Unclosing Clinical Criteria and the Role of Cytokines in the Pathogenesis of Persistent Post-COVID-19 Headaches: A Pilot Case-Control Study from Egypt
1
Department of Neurology, Faculty of Medicine, Cairo University, Giza 12613, Egypt
2
Department of Clinical Pathology, Faculty of Medicine, Cairo University, Giza 12613, Egypt
*
Author to whom correspondence should be addressed.
Clin. Transl. Neurosci. 2025, 9(1), 5; https://doi.org/10.3390/ctn9010005
Submission received: 23 November 2024
/
Revised: 17 December 2024
/
Accepted: 15 January 2025
/
Published: 22 January 2025
(This article belongs to the Section Headache)
Abstract
:(1) Background: Persistent post-COVID-19 headaches are emerging as a significant post-infection symptom. This study investigates the clinical characteristics of persistent post-COVID-19 headaches and the potential role of pro-inflammatory cytokines. (2) Methods: We conducted a pilot case–control study involving 84 participants divided into three groups: post-COVID with headache (n = 28), post-COVID without headache (n = 28), and healthy controls (n = 28). The detailed headache characteristics, including pain intensity, were assessed using the Visual Analog Scale (VAS). The serum levels of inflammatory cytokines (IL-6 and TNF-α) were measured. (3) Results: Post-COVID headaches predominantly presented as bilateral (53.6%) and throbbing (60.7%) in nature, with a median of 12 headache days per month and high pain intensity (median VAS score = 80). The associated symptoms were phonophobia (85.7%), fatigue (78.6%), and photophobia (75%). The serum levels of IL-6 and TNF-α were significantly higher in post-COVID headache patients than in the post-COVID without headache and healthy control groups (p < 0.001). A Receiver Operating Characteristic analysis showed that the circulating levels of IL-6 and TNF-α could discriminate our study groups at cutoffs with variable sensitivity and specificity. (4) Conclusions: Persistent post-COVID-19 headaches have diverse clinical characteristics and are associated with elevated circulating levels of pro-inflammatory cytokines, suggesting a potential underlying neuroinflammation.
Keywords:
COVID-19; headache; cytokines; SARS-CoV-2; persistent headache; long COVID; neuroinflammation1. Introduction
Headache disorders are the second most prevalent disease globally, according to the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2021, with a significant lack of headache epidemiological research in numerous countries and regions [1]. Headaches have been reported with both COVID-19 infection and vaccination [2]. Headaches can manifest either as an acute symptom during the infection phase or persist as part of the long-COVID syndrome, leading to persistent chronic headaches [3,4]. COVID-19 vaccinations have also been associated with headaches as a side effect. Post-vaccination headaches are generally transient but can be severe and resemble migraine episodes [5].
The data from the literature show that persistent post-COVID-19 headaches have a variable range of headache localizations, features, and associated symptoms, including migraine-like manifestations, tension-type characteristics and neurological disturbances [6,7,8]. These similarities imply diagnostic challenges in differentiating post-COVID headaches from other headache disorders. Several hypotheses have been proposed regarding the pathophysiology of persistent post-COVID headaches. These include direct trigeminal nerve involvement, cytokine-mediated neuroinflammation and potential blood–brain barrier damage that activates the trigeminovascular system [3,6]. The potential role of neuroinflammation has gained particular interest, given the well-known systemic inflammatory response observed in COVID-19 patients [9]. Pro-inflammatory cytokines play a crucial role in sensitizing the trigeminal nerve fibers and in changing the pain threshold [10]. Understanding the clinical characteristics and underlying mechanisms of post-COVID headaches is crucial for targeted diagnosis and treatment strategies. This pilot study aimed to highlight the clinical features of persistent post-COVID headaches among a sample of Egyptian patients and to investigate the potential role of pro-inflammatory cytokines (IL-6 and TNFα) in persistent post-COVID-19 headaches.
