Inherited deficiency of the OAS-RNase L pathway in children with MIS-C

Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic dsRNA-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the ssRNA-degrading RNase L. Consistent with the absence of pneumonia in these patients, epithelial cells and fibroblasts defective for this pathway restricted SARS-CoV-2 normally. This contrasted with IFNAR1-deficient cells from patients prone to hypoxemic pneumonia without MIS-C. Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNASEL deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or SARS-CoV- 2 stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-but not RNase L- deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.Copyright © 2023 Elsevier Inc.

Corona With Lyme: A Long COVID Case Study.

The longevity of the coronavirus disease 2019 (COVID-19) pandemic has necessitated continued discussion about the long-term impacts of SARS-CoV-2 infection. Many who develop an acute COVID-19 infection will later face a constellation of enduring symptoms of varying severity, otherwise known as long COVID. As the pandemic reaches its inevitable endemicity, the long COVID patient population will undoubtedly grow and require improved recognition and management. The case presented describes the three-year arc of a previously healthy 26-year-old female medical student from initial infection and induction of long COVID symptomology to near-total remission of the disease. In doing so, the course of this unique post-viral illness and the trials and errors of myriad treatment options will be chronologized, thereby contributing to the continued demand for understanding this mystifying disease.

COVID-19 and the developing brain

As of June 2022, children represent 18.9% of total cumulated cases of COVID-19 in the United States. While most children have mild symptoms, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect the central and peripheral nervous system function. The most common neurological symptoms in children with COVID-19 are headache, fatigue, anosmia, dysgeusia, and myalgia. In hospitalized children, the most common symptoms are headache, encephalopathy, and seizures. Neurological symptoms are associated with a more severe disease course, and up to a third of hospitalized children with COVID-19 require intensive care intervention. A rare and feared complication is multisystem inflammatory syndrome (MIS-C), a serious condition that involves severe inflammation of different organs, including the brain. Treatment for MIS-C has not been validated and primarily consists of supportive care and immune modulation. Some children with a history of COVID-19 develop persistent symptoms, also known as long COVID. However, recent evidence suggests that long COVID symptoms appear as frequently as in children without a history of COVID-19. Similarly, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2, is associated with differences in neurodevelopmental milestones. Almost 3years into the pandemic, the evidence in children is limited. Large-scale studies with adequate pre- and post-pandemic control groups are needed to establish the associations between COVID-19 and short and long-term neurological complications. © 2023 Elsevier Inc. All rights reserved

Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC).

COVID-19, with persistent and new onset of symptoms such as fatigue, post-exertional malaise, and cognitive dysfunction that last for months and impact everyday functioning, is referred to as Long COVID under the general category of post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is highly heterogenous and may be associated with multisystem tissue damage/dysfunction including acute encephalitis, cardiopulmonary syndromes, fibrosis, hepatobiliary damages, gastrointestinal dysregulation, myocardial infarction, neuromuscular syndromes, neuropsychiatric disorders, pulmonary damage, renal failure, stroke, and vascular endothelial dysregulation. A better understanding of the pathophysiologic mechanisms underlying PASC is essential to guide prevention and treatment. This review addresses potential mechanisms and hypotheses that connect SARS-CoV-2 infection to long-term health consequences. Comparisons between PASC and other virus-initiated chronic syndromes such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome will be addressed. Aligning symptoms with other chronic syndromes and identifying potentially regulated common underlining pathways may be necessary for understanding the true nature of PASC. The discussed contributors to PASC symptoms include sequelae from acute SARS-CoV-2 injury to one or more organs, persistent reservoirs of the replicating virus or its remnants in several tissues, re-activation of latent pathogens such as Epstein-Barr and herpes viruses in COVID-19 immune-dysregulated tissue environment, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation dysregulation, dysfunctional brainstem/vagus nerve signaling, dysautonomia or autonomic dysfunction, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage specific patients.

The Incidence of Long-Term Fatigue in Patients Who Achieved Remission From COVID-19 at King Abdulaziz Medical City.

