The pathophysiology of COVID-19 symptoms has not yet been fully elucidated. COVID-19 is a neurotropic virus by nature and may be a source of neuropathic pain, nociceptive/nociplastic pain due to inflammatory mediators, or central functional pain¹. Some studies that investigated the effect of COVID-19 on the central nervous system suggested that the virus can cross the blood-brain barrier due to endothelial damage, which may explain the central involvement of this pathway. Alternatively, the central transmission may be via the olfactory bulb, referring to the high frequency of an-osmia-hyposmia^2,3.

Su et al.³ reported that inflammation caused by cy-tokines, such IL-1, IL-6, and tumor necrosis factor, which play an important role in a cytokine storm, led to symptoms, such as arthralgia and myalgia with tissue damage. Sheraton et al.⁴ reported that the effects on the neuromuscular system might be related to inflam-mation, immune-mediated mechanisms, and direct damage. Studies reported that headache, encephalitis, and epilepsy might develop because of increased in-flammation, edema, or neural invasion in the central nervous system. Hypoxia, which develops because of pulmonary damage, may aggravate symptoms by increasing congestion and edema in the brain⁵.

A physiological phenomenon known as CS occurs when the central nervous system neurons become hy-perexcitable, leading to increased sensitivity to both noxious and non-noxious stimuli. Chronic pain is usu-ally thought to be caused by neural plasticity in pain coding pathways and circuits. Neuronal plasticity in-volves central sensitization of pain-processing neurons in the brain and spinal cord, and peripheral sensitiza-tion of primary sensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia^6-8

Central sensitization syndromes (CSS) refer to a range of medically nonspecific conditions, including fibrom-yalgia (FM), chronic fatigue syndrome (CFS), and irri-table bowel syndrome. CS may represent a common etiology for these conditions. Additionally, CS may also be the etiology of the chronic pain experienced by patients after COVID-19.

The COVID-19 pandemic causes significant stress worldwide. A study showed that the pain sensitivity syndrome epidemic worsened people's physical and mental health. Thus, interdisciplinary approaches are urgently required to deliver optimal healthcare to this group^9-12. Another study showed that all groups, except for chest pain and dyspnea, were associated with CS in patients who were divided into clinical groups (such as fatigue, myalgia, dyspnea, headache, chest pain, orthostatic tachycardia after COVID-19 infection. A female predominance was observed in these groups^10-13. To the best of our knowledge, these persistent chronic symptoms in the post-COVID period are similar to CSS, FM, CFS, and postural or-thostatic tachycardia syndrome and can often develop during the post-infection period.

This study aimed to investigate the symptoms that per-sisted after COVID-19 infection. The presence of CS, which plays a role in the etiology of chronic pain after COVID-19 infection, and its relationship with various parameters will be discussed.

This study was conducted in accordance with the prin-ciples of the Declaration of Helsinki 2008. Ethics committee approval Firat was obtained from the Uni-versity Non-Interventional Ethics Committee, and T.C. Necessary permissions were obtained from the Minis-try of Health (26.04.2022-8148). All patients signed the informed consent forms. We recorded the date when polymerase chain reaction (PCR) became posi-tive, hospitalization, and the need for intensive care. The present pain of the patients was evaluated using the visual analog scale (VAS), and accompanying symptoms were determined.

Central sensitization inventory (CSI); Initial CSI has two components. The first part contains 25 items, in-cluding pain-related, psychosocial, cognitive, and func-tional items. The second part includes restless legs, CFS, FM, temporomandibular joint disorder, migraine or tension headache, irritable bowel, multiple chemical sensitivities, and three disorders related to CSS^11-14.

The centrality of pain scale (COPS); COPS is a 10-item self-report questionnaire measuring how patients with chronic pain assess pain in their daily life. Each of the 10 items is graded on a five-point Likert scale. Higher scores show a more “centralized” pain^12-16

Pain quality assessment scale (PQAS); The respond-ents were instructed to rate the severity of each of the 20 pain domains using 0-10 numerical rating scales, and PQAS has 16 specific pain quality questions com-mon to patients with both neuropathic and non-neuropathic pain, in addition to 20 items measuring global pain intensity and unpleasantness^14-17.

The patients were classified into two groups based on the time elapsed after infection. Group 1 comprised patients with subacute or prolonged COVID (clinical presentation between 4-12 weeks after onset of acute disease). Group 2 comprised those with the chronic or post-COVID-19 syndrome (clinical presentation lasting >12 weeks after onset of acute disease and not ex-plained by alternative diagnoses). We excluded those whose current symptoms and findings were explained by different diagnoses. Those with a CS scale score of ≥40 were considered positive.