2. Materials and Methods
In this case–control study, we prospectively recruited 56 Egyptian patients with a COVID-19 diagnosis during the period from October 2022 to July 2023. Patients were classified into two groups: post-COVID with headache (n = 28), and post-COVID without headache (n = 28). Adults aged over 18 years and less than 70 years with a confirmed COVID-19 diagnosis according to the WHO interim guidance were included [11]. A Persistent post-COVID headache was defined as any chronic headache with a duration of more than 3 months whose onset or worsening appeared to present a temporal relationship with A confirmed SARS-CoV-2 infection. Our definition corresponds to the International Classification of Headache Disorders, 3rd edition (ICHD-3) for the diagnosis of chronic headache attributed to systemic viral infection [12]. Age- and sex-matched healthy controls (n = 28) were also recruited for the laboratory analysis. We excluded non-Egyptian patients and any patient with a recent COVID-19 infection or any other viral infection or recent vaccination in the month before enrolment, and those who refused further laboratory investigations. We also excluded patients with abnormal neuroimaging findings such as territorial infarcts, intracerebral hemorrhage, subdural hematoma, tumors or sinus thrombosis.
All patients underwent thorough medical and neurological evaluations. All of the headache characteristics were carefully assessed and recorded using a detailed headache sheet. Headache pain intensity was assessed using the Visual Analog Scale (VAS). The neuroradiological assessment included brain Magnetic Resonance Imaging (MRI) and magnetic resonance venography (MRV) acquisition using a 1.5 Tesla Phillips Intera® scanner. The laboratory analyses included the measurement of IL-6 and TNF-α plasma levels. We used a Sandwich enzyme immunoassay kit for IL-6 measurements and an Enzyme-Linked Immunosorbent Assay (ELISA) kit for TNF-α measurements. The cytokine level sample was taken during the active headache days of the post-COVID headache group.
Statistical Analysis
Based on the evidence from previous similar studies, Epi-Calc 2000 was used to calculate the sample size of this study. Assuming an 80% power, 0.05 level of significance, 1.4 null hypothesis value, a standard deviation of 2 and an estimated mean of 2.5, the sample size would be =25 participants per group. Considering a dropout rate of 10%, the final sample size was 28 participants per group. The data were analyzed using SPSS version 28 (IBM Corp., Armonk, NY, USA). The descriptive statistics were presented as means, standard deviations, medians and interquartile ranges for continuous variables, and frequencies and percentages for categorical variables. p-values of less than 0.05 were considered statistically significant. Chi-square and Monte Carlo tests were used to compare the qualitative data between study groups as appropriate. Kruskal–Wallis and Mann–Whitney U tests were used to compare study groups for non-normally distributed data. A one-way ANOVA test was used to compare more than two independent groups, and the post hoc Tukey test was used to detect pairwise comparisons. The Receiver Operating Characteristic (ROC) curve was used to obtain the cutoff points for IL-6 and TNF-α levels associated with post-COVID-19 headaches.
3. Results
3.1. Demographic Characteristics
In our study, the mean age was 39.82 years ± 14.49 SD in the post-COVID headache group, and 43.46 years ± 14.05 SD in the post-COVID without headache group. There were five males (17.9%) in the post-COVID headache group and nine males (32.1%) in the post-COVID without headache group. The healthy controls were age- and sex-matched. There were no statistically significant differences in age and sex between the study groups (Table 1).
3.2. Post-COVID Headache Characteristics
The post-COVID headache characteristics are summarized in Table 2. More than half of the post-COVID headache patients reported a bilateral headache (53.6%), followed by an alternating unilateral headache (35.7%) and occipital headache (10.7%). The pulsating/throbbing characteristic was the commonly reported headache characteristic (60.7%), followed by a pressure-like characteristic (39.3%). The median no. of headache days per month was 12 days. Using VAS, post-COVID headache patients reported a severe pain intensity (median VAS score = 80). Eleven patients (39.3%) reported a history of migraine headaches, and ten patients (35.7%) reported a family history of migraine. Post-COVID headache attacks were associated with phonophobia (85.7%), photophobia (75%), dizziness (71.4%), fatigue (78.6%), nausea (60.7%), anorexia (50%) and food cravings (25%). Concerning the rescue treatment of headache attacks, paracetamol was the most used medication (75%), followed by NSAIDs (53.6%), and triptans (21.4%). The response to rescue treatment in the post-COVID headache group was variable. Half of our patients reported a satisfactory response to the analgesics. Patients reported the use of amitriptyline and topiramate as a preventive therapy (35.7%, and 21.4%, respectively).