Introduction Long-term fatigue is a common condition that involves both physical and psychiatric symptoms, and it affects multiple age groups and causes morbidity and disabling symptoms that range from mild to severe symptoms. Many patients are discharged following coronavirus disease 2019 (COVID-19) infection without proper follow-up and evaluation of long-term effects, resulting in the improper treatment of the long-term symptoms, which increases the burden on the patients and healthcare systems. Coronavirus disease 2019 (COVID-19) is a disease caused by the novel SARS-CoV-2. It results in a variety of symptoms, including fever, cough, respiratory distress, the loss of the sense of smell and taste, and long-term effects such as post-severe acute respiratory syndrome (SARS), which is characterized by chronic fatigue, sleep disturbances, myalgia, weakness, and depression. The aim of this study is to assess the incidence of long-term fatigue in patients who achieved remission from COVID-19 at King Abdulaziz Medical City (KAMC), National Guards Health Affairs, Riyadh. Methods We conducted a cross-sectional, non-probability convenience sampling study. All participants who were diagnosed with COVID-19 and achieved remission were approached in an outpatient department (OPD) setting and signed an informed consent form and were evaluated by standard questionnaires at clinics after remission from COVID-19 at King Abdulaziz Medical City in Riyadh, Saudi Arabia. A total of 343 subjects who fit the inclusion criteria of any patients who have been diagnosed with COVID-19 and achieved remission were included in the study. This study included patients from the National Guard Hospital, students, and staff members. The primary outcome variable was the incidence of long-term fatigue in patients who achieved remission from COVID-19 as measured by the Chalder fatigue scale (CFQ). The participants were approached in clinics and general OPD by one of the research teams. Results Based on the study design, 343 patients were selected from King Abdulaziz Medical City in Riyadh, the incidence of long-term fatigue in patients who achieved remission from COVID-19 was 55.7%, and the rest were normal (44.3%). The incidence of long-term fatigue was statistically significantly higher in females and those who had been diagnosed with COVID-19 and achieved remission for more than two months. The age of the participants ranged from 18 to more than 45, with a predominance of females (60.6%). Regarding body mass index (BMI), 39.9% were overweight, and 29.2% were obese. Additionally, the incidence of patients with associated chronic disease was 27.4%; among these chronic diseases, hypertension was the most common one (18.1%), followed by diabetes (17%) and thyroid diseases (14.9%). Conclusion To the best of our knowledge, this is one of the few studies that were carried out in Saudi Arabia that assess long-term fatigue post COVID-19 infection. In our study, we discovered that long-term fatigue was highly prevalent (55.7%). We found that among those participants, more than half of those who reported chronic fatigue had a COVID-19 diagnosis for longer than two months. Furthermore, females made up the majority of those who had long-term fatigue. We urge that additional longitudinal and standardized studies be carried out in order to thoroughly determine the severity of long-term fatigue in patients who obtained remission from COVID-19.

A patient who recovered from post-COVID myalgic encephalomyelitis/chronic fatigue syndrome: a case report.

BACKGROUND: Some patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) complain of persistent fatigue, dyspnea, pain, and cognitive dysfunction. These symptoms are often described as "long COVID". Whether a patient with long COVID might develop myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is of interest, as is the treatment and management of ME/CFS in a post-COVID patient. Here I report a patient, who, after an infection with SARS-CoV-2, developed ME/CFS and recovered after treatment. CASE PRESENTATION: The patient was a previously healthy 55-year-old woman who worked as a nurse and became ill with COVID-19 pneumonia. She then presented with severe fatigue, post-exertional malaise, dyspnea, pain, cognitive dysfunction, tachycardia, and exacerbation of fatigue on physical exertion, which persisted for more than 6 months after her recovery from COVID-19 pneumonia. She was bedridden for more than half of each day. The patient was treated from multiple perspectives, which included (1) instructions on eating habits and supplements; (2) cognitive and behavioral modifications for coping with physical, emotional, and cognitive fatigue; (3) instructions on conditioning exercises to improve deconditioning due to fatigue and dyspnea; and (4) pharmacotherapy with amitriptyline and hochuekkito, a Japanese herbal (Kampo) medicine. The patient made a complete recovery after completing the prescribed regimen and was able to return to work as a nurse. CONCLUSIONS: To the best of my knowledge, this is the first detailed report on a patient infected with SARS-CoV-2 followed by long COVID with the signs/symptoms of ME/CFS who recovered after treatment. I hope this case report will be helpful to health care practitioners by its presentation of some of the therapeutic options for alleviating disabling signs/symptoms in patients with post-COVID ME/CFS.

