Long COVID: An inevitable sequela of SARS-CoV-2 infection

At present, there are more than 560 million confirmed cases of the coronavirus disease 2019 (COVID-19) worldwide. Although more than 98% of patients with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection can survive acute COVID, a significant portion of survivors can develop residual health problems, which is termed as long COVID. Although severe COVID-19 is generally associated with a high risk of long COVID, patients with asymptomatic or mild disease can also show long COVID. The definition of long COVID is inconsistent and its clinical manifestations are protean. In addition to general symptoms, such as fatigue, long COVID can affect many organ systems, including the respiratory, neurological, psychosocial, cardiovascular, gastrointestinal, and metabolic systems. Moreover, patients with long COVID may experience exercise intolerance and impaired daily function and quality of life. Long COVID may be caused by SARS-CoV-2 direct injury or its associated immune/inflammatory response. Assessment of patients with long COVID requires comprehensive evaluation, including history taking, physical examination, laboratory tests, radiography, and functional tests. However, there is no known effective treatment for long COVID. Based on the limited evidence, vaccines may help to prevent the development of long COVID. As long COVID is a new clinical entity that is constantly evolving, there are still many unknowns, and further investigation is warranted to enhance our understanding of this disease.


Cytokines and biomarkers
Several studies evaluated the cytokine and biomarker profiles of patients with long COVID. [42][43][44][45] QueirozIn et al. found that compared with 90 patients without sequelae, 135 cases with long COVID had higher levels of interleukin (IL)-17 and IL-2 (p < 0.05), and lower levels of IL-10, IL-6, and IL-4 (p < 0.05). 42 Further studies also reported the potential roles of biomarkers according to the specific manifestations. Several markers, including SLC6A19, ACE2, TMRSS2, TMPRSS4, IFN-g, IL-17A, and zonulin, were found to be associated with neurological sequelae. 43 For pulmonary fibrosis in post-COVID-19 patients, several biomarkers, such as TNF-a, IL-17A, IL-17D, VCAM-1, ICAM-1, PIGF, or KL-6, may be associated with a high risk of susceptibility. 44 For exercise endurance, three inflammatory markers, including hsCRP, IL-6, and TNF-a, and the SARS-CoV-2 receptor-binding domain (RBD) immunoglobulin G, were negatively correlated with exercise capacity (peak VO 2) more than 1 year later. 45 However, no specific circulating, coagulation, and inflammatory markers, were highly predictive of the cardiovascular outcome of long COVID when measured 3 months after SARS-CoV-2 infection. 46 Therefore, further studies are needed to identify specific biomarkers to guide future preventive or treatment strategies for long COVID.

Imaging characteristics
Regarding chest imaging findings, Mandal et al. evaluated the follow-up radiographs (4e6 weeks after COVID-19) of 244 patients and found that 151 (62%) radiographs were normal, 66 (27%) demonstrated significant improvement, 4 (2%) remained unchanged, and 23 (9%) showed significant deterioration. 30 Of the 23 patients who had deteriorated radiographs at follow-up, 10 (43%) were typical for COVID-19 and 11 (48%) were indeterminate for or unlikely to represent COVID-19. 30 The study by Arnold et al. showed similar findings that only 14% (15/110) patients had abnormal follow-up radiographs (n Z 10 moderate group; n Z 5 severe group), and two had worsened after hospital admission with high radiographic severity scores. 31 The abnormal radiographic findings included reticulation (n Z 8), atelectasis (n Z 5), consolidation (n Z 1), and pleural effusion (n Z 1). In addition, abnormal highresolution CT findings, including fibrotic changes (n Z 2), minor persistent ground glass changes (n Z 2), and pleural effusion (n Z 1), were found in 5/9 patients. 31 In contrast, one study including 171 patients who underwent CT scanning found that 63.2% (n Z 108) had abnormal image findings, in which persistent ground glass opacity was the most common abnormality (n Z 72, 42.4%). 20 Another study of 60 patients showed that ground glass abnormality was more common than reticulation, with 83% patients having ground glass, 65% having reticulation, and only 12% with no imaging abnormality. 47 In rare cases, pulmonary embolus or lung infarcts could be found. 48 Fortunately, one sequential follow-up evaluation at 60 and 100 d after COVID-19 onset demonstrated that these CT abnormalities can be significantly improved over time. 34

