Original Article Cephalalgia 2020, Vol. 40(13) 1410–1421 Headache: A striking prodromal and ! International Headache Society 2020 persistent symptom, predictive of Article reuse guidelines: sagepub.com/journals-permissions COVID-19 clinical evolution DOI: 10.1177/0333102420965157 journals.sagepub.com/home/cep Edoardo Caronna1,2 , Alejandro Ballv e1, Arnau Llaurad o1, e Gallardo2, Diana Marıa Ariton1, Sofia Lallana1, Victor Jos Samuel L opez Maza1, Marta Olive Gadea1, Laura Quibus1, Juan Luis Restrepo1 , Marc Rodrigo-Gisbert1, Andreu Vilaseca1, Manuel Hernandez Gonzalez3, Monica Martinez Gallo3, Alicia Alpuente1,2, Marta Torres-Ferrus1,2, Ricard Pujol Borrell3, e Alvarez-Sabin1 and Patricia Pozo-Rosich1,2 Jos Abstract Objective: To define headache characteristics and evolution in relation to COVID-19 and its inflammatory response. Methods: This is a prospective study, comparing clinical data and inflammatory biomarkers of COVID-19 patients with and without headache, recruited at the Emergency Room. We compared baseline with 6-week follow-up to evaluate disease evolution. Results: Of 130 patients, 74.6% (97/130) had headache. In all, 24.7% (24/97) of patients had severe pain with migraine- like features. Patients with headache had more anosmia/ageusia (54.6% vs. 18.2%; p < 0.0001). Clinical duration of COVID-19 was shorter in the headache group (23.9  11.6 vs. 31.2  12.0 days; p ¼ 0.028). In the headache group, IL-6 levels were lower at the ER (22.9 (57.5) vs. 57.0 (78.6) pg/mL; p ¼ 0.036) and more stable during hospitalisation. After 6 weeks, of 74 followed-up patients with headache, 37.8% (28/74) had ongoing headache. Of these, 50% (14/28) had no previous headache history. Headache was the prodromal symptom of COVID-19 in 21.4% (6/28) of patients with persistent headache (p ¼ 0.010). Conclusions: Headache associated with COVID-19 is a frequent symptom, predictive of a shorter COVID-19 clinical course. Disabling headache can persist after COVID-19 resolution. Pathophysiologically, its migraine-like features may reflect an activation of the trigeminovascular system by inflammation or direct involvement of SARS-CoV-2, a hypothesis supported by concomitant anosmia. Keywords Headache, COVID-19, SARS-CoV-2, prognosis, loss of smell Date received: 12 June 2020; revised: 10 August 2020; 31 August 2020; accepted: 1 September 2020 1 Neurology Department, Hospital Universitari Vall d’Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain 2 Headache and Neurological Pain Research Group, Vall d’Hebron Introduction Research Institute, Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain The global pandemic caused by the Severe Acute 3 Immunology Department, Hospital Universitari Vall d’Hebron, Vall Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) is d’Hebron Research Institute, Barcelona, Spain putting our healthcare systems at stake. COVID-19 is the infectious disease caused by this viral pathogen, and Corresponding author: Patricia Pozo-Rosich, Headache Unit, Neurology Department, Hospital which can lead, in some patients, to respiratory failure Universitari Vall d’Hebron, Passeig de la Vall d’Hebron 119-129, 08035 amongst other severe symptoms, requiring urgent medical Barcelona, Spain. aid. In Spain, COVID-19 had been diagnosed in as many Email: ppozo@vhebron.net Caronna et al. 1411 as 200,210 people by 19 April 2020 (1), forcing hospitals to headache at any time during COVID-19, we collected reorganise in a profound, quick way. Specifically, neurol- the date of onset and cessation in relation to other ogists have been attending COVID-19 patients at the COVID-19 symptoms as well as headache character- emergency room (ER), which has enabled them to observe istics. Headache pain severity was defined as mild if the presence of neurological symptoms associated with patients considered that, in the absence of other COVID-19 otherwise not analysed in detail. At the ER, COVID-19 symptoms, headache alone would allow severe, difficult-to-treat headache, together with anosmia them to carry on with their daily activities as usual; and ageusia, has been a major initial neurological com- moderate if they had to reduce their daily activities, plaint. Despite the fact that the Centres for Disease and severe if they had to stop doing any kind of task. Control and Prevention (2) include headache as one of In our hospital, according to the COVID-19 ER the main symptoms of COVID-19, a better definition of protocol, we recorded vital signs and performed a headache itself is lacking and no data on its evolution are physical examination and a chest X-ray to rule out available at present. Moreover, it is unknown whether pneumonia. At the ER, patients with COVID-19 symp- headache may