Corticosteroid nasal irrigation as early treatment of olfactory dysfunction in COVID-19: A prospective randomised controlled trial.

OBJECTIVE: This study aimed to evaluate the efficacy of corticosteroid irrigation compared to saline to no nasal irrigation in COVID-19 patients with olfactory loss. DESIGN AND SETTING: A randomised controlled study was conducted at the Otolaryngology-Head & Neck Surgery Department, Ramathibodi Hospital, Faculty of Medicine, Mahidol University. PARTICIPANTS: Two hundred thirty-seven COVID-19 participants with a new-onset smell loss were recruited into the study. Two hundred twenty-two participants met the inclusion criteria and were randomised into three groups: corticosteroid irrigation, saline irrigation and no treatment. MAIN OUTCOME MEASURES: The primary outcome was the mean difference in the smell sensation score among the groups after treatment at 1, 2 and 6 weeks. The secondary outcomes measurements included (1) a self-rating quality of life (QOL)-related smell dysfunction score, (2) the change over time in smell sensation score and self-rating QOL-related smell dysfunction score and (3) the median time to complete recovery of smell loss. RESULTS: The mean differences in smell sensation scores among the three groups were not statistically significant at any follow-up period. The mean score of self-rating QOL-related smell dysfunction in the corticosteroid group was significantly better than the other groups at 1 week. The change of outcome scores showed significant improvement over time, regardless of the treatments. The median time to complete smell recovery was similar: 3 weeks. CONCLUSION: This study emphasised that corticosteroid nasal irrigation is not superior to saline or no nasal irrigation in restoring the sense of smell in COVID-19-associated olfactory loss.

Post-exertional malaise among people with long COVID compared to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

BACKGROUND: Long COVID describes a condition with symptoms that linger for months to years following acute COVID-19. Many of these Long COVID symptoms are like those experienced by patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). OBJECTIVE: We wanted to determine if people with Long COVID experienced post-exertional malaise (PEM), the hallmark symptom of ME/CFS, and if so, how it compared to PEM experienced by patients with ME/CFS. METHODS: A questionnaire that asked about the domains of PEM including triggers, experience, recovery, and prevention was administered to 80 people seeking care for Long COVID at Bateman Horne Center. Their responses were compared to responses about PEM given by 151 patients with ME/CFS using chi-square tests of independence. RESULTS: All but one Long COVID respondent reported having PEM. There were many significant differences in the types of PEM triggers, symptoms experienced during PEM, and ways to recover and prevent PEM between Long COVID and ME/CFS. Similarities between Long COVID and ME/CFS included low and medium physical and cognitive exertion to trigger PEM, symptoms of fatigue, pain, immune reaction, neurologic, orthostatic intolerance, and gastrointestinal symptoms during PEM, rest to recover from PEM, and pacing to prevent PEM. CONCLUSION: People with Long COVID experience PEM. There were significant differences in PEM experienced by people with Long COVID compared to patients with ME/CFS. This may be due to the newness of Long COVID, not knowing what exertional intolerance is or how to manage it.

Post-Acute COVID-19 Respiratory Symptoms in Patients With Asthma: An Electronic Health Records-Based Study.

BACKGROUND: Post-viral respiratory symptoms are common among patients with asthma. Respiratory symptoms after acute COVID-19 are widely reported in the general population, but large-scale studies identifying symptom risk for patients with asthma are lacking. OBJECTIVE: To identify and compare risk for post-acute COVID-19 respiratory symptoms in patients with and without asthma. METHODS: This retrospective, observational cohort study included COVID-19-positive patients between March 4, 2020, and January 20, 2021, with up to 180 days of health care follow-up in a health care system in the Northeastern United States. Respiratory symptoms recorded in clinical notes from days 28 to 180 after COVID-19 diagnosis were extracted using natural language processing. Cohorts were stratified by hospitalization status during the acute COVID-19 period. Univariable and multivariable analyses were used to compare symptoms among patients with and without asthma adjusting for demographic and clinical confounders. RESULTS: Among 31,084 eligible patients with COVID-19, 2863 (9.2%) had hospitalization during the acute COVID-19 period; 4049 (13.0%) had a history of asthma, accounting for 13.8% of hospitalized and 12.9% of nonhospitalized patients. In the post-acute COVID-19 period, patients with asthma had significantly higher risk of shortness of breath, cough, bronchospasm, and wheezing than patients without an asthma history. Incident respiratory symptoms of bronchospasm and wheezing were also higher in patients with asthma. Patients with asthma who had not been hospitalized during acute COVID-19 had additionally higher risk of cough, abnormal breathing, sputum changes, and a wider range of incident respiratory symptoms. CONCLUSION: Patients with asthma may have an under-recognized burden of respiratory symptoms after COVID-19 warranting increased awareness and monitoring in this population.

