Headache as a Cardinal Symptom of Coronavirus Disease 2019

A Cross-Sectional Study

Javier A. Membrilla, MD; Íñigo de Lorenzo, MD; María Sastre, MD; Javier Díaz de Terán, MD


Headache. 2020;60(10):2176-2191. 

In This Article



According to International Recommendations for Observational Studies, items on the Strengthening the Reporting of Observational Studies in Epidemiology checklist were followed for this study.[28] This was a cross-sectional study carried out in the city of Madrid, Spain, in a tertiary hospital highly affected by COVID-19. The inclusion period ranged from March 31 to April 27, 2020, when the disease was at its peak in our country. All the procedures were reviewed and approved by the local Ethics Committee for Clinical Research (PI-4148), and written informed consent was obtained from all patients.

Study Population and Eligibility

Patients attending the emergency department of our hospital were included if they met all of the following inclusion criteria: (1) patients classified by the Manchester Triage System[29] as priority levels 5 (non-urgent) and 4 (standard); (2) fulfilled the criteria for a "probable COVID-19 case" or "confirmed COVID-19 case" according to the WHO guidance on global surveillance for COVID-19;[30] (3) and presented with headache alongside other COVID-19-related symptoms. Patients presenting any condition requiring an emergency diagnostic or therapeutic intervention were excluded.

All the patients underwent thoracic imaging (chest radiography or computerized tomography, depending on the clinical suspicion and availability). Microbiological testing for SARS-CoV-2 was performed by PCR using samples obtained from nasopharyngeal swabs if the patient was ≥60 years old or presented with significant comorbidities (high blood pressure, diabetes mellitus, chronic renal insufficiency, liver disease, cancer, ischemic heart disease, chronic obstructive pulmonary disease, or immunosuppression). Younger patients without these comorbidities underwent microbiological testing if chest imaging showed radiological signs compatible with COVID-19 or if they were healthcare workers, according to the national government recommendations at the time this study was developed.[31]

Data Collection

A headache specialist designed a structured questionnaire containing the main semiological aspects of headache. Convenience sampling was used to maximize resources. Demographic data, anthropometric measures, and prior history of depression, anxiety, or headache were also recorded. The questionnaire included headache features such as location, intensity measured by the visual analog scale (VAS), quality and duration of pain, associated symptoms, possible triggers and chronological relationship with other COVID-19 symptoms (whether headache was present at the time of onset of fever and respiratory symptoms). The VAS variable was categorized into 2 groups: mild (VAS score <5) and moderate-to-severe (VAS score ≥5). The presence of anosmia and pneumonia, and the oxygen saturation were recorded. Following our Emergency Department protocol, laboratory analysis was not performed in all patients. Apart from laboratory data, there were no missing data. All patients were classified as confirmed COVID-19 cases (laboratory confirmation: positive SARS-CoV-2 PCR) or probable COVID-19 cases (suspected case for whom testing could not be performed) as per WHO guidelines. A suspected case was a patient with acute respiratory illness, fever and at least 1 sign/symptom of respiratory illness, residing in a location where community transmission of COVID-19 was reported, as is the case in Spain. Patients with pneumonia, epidemiological contact history, and typical laboratory findings (such as lymphopenia and high lactate dehydrogenase [LDH])[32] were classified with probable COVID-19 even if PCR was negative (contemplating the possibility of a false-negative result) and no other etiology of pneumonia was found.

Statistical Analysis

No statistical power calculation was performed before the study. The sample size was based on our previous experience with this design. Nominal variables were reported as percentages and compared using a chi-square or Fisher's exact test, when applicable. A 2-tailed Kolmogorov-Smirnov test was applied to examine whether the ratio variables followed a Gaussian distribution. Ratio variables were reported as mean ± standard deviation (SD) if they followed a Gaussian distribution; otherwise, they were represented as median ± interquartile range [p25-p75] (IR). A 2-tailed Mann-Whitney U-test was used to compare the differences between ordinal variables in 2 independent groups (personal history of migraine and no previous headache). Bivariate correlation between VAS score and laboratory parameters were studied using the Spearman's test. The statistical significance was set at P < .05. Data analysis was performed using the Statistics Package for Social Science (SPSS 23.00 – IBM Inc., USA).