Functional tests
Abnormal pulmonary function can be found in >50% of patients during the follow-up after COVID-10-related hospitalization, 47 and pulmonary diffusion capacity is the most commonly impaired lung function in recovered patients with COVID-19. 20 50 In the cardiovascular surveillance of 106 patients by the Yale Heart and Vascular Center, Wang et al. found that 11 patients (9%) had left ventricular systolic dysfunction, 10 patients (8%) had left ventricular diastolic dysfunction, and 9 patients (7%) had right ventricular systolic dysfunction. 32 Among 48 patients receiving Holter monitoring, 43 had symptomatic sinus tachycardia, 3 had new atrial fibrillation, and 2 had supraventricular tachycardia. 32 Finally, 4 of 53 patients undergoing stress test showed evidence of new ischemia and 19 (76%) of 25 patients showed evidence of late gadolinium enhancement and/or T2 inflammation on a cardiac magnetic resonance imaging (MRI) examination. 32 Exercise intolerance was not uncommon in patients with long-term COVID. One study involving 1733 discharged patients with COVID-19 at 6 months reported that the proportions of median 6-min walking distance at 6 months less than the lower limit of the normal range were 24, 22, and 29% for those at severity scale of 3, 4, and 5e6, respectively. 29 Another study reported that 20% (34/170) patients had an oxygen desaturation of greater than 4% while undergoing the 6-min walking test. 48 Furthermore, Skjørten et al. assessed the cardiopulmonary exercise capacity of 156 patients using a cardiopulmonary function and found peak oxygen uptake <80% than predicted in 31% (n Z 49) patients 3 months after discharge. 52 They also found that there were no differences in the ventilation, breathing reserve, and ventilatory efficiency between the ICU and non-ICU groups. 52

Mechanisms
As long COVID has recently developed in the past two years and its disease pattern is still evolving, its exact mechanisms are poorly understood at present. 53 Several possible mechanisms have been proposed: (1) direct cell damage of ACE2-expressing organ system by the entry of SARS-CoV-2 through ACE-2 receptors; (2) the inflammation related to persistent viral reservoir and antigen even after infection resolution; (3) activation of immune system causing autoimmunity because of the cross-reacting antibodies against SARS-CoV-2; (4) host's counter response including overproduction of counter-regulatory hormones and cytokines; (5) delayed resolution of inflammation altering the homeostatic milieu of the organ, increasing the amount of proinflammatory cells, and altering the cytokine production and immunometabolic pathway; and (6) the damage of vascular endothelial system enhancing platelet adhesion and coagulation, and resulting in the impairment of various organ functions. 53,54 Several response signaling mechanisms, such as the increased phosphorylation of nuclear factor-kb and Janus kinaseesignal transducer and activator of transcription pathway molecules and cytokines, including type I and type III interferons, interleukin (IL)-1b, IL-6, and transforming growth factor-b, are involved in this process. 53,55 In addition, residual organ damage in acute COVID-19, an adverse effect of anti-COVD-19 treatment, and exacerbation of underlying medical and psychiatric illnesses are also observed. 53,56 Journal of Microbiology, Immunology and Infection 56 (2023) 1e9

Diagnostic tools
Since long COVID can present with only non-specific symptoms or involve multiorgan systems, the appropriate evaluation criteria for patients with suspected long COVID remain unclear. An appropriate diagnostic strategy should be guided by the history, physical examination results, and clinical manifestations of the patient. Basic diagnostic laboratory tests determine the blood count, electrolyte levels, renal function, liver function, inflammatory markers (C-reactive protein and ferritin), thyroid function, and vitamin D and B12 levels. Specialized tests include the determination of autoantibody (for rheumatologic conditions), D-dimer and fibrinogen (for coagulation disorder), troponin (for myocardial injury), and B-type natriuretic peptide (for differentiating the cause of dyspnea) levels.
Specific functional assessment tools can be applied according to the patient's condition. Patient-reported outcome measurement information system, post-COVID-19 function status scale, and EuroQol-5D can be used to evaluate the functional status or quality of life of the patient. The modified Medical Research Council dyspnea scale can be used in patients with dyspnea. For neurological conditions, Montreal cognitive assessment, mini mental status examination, Compass 31, and neurobehavioral system inventory are useful tools. For psychiatric conditions, general anxiety disorder-7, patient health questionnaire-9, PTSD symptom scale, screen for posttraumatic stress symptoms, PTSD checklist for DSM-5, impact of event scalerevised, hospital anxiety, and depression scale, may be used.
Additionally, chest radiography, pulmonary function tests, electrocardiograms, or echocardiograms are used for persistent or new respiratory or cardiac concerns. The diagnostic value of computed tomography (CT) images is low in patients with normal chest X-rays and normal oxygen saturation. Similarly, the yield of CT pulmonary angiography for diagnosing pulmonary embolisms is low in patients without elevated D-dimer levels and compatible symptoms, and brain MRI may not reveal any pathological findings in the absence of focal neurological deficits in patients with brain fog symptoms.

