Cytokine and interleukin profile in patients with headache and COVID-19: A pilot, CASE-control, study on 104 patients.

BACKGROUND: The presence of headache during the acute phase of COVID-19 could be associated with the innate response and the cytokine release. We aim to compare the cytokine and interleukin profile in hospitalized COVID-19 patients at the moment of admission with and without headache during the course of the disease. METHODS: An observational analytic study with a case control design was performed. Hospitalized patients from a tertiary hospital with confirmed COVID-19 disease were included. Patients were classified into the headache or the control group depending on whether they presented headache not better accounted for by another headache disorder other than acute headache attributed to systemic viral infection. Several demographic and clinical variables were studies in both groups. We determined the plasmatic levels of 45 different cytokines and interleukins from the first hospitalization plasma extraction in both groups. RESULTS: One hundred and four patients were included in the study, aged 67.4 (12.8), 43.3% female. Among them, 29 (27.9%) had headache. Patients with headache were younger (61.8 vs. 69.5 years, p = 0.005) and had higher frequency of fever (96.6 vs. 78.7%, p = 0.036) and anosmia (48.3% vs. 22.7%, p = 0.016). In the comparison of the crude median values of cytokines, many cytokines were different between both groups. In the comparison of the central and dispersion parameters between the two groups, GROa, IL-10, IL1RA, IL-21, IL-22 remained statistically significant. After adjusting the values for age, sex, baseline situation and COVID-19 severity, IL-10 remained statistically significant (3.3 vs. 2.2 ng/dL, p = 0.042), with a trend towards significance in IL-23 (11.9 vs. 8.6 ng/dL, p = 0.082) and PIGF1 (1621.8 vs. 110.6 ng/dL, p = 0.071). CONCLUSIONS: The higher levels of IL-10 -an anti-inflammatory cytokine- found in our sample in patients with headache may be explained as a counteract of cytokine release, reflecting a more intense immune response in these patients.

Frequency and phenotype of headache in covid-19: a study of 2194 patients.

To estimate the frequency of headache in patients with confirmed COVID-19 and characterize the phenotype of headache attributed to COVID-19, comparing patients depending on the need of hospitalization and sex, an observational study was done. We systematically screened all eligible patients from a reference population of 261,431 between March 8 (first case) and April 11, 2020. A physician administered a survey assessing demographic and clinical data and the phenotype of the headache. During the study period, 2194 patients out of the population at risk were diagnosed with COVID-19. Headache was described by 514/2194 patients (23.4%, 95% CI 21.7-25.3%), including 383/1614 (23.7%) outpatients and 131/580 (22.6%) inpatients. The headache phenotype was studied in detail in 458 patients (mean age, 51 years; 72% female; prior history of headache, 49%). Headache was the most frequent first symptom of COVID-19. Median headache onset was within 24 h, median duration was 7 days and persisted after 1 month in 13% of patients. Pain was bilateral (80%), predominantly frontal (71%), with pressing quality (75%), of severe intensity. Systemic symptoms were present in 98% of patients. Headache frequency and phenotype was similar in patients with and without need for hospitalization and when comparing male and female patients, being more intense in females.Trial registration: This study was supported by the Institute of Health Carlos III (ISCIII), code 07.04.467804.74011 and Regional Health Administration, Gerencia Regional de Salud, Castilla y Leon (GRS: 2289/A/2020).

Neurological symptoms in Covid-19 patients in the emergency department.

BACKGROUND: Coronavirus disease 2019 (Covid-19) might present neurological symptoms. We aimed to evaluate the frequency of them at the moment of emergency department (ED) visit and their impact in the prognosis. METHODS: Retrospective cohort study including all consecutive hospitalized cases between March 8th and April 11th, 2020. Covid-19 diagnosis was confirmed by polymerase chain reaction test and/or serology. We compared, in patients with and without neurological symptoms on admission, demographic, clinical presentation, and frequency and type of abnormal laboratory values. We analyzed the variables that were associated with in-hospital all-cause mortality by Cox-regression log-rank test. RESULTS: We included 576 hospitalized patients, 250 (43.3%) female, aged 67.2 years. At the moment of ED visit, 320 (55.6%) described neurological symptoms, including anosmia (146, 25.3%), myalgia (139, 24.1%), headache (137, 23.8%), and altered mental status (98, 17.0%). Neurological symptoms started the first symptomatic day in 198 (54.2%) cases. Patients with neurological symptoms presented later to the ED (7.9 versus. 6.6 days, p = .019). Only four (0.6%) cases had no typical Covid-19 general symptoms, and only six (1.9%) had a normal laboratory results, for a sensitivity of 98.7% (95% confidence interval (CI): 96.6%-99.6%) and 98.1% (95% CI: 95.7%-99.2%), respectively. In the multivariate Cox-regression of mortality predictors, anosmia (HR: 0.358, 95%CI: 0.140-0.916) and altered mental status (HR: 1.867, 95%CI: 1.162-3.001) were significant. CONCLUSION: Neurological symptoms were the most frequent extrapulmonary symptoms. They were present in half of the Covid-19 patients at the time of the ED visit. Anosmia on admission was an independent predictor of lower in-hospital mortality and altered mental status on admission predicted in-hospital mortality.

