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Table of Contents
REVIEW ARTICLE
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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  Abstract 


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.



 
  References Top

1.
World Health Organization. WHO Announces COVID-19 Outbreak A Pandemic: WHO; 2020. Available fwwrom: http://www.euro.who.int/en/heps//:coronavirus.jhu.edu/map.alth-topics/health-emergencies/coronavirus-covid-19/news/news/2020/3/who-announces-covid-19-outbreak-a-pandemic. [Last accessed on 2022 Sep 04].  Back to cited text no. 1
    
2.
Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for disease control and prevention. JAMA 2020;323:1239-42.  Back to cited text no. 2
    
3.
Reilev M, Kristensen KB, Pottegård A, Lund LC, Hallas J, Ernst MT, et al. Characteristics and predictors of hospitalization and death in the first 11 122 cases with a positive RT-PCR test for SARS-CoV-2 in Denmark: A nationwide cohort. Int J Epidemiol 2020;49:1468-81.  Back to cited text no. 3
    
4.
World Health Organization. WHO Coronavirus (COVID-19) Dashboard: WHO; 2022. Available from: >https://covid19.who.int/Back to cited text no. 4
    
5.
Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med 2021;27:601-15.  Back to cited text no. 5
    
6.
Ladds E, Rushforth A, Wieringa S, Taylor S, Rayner C, Husain L, et al. Persistent symptoms after Covid-19: Qualitative study of 114 "Long COVID" patients and draft quality principles for services. BMC Health Serv Res 2020;20:1144.  Back to cited text no. 6
    
7.
World Health Organization. Clinical Case Definition of Post-COVID-19 Condition by a Delphi Consensus; 2021. Available fr-om: https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021. [Last accessedon 2022 Jul 31].  Back to cited text no. 7
    
8.
National Institute for Health and Care Excellence (NICE), Scottish Intercollegiate Guidelines Network (SIGN), Royal College of General Practitioners (RCGP). COVID-19 Rapid Guideline: Managing the Long-term Effects of COVID-19; 2022. p. 1-104. Available from: https://www.nice.org.uk/guidance/ng88/resources/covid19-rapid-guideline-managing-the-longterm-effects-of-covid19-pdf-51035515742. [Last accessed on 2022 Sep 25].  Back to cited text no. 8
    
9.
Greenhalgh T, Knight M, A'Court C, Buxton M, Husain L. Management of post-acute covid-19 in primary care. BMJ 2020;370:m3026.  Back to cited text no. 9
    
10.
Logue JK, Franko NM, McCulloch DJ, McDonald D, Magedson A, Wolf CR, et al. Sequelae in adults at 6 months after COVID-19 infection. JAMA Netw Open 2021;4:e210830.  Back to cited text no. 10
    
11.
Tenforde MW, Kim SS, Lindsell CJ, Billig Rose E, Shapiro NI, Files DC, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network – United States, March-June 2020. MMWR Morb Mortal Wkly Rep 2020;69:993-8.  Back to cited text no. 11
    
12.
World Health Organization. Emergency use ICD Codes for COVID-19 Disease Outbreak: World Health Organization; 2020. Available from: https://www.who.int/standards/classifications/classification-of-diseases/emergency-use-icd-codes-for-covid-19-disease-outbreak. [Last accessed on 2022 Aug 22].  Back to cited text no. 12
    
13.
Newell KL, Waickman AT. Inflammation, immunity, and antigen persistence in post-acute sequelae of SARS-CoV-2 infectionImmunity and inflammaion in post-acute sequelae of SARS-CoV-2 infection. Curr Opin Immunol 2022;77:102228.  Back to cited text no. 13
    
14.
Phetsouphanh C, Darley DR, Wilson DB, Howe A, Munier CM, Patel SK, et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol 2022;23:210-6.  Back to cited text no. 14
    
15.
Patterson BK, Guevara-Coto J, Yogendra R, Francisco EB, Long E, Pise A, et al. Immune-based prediction of COVID-19 severity and chronicity decoded using machine learning. Front Immunol 2021;12:700782.  Back to cited text no. 15
    
16.
Van Cleemput J, van Snippenberg W, Lambrechts L, Dendooven A, D'Onofrio V, Couck L, et al. Organ-specific genome diversity of replication-competent SARS-CoV-2. Nat Commun 2021;12:6612.  Back to cited text no. 16
    
17.
Chertow DS, Ramelli S, Grazioli A, Chung JY, Singh M, Yinda CK, et al. SARS-CoV-2 infection and persistence throughout the human body and brain. Res Sq 2021. Avaiable from: https://assets.researchsquare.com/files/rs-1139035/v1_covered.pdf?c=1640020576. [Last accessed on 2022 Sep 03]. [doi.org/10.21203/rs. 3.rs-1139035/v1 pre-print (In Review)].  Back to cited text no. 17
    
