ORIGINAL RESEARCH published: 17 December 2020 doi: 10.3389/fneur.2020.583870 Deep Phenotyping of Headache in Hospitalized COVID-19 Patients via Principal Component Analysis Álvaro Planchuelo-Gómez 1, Javier Trigo 2, Rodrigo de Luis-García 1, Ángel L. Guerrero 2,3,4*, Jesús Porta-Etessam 5 and David García-Azorín 2,3 1 Imaging Processing Laboratory, Universidad de Valladolid, Valladolid, Spain, 2 Headache Unit, Department of Neurology, Hospital Clínico Universitario de Valladolid, Valladolid, Spain, 3 Neuroscience Research Unit, Institute for Biomedical Research of Salamanca, Salamanca, Spain, 4 Department of Medicine, Universidad de Valladolid, Valladolid, Spain, 5 Headache Unit, Department of Neurology, Hospital Clínico San Carlos, Madrid, Spain Objectives: Headache is a common symptom in systemic infections, and one of the symptoms of the novel coronavirus disease 2019 (COVID-19). The objective of this study Edited by: was to characterize the phenotype of COVID-19 headache via machine learning. Raquel Gil-Gouveia, Hospital da Luz Lisboa, Portugal Methods: We performed a cross-sectional study nested in a retrospective cohort. Reviewed by: Hospitalized patients with COVID-19 confirmed diagnosis who described headache were Lanfranco Pellesi, included in the study. Generalized Linear Models and Principal Component Analysis Rigshospitalet, Denmark Elizabeth Seng, were employed to detect associations between intensity and self-reported disability Yeshiva University, United States caused by headache, quality and topography of headache, migraine features, COVID-19 *Correspondence: symptoms, and results from laboratory tests. Ángel L. Guerrero [email protected] Results: One hundred and six patients were included in the study, with a mean age orcid.org/0000-0001-7493-6002 of 56.6 ± 11.2, including 68 (64.2%) females. Higher intensity and/or disability caused by headache were associated with female sex, fever, abnormal platelet count and Specialty section: This article was submitted to leukocytosis, as well as migraine symptoms such as aggravation by physical activity, Headache Medicine and Facial Pain, pulsating pain, and simultaneous photophobia and phonophobia. Pain in the frontal area a section of the journal (83.0% of the sample), pulsating quality, higher intensity of pain, and presence of nausea Frontiers in Neurology were related to lymphopenia. Pressing pain and lack of aggravation by routine physical Received: 15 July 2020 Accepted: 30 November 2020 activity were linked to low C-reactive protein and procalcitonin levels. Published: 17 December 2020 Conclusion: Intensity and disability caused by headache attributed to COVID-19 Citation: Planchuelo-Gómez Á, Trigo J, de are associated with the disease state and symptoms. Two distinct headache Luis-García R, Guerrero ÁL, phenotypes were observed in relation with COVID-19 status. One phenotype seems to Porta-Etessam J and García-Azorín D associate migraine symptoms with hematologic and inflammatory biomarkers of severe (2020) Deep Phenotyping of Headache in Hospitalized COVID-19 COVID-19; while another phenotype would link tension-type headache symptoms to Patients via Principal Component milder COVID-19. Analysis. Front. Neurol. 11:583870. doi: 10.3389/fneur.2020.583870 Keywords: COVID-19, headache disorders, migraine, tension-type headache, machine learning Frontiers in Neurology | www.frontiersin.org 1 December 2020 | Volume 11 | Article 583870 Planchuelo-Gómez et al. Phenotyping of Headache in COVID-19 INTRODUCTION (11); (2) death during the hospitalization; (3) previous dementia or cognitive impairment that made difficult a detailed description Headache is one of the most common symptoms in coronavirus of the suffered headache; (4) poor medical condition that disease 2019 (COVID-19) (1, 2). However, differently to other difficulted the precise description of the headache phenotype; symptoms, as anosmia or myalgia, the headache phenotype (5) no answer to the invitation to participate in the study; (6) appears to be non-uniform (3). The most reported phenotype is rejection to take part in the study. bilateral pain, pulsating or pressing quality in temporoparietal or All the patients admitted to the Hospital Clínico Universitario frontal region, with moderate to severe intensity (4). de Valladolid (Valladolid, Spain) from March 8th to April 11th, The clinical presentation of COVID-19 is linked to its 2020 were screened. The information employed in this study pathophysiology. Interferon gamma type I-III seem related was collected from the primary care electronic digital records, to general systemic symptoms, such as fever and myalgia, the emergency room records and the hospitalization reports. among others. The cytokine release, macrophage activation and Every patient was