Serum Protein Profiling Reveals a Landscape of Inflammation and Immune Signaling in Early-stage COVID-19 Infection.

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.

Prevalence of Symptoms More Than Seven Months After Diagnosis of Symptomatic COVID-19 in an Outpatient Setting.

BACKGROUND: With millions of SARS-CoV-2 infections worldwide, increasing numbers of patients are coming forward with long-term clinical effects of the disease lasting several weeks to months. OBJECTIVE: To characterize symptoms 7 to 9 months after diagnosis of COVID-19. DESIGN: Self-reported surveys and semistructured telephone interviews at enrollment and 30 to 45 days and 7 to 9 months from diagnosis. SETTING: From 18 March to 15 May 2020, symptomatic persons who tested positive for SARS-CoV-2 at the Geneva University Hospitals were followed by CoviCare, a virtual, clinical, outpatient follow-up program. Persons were contacted again at 30 to 45 days and 7 to 9 months from diagnosis. PARTICIPANTS: Persons who were a part of the CoviCare program from 18 March to 15 May 2020. MEASUREMENTS: A standardized interview of symptoms consistent with COVID-19, with grading of intensity. RESULTS: Of the 629 participants in the study who completed the baseline interviews, 410 completed follow-up at 7 to 9 months after COVID-19 diagnosis; 39.0% reported residual symptoms. Fatigue (20.7%) was the most common symptom reported, followed by loss of taste or smell (16.8%), dyspnea (11.7%), and headache (10.0%). LIMITATION: Limitations include generalizability and missing data for 34.8% of participants. CONCLUSION: Residual symptoms after SARS-CoV-2 infection are common among otherwise young and healthy persons followed in an outpatient setting. These findings contribute to the recognition of long-term effects in a disease mostly counted by its death toll to date by promoting communication on postacute sequelae of SARS-CoV-2 and encouraging physicians to continue long-term monitoring of their patients. PRIMARY FUNDING SOURCE: None.

Neurological Sequelae of COVID-19.

BACKGROUND: Though primarily a pulmonary disease, Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus can generate devastating disease states that affect multiple organ systems including the central nervous system (CNS). The various neurological disorders associated with COVID-19 range in severity from mild symptoms such as headache, or myalgias to more severe symptoms such as stroke, psychosis, and anosmia. While some of the COVID-19 associated neurological complications are mild and reversible, a significant number of patients suffer from stroke. Studies have shown that COVID-19 infection triggers a wave of inflammatory cytokines that induce endothelial cell dysfunction and generate coagulopathy that increases the risk of stroke or thromboses. Inflammation of the endothelium following infection may also destabilize atherosclerotic plaque and induce thrombotic stroke. Although uncommon, there have also been reports of hemorrhagic stroke associated with COVID-19. The proposed mechanisms include a blood pressure increase caused by infection leading to a reduction in angiotensin converting enzyme-2 (ACE-2) levels that results in an imbalance of the renin-angiotensin system ultimately manifesting inflammation and vasoconstriction. Coagulopathy, as demonstrated by elevated prothrombin time (PT), has also been posited as a factor contributing to hemorrhagics stroke in patients with COVID-19. Other neurological conditions associated with COVID-19 include encephalopathy, anosmia, encephalitis, psychosis, brain fog, headache, depression, and anxiety. Though there are several hypotheses reported in the literature, a unifying pathophysiological mechanism of many of these disorders remains unclear. Pulmonary dysfunction leading to poor oxygenation of the brain may explain encephalopathy and other disorders in COVID-19 patients. Alternatively, a direct invasion of the CNS by the virus or breach of the blood-brain barrier by the systemic cytokines released during infection may be responsible for these conditions. Notwithstanding, the relationship between the inflammatory cytokine levels and conditions such as depression and anxiety is contradictory and perhaps the social isolation during the pandemic may in part be a contributing factor to some of the reported CNS disorders. OBJECTIVE: In this article, we review the current literature pertaining to some of the most significant and common neurological disorders such as ischemic and hemorrhagic stroke, encephalopathy, encephalitis, brain fog, Long COVID, headache, Guillain-Barre syndrome, depression, anxiety, and sleep disorders in the setting of COVID-19. We summarize some of the most relevant literature to provide a better understanding of the mechanistic details regarding these disorders in order to help physicians monitor and treat patients for significant COVID-19 associated neurologic impairments. METHODS: A literature review was carried out by the authors using PubMed with the search terms "COVID-19" and "Neurology", "Neurological Manifestations", "Neuropsychiatric Manifestations", "Stroke", "Encephalopathy", "Headache", "Guillain-Barre syndrome", "Depression", "Anxiety", "Encephalitis", "Seizure", "Spasm", and "ICUAW". Another search was carried out for "Long-COVID" and "Post-Acute COVID-19" and "Neurological Manifestations" or "Neuropsychiatric Manifestations". Articles such as case reports, case series, and cohort studies were included as references. No language restrictions were enforced. In the case of anxiety and depression, attempts were made to focus mainly on articles describing these conditions in infected patients. RESULTS: A total of 112 articles were reviewed. The incidence, clinical outcomes, and pathophysiology of selected neurological disorders are discussed below. Given the recent advent of this disease, the incidence of certain neurologic sequelae was not always available. Putative mechanisms for each condition in the setting of COVID-19 are outlined.

