COVID-19 Biomarkers at the Crossroad between Patient Stratification and Targeted Therapy: The Role of Validated and Proposed Parameters.

Clinical knowledge about SARS-CoV-2 infection mechanisms and COVID-19 pathophysiology have enormously increased during the pandemic. Nevertheless, because of the great heterogeneity of disease manifestations, a precise patient stratification at admission is still difficult, thus rendering a rational allocation of limited medical resources as well as a tailored therapeutic approach challenging. To date, many hematologic biomarkers have been validated to support the early triage of SARS-CoV-2-positive patients and to monitor their disease progression. Among them, some indices have proven to be not only predictive parameters, but also direct or indirect pharmacological targets, thus allowing for a more tailored approach to single-patient symptoms, especially in those with severe progressive disease. While many blood test-derived parameters quickly entered routine clinical practice, other circulating biomarkers have been proposed by several researchers who have investigated their reliability in specific patient cohorts. Despite their usefulness in specific contexts as well as their potential interest as therapeutic targets, such experimental markers have not been implemented in routine clinical practice, mainly due to their higher costs and low availability in general hospital settings. This narrative review will present an overview of the most commonly adopted biomarkers in clinical practice and of the most promising ones emerging from specific population studies. Considering that each of the validated markers reflects a specific aspect of COVID-19 evolution, embedding new highly informative markers into routine clinical testing could help not only in early patient stratification, but also in guiding a timely and tailored method of therapeutic intervention.

Serum alpha-CGRP levels are increased in COVID-19 patients with headache indicating an activation of the trigeminal system.

BACKGROUND: Headache is among the most frequent symptoms of acute COVID-19 infection. Its mechanisms remain obscure, but due to its migraine-like characteristics, the activation of the trigeminal system could account for its underlying pathophysiology. METHODS: Our aim was to compare the serum levels of CGRP, as a theoretical marker of trigemino-vascular activation, in 25 COVID-19 inpatients with lung involvement experiencing headache, against 15 COVID-19 inpatients without headache and with those of 25 matched healthy controls with no headache history. RESULTS: Morning serum alpha-CGRP levels, as measured by ELISA (Abbexa, UK), were increased in COVID-19 patients with headache (55.2±34.3 pg/mL) vs. controls (33.9±14.0 pg/mL) (p < 0.01). Alpha-CGRP levels in COVID-19 patients without headache were also significantly increased (43.3 ± 12.8 pg/mL; p = 0.05) versus healthy controls, but were numerically lower (-28.2%; p = 0.36) as compared to COVID-19 patients with headache. CONCLUSION: CGRP levels are increased in COVID-19 patients experiencing headache in the acute phase of this disease, which could explain why headache frequently occurs in COVID-19 and strongly supports a role for trigeminal activation in the pathophysiology of headache in this viral infection.

Unusual Presentation of COVID-19 Headache and Its Possible Pathomechanism.

Headache was the most common neurological symptom during the H1N1 pandemic in 2009 and the most recrudescing symptom of human coronavirus (hCoV) in 2016. Even in this prevailing global coronavirus disease 2019 (COVID-19) pandemic, the main neurological symptom is found to be a headache. Headache phenotypes identified with COVID-19 are largely migraine, tension-type headache, or cough headache located in the frontotemporal or occipital region with wavering intensity and essentially of acute onset. We present two cases of unusual headache phenotypes with COVID-19 infection and attempt to shed light on their pathomechanism. Trigeminal autonomic cephalgia may be a possibility in our case, triggered by the virus itself, either directly or through an indirect path elaborated well in the pathomechanism segment. Severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2) located in the peripheral nerve and intracranial vascular endothelium, sensitizing the trigeminovascular system by further interacting with higher cortical pain centers via the thalamic and hypothalamic nuclei, producing pain. CSF analysis along with opening pressure measurement in Case 2 may portray a comprehensive understanding of our patient's headache. Coupling with the dorsal pons and trigeminal nucleus caudalis (TNC), the hypothalamus could be the supreme generator for an attack. Hypothalamic perturbance could be a possible phenomenon for abnormal headache experiences and requires further validation. The possible COVID-19 pain pathway pathomechanism engaging interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) alpha aided with a cortical spreading depression disturbing the hypothalamus is also described in this study. Undoubtedly, this pandemic could prove to be a guiding tool for mankind, for a comprehensive understanding of the enigmatic concepts of headaches.