represent a relevant clinical symptom, pre- toms but with normal vital signs, negative X-ray and dicting the course of COVID-19 itself, a fact that could normal physical examination could be immediately dis- guide clinicians in their evaluations of COVID-19 patients charged without undergoing nasopharyngeal swabs to in future waves of the pandemic. confirm SARS-CoV-2 infection. In all other cases, “Headache attributed to systemic viral infection” is patients were admitted for further testing and/or included in the International Classification of treatment, including a real-time reverse transcriptase Headache Disorders third edition (ICHD-3) (3) and, polymerase -chain reaction (RT-PCR) assay by naso- although commonly reported (4), specific data are lack- pharyngeal swabs to confirm SARS-Cov-2 and blood ing. COVID-19 gives the opportunity to define its testing with inflammatory markers (C-reactive protein– headache characteristics, which until now have CRP: 0.03–0.50 mg/dL; interleukin-6-IL-6: 0–4.3 pg/ mainly been described in terms of prevalence, with dis- mL; ferritin: 25–250 ng/mL; Lactate Dehydrogenase– crepant results, the prevalence in studies based on clin- LDH: 0–248 UI/L; D-dimer: 0–243 ng/mL). In hospi- ical charts review in China (8–23%) (5–8) or Spain talised patients, we recorded treatment administered, (14.1%) (9) being substantially different from presence of other medical complications, hospital and interview-based cross-sectional study (70%) (10). intensive care unit (ICU) length of stay and mortality, As studies related to headache associated with viral by periodically revising electronic medical charts. Then, infections are lacking, and COVID-19 is clearly associ- we analysed all data, described the cohort of patients ated with headache, we decided to define and describe with headache associated with COVID-19, and com- headache characteristics and evolution in relation to pared them with those not having headache. COVID-19, focusing on it as a possible prognostic After 6 weeks from admission, we followed up factor. Moreover, we decided to correlate the presence patients by phone call to evaluate persistence of head- of headache with systemic inflammatory responses and ache and its characteristics as well as other COVID-19 hypothesise about its pathophysiological mechanisms. symptoms through a structured survey. Then, we com- pared baseline and post-6-week data. Methods To define prognosis in our cohort, we used these variables: COVID-19 disease duration, defined as the This is a prospective study conducted in a Spanish ter- number of days between the onset of the first and the tiary hospital in Barcelona (Vall d’Hebron Hospital). resolution of the last COVID-19 symptom, hospital During the COVID-19 pandemic, neurologists length of stay, and all-cause in-hospital mortality. started working 24/7 at the ER as general clinicians. They recruited, during a 3-week period (28 March to 22 April 2020), all the consecutive patients with Statistical analysis COVID-19 symptoms attended by them (ER patients We obtained descriptive and frequency statistics and were assigned randomly by triage to clinicians to be made comparisons using the SPSS, version 21.0 for visited), including only those who could give consent Windows. We reported nominal (categorical) variables and undergo a full interview. COVID-19 symptoms as frequencies (percentages), and continuous variables were pre-specified for all neurologists and were based as mean  standard deviation (age, temperature, CRP on the list of symptoms reported by the World Health and LDH) or median and interquartile range (IQR) Organization (11). We collected demographic data, (IL-6, D-dimer and ferritin). We checked the normality COVID-19 symptoms, family and personal history of assumption of quantitative variables through visual any headache (ICHD-3) (3), categorising patients as methods (Q-Q plots) and normality tests episodic or chronic. If patients had experienced (Kolmogorov-Smirnov test). We assessed statistical 1412 Cephalalgia 40(13) significance for intergroup variables by Pearson’s chi- written informed consent for the analysis of patients’ square when comparing categorical variables. In the data which was collected according to Spanish regula- case of having an expected count of less than 5 in tion on clinical trials. more than 20% of cells in the contingency table, we used Fisher’s exact test. We used linear trend chi- square for ordinal variables, independent t-test for con- Results tinuous variables that followed a normal distribution and the Mann-Whitney U test for the rest of the con- We included 130 adult patients. Table 1 shows their tinuous variables. In order to evaluate the COVID-19 characteristics