Non-Pharmacological Therapies for Post-Viral Syndromes, Including Long COVID: A Systematic Review.

BACKGROUND: Post-viral syndromes (PVS), including Long COVID, are symptoms sustained from weeks to years following an acute viral infection. Non-pharmacological treatments for these symptoms are poorly understood. This review summarises the evidence for the effectiveness of non-pharmacological treatments for PVS. METHODS: We conducted a systematic review to evaluate the effectiveness of non-pharmacological interventions for PVS, as compared to either standard care, alternative non-pharmacological therapy, or placebo. The outcomes of interest were changes in symptoms, exercise capacity, quality of life (including mental health and wellbeing), and work capability. We searched five databases (Embase, MEDLINE, PsycINFO, CINAHL, MedRxiv) for randomised controlled trials (RCTs) published between 1 January 2001 to 29 October 2021. The relevant outcome data were extracted, the study quality was appraised using the Cochrane risk-of-bias tool, and the findings were synthesised narratively. FINDINGS: Overall, five studies of five different interventions (Pilates, music therapy, telerehabilitation, resistance exercise, neuromodulation) met the inclusion criteria. Aside from music-based intervention, all other selected interventions demonstrated some support in the management of PVS in some patients. INTERPRETATION: In this study, we observed a lack of robust evidence evaluating the non-pharmacological treatments for PVS, including Long COVID. Considering the prevalence of prolonged symptoms following acute viral infections, there is an urgent need for clinical trials evaluating the effectiveness and cost-effectiveness of non-pharmacological treatments for patients with PVS. REGISTRATION: The study protocol was registered with PROSPERO [CRD42021282074] in October 2021 and published in BMJ Open in 2022.

Post Viral Olfactory Dysfunction After SARS-CoV-2 Infection: Anticipated Post-pandemic Clinical Challenge.

Persistent olfactory dysfunction (OD) is the second most common symptom of post coronavirus disease-19 (COVID-19) now being termed long-COVID. Its prevalence after recovery from COVID-19 is estimated to be 12% after nearly 6 months of follow-up. It thus becomes imperative for the treating clinicians to update themselves with the pathophysiology of this post COVID disability as well as the tools for diagnosis and the available treatment options. A systematic literature search was performed as per PRISMA guidelines in MEDLINE, Cochrane Library, LILACS, Google Scholar, ClinicalTrials.gov, and medRxiv databases. The keywords used were covid-19, Olfactory Disorders, Smell, Anosmia, PVOD, Post Viral Olfactory Disorders, post-covid and post haul. All articles were studied for definition, mechanism, diagnostic tests and treatment options for post COVID OD. 33 published articles and 8 ongoing trials were found relevant and included after full-text review. SARS-CoV-2 can cause conductive, neural and central OD. Olfactory evaluation can be done both subjectively (visual analogue scale) and objectively (Sniffin' sticks, Sinonasal Outcome Test, University of Pennsylvania Smell Identification Test and modified Davidson's alcohol sniff test). They can be used to detect and follow-up patients. Despite several on-going clinical trials, the most reliable and advisable treatment option available till date is olfactory training.

Rehabilitation of Neuropsychiatric Symptoms in Patients with Long-COVID: Position Statement.