Neurological features and outcome in COVID-19: dementia can predict severe disease.

The COVID-19 pandemic has infected more than 22 million people worldwide. Although much has been learned about COVID-19, we do not know much about its neurological features and their outcome. This observational study was conducted on the patients of Imam Hossein Hospital, and 361 adult patients (214 males) with confirmed diagnosis of COVID-19 from March 5, 2020 to April 3, 2020, were enrolled. Data was gathered on age, sex, comorbidities, initial symptoms, symptoms during the disease course, neurological symptoms, and outcome. The mean age of the patients was 61.90 ± 16.76 years. The most common initial symptoms were cough, fever, and dyspnea. In 21 patients (5.8%), the initial symptom was neurological. History of dementia was associated with severe COVID-19 disease (odds ratio = 1.28). During the course of the disease, 186 patients (51.52%) had at least one neurological symptom, the most common being headache (109 [30.2%]), followed by anosmia/ageusia (69, [19.1%]), and dizziness (54, [15%]). Also, 31 patients had neurological complications (8.58%). Anosmia, ageusia, dizziness, and headache were associated with favorable outcome (P < 0.001), while altered mental status and hemiparesis were associated with poor outcome. The mortality rate of patients who had neurological complications was more than twice than that of patients without neurological complication (P = 0.008). Almost half of the patients experienced at least one neurological symptom, which may be the initial presentation of COVID-19. Dementia appears to be associated with severe COVID-19. Mortality was higher in patients with neurological complications, and these patients needed more intensive care.

'Long COVID': persistent COVID-19 symptoms in survivors managed in Lagos State, Nigeria.

BACKGROUND: Coronavirus disease once thought to be a respiratory infection is now recognised as a multi-system disease affecting the respiratory, cardiovascular, gastrointestinal, neurological, immune, and hematopoietic systems. An emerging body of evidence suggests the persistence of COVID-19 symptoms of varying patterns among some survivors. This study aimed to describe persistent symptoms in COVID-19 survivors and investigate possible risk factors for these persistent symptoms. METHODS: The study used a retrospective study design. The study population comprised of discharged COVID-19 patients. Demographic information, days since discharge, comorbidities, and persistent COVID-19 like symptoms were assessed in patients attending the COVID-19 outpatient clinic in Lagos State. Statistical analysis was done using STATA 15.0 software (StataCorp Texas) with significance placed at p-value < 0.05. RESULTS: A total of 274 patients were enrolled in the study. A majority were within the age group > 35 to ≤49 years (38.3%), and male (66.1%). More than one-third (40.9%) had persistent COVID-19 symptoms after discharge, and 19.7% had more than three persistent COVID-like symptoms. The most persistent COVID-like symptoms experienced were easy fatigability (12.8%), headaches (12.8%), and chest pain (9.8%). Symptomatic COVID-19 disease with moderate severity compared to mild severity was a predictor of persistent COVID-like symptoms after discharge (p < 0.05). CONCLUSION: Findings from this study suggests that patients who recovered from COVID-19 disease may still experience COVID-19 like symptoms, particularly fatigue and headaches. Therefore, careful monitoring should be in place after discharge to help mitigate the effects of these symptoms and improve the quality of life of COVID-19 survivors.