18.
Antonelli M, Penfold RS, Merino J, Sudre CH, Molteni E, Berry S, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID symptom study app: A prospective, community-based, nested, case-control study. Lancet Infect Dis 2022;22:43-55.  Back to cited text no. 18
    
19.
Fang H, Wegman AD, Ripich K, Friberg H, Currier JR, Thomas SJ, et al. Persistent COVID-19 symptoms minimally impact the development of SARS-CoV-2-Specific T cell immunity. Viruses 2021;13:916.  Back to cited text no. 19
    
20.
Files JK, Sarkar S, Fram TR, Boppana S, Sterrett S, Qin K, et al. Duration of post-COVID-19 symptoms is associated with sustained SARS-CoV-2-specific immune responses. JCI Insight 2021;6:151544.  Back to cited text no. 20
    
21.
Gaebler C, Wang Z, Lorenzi JC, Muecksch F, Finkin S, Tokuyama M, et al. Evolution of antibody immunity to SARS-CoV-2. Nature 2021;591:639-44.  Back to cited text no. 21
    
22.
Poon MM, Rybkina K, Kato Y, Kubota M, Matsumoto R, Bloom NI, et al. SARS-CoV-2 infection generates tissue-localized immunological memory in humans. Sci Immunol 2021;6:eabl9105.  Back to cited text no. 22
    
23.
Cheon IS, Li C, Son YM, Goplen NP, Wu Y, Cassmann T, et al. Immune signatures underlying post-acute COVID-19 lung sequelae. Sci Immunol 2021;6:eabk1741.  Back to cited text no. 23
    
24.
Groff D, Sun A, Ssentongo AE, Ba DM, Parsons N, Poudel GR, et al. Short-term and long-term rates of postacute sequelae of SARS-CoV-2 infection: A systematic review. JAMA Netw Open 2021;4:e2128568.  Back to cited text no. 24
    
25.
Malik P, Patel K, Pinto C, Jaiswal R, Tirupathi R, Pillai S, et al. Post-acute COVID-19 syndrome (PCS) and health-related quality of life (HRQoL)-a systematic review and meta-analysis. J Med Virol 2022;94:253-62.  Back to cited text no. 25
    
26.
Yan Z, Yang M, Lai CL. Long COVID-19 syndrome: A comprehensive review of its effect on various organ systems and recommendation on rehabilitation plans. Biomedicines 2021;9:966.  Back to cited text no. 26
    
27.
Hastie CE, Lowe DJ, McAuley A, Winter AJ, Mills NL, Black C, et al. Outcomes among confirmed cases and a matched comparison group in the Long-COVID in Scotland study. Nat Commun 2022;13:5663.  Back to cited text no. 27
    
28.
Wild CJ, Norton L, Menon DK, Ripsman DA, Swartz RH, Owen AM. Disentangling the cognitive, physical, and mental health sequelae of COVID-19. Cell Rep Med 2022;3:100750.  Back to cited text no. 28
    
29.
Xu E, Xie Y, Al-Aly Z. Long-term neurologic outcomes of COVID-19. Nat Med 2022;28:2406-15.  Back to cited text no. 29
    
30.
Premraj L, Kannapadi NV, Briggs J, Seal SM, Battaglini D, Fanning J, et al. Mid and long-term neurological and neuropsychiatric manifestations of post-COVID-19 syndrome: A meta-analysis. J Neurol Sci 2022;434:120162.  Back to cited text no. 30
    
31.
Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: A cohort study. Lancet 2021;397:220-32.  Back to cited text no. 31
    
32.
Al-Aly Z, Xie Y, Bowe B. High-dimensional characterization of post-acute sequelae of COVID-19. Nature 2021;594:259-64.  Back to cited text no. 32
    
33.
Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: A retrospective cohort study using electronic health records. Lancet Psychiatry 2021;8:416-27.  Back to cited text no. 33
    
34.
Halpin SJ, McIvor C, Whyatt G, Adams A, Harvey O, McLean L, et al. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: A cross-sectional evaluation. J Med Virol 2021;93:1013-22.  Back to cited text no. 34
    
35.
van den Borst B, Peters JB, Brink M, Schoon Y, Bleeker-Rovers CP, Schers H, et al. Comprehensive health assessment 3 months after recovery from acute coronavirus disease 2019 (COVID-19). Clin Infect Dis 2021;73:e1089-98.  Back to cited text no. 35
    
36.
Estiri H, Strasser ZH, Brat GA, Semenov YR, Consortium for Characterization of COVID-19 by EHR (4CE), Patel CJ, et al. Evolving phenotypes of non-hospitalized patients that indicate long COVID. BMC Med 2021;19:249.  Back to cited text no. 36
    