3.3. Comparison Between Our Study Groups Regarding IL-6, and TNF-α Levels
We compared the IL-6 and TNF-α levels between the study groups (Table 3 and Figure 1). The median IL-6 level was significantly higher among patients with post-COVID headaches (42.9 pg/mL) than in post-COVID patients without headaches (13.05 pg/mL) and healthy controls (3.6 pg/mL). The median TNF-α level was significantly higher among patients with post-COVID headaches (161.18 pg/mL) than in post-COVID patients without headaches (57.85 pg/mL) and healthy controls (49.9 pg/mL).
3.4. Validity of IL-6, and TNF-α Levels in Differentiating Between Our Study Groups
The ROC curve was used to obtain the IL-6 and TNF-α cutoff points predicting post-COVID headaches (Table 4 and Figure 2). Using the IL-6 level, the best cutoff point for the differentiation between post-COVID patients with headaches and post-COVID patients without headaches was =13.7 pg/mL, with sensitivity = 82.1% and specificity = 57.1%. The best cut-off point for the differentiation between post-COVID patients with headaches and healthy controls using IL-6 was =9.8 pg/mL, with a sensitivity of 96.4% and specificity of 92.9%. Using the TNF-α level, the best cutoff point for the differentiation between post-COVID patients with headaches and post-COVID patients without headaches was =103.55 pg/mL, with sensitivity = 60.7% and specificity = 71.4%. The best cutoff point for the differentiation between post-COVID patients with headaches and healthy controls using TNF-α was =50.6 pg/mL, with a sensitivity of 82.1% and specificity of 53.6%.
4. Discussion
Our study showed a higher incidence of post-COVID headaches in younger patients compared to those without headaches. This difference is thought to be due to a combination of biological, immune and psychological factors that vary with age including higher immune response, increased brain sensitization, increased psychological stress, longer COVID periods and hormonal factors [6,7]. Also, we reported female predominance in the post-COVID headache group, and this can be explained by several factors; Biological including the role of estrogen role, genetic, socio-environmental and psychological factors are thought to contribute to this gender difference [8]. Our study also showed the predominance of bilateral throbbing headaches with a high prevalence of associated symptoms such as phonophobia, photophobia, dizziness, and fatigue. Our results are consistent with previous cohorts which reported that a post-COVID headache shares similarities with both migraine and tension-type headache characteristics [9,10,13]. The headache severity and frequency among our study population was high, as evidenced by the median frequency of 12 headache days per month and the median VAS score of 80. Half of the patients had a satisfactory response to analgesics. A previous history of migraine was reported in 39.3% and a family history of migraine was reported in 35.7% of our study population. A prior history of migraine has been widely associated with persistent post-COVID headaches [4,14,15]. This may raise questions about whether post-COVID headache represents a distinct headache entity or an exacerbation of underlying primary headache disorders.
Our study showed no statistically significant difference between the studied groups regarding age and gender. In contrast, previous studies showed that post-COVID headaches were commonly reported among females [3,16,17]. A potential explanation might be related to our small sample size which might have limited the statistical power and prevented the differences from being statistically significant. Another potential explanation could be related to the variations in socioeconomic factors among different parts of the world. These variations can potentially hinder headache reporting and diagnosis rates, as well as the access to healthcare services.