Diagnostic accuracy of symptoms as a diagnostic tool for SARS-CoV 2 infection: a cross-sectional study in a cohort of 2,173 patients.

BACKGROUND: The SARS-CoV-2 pandemic continues to be a priority health problem; According to the World Health Organization data from October 13, 2020, 37,704,153 confirmed COVID-19 cases have been reported, including 1,079,029 deaths, since the outbreak. The identification of potential symptoms has been reported to be a useful tool for clinical decision-making in emergency departments to avoid overload and improve the quality of care. The aim of this study was to evaluate the performances of symptoms as a diagnostic tool for SARS -CoV-2 infection. METHODS: An observational, cross-sectional, prospective and analytical study was carried out, during the period of time from April 14 to July 21, 2020. Data (demographic variables, medical history, respiratory and non-respiratory symptoms) were collected by emergency physicians. The diagnosis of COVID-19 was made using SARS-CoV-2 RT-PCR. The diagnostic accuracy of these characteristics for COVID-19 was evaluated by calculating the positive and negative likelihood ratios. A Mantel-Haenszel and multivariate logistic regression analysis was performed to assess the association of symptoms with COVID-19. RESULTS: A prevalence of 53.72% of SARS-CoV-2 infection was observed. The symptom with the highest sensitivity was cough 71%, and a specificity of 52.68%. The symptomatological scale, constructed from 6 symptoms, obtained a sensitivity of 83.45% and a specificity of 32.86%, taking ≥2 symptoms as a cut-off point. The symptoms with the greatest association with SARS-CoV-2 were: anosmia odds ratio (OR) 3.2 (95% CI; 2.52-4.17), fever OR 2.98 (95% CI; 2.47-3.58), dyspnea OR 2.9 (95% CI; 2.39-3.51]) and cough OR 2.73 (95% CI: 2.27-3.28). CONCLUSION: The combination of ≥2 symptoms / signs (fever, cough, anosmia, dyspnea and oxygen saturation < 93%, and headache) results in a highly sensitivity model for a quick and accurate diagnosis of COVID-19, and should be used in the absence of ancillary diagnostic studies. Symptomatology, alone and in combination, may be an appropriate strategy to use in the emergency department to guide the behaviors to respond to the disease. TRIAL REGISTRATION: Institutional registration R-2020-3601-145, Federal Commission for the Protection against Sanitary Risks 17 CI-09-015-034, National Bioethics Commission: 09 CEI-023-2017082 .

A Review of Neurological Involvement in Patients with SARS-CoV-2 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative pathogen of the recent pandemic of coronavirus disease 19 (COVID-19). As the infection spreads, there is increasing evidence of neurological and psychiatric involvement in COVID-19. Headache, impaired consciousness, and olfactory and gustatory dysfunctions are common neurological manifestations described in the literature. Studies demonstrating more specific and more severe neurological involvement such as cerebrovascular insults, encephalitis and Guillain-Barre syndrome are also emerging. Respiratory failure, a significant condition that leads to mortality in COVID-19, is hypothesized to be partly due to brainstem impairment. Notably, some of these neurological complications seem to persist long after infection. This review aims to provide an update on what is currently known about neurological involvement in patients with COVID-19 due to SARS-CoV-2 infection. In this review, we demonstrate invasion routes of SARS-CoV-2, provide evidence to support the neurotropism hypothesis of the virus, and investigate the pathological mechanisms that underlie neurological complications associated with SARS-CoV-2.

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.

Following the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), another highly pathogenic coronavirus named SARS-CoV-2 (previously known as 2019-nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS-CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID-19) with clinical symptoms similar to those reported for SARS-CoV and MERS-CoV. The most characteristic symptom of patients with COVID-19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID-19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS-CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse-connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Considering the high similarity between SARS-CoV and SARS-CoV2, it remains to make clear whether the potential invasion of SARS-CoV2 is partially responsible for the acute respiratory failure of patients with COVID-19. Awareness of this may have a guiding significance for the prevention and treatment of the SARS-CoV-2-induced respiratory failure.