37.
Jahrami H, Haji EA, Saif ZQ, Aljeeran NO, Aljawder AI, Shehabdin FN, et al. Sleep quality worsens while perceived stress improves in healthcare workers over two years during the COVID-19 pandemic: Results of a longitudinal study. Healthcare (Basel) 2022;10:1588.  Back to cited text no. 37
    
38.
Merikanto I, Dauvilliers Y, Chung F, Wing YK, De Gennaro L, Holzinger B, et al. Sleep symptoms are essential features of long-COVID – Comparing healthy controls with COVID-19 cases of different severity in the international COVID sleep study (ICOSS-II). J Sleep Res 2022. p. e13754. doi: 10.1111/jsr.13754.  Back to cited text no. 38
    
39.
Lee MH, Perl DP, Steiner J, Pasternack N, Li W, Maric D, et al. Neurovascular injury with complement activation and inflammation in COVID-19. Brain 2022;145:2555-68.  Back to cited text no. 39
    
40.
Cabrera Martimbianco AL, Pacheco RL, Bagattini ÂM, Riera R. Frequency, signs and symptoms, and criteria adopted for long COVID-19: A systematic review. Int J Clin Pract 2021;75:e14357.  Back to cited text no. 40
    
41.
Tomassetti S, Oggionni T, Barisione E, Bargagli E, Bonifazi M, Confalonieri M, editors. A Multidisciplinary Multicenter Study Evaluating Risk Factors, Prevalence and Characteristics of Post-COVID-19 InterstitialLung Syndrome PCOILS. USA: American Thoracic Society International Conference; 2021.  Back to cited text no. 41
    
42.
Huntley CC, Patel K, Bil Bushra SE, Mobeen F, Armitage MN, Pye A, et al. Pulmonary function test and computed tomography features during follow-up after SARS, MERS and COVID-19: A systematic review and meta-analysis. ERJ Open Res 2022;8:00056-2022.  Back to cited text no. 42
    
43.
González J, Benítez ID, Carmona P, Santisteve S, Monge A, Moncusí-Moix A, et al. Pulmonary function and radiologic features in survivors of critical COVID-19: A 3-Month prospective cohort. Chest 2021;160:187-98.  Back to cited text no. 43
    
44.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9.  Back to cited text no. 44
    
45.
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir Med 2020;8:475-81.  Back to cited text no. 45
    
46.
María C, García-Hidalgo RP, González J, Santisteve S, Benítez ID, Molinero M, et al. Genome-wide transcriptional profiling of pulmonary functional sequelae in ARDS- secondary to SARS-CoV-2 infection. Biomed Pharm 2022;154:113617.  Back to cited text no. 46
    
47.
Ali UA, Sadiq MS, Yunus MJ. Cardiorenal syndrome in COVID-19. BMJ Case Rep 2021;14:e241914.  Back to cited text no. 47
    
48.
Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nat Med 2022;28:583-90.  Back to cited text no. 48
    
49.
Farshidfar F, Koleini N, Ardehali H. Cardiovascular complications of COVID-19. JCI Insight 2021;6:e148980.  Back to cited text no. 49
    
50.
Nishiga M, Wang DW, Han Y, Lewis DB, Wu JC. COVID-19 and cardiovascular disease: From basic mechanisms to clinical perspectives. Nat Rev Cardiol 2020;17:543-58.  Back to cited text no. 50
    
51.
Puntmann VO, Martin S, Shchendrygina A, Hoffmann J, Ka MM, Giokoglu E, et al. Long-term cardiac pathology in individuals with mild initial COVID-19 illness. Nat Med 2022;28:2117-23.  Back to cited text no. 51
    
52.
Tian Y, Rong L, Nian W, He Y. Review article: Gastrointestinal features in COVID-19 and the possibility of faecal transmission. Aliment Pharmacol Ther 2020;51:843-51.  Back to cited text no. 52
    
53.
Wong SH, Lui RN, Sung JJ. Covid-19 and the digestive system. J Gastroenterol Hepatol 2020;35:744-8.  Back to cited text no. 53
    
54.
Ghoshal UC, Ghoshal U, Rahman MM, Mathur A, Rai S, Akhter M, et al. Post-infection functional gastrointestinal disorders following coronavirus disease-19: A case-control study. J Gastroenterol Hepatol 2022;37:489-98.  Back to cited text no. 54
    
55.
Balaphas A, Gkoufa K, Meyer J, Peloso A, Bornand A, McKee TA, et al. COVID-19 can mimic acute cholecystitis and is associated with the presence of viral RNA in the gallbladder wall. J Hepatol 2020;73:1566-8.  Back to cited text no. 55
    
56.
Roth NC, Kim A, Vitkovski T, Xia J, Ramirez G, Bernstein D, et al. Post-COVID-19 cholangiopathy: A novel entity. Am J Gastroenterol 2021;116:1077-82.  Back to cited text no. 56
    