Long-COVID, a term used to describe ongoing symptoms following SARS-CoV-2 (COVID-19) infection, parallels the course of other post-viral syndromes. Neuropsychiatric symptoms of Long-COVID can be persistent and interfere with quality of life and functioning. Within the biopsychosocial framework of chronic illness, rehabilitation professionals can address the neuropsychiatric sequelae of Long-COVID. However, current practice models are not designed to address concurrent psychiatric and cognitive symptoms in adults living with Long-COVID. Thus, we present a biopsychosocial framework for Long-COVID and provide treatment strategies based on evidence from current literature of post-viral chronic illness. These recommendations will guide rehabilitation professionals in 1) identifying common neuropsychiatric symptoms in Long-COVID that can be targeted for intervention and 2) addressing these symptoms via integrative interventions taking into account the biopsychosocial presentation of Long-COVID symptoms.

Neutrophils play a major role in the destruction of the olfactory epithelium during SARS-CoV-2 infection in hamsters.

The loss of smell (anosmia) related to SARS-CoV-2 infection is one of the most common symptoms of COVID-19. Olfaction starts in the olfactory epithelium mainly composed of olfactory sensory neurons surrounded by supporting cells called sustentacular cells. It is now clear that the loss of smell is related to the massive infection by SARS-CoV-2 of the sustentacular cells in the olfactory epithelium leading to its desquamation. However, the molecular mechanism behind the destabilization of the olfactory epithelium is less clear. Using golden Syrian hamsters infected with an early circulating SARS-CoV-2 strain harboring the D614G mutation in the spike protein; we show here that rather than being related to a first wave of apoptosis as proposed in previous studies, the innate immune cells play a major role in the destruction of the olfactory epithelium. We observed that while apoptosis remains at a low level in the damaged area of the infected epithelium, the latter is invaded by Iba1+ cells, neutrophils and macrophages. By depleting the neutrophil population or blocking the activity of neutrophil elastase-like proteinases, we could reduce the damage induced by the SARS-CoV-2 infection. Surprisingly, the impairment of neutrophil activity led to a decrease in SARS-CoV-2 infection levels in the olfactory epithelium. Our results indicate a counterproductive role of neutrophils leading to the release of infected cells in the lumen of the nasal cavity and thereby enhanced spreading of the virus in the early phase of the SARS-CoV-2 infection.

Is SARS-CoV-2 the only cause of long-COVID?

Around 10% of adults infected with SARS-CoV-2 that survive a first episode of COVID-19 appear to experience long-term clinical manifestations. The signs and symptoms of this post-acute COVID-19 syndrome (PACS) include fatigue, dyspnea, joint pain, myalgia, chest pain, cough, anosmia, dysgeusia, headache, depression, anxiety, memory loss, concentration difficulties, and insomnia. These sequelae remind the constellation of clinical manifestations previously recognized as myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS). This condition has been described following distinct infectious events, mostly acute viral illnesses. In this way, the pathophysiology of PACS might overlap with mechanisms involved in other post-infectious fatigue syndromes. The risk of PACS is more frequent in women than men. Additional host genetic factors could be involved. There is a dysregulation of multiple body organs and systems, involving the immune system, the coagulation cascade, endocrine organs, autonomic nervous system, microbiota-gut-brain axis, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-thyroid axis, etc. Hypothetically, an abnormal response to certain infectious agents could trigger the development of postinfectious fatigue syndromes.

Post-Viral Fatigue Following SARS-CoV-2 Infection during Pregnancy: A Longitudinal Comparative Study.

Studies reported post-COVID-19 fatigue in the general population, but not among pregnant women. Our objectives were to determine prevalence, duration, and risk factors of post-viral fatigue among pregnant women with SARS-CoV-2. This study involved 588 pregnant women with SARS-CoV-2 during pregnancy or delivery in Brazil. Three groups were investigated: G1 (n = 259, symptomatic infection during pregnancy); G2 (n = 131, positive serology at delivery); G3 (n = 198, negative serology at delivery). We applied questionnaires investigating fatigue at determined timepoints after infection for G1, and after delivery for all groups; fatigue prevalence was then determined. Cox regression was used to estimate hazard ratio (HR) and 95% CI of the risk of remaining with fatigue in G1. Overall fatigue prevalence in G1 at six weeks, three months and six months were 40.6%, 33.6%, and 27.8%, respectively. Cumulative risk of remaining with fatigue increased over time, with HR of 1.69 (95% CI: 0.89-3.20) and 2.43 (95% CI: 1.49-3.95) for women with moderate and severe symptoms, respectively. Multivariate analysis showed cough and myalgia as independent risk factors in G1. Fatigue prevalence was significantly higher in G1 compared to G2 and G3. Post-viral fatigue prevalence is higher in women infected during pregnancy; fatigue's risk and duration increased with the severity of infection.