and all COVID-19 symptoms reported prognosis (COVID-19 disease duration, hospital length at ER. From the 130 patients included, 74.6% (97/130) of stay and mortality) at the follow-up, we used one- had experienced headache as a COVID-19 symptom, way analysis of covariance (ANCOVA), adjusted for while the other 33 did not. the effect of age and gender, for the group with and without headache. The false discovery rate (FDR) with Table 1. Clinical characteristics of COVID-19 patients at ER. Benjamini-Hochberg procedure was used to correct p- Demographic characteristics (n ¼ 130) values for multiple comparisons. Finally, we studied the role of inflammatory bio- Sex, n (%) markers and fever (37.5 C) in a subgroup of patients Male 64 (49.2) with ongoing headache at the ER and an equally age/ Female 66 (50.8) Age (years), n (%) gender matched group without headache in order to Mean (SD) 53.9 (16.4) avoid biased results. We also conducted a longitudinal <34 16 (12.3) data analysis in order to model the inflammatory bio- 35–44 23 (17.7) marker changes over the course of COVID-19 between 45–54 30 (23.1) patients with and without headache. We only selected 55–64 25 (19.2) hospitalised patients with at least three available blood 65 36 (27.7) tests that had been done at the same timepoints in the COVID-19 characteristics course of COVID-19 disease, starting from the onset of Reported symptoms at ER, n (%) Headache 97 (74.6) their COVID-19 symptoms. Longitudinal analysis was Fever 115 (88.5) performed using linear mixed-effects models fitted by Malaise 60 (46.2) maximum likelihood and adjusted by age. Models were Myalgia 39 (30.0) computed using the nlme (v3.1-144) package from R. Dizziness 19 (14.6) We did not conduct a statistical power calculation Cough 105 (80.2) prior to the study because the sample size was based on Dyspnea 81 (62.3) the available data. Missing values were imputed using Chest pain 4 (3.0) the MICE (Multivariate Imputation via Chained Expectoration 19 (14.6) Equations) package from R (v3.8.0) (12). Concerning Odynophagia 12 (9.2) Loss of smell/taste 59 (45.4) missing values, there was <5% of missingness in nom- Diarrhea 36 (27.7) inal variables (headache localisation, quality of pain, Radiological findings at ER, n (%) and pain severity). Hence, we used a Bayesian Pneumonia 103 (79.2) polytomous regression as a method of imputation for Bilateral pneumonia 77 (59.2) headache localisation and quality of pain and a pro- COVID-19 Confirmation (positive RT-PCR), n (%) 89 (68.5) portional odds model for headache pain severity. The Hospitalisation, n (%) 104 (80.0) missingness in continuous variables (temperature, Vital signs and inflammatory markers at the ER CRP, IL-6, D-dimer, ferritin, LDH) was rated between O2 requirements, n (%) 31 (23.8) 2% (temperature) to 18% (LDH). In that case, we used Fever, n (%) 45 (34.6) Lymphopenia, n (%) 70 (53.8) random forest imputations in order to estimate these CRP, mean  SD, mg/ml 9.3  8.4 values according to their other variables. IL-6, median (IQR), pg/ml 34.0 (62.1) p-values presented are for a two-tailed test and we D-dimer, median (IQR), ng/ml 231.0 (243) considered p-values < 0.05 statistically significant. Ferritin, median (IQR), ng/ml 354.0 (406) LDH, mean  SD, UI/L 369.4  221.4 Ethics approval and patients’ consent ER: Emergency room; SD: standard deviation; IQR: interquartile range; ICU: intensive care unit; RT-PCR: real-time reverse transcriptase poly- The study was approved by the Vall d’Hebron Ethics merase-chain reaction; O2: oxygen; lymphopenia (<1.0  109/L); Committee (PR(AG)227/2020). All patients gave CRP: C-reactive protein; IL-6: interleukin-6; LDH: lactate dehydrogenase. Caronna et al. 1413 Headache and COVID-19 at ER COVID-19 evolution: Headache as a In our cohort of headache patients, 57.7% (56/97) were prognostic factor female, the mean age was 50.6  15.3 years old and Of 130 patients, 80.0% (104/130) were hospitalised 19.6% (19/97) had a personal history of episodic after ER evaluation. In all hospitalised patients, we migraine. No patients had a history of chronic could follow their clinical course by electronic chart migraine. Headache-associated symptoms reported by and observed that 8.5% (11/130) required ICU. patients were nausea and vomiting (25/97), worsening Mortality was 3.1% (4/130, one patient belonging to with movement (12/97) photo/phonophobia (10/97), the headache group and three to the group without vertigo (4/97) and subjective neck stiffness (3/97). headache). We did not detect new onset headaches Specific headache features are reported in Figure 1. through chart review during hospitalisation. At the ER, the neurological examination together After 6 weeks, we could get in touch with 