The emergence of a novel coronavirus (SARS-CoV-2) disease and their neuroinvasive propensity may affect in COVID-19 patients.

An outbreak of a novel coronavirus (SARS-CoV-2) infection has recently emerged and rapidly spreading in humans causing a significant threat to international health and the economy. Rapid assessment and warning are crucial for an outbreak analysis in response to serious public health. SARS-CoV-2 shares highly homological sequences with SARS-CoVs causing highly lethal pneumonia with respiratory distress and clinical symptoms similar to those reported for SARS-CoV and MERS-CoV infections. Notably, some COVID-19 patients also expressed neurologic signs like nausea, headache, and vomiting. Several studies have reported that coronaviruses are not only causing respiratory illness but also invade the central nervous system through a synapse-connected route. SARS-CoV infections are reported in both patients and experimental animals' brains. Interestingly, some COVID-19 patients have shown the presence of SARS-CoV-2 virus in their cerebrospinal fluid. Considering the similarities between SARS-CoV and SARS-CoV-2 in various aspects, it remains to clarify whether the potent invasion of SARS-CoV-2 may affect in COVID-19 patients. All these indicate that more detailed criteria are needed for the treatment and the prevention of SARS-CoV-2 infected patients. In the absence of potential interventions for COVID-19, there is an urgent need for an alternative strategy to control the spread of this disease.

Ageusia and anosmia, a common sign of COVID-19? A case series from four countries.

Over the course of the pandemic due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), multiple new clinical manifestations, as the consequence of the tropism of the virus, have been recognized. That includes now the neurological manifestations and conditions, such as headache, encephalitis, as well as olfactory and taste disorders. We present a series of ten cases of RT-PCR-confirmed SARS-CoV-2-infected patients diagnosed with viral-associated olfactory and taste loss from four different countries.

Herpes simplex virus type 2 meningitis as a manifestation of Good's syndrome.

Good's syndrome is a primary immunodeficiency phenocopy characterized for thymoma and immunodeficiency. The most frequent clinical presentation is recurrent or opportunistic infections, hematological alterations, and chronic diarrhea. We treated a 66-year-old man who consulted for 5 days of headache and diplopia with right sixth cranial nerve palsy at examination. Patient reported chronic diarrhea and prolonged febrile syndrome accompanied by weight loss of 23 kg in the last year. Exhaustive evaluation revealed Herpes simplex virus (HSV) type 2 meningitis, eosinophilic colitis, and type A thymoma. Severe antibody deficiency (hypogammaglobulinemia) associated with thymoma confirmed the diagnosis of Good's syndrome.

COVID-19 and the nervous system.

A pandemic due to novel coronavirus arose in mid-December 2019 in Wuhan, China, and in 3 months' time swept the world. The disease has been referred to as COVID-19, and the causative agent has been labelled SARS-CoV-2 due to its genetic similarities to the virus (SARS-CoV-1) responsible for the severe acute respiratory syndrome (SARS) epidemic nearly 20 years earlier. The spike proteins of both viruses dictate tissue tropism using the angiotensin-converting enzyme type 2 (ACE-2) receptor to bind to cells. The ACE-2 receptor can be found in nervous system tissue and endothelial cells among the tissues of many other organs.Neurological complications have been observed with COVID-19. Myalgia and headache are relatively common, but serious neurological disease appears to be rare. No part of the neuraxis is spared. The neurological disorders occurring with COVID-19 may have many pathophysiological underpinnings. Some appear to be the consequence of direct viral invasion of the nervous system tissue, others arise as a postviral autoimmune process, and still others are the result of metabolic and systemic complications due to the associated critical illness. This review addresses the preliminary observations regarding the neurological disorders reported with COVID-19 to date and describes some of the disorders that are anticipated from prior experience with similar coronaviruses.

Neurological manifestations of COVID-19: available evidences and a new paradigm.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

Daily persistent headache after a viral illness during a worldwide pandemic may not be a new occurrence: Lessons from the 1890 Russian/Asiatic flu.