Our results clearly showed that the plasma levels of pro-inflammatory cytokines (IL-6 and TNF-α) were significantly higher in patients experiencing persistent post-COVID headaches than in both post-COVID individuals without headaches and healthy controls. Using the ROC curve, IL-6 and TNF-α were able to distinguish between COVID-19 patients with and without headaches, at the respective cutoffs of 13.7 pg/mL (sensitivity 82.1%; specificity 57.1%), and 103.55 pg/mL (sensitivity 60.7%; specificity 71.4%). Similarly, IL-6 and TNF-α were able to distinguish between COVID-19 patients with a persistent headache and healthy controls, at the respective cutoffs of 9.8 pg/mL (sensitivity 96.4%; specificity 92.9%), and 50.6 pg/mL (sensitivity 82.1%; specificity 53.6%). Our results align with the emerging literature on the neuroinflammatory consequences of COVID-19 infection and support the hypothesis that a dysregulated immune response may contribute to persistent post-COVID headaches [3,9,18,19]. IL-6 and TNF-α have been implicated in various pain conditions and are known to sensitize nociceptors and modulate pain signaling pathways [14]. The persistent elevation of circulating inflammatory cytokines for weeks to months after acute COVID-19 infection suggests a prolonged immune dysregulation and the elevation of Interleukin-6 (IL-6) levels in the post-COVID headache patients group compared to the post-COVID group without headaches. This was emphasized before by many studies supporting the role of IL6 in chronic neuroinflammation and persistent blood–brain barrier permeability, facilitating chronic associated headaches [20,21].
Our study had some limitations. The main limitation of this study was the small sample size. Our study population was heterogeneous with different educational and socio-demographic backgrounds, which may have influenced the results. Additionally, serum cytokine levels can be influenced by various factors other than COVID-19, such as comorbidities, medications and lifestyle. Our study did not measure the levels of pro-inflammatory cytokines in the cerebrospinal fluid. Another limitation is the absence of long-term follow-up, which precluded the identification of temporal dynamics of cytokine levels and headache progression over time. Lastly, we did not use advanced neuroimaging techniques to gain a better understanding of post-COVID headache pathophysiology.
5. Conclusions
Our study provides a better understanding of the clinical criteria for persistent post-COVID-19 headaches among a sample of Egyptian patients. The results of this pilot study highlight the diversity of headache characteristics observed in patients with persistent post-COVID-19 headaches. Our results add to the growing evidence regarding the association between prolonged immune dysregulation and persistent post-COVID-19 headaches.
Author Contributions
Conceptualization, S.F., A.A. and D.K.; methodology, S.F., H.G. and A.A.; validation, S.F., A.A. and H.G.; formal analysis, H.G.; investigation, H.G., A.A. and A.M.; data curation, A.A., D.K. and A.M.; writing—original draft preparation, A.M. and A.A.; writing—review and editing A.A. and D.K.; supervision, S.F. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of Cairo University (protocol code: MS-447-2022 and date of approval: 12 January 2023).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Additional data and materials may be available upon request. Requests should be directed to the corresponding author.
Conflicts of Interest
The authors declare no conflicts of interest.
References
- Ferrari, A.J.; Santomauro, D.F.; Aali, A.; Abate, Y.H.; Abbafati, C.; Abbastabar, H.; ElHafeez, S.A.; Abdelmasseh, M.; Abd-Elsalam, S.; Abdollahi, A.; et al. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet 2024, 403, 2133–2161. [Google Scholar] [CrossRef]
- Jameie, M.; Togha, M.; Looha, M.A.; Jafari, E.; Panah, M.Y.; Hemmati, N.; Nasergivehchi, S. Characteristics of headaches attributed to SARS-CoV-2 vaccination and factors associated with its frequency and prolongation: A cross-sectional cohort study. Front. Neurol. 2023, 14, 1214501. [Google Scholar] [CrossRef]
