In the present study, we compared, for the first time, the cytokine profile between patients with and without headache during COVID-19 infection. In this pilot study, we analysed 45 different cytokines and interleukins. The main finding of our study was that IL-10 levels were significantly higher in patients with headache while other interleukins, such as IL-23 and PIGF1, also showed a trend to be higher in this group.
Our results should be interpreted with caution. In ideal conditions, considering that COVID-19 is a dynamic disease, the analytic parameters should have been obtained in the same stage of disease, and after the same time since the onset of the clinical symptoms. However, in order to make this study reproducible and with clinical relevance and practical utility, the samples were collected in the first extraction after the hospital admission. We tried to minimize this problem by statistically adjusting for days of evolution of the symptoms, but this adjustment subtracted statistical power to the study. Besides, this was an exploratory study and instead of testing a single hypothesis, a high number of different cytokines were studied.
Despite the cytokine storm have been hypothesized as one of the possible mechanisms underlying headache in in COVID-19 patients (14), few previous studies had analysed the relationship between cytokines levels and headache. To date, only IL-6 levels have been studied in COVID-19 patients with and without headache, in retrospective studies with contradictory results (6, 15). Studies addressing differences in other interleukins were still lacking in the literature.
Our findings could support the hypothesis of a cytokine mediated mechanism underlying headache in COVID-19. The relationship between cytokines and headache have been studied for a long time (16). The external administration of different cytokines, such as TNF, INF alfa, INF beta, INF gamma or IL-2, causes headache and toxicity in humans (17, 18). In addition, several studies have found relationship between primary headaches and elevated levels of cytokines. Regarding migraine, although there are discrepancies in literature, probably as a consequence of different patterns of sample collection relative to the time of attack (19), elevated serum levels of TNF a, IL-1b, IL-6, GM-CSF and IL-10 have been found during attacks and in attack free intervals (20–24). Tension type headache also have been associated with elevated levels of IL-6 o IL-8 (25, 26). Finally, in the case of systemic infections, cytokine cascade is thought to be the primary mechanism of headache and other accompanied symptoms, as fatigue, anorexia or nausea (12, 27).
Several studies have suggested a main role of the cytokine storm in the evolution of COVID19 illness (9, 10, 28). This supports the idea of this mechanism as the cause of headache, compared to other suggested hypotheses such as direct viral invasion of the central nervous system, hypoxia or dehydration (14). In addition, the clinical similarities between COVID-19 and headache associated to viral systemic infections are in this line (7).
Pain secondary to cytokine relapse is thought to be secondary to the activating of nociceptive sensory neurons and the nerve injury or inflammation by proinflammatory cytokines inducing central sensibilization (29). However, in our study we found elevated levels of IL-10, an anti-inflammatory cytokine with a major role in mitigating inflammation through the ability to inhibit synthesis of non-specific proinflammatory cytokines such as IL-1, IL-6, TNF (30), In view of its anti-inflammatory properties, the IL-10 elevated levels in our sample may counteract the effect of some cytokines released during acute COVID-19 illness, reflecting a more efficient immunologic response to the virus in patients with headache. This hypothesis could explain the better outcome in COVID19 patients with headache, compared with those patients without headache, observed in previous studies (4, 15).
Finally, if our findings are confirmed by further studies, they might have relevant implications. During SARS-COV2 pandemic the attribution of a central role of the cytokine storm in COVID-19 pathophysiology led to different therapeutic approaches targeting the pro-inflammatory body state (31) or different cytokines (32, 33). In the same way, knowing the physiopathology of COVID-19 headache and which inflammatory factors are more implicated, could be helpful in the search of targeting therapies for persistent or treatment resistant headache in COVID-19 patients.
This study has important limitations. As previously mentioned, the analytic parameters were obtained in the same first day of hospitalization, but in different moments of the disease, which may reflect different inflammatory stages. On the other hand, the sample size was small, which limited the power of the study. The sample only included hospitalized patients, which could imply a selection bias. Finally, there are some statistical issues, as the large number of parameters that were compared which could difficult us to detect differences between the two groups. Despite these limitations, we consider that this pilot study may be helpful for the design of future validation studies.