Factors associated with the presence of headache in hospitalized COVID-19 patients and impact on prognosis: a retrospective cohort study.

INTRODUCTION: Headache is one of the most frequent neurologic manifestations in COVID-19. We aimed to analyze which symptoms and laboratory abnormalities were associated with the presence of headache and to evaluate if patients with headache had a higher adjusted in-hospital risk of mortality. METHODS: Retrospective cohort study. We included all consecutive patients admitted to the Hospital with confirmed SARS-CoV-2 infection between March 8th and April 11th, 2020. We collected demographic data, clinical variables and laboratory abnormalities. We used multivariate regression analysis. RESULTS: During the study period, 576 patients were included, aged 67.2 (SD: 14.7), and 250/576 (43.3%) being female. Presence of headache was described by 137 (23.7%) patients. The all-cause in-hospital mortality rate was 127/576 (20.0%). In the multivariate analysis, patients with headache had a lower risk of mortality (OR: 0.39, 95% CI: 0.17-0.88, p = 0.007). After adjusting for multiple comparisons in a multivariate analysis, variables that were independently associated with a higher odds of having headache in COVID-19 patients were anosmia, myalgia, female sex and fever; variables that were associated with a lower odds of having headache were younger age, lower score on modified Rankin scale, and, regarding laboratory variables on admission, increased C-reactive protein, abnormal platelet values, lymphopenia and increased D-dimer. CONCLUSION: Headache is a frequent symptom in COVID-19 patients and its presence is an independent predictor of lower risk of mortality in COVID-19 hospitalized patients.

Deep Phenotyping of Headache in Hospitalized COVID-19 Patients via Principal Component Analysis.

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 was to characterize the phenotype of COVID-19 headache via machine learning. Methods: We performed a cross-sectional study nested in a retrospective cohort. Hospitalized patients with COVID-19 confirmed diagnosis who described headache were included in the study. Generalized Linear Models and Principal Component Analysis were employed to detect associations between intensity and self-reported disability caused by headache, quality and topography of headache, migraine features, COVID-19 symptoms, and results from laboratory tests. Results: One hundred and six patients were included in the study, with a mean age 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 leukocytosis, as well as migraine symptoms such as aggravation by physical activity, pulsating pain, and simultaneous photophobia and phonophobia. Pain in the frontal area (83.0% of the sample), pulsating quality, higher intensity of pain, and presence of nausea were related to lymphopenia. Pressing pain and lack of aggravation by routine physical activity were linked to low C-reactive protein and procalcitonin levels. Conclusion: Intensity and disability caused by headache attributed to COVID-19 are associated with the disease state and symptoms. Two distinct headache phenotypes were observed in relation with COVID-19 status. One phenotype seems to associate migraine symptoms with hematologic and inflammatory biomarkers of severe COVID-19; while another phenotype would link tension-type headache symptoms to milder COVID-19.

Anosmia is associated with lower in-hospital mortality in COVID-19.