100 with symptoms evaluation, performed by neurologists, patients of our cohort (74 with headache and 26 with- ruled out meningitis in all recruited patients with head- out headache) and interviewed them about disease evo- ache. Based on the striking clinical observation of some lution. There were no statistically significant differences patients with severe headache at ER, we compared with regard to the demographic variables in patients patients with severe headache (24/97) with the ones that were not followed up. with mild-moderate pain (73/97), specifically analysing From these, 27.0% (27/100) was still experiencing migraine-like features (Table 2). at least one symptom of COVID-19 other than Then, comparing patients with or without headache, headache. Those without any more symptoms of we observed that the first group were younger (50.6  COVID-19 had a mean duration of disease of 25.8  15.3 vs. 63.6  15.7; p < 0.0001), there were more 11.9 days. females (57.7% vs. 30.3%; p ¼ 0.009) and reported Interestingly, comparing patients with and without higher headache history of any type (32.0% vs. headache, for whom data were available at follow-up, 12.1%; p ¼ 0.039). In regards to COVID-19 symptoms, and adjusting for age and gender, we observed shorter the most relevant result was that in the headache group COVID-19 disease duration in the headache group more patients had anosmia/ageusia (54.6% vs. 18.2%; (23.9  11.6 vs. 31.2  12.0 days; p ¼ 0.028). We did p < 0.0001). All other variables are shown in Table 3. not observe any difference in mortality (no mortality Figure 1. Headache associated with COVID-19 characteristics. *Other headache locations reported were frontocervical (6.2%), hemicranial (5.2%) and cervical (4.1%). †Other reported pain qualities were drilling (5.2%), shooting (4.1%) and burning (1.0%). 1414 Cephalalgia 40(13) Table 2. Comparison between patients with severe and mild-moderate headache at ER (n ¼ 97). Severe headache Mild-moderate Adjusted (n ¼ 24) headache (n ¼ 73) p-valuea Demographic characteristics Age (years), mean  SD 44.8  14.9 52.5  15.1 0.049* Sex (female), n (%) 20 (83.3) 36 (49.3) 0.004** History of any type of headache, n (%) 10 (41.7) 21 (28.8) 0.313 History of migraine, n (%) 6 (25.0) 13 (17.8) 0.554 Headache characteristics Onset before another COVID-19 symptom, n (%) 6 (25.0) 3 (4.1) 0.007** Time since headache onset to ER presentation (days), median (IQR) 10.5 (10.0) 6.0 (6.0) 0.002** Holocraneal pain, n (%) 9 (37.5) 28 (38.4) 1.000 Pain quality, n (%) Pressing 11 (45.8) 57 (78.1) 0.004** Throbbing 9 (37.5) 10 (13.7) 0.017* Other migraine features, n (%) Worsening with movement 6 (25.0) 6 (8.2) 0.066 Nausea and vomiting 11 (45.8) 14 (19.2) 0.015* Photo/phonophobia 5 (20.8) 5 (6.8) 0.114 Daily constant pain, n (%) 18 (75.0) 30 (41.1) 0.005** Response to acute treatment, n (%) 9 (37.5) 48 (65.8) 0.018* a Adjusted p-value with Benjamini-Hochberg procedure. *p-value 0.05. **p-value 0.01. ER: Emergency room; SD: standard deviation; IQR: interquartile range. Table 3. Comparison between COVID-19 patients with and without headache at the ER. No headache (n ¼ 33) Headache (n ¼ 97) Adjusted p-valuea Demographic characteristics Age (years), mean  SD 63.6  15.7 50.6  15.3 <0.0001** Sex (female), n (%) 10 (30.3) 56 (57.7) 0.009** History of any type of headache, n (%) 4 (12.1) 31 (32.0) 0.039* History of migraine, n (%) 2 (6.1) 19 (19.6) 0.099 COVID-19 characteristics Reported symptoms at ER, n (%) Fever 28 (84.8) 87 (89.7) 0.529 Malaise 8 (24.2) 52 (53.6) 0.004** Myalgia 7 (21.2) 32 (33.0) 0.272 Dizziness 1 (3.0) 18 (18.6) 0.042* Cough 24 (72.7) 81 (83.5) 0.204 Dyspnea 21 (63.6) 60 (61.9) 1.000 Chest pain 2 (6.1) 1 (1.0) 0.158 Expectoration 1 (3.0) 18 (18.6) 0.042* Odynophagia 1 (3.0) 11 (11.3) 0.294 Loss of smell/taste 6 (18.2) 53 (54.6) <0.0001** Diarrhea 8 (24.2) 28 (28.9) 0.660 Pneumonia 25 (75.8) 78 (80.4) 0.622 Bilateral pneumonia 21 (63.6) 56 (57.7) 0.682 COVID-19 confirmation (RT-PCR), n (%) 23 (69.7) 66 (68.0) 1.000 Hospitalisation, n (%) 27 (81.8) 77 (79.4) 1.000 a Adjusted p-value with Benjamini-Hochberg procedure. *p-value 0.05. **p-value 0.01. ER: Emergency room; RT-PCR: real-time reverse transcriptase polymerase-chain reaction. Caronna et al. 1415 in this subgroup) or hospital length of stay (9.1  9.0 Clinical presentation of headache associated with vs. 10.9  9.0 days; p ¼ 0.854). COVID-19 Headache attributed to COVID-19 is common in both Headache evolution genders and middle-aged people, while patients without After 6 weeks, of the 74 headache patients, 37.8% (28/ headache are older and male. History of headache of 74) still had headache. Those patients whose headache any type is more common in patients presenting head- had stopped had a mean duration of the symptom of ache as a COVID-19 symptom, but not exclusive. 