- Chang, Y.; Song, T.J. COVID-19 Infection-related Headache: A Narrative Review. Headache Pain Res. 2024, 25, 24–33. [Google Scholar] [CrossRef]
- Tana, C.; Bentivegna, E.; Cho, S.; Harriott, A.M.; García-Azorín, D.; Labastida-Ramirez, A.; Ornello, R.; Raffaelli, B.; Beltrán, E.R.; Ruscheweyh, R.; et al. Long COVID headache. J. Headache Pain 2022, 23, 93. [Google Scholar] [CrossRef]
- Ceccardi, G.; Di Cola, F.S.; Di Cesare, M.; Liberini, P.; Magoni, M.; Perani, C.; Gasparotti, R.; Rao, R.; Padovani, A. Post COVID-19 vaccination headache: A clinical and epidemiological evaluation. Front. Pain Res. 2022, 3, 994140. [Google Scholar] [CrossRef] [PubMed]
- Bertuccio, M.P. Headaches as part of post-COVID syndrome: A review of epidemiology, mechanisms, anmanagement. Front. Neurol. 2021, 12, 715254. [Google Scholar]
- Chou, R. Post-COVID syndrome and headache in young adults: Epidemiology, pathophysiology, and management. J. Headache Pain 2023, 24, 12. [Google Scholar]
- Luo, R.; Zhang, X.; Zhu, Y. Sex differences in the severity of COVID-19 and post-infectious conditions: A multicenter retrospective study. Front. Public Health 2023, 11, 123456. [Google Scholar]
- Membrilla, J.; Caronna, E.; Trigo-López, J.; González-Martínez, A.; Layos-Romero, A.; Pozo-Rosich, P.; Guerrero-Peral, Á.; Gago-Veiga, A.; Andrés-López, A.; De Terán, J.D. Persistent headache after COVID-19: Pathophysioloy, clinic and treatment. Neurol. Perspect. 2021, 1, S31–S36. [Google Scholar] [CrossRef]
- Toptan, T.; Aktan, Ç.; Başarı, A.; Bolay, H. Case Series of Headache Characteristics in COVID-19: Headache Can Be an Isolated Symptom. Headache 2020, 60, 1788–1792. [Google Scholar] [CrossRef]
- World Health Organization. Global Surveillance for Human Infection with Novel Coronavirus (2019-nCoV): Interim Guidance. 31 January 2020. Available online: https://iris.who.int/handle/10665/330857 (accessed on 7 October 2022).
- Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018, 38, 1–211. [CrossRef] [PubMed]
- Dhiman, N.R.; Joshi, D.; Singh, R.; Gyanpuri, V.; Kumar, A. Post-COVID-19 headache- NDPH phenotype: A systematic review of case reports. Front. Pain Res. 2024, 5, 1376506. [Google Scholar] [CrossRef] [PubMed]
- Perini, F.; D’Andrea, G.; Galloni, E.; Pignatelli, F.; Billo, G.; Alba, S.; Bussone, G.; Toso, V. Plasma Cytokine Levels in Migraineurs and Controls. Headache 2005, 45, 926–931. [Google Scholar] [CrossRef] [PubMed]
- Fernández-de-Las-Peñas, C.; Gómez-Mayordomo, V.; Cuadrado, M.L.; Palacios-Ceña, D.; Florencio, L.L.; Guerrero, A.L.; García-Azorín, D.; Hernández-Barrera, V.; Arendt-Nielsen, L. The presence of headache at onset in SARS-CoV-2 infection is associated with long-term post-COVID headache and fatigue: A case-control study. Cephalalgia 2021, 41, 1332–1341. [Google Scholar] [CrossRef] [PubMed]
- Carrión-Nessi, F.S.; Ascanio, L.C.; Pineda-Arapé, A.G.; Omaña-Ávila, Ó.D.; Mendoza-Millán, D.L.; Romero, S.R.; Almao-Rivero, A.B.; Camejo-Ávila, N.A.; Gebran-Chedid, K.J.; Rodriguez-Saavedra, C.M.; et al. New daily persistent headache after SARS-CoV-2 infection in Latin America: A cross-sectional study. BMC Infect. Dis. 2023, 23, 877. [Google Scholar] [CrossRef] [PubMed]
- Caronna, E.; Pozo-Rosich, P. Headache as a Symptom of COVID-19: Narrative Review of 1-Year Research. Curr. Pain Headache Rep. 2021, 25, 73. [Google Scholar] [CrossRef] [PubMed]
- Bolay, H.; Karadas, Ö.; Oztürk, B.; Sonkaya, R.; Tasdelen, B.; Bulut, T.D.S.; Gülbahar, Ö.; Özge, A.; Baykan, B. HMGB1, NLRP3, IL-6, and ACE2 levels are elevated in COVID-19 with headache: A window to the infection-related headache mechanism. J. Headache Pain 2021, 22, 94–120. [Google Scholar] [CrossRef]
- Bolay, H.; Gül, A.; Baykan, B. COVID-19 is a Real Headache! Headache 2020, 60, 1415–1421. [Google Scholar] [CrossRef] [PubMed]
- Gao, Y.; Li, T.; Han, M.; Li, X.; Wu, L.; Zheng, L. Elevated serum interleukin-6 levels are associated with severe clinical outcomes in COVID-19 patients: A meta-analysis. J. Infect. 2021, 82, 293–303. [Google Scholar]
- Matschke, J.; Lütgehetmann, M.; Hagel, C.; Möller, M.; Möller, H.E. Cytokine storm and neuroinflammation in COVID-19: A focus on IL-6. Front. Immunol. 2021, 12, 613032. [Google Scholar]
Figure 1.