New daily persistent headache was first documented in the medical literature in the 1980s. The leading trigger is a viral illness. As we navigate our way thru the current SARS-CoV-2 pandemic, looking back at past viral epidemics may help guide us for what to expect in the near future in regard to headaches as a persistent manifestation of the SARS-CoV-2 infection. The 1890 viral pandemic known as the "Russian or Asiatic flu", has extensive documentation about the neurologic sequelae that presented months to years after the pandemic ended. One of the complications was daily persistent headache. There are actually many similarities between the viral presentation of the 1890 pandemic and the current SARS-CoV-2 pandemic, which may then suggest that not only will NDPH be part of the neurological sequelae but a possible key consequence of the SARS-CoV-2 infection.

Characteristics of headache attributed to COVID-19 infection and predictors of its frequency and intensity: A cross sectional study.

OBJECTIVE: To study the characteristics of headache attributed to COVID-19 infection and predictors of its severity. METHODS: A cross-sectional study involved 172 individuals who had headache due to COVID-19 infection. A detailed analysis of such headache was done through a face-to-face interview. Patients with any other form of secondary headache were excluded. Labs, including lymphocytic count, C-reactive protein, D-dimer and ferritin and chest imaging, were made available. RESULTS: THE: majority of our patients had a diffuse headache (52.9%). It was pressing in 40.7%, with median intensity of 7 (assessed by visual analogue scale) and median frequency of 7 days/week. Patients with preexisting primary headache (52.9%) had significantly more frequent COVID-19 related headache than those without (47.1%) (p = 0.001). Dehydrated patients (64.5%) had more frequent COVID-19 related headache than those who were not dehydrated (35.5%) (p = 0.029). Patients with fever (69.8%) had significantly higher frequency and intensity of COVID-19 related headache compared to those without fever (30.2%) (p = 0.003, 0.012). Patients with comorbidities (19.8%) had significantly higher frequency and intensity of headache than those without comorbidities (80.2%) (p = 0.006, 0.003). After multiple linear regression, primary headache disorders, dehydration and comorbidities were considered predictors of frequency of COVID-19 related headache. Meanwhile, fever and dehydration were predictors of pain intensity. CONCLUSION: Healthcare providers of COVID-19 patients need to be aware of frequency and intensity predictors of COVID-19 related headache: Primary headache disorders, fever, dehydration, and comorbidities.

Headache associated with COVID-19: Frequency, characteristics and association with anosmia and ageusia.

OBJECTIVES: To assess the frequency and characteristics of headache in patients with COVID-19 and whether there is an association between headache and anosmia and ageusia. METHODS: This was a cross-sectional study. Consecutive patients admitted to hospital with COVID-19, confirmed by reverse transcription polymerase chain reaction (RT-PCR) technique, were assessed by neurologists. RESULTS: Seventy-three patients were included in the study, 63% were male; the median age was 58 years (IQR: 47-66). Forty-seven patients (64.4%) reported headaches, which had most frequently begun on the first day of symptoms, were bilateral (94%), presenting severe intensity (53%) and a migraine phenotype (51%). Twelve patients (16.4%) presented with headache triggered by coughing. Eleven (15%) patients reported a continuous headache. Twenty-eight patients (38.4%) presented with anosmia and 29 (39.7%) with ageusia. Patients who reported hyposmia/anosmia and/or hypogeusia/ageusia experienced headache more frequently than those without these symptoms (OR: 5.39; 95% CI:1.66-17.45; logistic regression). Patients with anosmia and ageusia presented headache associated with phonophobia more often compared to those with headache without these complaints (Chi-square test; p < 0.05). Headache associated with COVID-19 presented a migraine phenotype more frequently in those experiencing previous migraine (p < 0.05). CONCLUSION: Headaches associated with COVID-19 are frequent, are generally severe, diffuse, present a migraine phenotype and are associated with anosmia and ageusia.

Headache: A striking prodromal and persistent symptom, predictive of COVID-19 clinical evolution.

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 = 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 = 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 = 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.

Phenotypic characterization of acute headache attributed to SARS-CoV-2: An ICHD-3 validation study on 106 hospitalized patients.