15.4  11.1 days. Then, we analysed patients with Interestingly, the presence of headache in COVID-19 ongoing headache after 6 weeks, observing that 50% is significantly associated with other cranial symptoms, of them (14/28) had never suffered from recurrent anosmia/ageusia. Specifically, these symptoms have headache before. A total of 60.7% of patients (17/28) been frequently reported in case reports of patients had daily constant headache. Response to acute treat- with headache during COVID-19 (13–14). ment was insufficient both at baseline and follow-up, Concerning headache characteristics in COVID-19, without statistically significant differences at the two a recent study conducted in Spain (15) has detected timepoints (32.1% vs. 28.6%; p ¼ 0.701). different phenotypes on the basis of headache features Then, we compared patients with ongoing headache and the presence of personal history of primary head- after 6 weeks with those who were headache free. aches. In our cohort, we observed that in the majority Significant variables associated with persisting head- of patients headache is mild/moderate, while one ache are shown in Table 4. fourth, especially women and younger subjects, have a severe “migraine-like” headache that is not associated Headache related to inflammation and fever with a more personal migraine history. Although head- ache attributed to COVID-19 usually starts with the We selected patients with ongoing headache at the ER, other COVID-19 symptoms, patients with severe pain when vital signs and blood samples were collected, and more often have it as a prodromal symptom. Headache an equally age/gender-matched group without head- as the first COVID-19 symptom has been described in a ache. We included 60 patients, 36 with headache and recent case report (16). 24 without. We observed statistically significantly lower Concerning headache evolution, surprisingly we levels of IL-6 and LDH. We found no differences in observed that one third of followed-up patients had presence of fever at the ER between the two groups. persistent disabling daily headache after 6 weeks, with Other variables are shown in Table 5. poor response to acute treatment and, in more than To specifically analyse the evolution of inflammato- 30%, representing the only symptom left of COVID- ry biomarkers over time, we included 24 patients in this 19. Interestingly, up to 50% of these patients had no sub-analysis: 18 had headache, while six did not. There history of recurrent headache at all, a fact that could were no statistically significant differences either in lead to the onset of a “new daily” headache. Moreover, patients’ age (headache: 56.6  9.8 vs. no-headache: in a relevant number of these cases, headache was an 63.3  6.7 years; p ¼ 0.130) or in gender (female – head- initial prodromal symptom of COVID-19. In our ache: 55.6% vs. no-headache: 66.7%; p ¼ 1.000). Only study, headache was more likely to persist in females IL-6 significantly changed over time between the two and patients with a headache history, although no groups (p ¼ 0.003), observing more stable levels of IL-6 patients had a chronic primary headache before during COVID-19 in patients with headache (Figure 2). COVID-19. Discussion Relevance of assessing headache in COVID-19 for In March 2020, during the COVID-19 pandemic, we prognosis noticed that some patients were complaining of head- As of 13 May 2020, the seroprevalence of antibodies ache while others were not, which made us wonder against COVID-19 in the Spanish population is only why. 5%, making SARS-CoV-2 an ongoing health threat in Our study aimed to first describe the characteristics our country (17). In our study, we observed that, and evolution of headache associated with COVID-19, among patients’ reported COVID-19 symptoms, only to correlate it with the evolution of the disease, and the presence of headache is predictive of better prog- generate a hypothesis on the underlying pathophysio- nosis, in terms of an almost 1-week shorter COVID-19 logical mechanisms, with the final goal of helping clini- disease. Although recent studies (18–19) have shown cians to better understand this symptom and its clinical that anosmia could be useful in detecting COVID-19 relevance. cases, more specifically pointing to SARS-CoV-2 1416 Cephalalgia 40(13) Table 4. Comparison between patients with ongoing headache and with headache resolution during follow-up (n ¼ 76). Ongoing headache Headache resolution Adjusted (n ¼ 28) (n ¼ 46) p-valuea Demographic characteristics Age (years), mean  SD 49.2  15.7 52.5  15.7 0.386 Sex (female), n (%) 23 (82.1) 22 (47.8) 0.004** History of