CGRP Plasma Levels Correlate with the Clinical Evolution and Prognosis of Hospitalized Acute COVID-19 Patients.

SARS-CoV-2 is the etiological agent of COVID-19, an extremely heterogenous disease that can cause severe respiratory failure and critical illness. To date, reliable biomarkers allowing for early patient stratification according to disease severity are still lacking. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in lung pathophysiology and immune modulation and is poorly investigated in the COVID-19 context. In this observational, prospective cohort study, we investigated the correlation between CGRP and clinical disease evolution in hospitalized moderate to severe COVID-19 patients. Between January and May 2021 (Italian third pandemic wave), 135 consecutive SARS-CoV-2 patients were diagnosed as being eligible for the study. Plasma CGRP level evaluation and routine laboratory tests were performed on blood samples collected at baseline and after 7 days of hospitalization. At baseline, the majority our patients had a moderate to severe clinical presentation, and higher plasma CGRP levels predicted a higher risk of in-hospital negative evolution (odds-ratio OR 2.84 [IQR 1.07-7.51]) and were correlated with pulmonary intravascular coagulopathy (OR 2.92 [IQR 1.19-7.17]). Finally, plasma CGRP levels were also correlated with plasma IP10 levels. Our data support a possible crosstalk between the lung and the neuroimmune axis, highlighting a crucial role for plasma CGRP in sustaining COVID-19-related hyperinflammation.

Is Persistent Post-COVID Headache Associated With Protein-Protein Interactions Between Antibodies Against Viral Spike Protein and CGRP Receptor?: A Case Report.

Background: After the acute pandemic of coronavirus disease 2019 (COVID-19), a wide variety of symptoms are identified under the term post-COVID syndrome, such as persistent headache. Post-COVID headache can be presented in a broad spectrum like headache attributed to systemic infection, chronification of already existing primary headache, or long-lasting, and also late-onset new daily persistent headache. Still, little is known about the pathophysiology of post-COVID headache, but activation of the trigeminovascular system may be one of the players. Case Report: Here, we present a case with a severe, long-lasting post-COVID headache and its sudden cessation with calcitonin gene-related peptide (CGRP) monoclonal antibody treatment. Conclusion: In our previous protein mimicry study, we have pointed at mimicry of virus spike protein and CGRP receptors. This mechanism may enlighten the current, common, and yet unsolved post-COVID headache cases.

COVID-19 and Headache Disorders

Headache is a common symptom and the most common neurological manifestation in COVID-19. Its pathophysiology in COVID-19 remains elusive. It is largely managed by usual headache treatments that are dependent on clinical phenotype. When managing headache patients with or without a history of a primary headache disorder, one should take into consideration access to care, particularly in virus hotspots. © 2021 Elsevier Inc. All rights reserved.

New Generation Gepants: Migraine Acute and Preventive Medications.

Migraine is a debilitating disease whose clinical and social impact is out of debate. Tolerability issues, interactions, contraindications, and inefficacy of the available medications make new options necessary. The calcitonin-gene-related peptide (CGRP) pathway has shown its importance in migraine pathophysiology and specific medications targeting this have become available. The first-generation CGRP receptor antagonists or gepants, have undergone clinical trials but their development was stopped because of hepatotoxicity. The new generation of gepants, however, are efficacious, safe, and well tolerated as per recent clinical trials. This led to the FDA-approval of rimegepant, ubrogepant, and atogepant. The clinical trials of the available gepants and some of the newer CGRP-antagonists are reviewed in this article.