Statistical analysis
Data were entered into software SPSS (Version 23) and T-test, ANOVA, Regression methods were used for data analysis. The Shapiro-Wilk test was used to evalu-ate the conformity to the normal distribution. Subsequently, the Mann-Whitney U test was used to compare data that were not normally distributed based on the paired groups. Yates correction, Pearson’s Chi-square, and Fisher’s exact test statistics were used to examine the relationship between categorical variables accord-ing to groups. Binary logistic regression analysis was used to analyze the independent risk factors affecting central sensitization. Analysis results were presented as mean ±standard deviation and median (minimum-maximum) for quantitative data and frequency (percent) for categorical variables. p < 0.05 was considered statistically significant.

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Table 1: Frequency and percentage values of categorical variables.

The patients were classified into two groups based on symptom duration after COVID-19 infection. Hospital-ization (p =0.017), pulmonary involvement (p =0.019), fatigue (p =0.007), joint pain (p =0.013), dyspnea (p =0.038), and admission to intensive care (p =0.021) were significantly different in Group 2. Moreover, my-algia, headache, gastrointestinal symptoms, cognitive dysfunction, paresthesia, weight loss, and palpitations did not differ between the groups. Table 2 shows the comparison of categorical variables based on the groups.

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Table 2: Comparison of categorical variables according to groups.

Comparison of quantitative data in both groups showed that pain severity determined by VAS, depression-anxiety scale, pain centering scale, PQAS, and CS inventory scoring were significantly higher in Group 2 (p <0.005). Table 3 shows the comparison of quantitative variables by groups.

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Table 3: Comparison of quantitative variables by groups.

Univariate analysis showed that symptom duration is an independent risk factor in CS. The CS risk increases 1.105 times as symptom duration increases (p =0.003). The CS risk in Group 1 was 0.15 times less than that in Group 2 (p =0.001). The CS risk was 260,211 times (p <0.001), 43,361 times (p <0.001), 2429 times (p =0.048), and 51,610 times higher (p <0.001) in those who were hospitalized, requiring intensive care, with joint pain, and with headache, respectively. Table 4 shows the logistic regression analysis of the risk factors affecting the CS status and examination results.

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Table 4: Examination of risk factors affecting central sensitization using logistic regression analysis.

Studies showed that symptoms (fatigue, weakness, headache, sleep disorders, cognitive dysfunction) persist after infectious diseases with the severe high inflammatory process, such as Epstein-Barr virus, West Nile virus, Zika, Chikungunya, severe acute respiratory syndrome (SARS), and Borrelia^15-17,19. Similarly, post-infection pain has been reported in SARS CoV-2^1,20. However, the prevalence of chronic pain after COVID-19 infection remains unknown.

Current ideas suggest that SARS-CoV-2-induced cyto-kines and interleukin storms may increase the sensiti-vity of pain pathways^21,22. SARS‐CoV‐2 infection could trigger nociplastic pain responses by altering the balance between those neuromodulation systems of nociception²³. Widespread symptomatology has also been linked to inadequate immune regulatory mecha-nisms which may suggest a prolonged immune system impact in individuals with post-COVID pain, ultima-tely leading to increased sensitization²⁴. There is evidence that up to 60% of patients experience multiple symptoms following the acute phase of COVID-19 infection. The most common post-COVID symptoms are fatigue and dyspnea^25,26. In the current study, fatigue, myalgia, and pain were also highly prevalent symptoms²⁷. There's growing evidence that post-COVID pain bears similarities to musculoskeletal cha-racteristics²⁸. In the present study joint pain and myalgia were seen %46.8. The fundamental idea be-hind the term "nociplastic pain" is that sensitization-associated symptoms can be linked to both neuropathic pain disorders and chronic musculoskeletal pain²⁹.

The term "nociplastic pain" refers to pain that results from altered nociception without conclusive proof of disease or somatosensory system lesion causing pain, or proof of tissue damage activating peripheral nociceptors³⁰. In addition to exaggerated pain responses, nociceptive pain conditions are linked to symptoms originating from the central nervous system, including exhaustion, insomnia, memory loss, and psychological disruptions³¹. Since exhaustion and memory loss are two of the most common post-COVID symptoms, all these characteristics have been seen in people with prolonged COVID^25,26. In the current study,%29.1 of the patients had cognitive dysfunction.

