction biomarkers were uncommon in symptomatic patients.[51] However, a later follow-up, 329 days later, showed that 57% of patients still experienced chronic heart symptoms. Moreover, individuals with continuing symptoms during follow-up showed more significant diffuse myocardial edema than those with alleviated symptoms. The occurrence of cardiac complaints at follow-up was independently predicted by the female sex and diffuse myocardial involvement on imaging at recruitment (baseline).[51] The above suggests that subclinical cardiac inflammation is a potential risk factor for chronic autoimmune systemic diseases; therefore, more research is required to determine long-term outcomes in post-COVID.

Gastrointestinal and biliary system

Post-COVID-19 patients commonly have gastrointestinal (GI) symptoms that include diarrhea, abdominal pain, belching, vomiting, and GI bleeding, and the incidence is 3%–79%.[52],[53] Recently Ghosahal et al. studied 280 COVID-19 patients and found that functional GI disorders (FGIDs) (are renamed currently as disorders of the gut-brain interaction (DGBI)), including irritable bowel syndrome (IBS), un-investigated dyspepsia (UD) and IBS-UD overlap were found in 5.3%, 2.1% and 1.8% at 6 months.[54] In addition, case reports of acalculous cholecystitis and severe cholangiopathy were also reported among COVID-19 patients who recovered.[55],[56]

Recently, a systematic review and meta-analysis included 50 articles reporting GI complaints in LC. In patients with LC, the rates of GI symptoms were 0.22 (95% confidence interval, 0.10–0.41, I2 = 97%).[57] Following COVID-19, the frequency of abdominal pain, nausea/vomiting, appetite loss, and loss of taste were 0.14, 0.06, 0.20, and 0.17, respectively. Diarrhea, dyspepsia, and IBS all occurred with a frequency of 0.10, 0.20, and 0.17, respectively.[57]

The underlying mechanisms for these symptoms are similar to any postinfectious FGID/DGBI. Proposed mechanisms include: (1) Mucosal injury during acute episode activating T-cells resulting in inflammatory cascade which persists even after 3 months of infection, (2) Mast cell hyperplasia and neuronal activation, (3) Gut dysbiosis, (4) Psychological factors, and (5) Enteric Nervous system dysfunction due to SARS-CoV2 mediated ACE-2 downregulation which leads increased production of angiotensin-II which has adverse GI effects.[58]

Although liver chemistry abnormalities are common in COVID-19, they are often temporary and improve as the infection resolves. However, long-term sequelae may occur; for example, in one study, individuals who had recovered from severe COVID showed cholangiopathic alterations as a delayed manifestation in roughly 12 patients (11 men).[59]

The histopathology of cholangiopathy revealed evidence of bridging fibrosis, bile duct scarcity, cytokeratin-7 metaplasia of periportal hepatocytes, and cholangiocyte damage with microvascular alterations, all pointing to a risk of secondary biliary cirrhosis.[56]

Endocrine and metabolic functions

In LC, conditions such as newly developed diabetes mellitus and severe complications of previously diagnosed diabetes have been documented.[60] The yearly incidence rate of new-onset diabetes was calculated to be 2.9% in a large cohort of 47,780 discharged COVID-19 patients in the UK over a mean follow-up of 4.6 months.[61] Diabetes mellitus and COVID-19 have a bidirectional relationship (patients with diabetes are at high risk for severe COVID-19 and hospitalization; on the other hand, COVID-19 infection may result in new-onset diabetes during the long-COVID course).[60],[62] It was demonstrated that SARS-CoV binding to ACE2 receptors damages islets cells.[63]

Apart from diabetes mellitus, other reported endocrine abnormalities include: (1) hypothyroidism (5%), (2) thyrotoxicosis (20%), (3) central hypocortisolism (39%), and (4) diabetes insipidus.[64]

Pituitary autoptic tissues were studied by Wei et al. They discovered reduced number of cells producing hypophyseal somatotrophs, thyrotropes, and corticotropes.[65] Moreover, displayed alterations indicative of acute injuries, such as swelling and degeneration of the neurons have been reported.[65] Furthermore, since SARS-expressed CoV-2's amino acid sequences are similar to the residues in endogenous ACTH, the host's defense against SARS-CoV (and SARS-CoV-2) may result in the formation of cross-reacting antibodies that neutralize or destroy the endogenous ACTH.[66],[67]

Hematological system

During COVID-19 pandemic, micro- and macrovascular thrombosis were observed as common complications, especially in severe COVID-19.[68],[69] Venous thromboembolism (VTE) was observed in 18%–42% across different studies.[70] In LC, along with thrombosis, hemorrhagic and autoimmune hematological disorders have been reported. Giannis et al. analyzed 4906 discharged patients and discovered that 76 individuals (1.55%) had VTE.[71] In a group of 271 COVID-19 patients who were hospitalized, delayed-phase thrombocytopenia of suspected immune origin (immune thrombocytopenic purpura [ITP]) was noted in 11.8% of patients. In a systematic review, it was discovered that among 45 patients with ITP secondary to COVID-19, 9% had relapsed after a positive response to treatment during follow-up.[72]

COVID-19-induced coagulopathy (CIC) is more immune-thrombotic with fewer hemorrhagic complications.[73] SARS-CoV-2 invasion of endothelium causes pro-inflammatory and procoagulant cytokine release causing endotheliitis, causing the coagulation cascade to be activated, thrombin to be produced, and poor fibrinolysis to follow.[74] It is unknown till now how long this phase of CIC lasts; probably, the risk is determined by the length and intensity of the hyperinflammatory condition. In one hospitalized cohort, 52% of patients had antiphospholipid antibodies.[75]

  Economic and Societal Impacts Top

The longer-term illness and disability caused by LC will continue to have an impact on the economy and society. For instance, according to a poll, 44% of LC patients said they were unable to work at all compared to their pre-COVID-19 job capacity, and 51% had cut back on their working hours.[76] Due to LC, approximately one million workers may be unemployed at any given time, equating to approximately $50 billion annually in lost salary.[77] Apart from this, healthcare costs are expected to increase to deal with new chronic conditions that may be attributable to LC. To understand LC better, the United States of America is funding $1.2 billion in Researching COVID-19 to Enhance Recovery; by the end of this year, researchers hope to investigate 40,000 people, and they will keep track of them for 4 years while comparing those who have COVID-19 to those who have never had it.[78]

  Conclusion Top

Though we have accumulating data on the epidemiology of LC and some knowledge on the timing of the immune response and how immune cells interact with SARS-CoV-2, due to significant heterogeneity in the presentation of symptoms and duration, several questions related to this immune response on LC risk, resolution and severity are not answered yet. Therefore, more research is needed on this topic as a significant knowledge gap exists on the frequency, nature, and duration of persistent symptoms. It will be easier to develop treatment and management strategies at home or clinic by involving multidisciplinary teams.

Financial support and sponsorship

The Deanship of Scientific Research at Majmaah University funded this work under Project Number No (R-445-2020).

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]


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