Calcitonin gene-related peptide: A biomarker for stroke in SARS-CoV-2 infection?

COVID-19 infection was mainly associated with respiratory symptoms, but lately, ischemic stroke (IS) has been reported in several cases. The incidence of IS in SARS-CoV-2 infection is increasing, and its mechanism is still not fully understood. Calcitonin gene-related peptide (CGRP) -the abundantly expressed protein in the peripheral and central nervous system- showed low expression in SARS-CoV-2 patients. This peptide is strongly implicated in regulating cerebral blood flow (CBF) and improving neurological deficits after cerebral arterial occlusion. We assume that a possible interplay between the low circulating levels of CGRP may affect CBF, thus worsening the symptoms of IS in SARS-CoV-2 patients.

Safety of anti-CGRP monoclonal antibodies in patients with migraine during the COVID-19 pandemic: Present and future implications.

BACKGROUND AND OBJECTIVE: CGRP, a neuropeptide involved in migraine pathophysiology, is also known to play a role in the respiratory system and in immunological conditions such as sepsis. We analyzed the impact of the use of CGRP antagonists in patients with migraine during the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus. METHODS: This is a multicentre cross-sectional study. From May to November 2020, through a national survey distributed by the Spanish Society of Neurology, we collected data about the presence of COVID-19 symptoms including headache and their characteristics and severity in patients with migraine treated with anti-CGRP monoclonal antibodies (mAb), and compared them with patients with migraine not receiving this treatment. We also conducted a subanalysis of patients with COVID-19 symptoms. RESULTS: We recruited 300 patients with migraine: 51.7% (155/300) were taking anti-CGRP mAbs; 87.3% were women (262/300). Mean age (standard deviation) was 47.1 years (11.6). Forty-one patients (13.7%) met diagnostic criteria for COVID-19, with no statistically significant difference between patients with and without anti-CGRP mAb treatment (16.1% vs 11.0%, respectively; P=.320). Of the patients with COVID-19, 48.8% (20/41) visited the emergency department and 12.2% (5/41) were hospitalised. Likewise, no clinical differences were found between the groups of patients with and without anti-CGRP mAb treatment. CONCLUSION: Anti-CGRP mAbs may be safe in clinical practice, presenting no association with increased risk of COVID-19.

HMGB1, NLRP3, IL-6 and ACE2 levels are elevated in COVID-19 with headache: a window to the infection-related headache mechanism.

BACKGROUND AND AIM: Pathogenesis of COVID-19 -related headache is unknown, though the induction of the trigeminal neurons through inflammation is proposed. We aimed to investigate key systemic circulating inflammatory molecules and their clinical relations in COVID-19 patients with headache. METHODS: This cross-sectional study enrolled 88 COVID-19 patients, hospitalized on a regular ward during the second wave of the pandemic. Clinical characteristics of COVID-19 patients were recorded, and laboratory tests were studied. RESULTS: The mean ages of 48 COVID-19 patients with headache (47.71 ± 10.8) and 40 COVID-19 patients without headache (45.70 ± 12.72) were comparable. COVID-19 patients suffered from headache had significantly higher serum levels of HMGB1, NLRP3, ACE2, and IL-6 than COVID-19 patients without headache, whereas CGRP and IL-10 levels were similar in the groups. Angiotensin II level was significantly decreased in the headache group. COVID-19 patients with headache showed an increased frequency of pulmonary involvement and increased D- dimer levels. Furthermore, COVID-19 was more frequently associated with weight loss, nausea, and diarrhea in patients with headache. Serum NLRP3 levels were correlated with headache duration and hospital stay, while headache response to paracetamol was negatively correlated with HMGB1 and positively associated with IL-10 levels. CONCLUSION: Stronger inflammatory response is associated with headache in hospitalized COVID-19 patients with moderate disease severity. Increased levels of the circulating inflammatory and/or nociceptive molecules like HMGB1, NLRP3, and IL-6 may play a role in the potential induction of the trigeminal system and manifestation of headache secondary to SARS-CoV-2 infection.