asked about suffering from headache, and those lymphocyte depletion are related with endothelial dysfunction patients who answered with a positive response were invited and micro-thrombosis (5). In addition, the downregulation to take part in the study. Two neurologists with expertise in of type 2 angiotensin II receptors and the upregulation of headache medicine interviewed the patients according to a pre- type 1 angiotensin II receptors causes vasoconstriction and a specified structured interview. proinflammatory state (6). The laboratory correlate to COVID- 19 pathophysiology is observed by lymphopenia and increased Variables C-reactive protein (CRP), procalcitonin (PCT) and D-dimer, Six groups of variables related to headache were analyzed as among others (7). In patients with COVID-19 and headache, variables of interest: (1) Intensity of the pain (0–10 numeric there was at least one abnormal laboratory value in the first rating scale; 0: no pain, 10: maximum intensity); (2) disability measure, being the most common abnormal increased CRP caused by headache, self-rated by the patient (0–100 numeric levels (8). rating scale; 0: no disability, 100: complete disability); (3) The objective of this study was to analyze whether the presence of typical migraine and tension-type headache (TTH) headache phenotype did correlate with the laboratory biomarkers features (categorical variables showing presence of each symptom that have been linked to COVID-19 pathophysiology and/or the included in criteria C and D for migraine without aura from the COVID-19 clinical presentation, by performing an analysis based ICHD-3, and ICHD-3 criteria C and D for TTH, analyzing if on machine learning techniques. patients fulfilled the ICHD-3 criteria); (4) laterality (categorical variables indicating unilateral or bilateral pain); (5) topography MATERIALS AND METHODS (categorical variables for presence of pain in diverse areas, e.g., frontal); (6) quality of the pain (e.g., pressing). For the We conducted a cross-sectional study nested in cohort of topography and quality of pain, patients were asked to describe patients. The Ethics Review Board of Valladolid East health area the predominant one. The cranial territories or phenotypic approved the study (PI: 20-1738). characteristics present at least in 20% of the subjects were included, taking into account the number of possible regions, Participants with no consideration of simultaneous pain in more than The inclusion criteria for participants were: (1) Confirmed one region. COVID-19 diagnosis by real time reverse-transcriptase- As main independent variables, diverse COVID-19 symptoms polymerase-chain-reaction (RT-PCR) assay from respiratory (categorical variables describing the presence of each different tract samples, or by the presence of anti-SARS-CoV-2 IgM symptom) and results from laboratory tests were evaluated. The + IgA antibodies in patients with clinical symptoms, COVID-19 symptoms included in this study were arthralgia, according to the World Health Organization protocols chest pain, cough, diarrhea, dyspnea, expectoration, fatigue, (9, 10); (2) suffering from headache throughout the course fever, headache (100% in this sample), hyposmia or anosmia, of COVID-19; (3) hospitalization because of COVID-19; (4) lightheadedness, myalgia, nausea, odynophagia, rhinorrhea, agreement to participate; (5) fulfillment of criteria for acute skin rash, weakness, and vomiting. We gathered different headache attributed to systemic viral infection according to the laboratory parameters on admission and worst values during International Classification of Headache Disorders, 3rd edition the stay. These values were represented as numerical variables (ICHD-3) (11). and categorical variables indicating abnormal levels. Reference The exclusion criteria were: (1) Acute secondary headache values and units are detailed in Supplementary Table 1. Other with better agreement for a diagnosis different to acute headache analyzed independent variables were demographic (age and sex), attributed to systemic viral infection according to the ICHD-3 prior medical history (more details in Supplementary Table 1), previous history of headache (including a 0–100 rating scale Abbreviations: COVID-19, coronavirus disease 2019; CRP, C-reactive to assess the level of similarity), modified Rankin scale, other protein; FDR, false discovery rate; GLM, generalized linear model; symptoms associated with the headache (cranial autonomic ICHD-3, The International Classification of Headache Disorders (3rd edition); IL-6, interleukin-6; LDH, lactate dehydrogenase; PCA, symptoms, hypersensitivity to stimuli, vegetative symptoms, and principal component analysis; CT, procalcitonin; RT-PCR, real-time aura), other headache features (duration,