any type of headache, n (%) 14 (50.0) 12 (26.1) 0.047* History of migraine, n (%) 8 (28.6) 8 (17.4) 0.383 COVID-19 characteristics Reported symptoms at ER, n (%) Fever 25 (89.3) 41 (89.1) 1.000 Malaise 15 (53.6) 26 (56.5) 0.815 Myalgia 12 (42.9) 14 (30.4) 0.321 Dizziness 9 (19.6) 5 (17.9) 1.000 Cough 22 (78.6) 40 (87.0) 0.352 Dyspnea 22 (78.6) 26 (56.5) 0.079 Chest pain 1 (3.6) 0 (0.0) 0.717 Expectoration 3 (10.7) 7 (15.2) 0.733 Odynophagia 4 (14.3) 3 (6.5) 0.415 Loss of smell/taste 16 (57.1) 29 (63.0) 0.632 Diarrhea 5 (17.9) 17 (37.0) 0.116 Pneumonia 39 (84.8) 21 (75.0) 0.364 Bilateral pneumonia 28 (60.9) 15 (53.6) 0.629 Persistent symptoms at follow-up, n (%) 19 (67.9) 9 (10.6) <0.001** COVID-19 disease duration (days), Median (IQR) 26.5 (21.5) 23.0 (12.5) 0.126 Hospitalisation, n (%) 21 (75.0) 39 (89.4) 0.364 Days of hospitalisation, median (IQR) 6.0 (13.5) 5.5 (7.5) 0.971 ICU, n (%) 4 (14.3) 4 (8.7) 0.467 Headache characteristics Onset before another COVID-19 symptom, n (%) 6 (21.4) 2 (4.4) 0.010** Holocraneal pain, n (%) 10 (35.7) 18 (39.1) 0.809 Pain quality, n (%) Pressing 19 (67.9) 33 (71.7) 0.796 Throbbing 5 (17.9) 9 (19.6) 1.000 Moderate-severe pain, n (%) 25 (89.3) 32 (69.6) 0.085 Daily constant pain, n (%) 17 (60.7) 22 (47.8) 0.341 Headache associated symptoms at ER, n (%) Nausea and vomiting 9 (32.1) 12 (26.1) 0.604 Photo/phonophobia 1 (3.6) 6 (8.1) 0.242 Vertigo 1 (3.6) 2 (4.4) 1.000 Neck stiffness 1 (3.6) 1 (2.2) 1.000 Worsening with movement 6 (21.4) 6 (13.0) 0.352 Response to acute treatment, n (%) 9 (32.1) 34 (73.9) 0.001** a Adjusted p-value with Benjamini-Hochberg procedure. *p-value 0.05. **p-value 0.01. ER: Emergency room; SD: standard deviation; IQR: interquartile range; ICU: intensive care unit. infection, we remark that headache represents a rele- its role in causing headache is still a matter of debate vant symptom of COVID-19 in terms of prognosis, and possible mechanisms involve increase of proinflam- raising awareness of the importance of its assessment. matory cytokines (20). In a recent study on COVID-19, headache seemed to present independently from fever Hypothesis on underlying pathophysiological (15), in line with our findings observing that headache was not associated with presence of fever at the ER or mechanisms as a reported symptom. Although our study was not Usually patients and clinicians blame fever as the cause specifically designed to address the relationship of headache associated with viral infections. However, between fever and headache, our findings support the Caronna et al. 1417 Table 5. Comparison in inflammatory biomarkers between age/gender-matched COVID-19 patients with and without headache. Headache No headache Adjusted (n ¼ 36) (n ¼ 24) p-valuea Demographic characteristics Age (years), mean  SD 59.1 14.2 61.1  14.9 0.594 Sex (female), n (%) 21 (58.3) 15 (41.7) 0.280 COVID-19 characteristics COVID-19 confirmation (RT-PCR), n (%) 25 (69.4) 15 (62.5) 0.708 COVID-19 disease duration at ER, days, median (IQR) 8.5 (7.5) 9.0 (9.8) 0.623 Vital signs and inflammatory biomarkers Fever, n (%) 11 (30.6) 4 (16.7) 0.482 Lymphopenia, n (%) 20 (55.6) 16 (66.7) 0.432 CRP, mean  SD, mg/ml 8.9  7.9 11.7  9.8 0.381 IL-6, median (IQR), pg/ml 22.9 (57.5) 57.0 (78.6) 0.036* D-dimer, median (IQR), ng/ml 300.0 (3300) 250.0 (1593.0) 0.481 Ferritin, median (IQR), ng/ml 488.0 (466.0) 287.0 (110.0) 0.052 LDH, mean  SD, UI/L 302.8  107.7 457.1  207.6 0.016* a Benjamini-Hochberg adjusted p-value with a false discovery rate greater than 0.05. *p value 0.05. **p value 0.01. SD: standard deviation; RT-PCR: real-time reverse transcriptase polymerase-chain reaction; ER: emergency room; IQR: interquartile range; CRP: C-reactive protein; IL-6: interleukin-6; LDH: lactate dehydrogenase. Interleukin-6 Ferritin 600 4000 Estimated value (ng/ml) Estimated value (pg/ml) 500 3500 3000 400 2500 300 2000 200 1500 1000 100 500 0 0 10 12 14 16 18 20 10 12 14 16 18 20 COVID-19 evloution (days) COVID-19 evloution (days) Without headache With headache C-Reactive protein D-dimer 40 8000 Estimated value (mg/ml) Estimated value (ng/ml) 35 7000 30 6000 25 5000 20 4000 15 3000 10 2000 5 1000 0 0 10 12 14 16 18 20 10 12 14 16 18 20 COVID-19 evloution (days) COVID-19 evloution (days) Figure 2. Evolution of inflammatory biomarkers (IL-6, CRP, ferritin and D-dimer) during the progression of COVID-19 disease. Once having analysed mean values of inflammatory biomarkers at the ER (baseline), we decided to exclusively evaluate the trends of their evolution over time. Of 24 hospitalised patients in whom IL-6, CRP, ferritin and D-dimer data were available at the same three points in time, 18 had headache while six did not. There were no differences in time passed between each