Impact of COVID-19 on chronic migraine treated with erenumab: a case report.

BACKGROUND: Headache is a frequent symptom of the novel coronavirus 19 disease (COVID-19). To date, there are limited information on how COVID-19 affects migraine and its treatment. CASE DESCRIPTION: A 47-year-old patient, suffering from chronic migraine and medication-overuse headache, in September 2020 started erenumab at 70 mg once monthly. Two months later, monthly migraine days decreased from 20 to 5. On the third month, the patient developed mild COVID-19 symptoms, experiencing extreme fatigue, hyposmia, and attention deficit, resulting positive for SARS-Cov-2 RNA. A significant increase in migraine attacks frequency was reported. Brain MRI and EEG were normal. Erenumab was increased to 140 mg/month, and attacks decreased to 3 monthly migraine days and remained stable. All the headaches experienced by our patient during the infection fulfilled the criteria of the migraine attacks, without tensive-like features. CONCLUSION: We report the first case showing the effects of SARS-CoV-2 infection in a patient with chronic migraine and medication-overuse headache treated with erenumab. Our case description suggests that inflammatory processes induced by SARS-CoV-2 infection may increase the frequency of migraine attacks, probably through an activation of the trigeminovascular system. Whether treatment with CGRP receptor antagonist may influence COVID is still debated. Additional studies regarding anti-CGRP monoclonal antibodies in COVID-19 patients are warranted.

Navigating migraine care through the COVID-19 pandemic: an update.

The worldwide treatment gap for migraine before COVID-19 inevitably widens as attention focuses on an international emergency. Migraine hits people particularly in their early and middle years, potentially reduces quality of life and productivity, and remains a common emergency presentation. This article examines the impact of COVID-19 on migraine, and changing aspects of migraine care during and after the pandemic. Many risk factors for severe COVID-19-older age, male gender, cardiac and respiratory diseases, diabetes, obesity, and immunosuppression-are less frequent in migraineurs. Telemedicine is effective for migraine follow-up, and needs ongoing evaluation. Most migraine treatments can start or continue in acute COVID-19, with care to avoid drug interactions. Close contact procedures (botulinum toxin, acupuncture and steroid injections) are avoided in lockdown or in the vulnerable. Secondary effects of COVID-19, including long COVID and its economic impact, are probably equal or greater in people with migraine. Migraine and other long-term conditions need adequate resourcing to prevent personal, social and economic suffering. Treating migraine, a sequel of COVID, potentially reduces the impact of long COVID.

Neurotransmitters and Neuropeptides decrease PD-1 in T cells of healthy subjects and patients with hepatocellular carcinoma (HCC), and increase their proliferation and eradication of HCC cells.