Potential treatment options
The symptoms and functional impairment in patients with long COVID symptoms can be multidimensional, as this disease can be episodic and unpredictable. 67 The management of long COVID requires prompt multidisciplinary assessment and its treatment should be focused on excluding serious complications, managing specific symptom clusters, and supporting whole-person rehabilitation. 9,68,69 In addition to specific treatment according to specific organ disorder and rehabilitation for general symptoms, hyperbaric oxygen therapy (HBOT) can be used as a potential treatment modality. 70 70 Moreover, these clinical improvements were associated with brain MRI perfusion and microstructural changes. 70 These findings suggest the promising role of HBOT for long COVID. Additionally, many registered trials are being conducted to investigate the effects of cognitive and neurorehabilitation interventions, physiotherapy, and physical rehabilitation in patients. More conclusive evidence can be obtained in the near future.
Although oral antivirals expand armament against COVID-19, their effects on long COVID remain unknown. A small series involving four cases reported the effect of nirmatrelvir on the symptoms of long COVID, in which two cases reported improvement in persistent COVID symptoms when nirmatrelvir was taken 25 and 60 days following initial symptom onset. 71 Moreover, one case with presumed long COVID for 2 years reported substantial improvement when taking nirmatrelvir following SARS-CoV-2 re-infection. 71 Despite these findings suggest the promising role of oral antivirals, further study is warranted to assess their clinical efficacy and safety for long COVID.

Outcomes
A large cohort study consisting of 47,780 patients discharged after COVID-19-related hospitalization found that 29.4% (n Z 14,060) required readmission and 12.3% (n Z 5875) died during the mean follow-up of 140 d, and the risks of readmission and death were 3.5 (95% CI, 3.4e3.6) and 7.7 (95% CI, 7.2e8.3) times greater, respectively, than those of the matched controls. 34 In addition, new onset respiratory diseases were diagnosed in 6085 patients, and the rate of new onset of respiratory disease was 539 (95% CI, 525e553) per 1000 people, which was 27.3 (95% CI, 24.0e31.2) times greater than that in the controls. 34 Moreover, new onset of diabetes, a major cardiovascular event disease, chronic kidney disease, and chronic liver disease were found in 36,100, 36,130, 41,705, and 46,395 patients after discharge, respectively, and their was 1.5e3.0 times more than that of the control group. 34 Finally, the subgroup analysis disclosed that rate ratios comparing patients with covid-19 and matched controls were greater in individuals aged less than 70 than those aged 70 or more for all these outcomes, especially for death (14.1% vs 7.7%) and respiratory disease (10.5% vs 4.6%). 34

Conclusions
In addition to the increase in the number of confirmed cases of COVID-19, 72-74 the number of cases with long COVID are expected to increase in the future. Based on the current knowledge, we can state that: (1) long COVID can develop in all patients with COVID-19 with different severities, although an increased risk is associated with severe COVID-19, (2) long COVID can have various clinical manifestations, and many of them may be non-specific, (3) the patients with long COVID can be associated with a worse clinical outcome than those without, and (4) based on limited evidence, vaccination is the only way to prevent long COVID. However, there are many unknowns regarding long COVID. Despite long COVID likes acute COVID, which can involve many organ systems and has various presentation in different populations during different wave, 75-80 but long COVID may be more complicated. Because of the various definitions of long COVID and its protean clinical manifestations, the epidemiology of this disease remains unclear. In addition, the diagnostic criteria are vague, and possible mechanisms and effective management of this disease require further investigation. Further studies using an established definition and diagnostic criteria for long COVID can help in better understanding this disease.

Funding
None.

Declaration of Competing Interest
The authors declare that they have no conflicts of interest.