Risk Factors and Multidimensional Assessment of Long Coronavirus Disease Fatigue: A Nested Case-Control Study.

BACKGROUND: Fatigue is the most prevalent and debilitating long-COVID (coronavirus disease) symptom; however, risk factors and pathophysiology of this condition remain unknown. We assessed risk factors for long-COVID fatigue and explored its possible pathophysiology. METHODS: This was a nested case-control study in a COVID recovery clinic. Individuals with (cases) and without (controls) significant fatigue were included. We performed a multidimensional assessment evaluating various parameters, including pulmonary function tests and cardiopulmonary exercise testing, and implemented multivariable logistic regression to assess risk factors for significant long-COVID fatigue. RESULTS: A total of 141 individuals were included. The mean age was 47 (SD: 13) years; 115 (82%) were recovering from mild coronavirus disease 2019 (COVID-19). Mean time for evaluation was 8 months following COVID-19. Sixty-six (47%) individuals were classified with significant long-COVID fatigue. They had a significantly higher number of children, lower proportion of hypothyroidism, higher proportion of sore throat during acute illness, higher proportions of long-COVID symptoms, and of physical limitation in daily activities. Individuals with long-COVID fatigue also had poorer sleep quality and higher degree of depression. They had significantly lower heart rate [153.52 (22.64) vs 163.52 (18.53); P = .038] and oxygen consumption per kilogram [27.69 (7.52) vs 30.71 (7.52); P = .036] at peak exercise. The 2 independent risk factors for fatigue identified in multivariable analysis were peak exercise heart rate (OR: .79 per 10 beats/minute; 95% CI: .65-.96; P = .019) and long-COVID memory impairment (OR: 3.76; 95% CI: 1.57-9.01; P = .003). CONCLUSIONS: Long-COVID fatigue may be related to autonomic dysfunction, impaired cognition, and decreased mood. This may suggest a limbic-vagal pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04851561.

Orthostatic Intolerance in Long-Haul COVID after SARS-CoV-2: A Case-Control Comparison with Post-EBV and Insidious-Onset Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.

BACKGROUND: As complaints of long-haul COVID patients are similar to those of ME/CFS patients and as orthostatic intolerance (OI) plays an important role in the COVID infection symptomatology, we compared 14 long-haul COVID patients with 14 ME/CFS patients with a post-viral Ebstein-Barr (EBV) onset and 14 ME/CFS patients with an insidious onset of the disease. METHODS: In all patients, OI analysis by history taking and OI assessed during a tilt test, as well as cerebral blood flow measurements by extracranial Doppler, and cardiac index measurements by suprasternal Doppler during the tilt test were obtained in all patients. RESULTS: Except for disease duration no differences were found in clinical characteristics. The prevalence of POTS was higher in the long-haul patients (100%) than in post-EBV (43%) and in insidious-onset (50%) patients (p = 0.0002). No differences between the three groups were present in the prevalence of OI, heart rate and blood pressure changes, changes in cerebral blood flow or in cardiac index during the tilt test. CONCLUSION: OI symptomatology and objective abnormalities of OI (abnormal cerebral blood flow and cardiac index reduction during tilt testing) are comparable to those in ME/CFS patients. It indicates that long-haul COVID is essentially the same disease as ME/CFS.

Persistent or new symptoms 1 year after a single high dose of vitamin D3 in patients with moderate to severe COVID-19.