T cells of aged people, and of patients with either cancer or severe infections (including COVID-19), are often exhausted, senescent and dysfunctional, leading to increased susceptibilities, complications and mortality. Neurotransmitters and Neuropeptides bind their receptors in T cells, and induce multiple beneficial T cell functions. Yet, T cells of different people vary in the expression levels of Neurotransmitter and Neuropeptide receptors, and in the magnitude of the corresponding effects. Therefore, we performed an individual-based study on T cells of 3 healthy subjects, and 3 Hepatocellular Carcinoma (HCC) patients. HCC usually develops due to chronic inflammation. The inflamed liver induces reduction and inhibition of CD4+ T cells and Natural Killer (NK) cells. Immune-based therapies for HCC are urgently needed. We tested if selected Neurotransmitters and Neuropeptides decrease the key checkpoint protein PD-1 in human T cells, and increase proliferation and killing of HCC cells. First, we confirmed human T cells express all dopamine receptors (DRs), and glutamate receptors (GluRs): AMPA-GluR3, NMDA-R and mGluR. Second, we discovered that either Dopamine, Glutamate, GnRH-II, Neuropeptide Y and/or CGRP (10nM), as well as DR and GluR agonists, induced the following effects: 1. Decreased significantly both %PD-1+ T cells and PD-1 expression level per cell (up to 60% decrease, within 1 h only); 2. Increased significantly the number of T cells that proliferated in the presence of HCC cells (up to 7 fold increase), 3. Increased significantly T cell killing of HCC cells (up to 2 fold increase). 4. Few non-conventional combinations of Neurotransmitters and Neuropeptides had surprising synergistic beneficial effects. We conclude that Dopamine, Glutamate, GnRH-II, Neuropeptide Y and CGRP, alone or in combinations, can decrease % PD-1+ T cells and PD-1 expression per cell, in T cells of both healthy subjects and HCC patients, and increase their proliferation in response to HCC cells and killing of HCC cells. Yet, testing T cells of many more cancer patients is absolutely needed. Based on these findings and previous ones, we designed a novel "Personalized Adoptive Neuro-Immunotherapy", calling for validation of safety and efficacy in clinical trials.

Safety of anti-CGRP monoclonal antibodies in patients with migraine during the COVID-19 pandemic: Present and future implications.

BACKGROUND AND OBJECTIVE: CGRP, a neuropeptide involved in migraine pathophysiology, is also known to play a role in the respiratory system and in immunological conditions such as sepsis. We analyzed the impact of the use of CGRP antagonists in patients with migraine during the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus. METHODS: This is a multicentre cross-sectional study. From May to November 2020, through a national survey distributed by the Spanish Society of Neurology, we collected data about the presence of COVID-19 symptoms including headache and their characteristics and severity in patients with migraine treated with anti-CGRP monoclonal antibodies (mAb), and compared them with patients with migraine not receiving this treatment. We also conducted a subanalysis of patients with COVID-19 symptoms. RESULTS: We recruited 300 patients with migraine: 51.7% (155/300) were taking anti-CGRP mAbs; 87.3% were women (262/300). Mean age (standard deviation) was 47.1 years (11.6). Forty-one patients (13.7%) met diagnostic criteria for COVID-19, with no statistically significant difference between patients with and without anti-CGRP mAb treatment (16.1% vs 11.0%, respectively; P=.320). Of the patients with COVID-19, 48.8% (20/41) visited the emergency department and 12.2% (5/41) were hospitalised. Likewise, no clinical differences were found between the groups of patients with and without anti-CGRP mAb treatment. CONCLUSION: Anti-CGRP mAbs may be safe in clinical practice, presenting no association with increased risk of COVID-19.

Circulating Levels of Calcitonin Gene-Related Peptide Are Lower in COVID-19 Patients.

BACKGROUND: To better understand the biology of COVID-19, we have explored the behavior of calcitonin gene-related peptide (CGRP), an angiogenic, vasodilating, and immune modulating peptide, in severe acute respiratory syndrome coronavirus 2 positive patients. METHODS: Levels of CGRP in the serum of 57 COVID-19 patients (24 asymptomatic, 23 hospitalized in the general ward, and 10 admitted to the intensive care unit) and healthy donors (n = 24) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, to better understand the physiological consequences of the observed variations, we investigated by immunofluorescence the distribution of receptor activity modifying protein 1 (RAMP1), one of the components of the CGRP receptor, in autopsy lung specimens. RESULTS: CGRP levels were greatly decreased in COVID-19 patients (P < 0.001) when compared to controls, and there were no significant differences due to disease severity, sex, age, or comorbidities. We found that COVID-19 patients treated with proton pump inhibitors had lower levels of CGRP than other patients not taking this treatment (P = 0.001). RAMP1 immunoreactivity was found in smooth muscle cells of large blood vessels and the bronchial tree and in the airways´ epithelium. In COVID-19 samples, RAMP1 was also found in proliferating type II pneumocytes, a common finding in these patients. CONCLUSIONS: The lower levels of CGRP should negatively impact the respiratory physiology of COVID-19 patients due to vasoconstriction, improper angiogenesis, less epithelial repair, and faulty immune response. Therefore, restoring CGRP levels in these patients may represent a novel therapeutic approach for COVID-19.