blood test and COVID-19 onset. Only IL-6 changes over COVID-19 progression were significant when comparing patients with and without headache (p ¼ 0.003) in the linear mixed-effects models adjusted by age. 1418 Cephalalgia 40(13) need to further evaluate whether fever has a minor role cerebral circulation (34), that SARS-CoV-2 can reach in directly causing headache, being more directly relat- through bloodstream dissemination (35). Thus, the ed to the initial response to the pathogen. presence of ACE2 in the meningeal endothelium, lead- Concerning specific pathophysiological mechanisms, ing to trigeminovascular sensitisation, should be fur- it has been hypothesised that SARS-CoV-2 may trigger ther investigated as a potential pathophysiological a hyperinflammatory state in some patients (cytokine mechanism for COVID-19 headache. storm) (21) especially through IL-6 (22–23), whose All the previously mentioned pathophysiological levels seem to correlate with dysregulation of other mechanisms are shown in Figure 3. coagulation and inflammatory biomarkers in a recent It could be interesting for future studies to assess proteomic study (24). The role of IL-6 has been also whether a sensitisation of the trigeminovascular demonstrated in neuroinflammation (25) and specifi- system persists once these pathological noxae have cally in migraine (26–27). Therefore, it is logical to resolved, leading to headache persistence and chronifi- wonder whether the suggested inflammatory state cation. In this context, it is worth noticing that a rele- observed in COVID-19 is also responsible for neuro- vant proportion of patients without a personal history inflammation, leading to headache. We observed lower of headache had persistent headache. This fact makes levels of IL-6 at the ER in the headache group, a find- us wonder whether a post-infectious aetiology may rep- ing that cannot be explained by different stages of the resent, in our clinical practice, an underdiagnosed disease between groups. This fact is surprising, consid- cause of new daily headache. However, we are aware ering that COVID-19 patients with headache had more that to fully assess headache persistence these patients personal headache history. Moreover, we observed that should be followed up for at least 3 months. during COVID-19 evolution, levels of IL-6 seemed to This is, at present, the only prospective study con- be more stable in patients with headache compared to ducted on headache and COVID-19. We report the the ones without it. Considering that headache patients highest proportion of headache observed in literature also had shorter COVID-19 disease evolution, their (5–9), which reflects the fact that, for the first time, lower and more stable IL-6 levels may indicate that neurologists, working as general clinicians at the ER, inflammation may be kept at a more localised level. could properly directly assess headache in the acute In this context, considering that headache attributed phase of a viral disease. However, we cannot estimate to COVID-19 could mimic migraine even in individuals in our study the real prevalence of headache attributed without a personal history of this condition, we to COVID-19 since we only included those patients hypothesise that there is a meningeal peripheral sensi- attended by the investigators, who were only a part tisation and therefore an activation of the trigemino- of the huge number of patients visited at the ER vascular system (28) underlying this headache type. daily during the study period. However, it is important Amongst possible mechanisms that could lead to the to point out that our results are in line with that of the activation of the trigeminovascular system, it is worth European COVID-19 cohort (10), where headache and mentioning our finding on the association between other COVID-19 symptoms were also directly assessed headache and anosmia/ageusia as distinctive symptoms by clinicians through a structured questionnaire. Our of COVID-19 (5,29). It has been hypothesised that strength is that the neurologists’ direct involvement SARS-CoV-2 has neurotropic characteristics, being made data collection on previous headache history able to invade peripheral nerve terminals and enter and headache characteristics more reliable. As for the the central nervous system through trans-synaptic other limitations, we could not include severe COVID- pathways (30–32). Inside the nasal cavity, concomitant 19 patients due to the impossibility of conducting a full anosmia may indicate a peripheral activation of the interview, or very mild patients who have gone undiag- trigeminovascular system mediated by the pathogen nosed and were unlikely to come to the ER, our cohort itself, acting