Dupilumab as a steroid-sparing treatment option in pediatric severe asthma and chronic rhinosinusitis with nasal polyps

Case report Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequent comorbidity in severe asthma in adults. Both diseases share key pathophysiological mechanisms that can involve type-2 inflammatory pathways. However, this is an uncommon presentation in pediatric patients. Dupilumab, a fully human monoclonal antibody against IL-4Ralpha, inhibits IL-4/ IL-13 signaling, which are key drivers of type-2 inflammation and interfere with both eosinophilic and allergic pathways. It is approved for patients >= 12-year- old with moderate to severe uncontrolled asthma, but its approval in CRSwNP is limited to adults. We report a case of a 12-year- old boy with severe uncontrolled asthma and highly symptomatic CRSwNP referred to our center in May 2021. He was sensitized to house dust mite and pollens, and a specific immunotherapy had been tried previously. He was treated with high dose inhaled corticosteroid, long-acting beta agonist, long-acting muscarinic antagonist, montelukast and daily intra-nasal corticosteroids. Furthermore, a bilateral endoscopic sinus surgery with polypectomy was performed in April 2021. Despite adherence to medication and surgical treatment, both diseases were uncontrolled with frequent exacerbations requiring unscheduled visits and multiple systemic corticosteroid courses. This led to failure to thrive and several missed school days. Oral corticosteroid (OCS) tapering was unachieved due to symptoms rebound and so maintenance therapy with prednisolone 10mg daily was attempted, with only a slight improvement. High levels of eosinophils (1010 cells/muL), FeNO (122 ppb) and IgE (2255 kU/L) were present. Treatment with subcutaneous dupilumab was started in July 2021. A clinical and analytical improvement was evident at the 3-month evaluation (Table 1). He was able to stop prednisolone, and no clinically relevant exacerbations occurred. He also was fully vaccinated and had an asymptomatic COVID-19 infection in December 2021. Patients with CRSwNP and comorbid asthma have a higher disease burden than patients with each disease alone. In this adolescent, dupilumab was effective as an add-on treatment, for both severe asthma and CRSwNP. It led to disease control, OCS withdrawal, reduced eosinophilic inflammation, improved lung function, smell recovery and absence of exacerbations during follow-up. Dupilumab, targeting the type 2 inflammatory process, may allow a better management of pediatric patients >=12 years old with severe CRSwNP and comorbid asthma. (Table Presented).

Evaluation of the Effect of Underlying Diseases on Mortality of COVID-19 Patients: A Study of 19,985 Cases

Background: The outbreak of a new coronavirus in China in 2019 (COVID-19) caused a global health crisis. Objective(s): This study was performed to investigate the effect of different underlying diseases on mortality in patients with COVID-19. Method(s): This retrospective cohort study was performed on COVID-19 patients admitted to the Shahid Rahimi and Sohada-ye Ashayer teaching hospitals in Khorramabad, Iran, from 2019 to 2021. Data on disease severity, clinical manifestations, mortality, and underlying disorders were collected and analyzed using the SPSS software version 22 at a 95% confidence interval and 0.05 sig-nificance level. Result(s): The study included 9653 men (48%) and 10332 women (52%). Patients with chronic kidney diseases, cancer, chronic obstruc-tive pulmonary disease, hypertension, cardiovascular disease, and diabetes were at higher mortality risk than those without these underlying diseases, respectively. However, there was no significant relationship between asthma and mortality. Also, age > 50 years, male gender, oxygen saturation < 93 on admission, and symptoms lasting <= 5 days were associated with increased mortality. Conclusion(s): Since patients with underlying diseases are at higher mortality risk, they should precisely follow the advice provided by health authorities and receive a complete COVID-19 vaccination series.Copyright © 2022, Author(s).

Risk stratified physician associate asthma review

Background: COVID-19 placed unprecedented care on the NHS. Patients with asthma had limited chronic disease management. We adopted a Proactive Asthma Care framework1 to help prioritise those that were at highest risk of attacks. Aim(s): To target asthma reviews such that patients at highest risk were reviewed first. Result(s): Patients were categorised as red (Long-acting beta agonist (LABA) no Inhaled Corticosteroid (ICS), >/=2 Oral corticosteroid (OCS) courses, No ICS and >3 Short-acting beta agonist (SABA) in the past year) or amber (ICS & >6 SABA) or Green (<6 ICS & >3 SABA). Two Physician Associates attempted to contact 1,289 patients and successfully reviewed 785 patients. 600 patients fell into the red/amber categories with 428 of them being successfully contacted. Of those contacted 396 were amber, and the remaining 32 were red. In the green group (689 patients), 357 were successfully contacted and reviewed. Asthma management was optimised in 361 patients (46%) and 134 patients (17%) were referred to secondary care services. Of the 361 patients optimised, 20 (6%) were started on an ICS, 119 (33%) originally on an ICS alone were changed to ICS/LABA and 55 (15%) had a Long-acting Muscarinic Antagonist (LAMA) added to their regime. Conclusion(s): Adopting a risk-based review algorithm led to an improved asthma management in 63% of patients (those with changes in management and referral to secondary care).