CGRP Receptor Antagonism in COVID-19: Potential Cardiopulmonary Adverse Effects.

Recently, the US FDA has authorized a drug repurposing trial with calcitonin gene-related peptide (CGRP) receptor antagonists to reduce lung inflammation in coronavirus 2019 (COVID-19). However, the well-established cardiopulmonary protective effects of CGRP raise concerns about the safety of antagonizing CGRP in COVID-19. Awareness regarding potential cardiopulmonary adverse effects may enable their early detection and prevent illness from worsening.

Hospital-based headache care during the Covid-19 pandemic in Denmark and Norway.

BACKGROUND: The Covid-19 pandemic is causing changes in delivery of medical care worldwide. It is not known how the management of headache patients was affected by the lockdown during the pandemic. The aim of the present study was to investigate how the initial phase of the Covid-19 pandemic affected the hospital management of headache in Denmark and Norway. METHODS: All neurological departments in Denmark (n = 14) and Norway (n = 18) were invited to a questionnaire survey. The study focused on the lockdown and all questions were answered in regard to the period between March 12th and April 15th, 2020. RESULTS: The responder rate was 91% (29/32). Of the neurological departments 86% changed their headache practice during the lockdown. The most common change was a shift to more telephone consultations (86%). Video consultations were offered by 45%. The number of new headache referrals decreased. Only 36% administered botulinum toxin A treatment according to usual schemes. Sixty% reported that fewer patients were admitted for in-hospital emergency diagnostics and treatment. Among departments conducting headache research 57% had to halt ongoing projects. Overall, 54% reported that the standard of care was worse for headache patients during the pandemic. CONCLUSION: Hospital-based headache care and research was impacted in Denmark and Norway during the initial phase of the Covid-19-pandemic.

Locking down the CGRP pathway during the COVID-19 pandemic lockdown: the PandeMig study.

OBJECTIVES: The COVID-19 pandemic and the consequent lockdown came as a storm disrupting people's everyday life. This study aimed at observing whether the COVID-19 related lockdown influenced migraine frequency and disability in migraine patients on therapy with monoclonal antibodies inhibiting the CGRP pathway. METHODS: In this longitudinal observational cohort study, 147 consecutive patients receiving monthly administration of erenumab or galcanezumab were enrolled in four Italian headache centers. All patients filled a questionnaire concerning working and household settings, recent flu symptoms or COVID-19 diagnosis, and family loss due to COVID-19 infection. Monthly migraine days (MMDs), monthly painkiller intake (MPI), and HIT-6 disability relative to the first month of lockdown imposition (T-lock) and the month before (T-free) were also collected. RESULTS: From T-free to T-lock, the cohort displayed a reduction in MMDs (from 10.5 ± 7.6 to 9.8 ± 7.6, p = .024) and HIT-6 scores (from 59.3 ± 8.3 men reduced MPI more frequently than women (p = .005). CONCLUSIONS: Our study observed that the lockdown impact to 57.8 ± 8.8, p = .009), while MPI resulted unchanged (from 11.6 ± 11.5 to 11.1 ± 11.7; p = .114). MMDs, MPI, and HIT-6 variations from T-free to T-lock did not differ according to work settings or household. Patients beyond the first 3 months of therapy presented less often a reduction in MMDs (p = .006) and on everyday life did not affect the migraine load in patients receiving monoclonal antibodies inhibiting the CGRP pathway. Patients in the first months of therapy experienced a greater improvement according to drug pharmacokinetics, while women more frequently needed rescue medications, possibly indicating presenteeism or cephalalgophobia.