According to a recent meta-analysis, the prevalence of post-COVID pain varied between 4.6% and 18.1% at various follow-ups in the first year following the infection²⁷. Indeed, a sizable cohort study found that, eight months after hospitalization, up to 45% of previ-ously hospitalized COVID-19 survivors experienced musculoskeletal post-COVID pain³². Actually, a Delphi study attempted to determine the sensitization phenotypes of people experiencing pain following COVID-19³³. According to that study, orthostatic intolerance, pain, fatigue, dyspnea, and gastrointestinal issues were among the symptoms linked to sensitization³³. In the present study symptoms associated with sensitization like gastrointestinal problems were seen %20.5, palpitation %31.7, and paresthesia were %35.7.

According to Ibañez et al. those with preexisting chro-nic pain sensitization syndromes were more likely to experience psychological distress during the global COVID-19 pandemic³⁴. Actually, the available data indicates that psychological variables and stress had a major influence on how the pain was processed. A pro-bable reason could be the dysfunction of serotonergic and noradrenergic neurons impacting somatic and psychological pain pathways³⁵.The finding that the CSI score was positively correlated with anxiety and depression levels is consistent with earlier research on individuals with chronic pain³⁶. In the present study Depression anxiety scale and vas Central sensitization inventory score were statically higher in group 2 with long covid patients, Centrality of pain scale, Pain quali-ty assessment scale were higher in group 1.

This results support the assumption that the CSI ques-tionnaire can exhibit a significant overlap with psycho-logical construct as previously suggested³⁷. One of the main symptoms of disorders linked to central sensitization is fatigue^38,39. This has led to the theory that patients with post-COVID-19 conditions and those with chronic pain may share a common etiology, which is central sensitization³³. Recent data indicates that a subset of patients with post-COVID-19 illness may have central sensitization. A Belgian study that used the central sensitization inventory (CSI), a self-rated questionnaire, revealed that 70% of people with post-COVID-19 condition had sensitization-associated symptomatology⁴⁰. In contrast, a Spanish study fo-und that only 34% of patients in a group exhibiting post-COVID pain had this prevalence⁴¹. The fact that people with post-COVID-19 condition display a number of symptoms related to the central nervous system, such as exhaustion, sleep issues, memory loss, concentration issues, or psychological disturbances, provides additional evidence in favor of the existence of central sensitization⁴².Along with acute symp-toms of infectious disease, they may include prolonged fatigue, sleep disturbances, nausea, headaches, and cognitive dysfunction, lasting in many cases for much longer than 6 months, and eventually, patients may satisfy the requirements for CFS or another CSS. Table 5 includes the criteria for CFS^43-47.

Recently, genes related to the epigenetics of FM, which is one of the CSS, are suggested to be dormant and activate the disease in long-term stressful situations, such as social, major medical, economic, or physical stressors^48-53. Following this activation, patients with CS disorders experience fatigue and an often sig-nificant symptom burden, which was detected by clini-cal testing due to central nervous system sensitivity to various stimuli, including vision, hearing, smell, and pain.

The etiology of symptoms persisting after COVID-19 infection may vary. This may be caused by the need for intensive care and ventilator, long hospitalization, and COVID-19. In present study, the CS in patients who were hospitalized, needed intensive care, and had lung involvement were significantly different compared who didn’t need hospitalization.

Previous studies determined that the most common infections related to patients with post-COVID-19 were EBV, West Nile virus, and Borrelia spp. Additionally, they exhibit similarities to other post-infectious disorders, including those linked to the disease^53-56

In this study, the most common symptoms were fatigue, joint pain, and myalgia. These patients may be clinically diagnosed with one of the prevalent CSS disorders if their symptoms last for 6 months without any other clear underlying cause. Data showed that the CS frequency after COVID-19 infection was 11%. However, only a few studies have investigated this subject. Bierle et al.³³ detected persistent COVID-19 symptoms in 9% (42/465) of patients with COVID-19, contributing to the definition of the post-COVID-19 syndrome. Currently, post-COVID-19 syndrome pre-sents a wide range of symptoms in all age groups, showing that individual factors also affect this condition^51-53. Studies have reported that secondary symptoms may develop in asymptomatic patients⁵⁵. Thus, patients with CSS may possibly develop new or worsening symptoms after COVID-19 infection.

This study has some limitations. First, the current re-sults can only be utilized by patients with mild-to-moderate COVID-19 who were hospitalized. Second, laboratory parameters were not investigated. Third, data on the presence of CSS in patients before infection were unavailable. Finally, asymptomatic–symptomatic questioning of patients in the acute period was lacking, and only a few patients were included in the study.

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