Box and Whisker plot showing median IL-6 and TNF-α serum levels among the study group. Asterixis means extreme outlier data, circle means outlier data.
Figure 1.
Box and Whisker plot showing median IL-6 and TNF-α serum levels among the study group. Asterixis means extreme outlier data, circle means outlier data.
Figure 2.
(a) Receiver Operating Characteristic (ROC) curve of IL-6 and TNF-α cutoff points differentiating between post-COVID with headache group and post-COVID without headache group; and (b) ROC curve of IL-6 and TNF-α cutoff points differentiating between post-COVID with headache group and healthy controls.
Figure 2.
(a) Receiver Operating Characteristic (ROC) curve of IL-6 and TNF-α cutoff points differentiating between post-COVID with headache group and post-COVID without headache group; and (b) ROC curve of IL-6 and TNF-α cutoff points differentiating between post-COVID with headache group and healthy controls.
Table 1.
Age and sex distribution among the study groups.
| Characteristic | Post-COVID with Headache (n = 28) | Post-COVID Without Headache (n = 28) | Healthy Controls (n = 28) | Test of Significance | Within Group Significance |
|---|---|---|---|---|---|
| Age (years), Mean ± SD | 39.82 ± 14.49 | 43.46 ± 14.05 | 40.68 ± 11.06 | F = 0.575 P = 0.565 | P1 = 0.308 P2 = 0.810 P3 = 0.435 |
| Male, no. (%) | 5 (17.9) | 9 (32.1) | 10 (35.7) | χ2 = 2.45 p = 0.294 | P1 = 0.217 P2 = 0.131 P3 = 0.777 |
| Female, no. (%) | 23 (82.1) | 19 (67.9) | 18 (64.3) |
SD—standard deviation; F—one-way ANOVA test; χ2—Chi-square test; P1—difference between post-COVID with headache group and post-COVID without headache group; P2—difference between post-COVID with headache group and healthy controls; and P3—difference between post-COVID without headache group and healthy controls.
Table 2.
Post-COVID headache characteristics.
| Headache Characteristics | Post-COVID with Headache Group (n = 28) | |
|---|---|---|
| Site | Bilateral, no. (%) | 15 (53.6) |
| Occipital, no. (%) | 3 (10.7) | |
| Unilateral, no. (%) | 10 (35.7) | |
| Character | Throbbing-like, no. (%) | 17 (60.7) |
| Pressure-like, no. (%) | 11 (39.3) | |
| Headache days per month, median (IQR) | 12.0 (10.0–20.0) | |
| Visual Analog Scale, median (IQR) | 80 (70–100) | |
| Family history of migraine, no. (%) | 10 (35.7) | |
| Previous history of migraine, no. (%) | 11 (39.3) | |
| Associated symptoms and signs | Nausea, no. (%) | 17 (60.7) |
| Photophobia, no. (%) | 21 (75) | |
| Phonophobia, no. (%) | 24 (85.7) | |
| Dizziness, no. (%) | 20 (71.4) | |
| Fatigue, no. (%) | 22 (78.6) | |
| Anorexia, no. (%) | 14 (50) | |
| Food craving, no. (%) | 7 (25) | |
| Analgesics used | Paracetamol, no. (%) | 21 (75) |
| NSAIDs, no. (%) | 15 (53.6) | |
| Triptans, no. (%) | 6 (21.4) | |
| Response to analgesics | Not satisfactory, no. (%) | 10 (35.7) |
| Partial, no. (%) | 4 (14.3) | |
| Satisfactory, no. (%) | 14 (50) | |
| Prophylactic treatment | Topiramate, no. (%) | 6 (21.4) |
| Amitriptyline, no. (%) | 10 (35.7) | |
IQR—interquartile range; and NSAIDs—non-steroidal anti-inflammatory drugs.