Purpose: The aim of this study was to investigate the reported persistent or new symptoms 1 year after a single dose of 200,000 IU of vitamin D3 and hospitalization in patients with moderate to severe COVID-19. Methods: This is a post-hoc, exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial from two hospitals in São Paulo, Brazil, registered in ClinicalTrials.gov, NCT04449718. Discharged patients were followed for up to 1 year and evaluated by telephone interviews at 6 and 12 months. The primary and secondary outcomes were previously published. These post-hoc exploratory secondary outcomes are the persistent or new symptoms and quality of life (QoL) at the post-viral stage of COVID-19. Generalized estimating equations (GEE) for repeated measures with Bonferroni's adjustment were used for testing outcomes. Results: Between 2 June and 27 August 2020, we randomized 240 patients of which 144 were included in this study [the vitamin D3 (n = 71) or placebo (n = 73) group]. The mean (SD) age was 54.3 (13.1) years, and body mass index (BMI) was 32.4 (6.5) kg/m2. Fever demonstrated a significant main effect of time (P < 0.001) with a reduction from baseline to 6 (52-0) and 12 months (52-0). No significant differences between groups were observed for fever, cough, fatigue, fever, myalgia, joint pain, runny nose, nasal congestion, sore throat, hypertension, diabetes, cardiovascular disease, rheumatic disease, asthma, chronic obstructive pulmonary, chronic kidney disease, QoL, and new or persistent symptoms up to 1-year of follow-up. Conclusion: The findings do not support the use of 200,000 IU of vitamin D3 compared to placebo for the management of persistence or new symptoms, and QoL reported by moderate to severe patients after hospitalization for COVID-19.

Post-COVID Headache: A Literature Review.

PURPOSE OF REVIEW: Post-COVID headache may be unique in presentation and mechanism, often presenting as a new phenotype in patients with a history of a primary headache disorder or resulting in a new headache syndrome in those without history of headache. This review presents a description of the literature published focused on post-COVID headache. Additionally, we discuss potential mechanisms and considerations for treatment of post-COVID headache. RECENT FINDINGS: Headache is one of the most common symptoms of COVID. Common characteristics are revealed when reviewing the phenotypes of headaches that have been described in patients with COVID-19, with most headache phenotypes resembling migraine and new persistent daily headache. Post-COVID headaches are often described as moderate to severe, persistent, and treatment refractory. This review highlights the diversity of presentation of headaches that present as a complication of COVID-19. Treatment of post-COVID headache is challenging, especially in the setting of a pandemic where resources are limited. CLINICAL CASE: A 42-year-old woman with a history of episodic migraine without aura presents over video visit with a new headache type. Her typical headaches are predominantly left sided, throbbing in nature, and associated with photophobia and phonophobia. They are fully relieved by oral sumatriptan 2 h after treatment. She describes this new headache as a constant, pulsating, holocephalic pain with no other migrainous features that have been ongoing for 6 weeks. She notes that the headache has been persistent since that time. She has tried over-the-counter acetaminophen and ibuprofen and her typical migraine abortive therapy without relief. She is debilitated and wonders if there is anything that will take the pain away. She shares that she tested positive for COVID-19 about 2 days prior to headache onset and has associated rhinorrhea, anosmia, and ageusia.

Qualitative Olfactory Dysfunction and COVID-19: An Evidence-Based Review with Recommendations for the Clinician.

BACKGROUND: Nearly 40% of patients who experience smell loss during SARS-CoV-2 infection may develop qualitative olfactory dysfunction, most commonly parosmia. Our evidence-based review summarizes the evolving literature and offers recommendations for the clinician on the management of patients experiencing parosmia associated with COVID-19. METHODS: We performed a systematic search using independent queries in PubMed, Embase, Ovid, and Cochrane databases, then categorized articles according to themes that emerged regarding epidemiology, effect on quality of life, disease progression, prognosis, pathophysiology, diagnosis, and treatment of parosmia. RESULTS: We identified 123 unique references meeting eligibility and performed title and abstract review with 2 independent reviewers, with 74 articles undergoing full-text review. An inductive approach to thematic development provided 7 central themes regarding qualitative olfactory dysfunction following COVID-19. CONCLUSIONS: While other respiratory viruses are known to cause qualitative olfactory disturbances, the incidence of parosmia following COVID-19 is notable, and correlates negatively with age. The presence of parosmia predicts persistent quantitative olfactory dysfunction. Onset can occur months after infection, and symptoms may persist for well over 7 months. Affected patients report increased anxiety and decreased quality of life. Structured olfactory training with essential oils is the preferred treatment, where parosmia predicts recovery of aspects of quantitative smell loss when undergoing training. There is limited evidence that nasal corticosteroids may accelerate recovery of olfactory function. Patients should be prepared for the possibility that symptoms may persist for years, and providers should guide them to resources for coping with their psychosocial burden.