INTRODUCTION: Headache is a common symptom of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we aimed to characterize the phenotype of headache attributed to SARS-CoV-2 infection and to test the International Classification of Headache Disorders (ICHD-3) phenotypic criteria for migraine and tension-type headache. METHODS: The study design was a cross-sectional study nested in a cohort. We screened all consecutive patients that were hospitalized and had a positive SARS-CoV-2 test. We included patients that described headache if the headache was not better explained by another ICHD-3 diagnosis. Patients were interviewed by two neurologists. RESULTS: We screened 580 patients and included 130 (mean age 56 years, 64% female). Headache was the first symptom of the infection in 26% of patients and appeared within 24 hours in 62% of patients. The headache was bilateral in 85%, frontal in 83%, and with pressing quality in 75% of patients. Mean intensity was 7.1, being severe in 64%. Hypersensitivity to stimuli occurred in 57% of patients. ICHD-3 criteria for headache attributed to systemic viral infection were fulfilled by 94% of patients; phenotypic criteria for migraine were fulfilled by 25% of patients, and tension-type headache criteria by 54% of patients. CONCLUSION: Headache attributed to SARS-CoV-2 infection in hospitalized patients has severe intensity, frontal predominance and oppressive quality. It occurs early in the course of the disease. Most patients fulfilled ICHD-3 criteria for headache attributed to systemic viral infection; however, the phenotype might resemble migraine in a quarter of cases and tension-type headache in half of the patients.

COVID-19 is a Real Headache!

After the emergence of a novel coronavirus named SARS-CoV-2, coronavirus disease 2019 (COVID-19) was initially characterized by fever, sore throat, cough, and dyspnea, mainly manifestations of respiratory system. However, other manifestations such as headache, abdominal pain, diarrhea, loss of taste and smell were added to the clinical spectrum, during the course of the COVID-19 pandemic. The reports on the neurological findings are increasing rapidly and headache seems to be the leader on the symptom list. Headache was reported in 11%-34% of the hospitalized COVID-19 patients, but clinical features of these headaches were totally missing in available publications. According to our initial experience, significant features of headache presentation in the symptomatic COVID-19 patients were new-onset, moderate-severe, bilateral headache with pulsating or pressing quality in the temporoparietal, forehead or periorbital region. The most striking features of the headache were sudden to gradual onset and poor response to common analgesics, or high relapse rate, that was limited to the active phase of the COVID-19. Symptomatic COVID-19 patients, around 6%-10%, also reported headache as a presenting symptom. The possible pathophysiological mechanisms of headache include activation of peripheral trigeminal nerve endings by the SARS-CoV-2 directly or through the vasculopathy and/or increased circulating pro-inflammatory cytokines and hypoxia. We concluded that as a common non-respiratory symptom of COVID-19, headache should not be overlooked, and its characteristics should be recorded with scrutiny.

Headaches During COVID-19: My Clinical Case and Review of the Literature.

OBJECTIVE: To analyze headaches related to COVID-19 based on personal case experience. BACKGROUND: COVID-19 is an infection caused by the new coronavirus SARS-CoV-2. The first reported case happened in Wuhan on December 1, 2019. At present, at least 1.8 million people are infected around the world and almost 110,000 people have died. Many studies have analyzed the clinical picture of COVID-19, but they are focused on respiratory symptoms and headache is generically treated. METHODS: I describe and discuss my headaches during my COVID-19 and I review the MEDLINE literature about headaches and COVID-19. RESULTS: More than 41,000 COVID-19 patients have been included in clinical studies and headache was present in 8%-12% of them. However, no headache characterization was made in these studies. As a headache expert and based on my own personal clinical case, headaches related to COVID-19 can be classified in the 2 phases of the disease. Acute headache attributed to systemic viral infection, primary cough headache, tension-type headache and headache attributed to heterophoria can appear in the first phase (the influenza-like phase); and headache attributed to hypoxia and a new headache, difficult to fit into the ICHD3, can appear if the second phase (the cytokine storm phase) occurs. CONCLUSIONS: Several headaches can appear during COVID-19 infection. All of them are headaches specified in the ICHD3, except 1 that occurs from the 7th day after the clinical onset. This headache is probably related to the cytokine storm that some patients suffer and it could be framed under the ICHD3 headache of Headache attributed to other non-infectious inflammatory intracranial disease. Although the reported prevalence of headaches as a symptom of COVID-19 infection is low, this experience shows that, very probably, it is underestimated.