Cardiac effects and toxicity of chloroquine: a short update.

There is currently increased interest in the use of the antimalarial drugs chloroquine and hydroxychloroquine for the treatment of other diseases, including cancer and viral infections such as coronavirus disease 2019 (COVID-19). However, the risk of cardiotoxic effects tends to limit their use. In this review, the effects of these drugs on the electrical and mechanical activities of the heart as well as on remodelling of cardiac tissue are presented and the underlying molecular and cellular mechanisms are discussed. The drugs can have proarrhythmic as well as antiarrhythmic actions resulting from their inhibition of ion channels, including voltage-dependent Na+ and Ca2+ channels, background and voltage-dependent K+ channels, and pacemaker channels. The drugs also exert a vagolytic effect due at least in part to a muscarinic receptor antagonist action. They also interfere with normal autophagy flux, an effect that could aggravate ischaemia/reperfusion injury or post-infarct remodelling. Most of the toxic effects occur at high concentrations, following prolonged drug administration or in the context of drug associations.

Donepezil Beyond Alzheimer’s Disease? A Narrative Review of Therapeutic Potentials of Donepezil in Different Diseases

Donepezil hydrochloride is an acetylcholine esterase inhibitor studied and approved to treat Alzheimer’s disease (AD). However, this drug can have positive therapeutic potential in treating different conditions, including various neurodegenerative disorders such as other types of dementia, multiple sclerosis, Parkinson’s disease, psychiatric and mood disorders, and even infectious diseases. Hence, this study reviewed the therapeutic potential of this drug in treating Alzheimer’s and other diseases by reviewing the articles from databases including Web of Science, Scopus, PubMed, Cochrane, and Science Direct. It was shown that donepezil could affect the pathophysiology of these diseases via mechanisms such as increasing the concentration of acetylcholine, modulating local and systemic inflammatory processes, affecting acetylcholine receptors like nicotinic and muscarinic receptors, and activating various cellular signaling via receptors like sigma-1 receptors. Despite many therapeutic potentials, this drug has not yet been approved for treating non-Alzheimer’s diseases, and more comprehensive studies are needed.

A RARE PRESENTATION OF RENAL CELL CARCINOMA: PARANEOPLASTIC COUGH

CASE: A 30-year-old woman with a history of hypertension, obesity, and reactive airway disease presents with a two-month history of persistent cough, wheeze, and diaphoresis. At that time, chest x-ray and COVID-19 PCR were negative and pulmonary function tests were within normal limits. Her symptoms were managed with inhaled corticosteroid/long-acting muscarinic antagonist, albuterol, guaifenesin, and second-generation antihistamines. However, she continued to be symptomatic. Two months after these symptoms arose, she presented to the ED with a sixhour history of sudden onset right non-radiating flank pain. Her symptoms were associated with acute onset nausea, vomiting, urinary frequency, urgency, hesitancy, and burning;negative for hematuria. She was hemodynamically stable and physical exam was significant for right flank tenderness. Urinalysis showed proteinuria of 100 mg/dL and gross hematuria. Imaging of the abdomen demonstrated an enlarged right kidney with a large mass involving the cortex with mass effect on the liver. Urology performed a right radical nephrectomy with pathology positive for chromophobe renal cell carcinoma. Following surgery, the patient's original symptoms of cough, wheezing, and diaphoresis resolved. IMPACT/DISCUSSION: The typical symptomatic presentation of renal carcinoma with flank pain, abdominal mass, hematuria, and weight loss occurs in roughly 9% of cases and is indicative of advanced disease. Renal cell carcinoma is most commonly found incidentally on imaging studies, leading to improved outcomes due to early recognition. Young patients, however, are more likely to present symptomatically. Our patients' initial presentation of cough could be due to two different mechanisms. One possibility is chronic irritation of the diaphragm due to mass effect from the growing tumor. This mechanism is possible in our case as there was minor mass effect on the liver which could then disturb the diaphragm. A more likely mechanism is a paraneoplastic process. This has been demonstrated in prior cases with a chronic unremitting cough associated with diaphoresis, not improved with anti-tussives, and resolves upon removal of the mass. The cough has been shown to return with metastases. The proposed mechanism is tumor secretion of prostaglandins which enhance the cough reflex. Our case displays an uncommon symptomatic presentation of renal cell carcinoma in a young woman due to paraneoplastic cough stimulation. This demonstrates the importance of digging deeper when common symptoms such as cough are not successfully resolved with typical treatments. CONCLUSION: Most commonly renal cancer is diagnosed on incidental imaging allowing clinicians to make a diagnosis before symptoms arise. An unremitting cough may be an early warning sign of renal cell carcinoma before urinary symptoms begin, making early diagnosis more likely. Due to this, seemingly minor symptoms such as cough should be followed through to diagnosis as they can have significant consequences.