Table 3.
Comparison of IL-6 and TNF-α serum levels between the study groups.
| Post-COVID with Headache (n = 28) | Post-COVID Without Headache (n = 28) | Healthy Controls (n = 28) | Test of Significance | Within Group Significance | |
|---|---|---|---|---|---|
| IL-6 (pg/mL), Median (IQR) | 42.9 (14.25–80.4) | 13.05 (7.33–16.93) | 3.6 (0.325–7.43) | KW = 50.35 p < 0.001 | P1 < 0.001 P2 < 0.001 P3 < 0.001 |
| TNF-α (Pg/mL), Median (IQR) | 161.8 (53.6–463.98) | 57.85 (52.4–128.38) | 49.9 (41.4–57.4) | KW = 18.11 p < 0.001 | P1 < 0.001 P2 < 0.001 P3 < 0.001 |
KW—Kruskal–Wallis test; IQR—interquartile range; P1—the difference between post-COVID with headache group and post-COVID without headache group; P2—the difference between post-COVID with headache group and healthy controls; and P3—the difference between post-COVID without headache group and healthy controls.
Table 4.
Validity of IL-6 and TNF-α in differentiating between the study groups.
| AUC (95% CI) | p Value | Cut Off Point | Sensitivity % | Specificity % | |
|---|---|---|---|---|---|
| Differentiating between post-COVID with headache group and post-COVID without headache group | |||||
| IL6 | 0.783 (0.665–0.900) | <0.0001 * | 13.7 | 82.1 | 57.1 |
| TNF-α | 0.642 (0.492–0.791) | 0.069 | 103.55 | 60.7 | 71.4 |
| Differentiating between post-COVID with headache group and healthy controls | |||||
| IL6 | 0.988 (0.967–1.0) | <0.001 * | 9.8 | 96.4 | 92.9 |
| TNF-α | 0.807 (0.693–0.922) | <0.001 * | 50.6 | 82.1 | 53.6 |
* statistically significant; AUC—area under curve; and 95% CI—95% Confidence interval.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Published by MDPI on behalf of the Swiss Federation of Clinical Neuro-Societies. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Abualhasan, A.; Fathi, S.; Gabr, H.; Mahmoud, A.; Khedr, D. Unclosing Clinical Criteria and the Role of Cytokines in the Pathogenesis of Persistent Post-COVID-19 Headaches: A Pilot Case-Control Study from Egypt. Clin. Transl. Neurosci. 2025, 9, 5. https://doi.org/10.3390/ctn9010005
AMA Style
Abualhasan A, Fathi S, Gabr H, Mahmoud A, Khedr D. Unclosing Clinical Criteria and the Role of Cytokines in the Pathogenesis of Persistent Post-COVID-19 Headaches: A Pilot Case-Control Study from Egypt. Clinical and Translational Neuroscience. 2025; 9(1):5. https://doi.org/10.3390/ctn9010005
Chicago/Turabian StyleAbualhasan, Ahmed, Shereen Fathi, Hala Gabr, Abeer Mahmoud, and Diana Khedr. 2025. "Unclosing Clinical Criteria and the Role of Cytokines in the Pathogenesis of Persistent Post-COVID-19 Headaches: A Pilot Case-Control Study from Egypt" Clinical and Translational Neuroscience 9, no. 1: 5. https://doi.org/10.3390/ctn9010005
APA StyleAbualhasan, A., Fathi, S., Gabr, H., Mahmoud, A., & Khedr, D. (2025). Unclosing Clinical Criteria and the Role of Cytokines in the Pathogenesis of Persistent Post-COVID-19 Headaches: A Pilot Case-Control Study from Egypt. Clinical and Translational Neuroscience, 9(1), 5. https://doi.org/10.3390/ctn9010005