BACKGROUND: Anosmia is common in Coronavirus disease 2019, but its impact on prognosis is unknown. We analysed whether anosmia predicts in-hospital mortality; and if patients with anosmia have a different clinical presentation, inflammatory response, or disease severity. METHODS: Retrospective cohort study including all consecutive hospitalized patients with confirmed Covid-19 from March 8th to April 11th, 2020. We determined all-cause mortality and need of intensive care unit (ICU) admission. We registered the first and worst laboratory parameters. Statistical analysis was done by multivariate logistic and linear regression. RESULTS: We included 576 patients, 43.3% female, and aged 67.2 years in mean. Anosmia was present in 146 (25.3%) patients. Patients with anosmia were more frequently females, younger and less disabled and had less frequently hypertension, diabetes, smoking habit, cardiac and neurological comorbidities. Anosmia was independently associated with lower mortality (OR: 0.180, 95% CI: 0.069-0.472) and ICU admission (OR: 0.438, 95% CI: 0.229-0.838, p = 0.013). In the multivariate analysis, patients with anosmia had a higher frequency of cough (OR: 1.96, 95%CI: 1.18-3.28), headache (OR: 2.58, 95% CI: 1.66-4.03), and myalgia (OR: 1.74, 95% CI: 1.12-2.71). They had higher adjusted values of hemoglobin (+0.87, 95% CI: 0.40-1.34), lymphocytes (+849.24, 95% CI: 157.45-1541.04), glomerular filtration rate (+6.42, 95% CI: 2.14-10.71), and lower D-dimer (-4886.52, 95% CI: -8655.29-(-1117.75)), and C-reactive protein (-24.92, 95% CI: -47.35-(-2.48)). CONCLUSIONS: Hospitalized Covid-19 patients with anosmia had a lower adjusted mortality rate and less severe course of the disease. This could be related to a distinct clinical presentation and a different inflammatory response.

Frequency and Type of Red Flags in Patients With Covid-19 and Headache: A Series of 104 Hospitalized Patients.

OBJECTIVE: In this study, we aimed to evaluate the frequency of the main red flags in patients with headache who do have Covid-19. BACKGROUND: Headache is one of the most frequent neurologic symptoms of Coronavirus disease 2019 (Covid-19). Diagnosis of secondary headache disorders is still based on the presence of red flags. DESIGN AND METHODS: Cross-sectional study of hospitalized patients with confirmed Covid-19 disease. We interrogated every patient about the presence of headache and if so, a headache expert conducted a structured interview assessing the presence and type of the main red flags. We evaluated the presence of laboratory abnormalities on admission. RESULTS: We screened 576 consecutive patients, 130/576 (22.6%) described headache, and 104 were included in the study. Mean age of patients was 56.7 (standard deviation: 11.2) and 66/104 (63.4%) were female. Red flags concerning prior medical history were present in 79/104 (76.0%) cases, and those related to the headache itself were observed in 99/104 (95.2%) patients. All patients 104/104 (100%) described systemic symptoms and 86/104 (82.7%) some neurologic symptoms. Laboratory results were abnormal in 98/104 (94.2%) cases. The most frequent red flags were fever, in 93/104 (89.4%) patients, cough, in 89/104 (85.6% cases), and increased C-reactive protein in 84/100 (84.0%) cases. CONCLUSION: In patients with Covid-19 that described the headache red flags were present in most cases. There was not any universal red flag, being necessary the comprehensive evaluation of all of them.

Neurological Comorbidity Is a Predictor of Death in Covid-19 Disease: A Cohort Study on 576 Patients.

Introduction: Prognosis of Coronavirus disease 2019 (Covid-19) patients with vascular risk factors, and certain comorbidities is worse. The impact of chronic neurological disorders (CND) on prognosis is unclear. We evaluated if the presence of CND in Covid-19 patients is a predictor of a higher in-hospital mortality. As secondary endpoints, we analyzed the association between CND, Covid-19 severity, and laboratory abnormalities during admission. Methods: Retrospective cohort study that included all the consecutive hospitalized patients with confirmed Covid-19 disease from March 8th to April 11th, 2020. The study setting was Hospital Clínico, tertiary academic hospital from Valladolid. CND was defined as those neurological conditions causing permanent disability. We assessed demography, clinical variables, Covid-19 severity, laboratory parameters and outcome. The primary endpoint was in-hospital all-cause mortality, evaluated by multivariate cox-regression log rank test. We analyzed the association between CND, covid-19 severity and laboratory abnormalities. Results: We included 576 patients, 43.3% female, aged 67.2 years in mean. CND were present in 105 (18.3%) patients. Patients with CND were older, more disabled, had more vascular risk factors and comorbidities and fewer clinical symptoms of Covid-19. They presented 1.43 days earlier to the emergency department. Need of ventilation support was similar. Presence of CND was an independent predictor of death (HR 2.129, 95% CI: 1.382-3.280) but not a severer Covid-19 disease (OR: 1.75, 95% CI: 0.970-3.158). Frequency of laboratory abnormalities was similar, except for procalcitonin and INR. Conclusions: The presence of CND is an independent predictor of mortality in hospitalized Covid-19 patients. That was not explained neither by a worse immune response to Covid-19 nor by differences in the level of care received by patients with CND.