not only on the specialised olfactory epi- not being representative of the entire spectrum of thelium, but also on trigeminal branches present at this COVID-19 patients. This fact makes it more difficult level or through the olfactory-trigeminal interactions. to properly assess possible associations between head- As for other pathophysiological mechanisms, endothe- ache and the clinical evolution of COVID-19 in a pop- litis may also have a relevant role in COVID-19 (33), ulation different from the hospitalised one. since inflammatory reactions could be generated Nevertheless, a more homogeneous group makes our through the interaction between the virus and its recep- findings more generalisable in this specific group and tor, angiotensin-converting enzyme 2 (ACE2), which is useful to guide clinicians in case of future new disease present in the endothelium of blood vessels. ACE2 is peaks. Another limitation is represented by the fact expressed in the endothelium of small vessels of that not all patients could have a confirmed diagnosis Caronna et al. 1419 Figure 3. Possible pathophysiological mechanisms of headache associated with COVID-19. (a) Head section representing trigeminal innervation, including meninges and nasal cavities (selected areas that are enlarged in (b) and (c). (b) At meningeal level, the trigeminal afferents (blue arrows) innervate meningeal vessels (represented in red), creating the trigeminovascular system. Its activation may be due to i) systemic inflammation that may facilitate meningeal sensitisation leading to a local release of inflammatory peptides that stimulates trigeminal terminals; ii) direct binding of SARS-CoV-2 from the bloodstream on ACE2, which is expressed by the endo- thelium of meningeal vessels, causing endothelitis and therefore inflammation. (c) In the nasal cavities, both the specialised olfactory epithelium and the nasal epithelium are present, the latter being innervated by trigeminal nerve afferents. iii) The supporting cells of the olfactory epithelium, in which the olfactory neurons are embedded, express ACE2, where the SARSCoV- 2 may bind, causing anosmia, a symptom that is significantly associated with presence of headache. iv) At the level of the nasal epithelium, the trigeminal system may be peripherally activated by the direct action of SARS-CoV-2 on the nasal epithelium or the trigeminal branches, or by an indirect pathway involving the interactions between the olfactory and trigeminal innervation. These mechanisms should be further studied. through an RT-PCR for SARS-CoV-2 due to hospital Conclusions protocols, although all patients in our cohort were Headache associated with COVID-19 is a frequent highly suspected cases. Moreover, we also have to con- symptom, predictive of a shorter COVID-19 duration. sider that, as observed in a recent study, the false neg- A relevant number of patients without a headache his- ative rate with RT-PCR can be high, reaching 29% tory have headache persisting for more than 6 weeks (36). In addition, we did not investigate secondary even when other COVID-19 symptoms resolve. causes of headache during disease evolution, making it Persistent headache often represents a prodromal, dif- difficult to exclusively attribute to SARS-CoV-2 possible ficult to treat and disabling symptom of COVID-19, for changes in headache features during the course of which patients may seek medical attention. Efforts in COVID-19. Finally, we are also aware that the analysis the future will have to focus on better understanding its of inflammatory biomarker evolution during hospitalisa- pathophysiological mechanisms, possibly involving the tion counts on a small sample size. These findings should peripheral activation of the trigeminovascular system be further assessed in larger patient groups, although they by inflammation or a direct role of SARS-CoV-2, in represent a starting point in hypothesising and studying order to provide better care and new therapeutic solu- the link between headache, COVID-19 and IL-6. tions to patients. 1420 Cephalalgia 40(13) Clinical implications • Headache is one of the most frequent and prominent symptoms of COVID-19, its presence being predictive of a shorter COVID-19 disease duration. • Headache attributed to COVID-19 can have migraine-like features and in some cases can be persistent and disabling, even in patients without a previous personal headache history. • Presence of headache, its different characteristics and evolution may reflect different pathophysiological mechanisms acting in COVID-19, making their study necessary to better understand both headache and COVID-19 itself and offer better therapeutic options. 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