Novel Agents for Treatment of Delirium: A Proposal for a Multimodal Approach

Background: Delirium, a syndrome characterized by impairment in attention and consciousness, commonly occurs in hospital setting and is associated with higher mortality and poor long-term outcomes. With precise etiology of delirium yet to be elucidated, our current understanding describes delirium as a state of multifactorial global brain dysfunction occurring in susceptible elderly and critically ill patients. (Maldonado, 2008) To treat such a multimodal disorder, we propose investigating two novel multimodal pharmacological approaches: Granulocyte-macrophage colony stimulating factor (GM-CSF) inhibitors and pro-cholinergic muscarinic-receptor agonists. Discussion: Neuroinflammation is a focus of inquiry in a number of neuropsychiatric diseases. Unlike individual cytokine (TNF, IL-6) inhibitors, GM-CSF inhibitors combat the entire inflammatory cascade implicated in delirium: blunting the cytokine response (IL-1, IL-6, TNF) to reduce inflammation, limiting chemotaxis (IL-8 inhibition), reducing cell degradation (H2O2, MMPs), and dulling the T- and B-cell response. (Patel, 2021) GC-CSF inhibitors (otilimab and TMJ2) have already been shown to be effective in and approved for the treatment of inflammatory conditions, such as Rheumatoid Arthritis, and have been effective in treatment of inflammatory processes of COVID-19. (Patel, 2021) Given the role of the neuroinflammatory cascade in delirium, we propose investigating the GM-CSF inhibitors to treat delirium. Acetylcholine dysregulation (‘anticholinergic surge’), on the other hand, has long been implicated in delirium and studies suggest some efficacy of acetylcholinesterase inhibitors in treatment of delirium. Novel schizophrenia treatment studies combine xanomeline, a M-receptor agonist, with trospium, a peripheral anticholinergic, to create a net-positive pro-cholinergic state in the brain while minimizing systemic side-effects. (Brannan, 2020) In addition to treating schizophrenia and cognitive impairment, this combination (KarXT), may be useful in reversing the anti-cholinergic state of the delirious brain. Currently in Phase III clinical trials, KarXT should be considered a viable candidate for delirium treatment, once FDA-approved. Conclusions: Pharmacological approaches to delirium have been limited to managing behavioral dysregulation and sleep-wake cycle disturbances. Presently, we are looking at two potential additional approaches to delirium treatment. One is limited to cholinergic circuitry and aims to restore AcH balance via direct M-receptor agonism. The other, based on Systems Integration Failure Hypothesis, addresses the entire inflammatory cascade via GM-CSF inhibition. As agents from both classes are either approved or are close to FDA-approval, we should consider them as candidates for delirium management. References: 1. Maldonado, J, Kapinos, G. (2008). Pathoetiological Model of Delirium, Critical care clinics. 24. 789-856, ix. 10.1016/j.ccc.2008.06.004. 2. Brannan, S, Sawchak, S, et al.(2020). Efficacy and Safety of Xanomeline, a M1/M4 Receptor Preferencing Agonist, Plus Trospium, a Peripheral Muscarinic Antagonist, in Schizophrenia. Biological Psychiatry, 87(9), S169. doi: 10.1016/j.biopsych.2020.02.446 3. Patel, S, Saxena, B., Mehta, P. (2021). Recent updates in the clinical trials of therapeutic monoclonal antibodies targeting cytokine storm for the management of COVID-19. Heliyon, 7(2), e06158. doi: 10.1016/j.heliyon.2021.e06158

Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms.

Impairment of health after overcoming the acute phase of COVID-19 is being observed more and more frequently. Here different symptoms of neurological and/or cardiological origin have been reported. With symptoms, which are very similar to the ones reported but are not caused by SARS-CoV-2, the occurrence of functionally active autoantibodies (fAABs) targeting G-protein coupled receptors (GPCR-fAABs) has been discussed to be involved. We, therefore investigated, whether GPCR-fAABs are detectable in 31 patients suffering from different Long-COVID-19 symptoms after recovery from the acute phase of the disease. The spectrum of symptoms was mostly of neurological origin (29/31 patients), including post-COVID-19 fatigue, alopecia, attention deficit, tremor and others. Combined neurological and cardiovascular disorders were reported in 17 of the 31 patients. Two recovered COVID-19 patients were free of follow-up symptoms. All 31 former COVID-19 patients had between 2 and 7 different GPCR-fAABs that acted as receptor agonists. Some of those GPCR-fAABs activate their target receptors which cause a positive chronotropic effect in neonatal rat cardiomyocytes, the read-out in the test system for their detection (bioassay for GPCR-fAAB detection). Other GPCR-fAABs, in opposite, cause a negative chronotropic effect on those cells. The positive chronotropic GPCR-fAABs identified in the blood of Long-COVID patients targeted the ß2-adrenoceptor (ß2-fAAB), the α1-adrenoceptor (α1-fAAB), the angiotensin II AT1-receptor (AT1-fAAB), and the nociceptin-like opioid receptor (NOC-fAAB). The negative chronotropic GPCR-fAABs identified targeted the muscarinic M2-receptor (M2-fAAB), the MAS-receptor (MAS-fAAB), and the ETA-receptor (ETA-fAAB). It was analysed which of the extracellular receptor loops was targeted by the autoantibodies.