57.
Choudhury A, Tariq R, Jena A, Vesely EK, Singh S, Khanna S, et al. Gastrointestinal manifestations of long COVID: A systematic review and meta-analysis. Therap Adv Gastroenterol 2022;15:17562848221118403.  Back to cited text no. 57
    
58.
Golla R, Vuyyuru SK, Kante B, Kedia S, Ahuja V. Disorders of gut-brain interaction in post-acute COVID-19 syndrome. Postgrad Med J 2022. p. j-141749. doi: 10.1136/pmj-2022-141749.  Back to cited text no. 58
    
59.
Faruqui S, Okoli FC, Olsen SK, Feldman DM, Kalia HS, Park JS, et al. Cholangiopathy after severe COVID-19: Clinical features and prognostic implications. Am J Gastroenterol 2021;116:1414-25.  Back to cited text no. 59
    
60.
Rubino F, Amiel SA, Zimmet P, Alberti G, Bornstein S, Eckel RH, et al. New-Onset diabetes in COVID-19. N Engl J Med 2020;383:789-90.  Back to cited text no. 60
    
61.
Sathish T, Anton MC, Sivakumar T. New-onset diabetes in "long COVID". J Diabetes 2021;13:693-4.  Back to cited text no. 61
    
62.
Landstra CP, de Koning EJP. COVID-19 and diabetes: Understanding the interrelationship and risks for a severe course. Front Endocrinol (Lausanne) 2021;12:649525.  Back to cited text no. 62
    
63.
Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010;47:193-9.  Back to cited text no. 63
    
64.
Lisco G, De Tullio A, Stragapede A, Solimando AG, Albanese F, Capobianco M, et al. COVID-19 and the endocrine system: A comprehensive review on the theme. J Clin Med 2021;10:2920.  Back to cited text no. 64
    
65.
Wei L, Sun S, Zhang J, Zhu H, Xu Y, Ma Q, et al. Endocrine cells of the adenohypophysis in severe acute respiratory syndrome (SARS). Biochem Cell Biol 2010;88:723-30.  Back to cited text no. 65
    
66.
Pal R, Banerjee M. COVID-19 and the endocrine system: Exploring the unexplored. J Endocrinol Invest 2020;43:1027-31.  Back to cited text no. 66
    
67.
Pal R. COVID-19, hypothalamo-pituitary-adrenal axis and clinical implications. Endocrine 2020;68:251-2.  Back to cited text no. 67
    
68.
Piazza G, Campia U, Hurwitz S, Snyder JE, Rizzo SM, Pfeferman MB, et al. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J Am Coll Cardiol 2020;76:2060-72.  Back to cited text no. 68
    
69.
Nadkarni GN, Lala A, Bagiella E, Chang HL, Moreno PR, Pujadas E, et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19. J Am Coll Cardiol 2020;76:1815-26.  Back to cited text no. 69
    
70.
Chen J, Wang X, Zhang S, Lin B, Wu X, Wang Y, et al. Characteristics of acute pulmonary embolism in patients with COVID-19 associated pneumonia from the city of Wuhan. Clin Appl Thromb Hemost 2020;26:1076029620936772.  Back to cited text no. 70
    
71.
Giannis D, Allen SL, Tsang J, Flint S, Pinhasov T, Williams S, et al. Postdischarge thromboembolic outcomes and mortality of hospitalized patients with COVID-19: The CORE-19 registry. Blood 2021;137:2838-47.  Back to cited text no. 71
    
72.
Bhattacharjee S, Banerjee M. Immune thrombocytopenia secondary to COVID-19: A systematic review. SN Compr Clin Med 2020;2:2048-58.  Back to cited text no. 72
    
73.
Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020;135:2033-40.  Back to cited text no. 73
    
74.
Escher R, Breakey N, Lämmle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res 2020;190:62.  Back to cited text no. 74
    
75.
Zuo Y, Estes SK, Ali RA, Gandhi AA, Yalavarthi S, Shi H, et al. Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19. Sci Transl Med 2020;12:eabd3876.  Back to cited text no. 75
    
76.
Cutler DM. The costs of long COVID. JAMA Health Forum 2022;3:e221809.  Back to cited text no. 76
    
77.
Bach K. Is "Long COVID" worsening the labor shortage? Brookings Metro; 2022. Available from: https://www.brookings.edu/research/is-long-covid-worsening-the-labor-shortage/. [Lastaccessed on 2022 Sep 01].  Back to cited text no. 77
    
78.
Kimball S. U.S. Scientists Enroll Nearly 40,000 Patients in High-Stakes, $1.2 Billion Study of Long COVID: CNBC; 2022. Available from: https://www.cnbc.com/2022/07/08/long-covid-us-scientists-to-enroll-40000-in-1point2-billion-study-.html. [Last accessed on 2022 Sep 03].  Back to cited text no. 78
    


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