Integrative Systems Immunology Analysis Reveals Elevated Anti-AGTR1 Levels with Accumulating COVID-19 Symptoms (preprint)

The coronavirus disease 2019 (COVID-19) displays a broad spectrum of symptoms, with the underlying reasons for this variability still not fully elucidated. Our study investigates the potential association between specific autoantibodies (AABs), notably those that targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS) related molecules, and the diverse clinical manifestations of COVID-19, commonly observed in patients with autoimmune conditions, including rheumatic diseases, such as systemic sclerosis. In a cross-sectional analysis, we explored the relationship between AAB levels and the presence of key COVID-19 symptoms. Hierarchical clustering analysis revealed a robust correlation between certain AABs and symptoms such as fever, muscle ache, anosmia, and dysgeusia, which emerged as significant predictors of disease severity. Specifically, AABs against CHRM5 and CXCR3 were strongly linked to fever, while AABs against CHRM5 and BDKRB1 correlated with muscle ache. Anosmia was predominantly associated with AABs against F2R and AGTR1, while dysgeusia was linked to AABs against BDKRB1 and AGTR1. Furthermore, we observed a rise in AAB levels with the accumulation of these symptoms, with the highest levels detected in patients presenting all four predictors. Multinomial regression analysis identified AABs targeting AGTR1 as a key predictor for one or more of these core symptoms. Additionally, our study indicated that anti-AGTR1 antibodies triggered a concentration-dependent degradation of eGC, which could be mitigated by the AGTR1 antagonist Losartan. This suggests a potential mechanistic connection between eGC degradation, the observed COVID-19 symptoms, and rheumatic diseases. In conclusion, our research underscores a substantial correlation between AABs, particularly those against GPCRs and RAS-related molecules, and the severity of COVID-19 symptoms. These findings open avenues for potential therapeutic interventions in the management of COVID-19.

Hydroxychloroquine safety, comparison between no Covid-19 and Covid-19 patients. Data from the Spanish Pharmacovigilance Database (preprint)

Aim: To compare the cases reported to the Spanish Pharmacovigilance System (SEFV-H) with HCQ used in COVID-19 vs. HCQ used in other indications. Methods. All cases of adverse drug reactions (ADR) submitted to the Spanish Pharmacovigilance database (FEDRA) from 1 January 1982 to 19 February 2021 suspected to be induced by HCQ were identified. Cases were classified into two groups: no-Covid patients and Covid patients. Frequencies of ADR were compared. Reporting Odds Ratios (ROR) with its lower limit of the 95% confidence interval (-ROR) and Omega (Ω) and its lower limit of the 95% credibility interval (Ω -025) were obtained to estimate disproportionalities. Results. More severe cases were reported with the use of HCQ in Covid. Main differences in frequency were observed in hepatobiliary, skin, gastrointestinal, eye, nervous system and heart ADRs. During the Covid-19 pandemic, disproportionality was found for Torsade de Pointes/QT prolongation with a ROR (-ROR) of 132.8 (76.7); severe hepatotoxicity, 18.7 (14.7); dyslipidaemias, 12.1 (6.1); shock, 9.5 (6.9) and ischaemic colitis, 8.9 (2.6). Myopathies, haemolytic disorders and suicidal behaviour increased their disproportionality during the pandemic. Disproportionality was observed for neoplasms, haematopoietic cytopaenias and interstitial lung disease in the pre-Covid period. Ω showed potential interactions between HCQ and azithromycin, ceftriaxone, lopinavir and tocilizumab . Conclusions. The use of HCQ in Covid-19 changed its safety profile. Of particular concern during the pandemic were arrhythmias, hepatotoxicity, severe skin reactions and suicide risk, but not ocular disorders. Some ADRs identified as signals would require more detailed analyses.

Inflammatory Myopathies.

PURPOSE OF REVIEW: This article outlines the salient clinical, serologic, electrophysiologic, imaging, and histopathologic findings and treatment options for the idiopathic inflammatory myopathies, including those related to immune checkpoint inhibitors and SARS-CoV-2. RECENT FINDINGS: The classification of idiopathic inflammatory myopathies has improved with the integration of myositis-specific antibodies and histopathologic findings. Characteristic features of immune checkpoint inhibitor-related myositis have been identified, allowing early recognition and treatment of the syndrome. The COVID-19 pandemic has had a profound impact on the care of patients with idiopathic inflammatory myopathies, and several mechanisms of virus-related muscle injury have been proposed. SUMMARY: A comprehensive evaluation including clinical examination, EMG, imaging, antibody testing, muscle biopsy, and cancer screening, when appropriate, can lead to an earlier accurate diagnosis and an individualized treatment approach for patients with idiopathic inflammatory myopathies.

Diaphragm Muscle Weakness Might Explain Exertional Dyspnea 15 Months after Hospitalization for COVID-19.

Rationale: Dyspnea is often a persistent symptom after acute coronavirus disease (COVID-19), even if cardiac and pulmonary function are normal. Objectives: This study investigated diaphragm muscle strength in patients after COVID-19 and its relationship to unexplained dyspnea on exertion. Methods: Fifty patients previously hospitalized with COVID-19 (14 female, age 58 ± 12 yr, half of whom were treated with mechanical ventilation, and half of whom were treated outside the ICU) were evaluated using pulmonary function testing, 6-minute-walk test, echocardiography, twitch transdiaphragmatic pressure after cervical magnetic stimulation of the phrenic nerve roots, and diaphragm ultrasound. Diaphragm function data were compared with values from a healthy control group. Measurements and Main Results: Moderate or severe dyspnea on exertion was present at 15 months after hospital discharge in approximately two-thirds of patients. No significant pulmonary function or echocardiography abnormalities were detected. Twitch transdiaphragmatic pressure was significantly impaired in patients previously hospitalized with COVID-19 compared with control subjects, independent of initial disease severity (14 ± 8 vs. 21 ± 3 cm H2O in mechanically ventilated patients vs. control subjects [P = 0.02], and 15 ± 8 vs. 21 ± 3 cm H2O in nonventilated patients vs. control subjects [P = 0.04]). There was a significant association between twitch transdiaphragmatic pressure and the severity of dyspnea on exertion (P = 0.03). Conclusions: Diaphragm muscle weakness was present 15 months after hospitalization for COVID-19 even in patients who did not require mechanical ventilation, and this weakness was associated with dyspnea on exertion. The current study, therefore, identifies diaphragm muscle weakness as a correlate for persistent dyspnea in patients after COVID-19 in whom lung and cardiac function are normal. Clinical trial registered with www.clinicaltrials.gov (NCT04854863).

Neurological and Neuropsychiatric Impacts of COVID-19 Pandemic.

BACKGROUND: Albeit primarily a disease of respiratory tract, the 2019 coronavirus infectious disease (COVID-19) has been found to have causal association with a plethora of neurological, neuropsychiatric and psychological effects. This review aims to analyze them with a discussion of evolving therapeutic recommendations. METHODS: PubMed and Google Scholar were searched from 1 January 2020 to 30 May 2020 with the following key terms: "COVID-19", "SARS-CoV-2", "pandemic", "neuro-COVID", "stroke-COVID", "epilepsy-COVID", "COVID-encephalopathy", "SARS-CoV-2-encephalitis", "SARS-CoV-2-rhabdomyolysis", "COVID-demyelinating disease", "neurological manifestations", "psychosocial manifestations", "treatment recommendations", "COVID-19 and therapeutic changes", "psychiatry", "marginalised", "telemedicine", "mental health", "quarantine", "infodemic" and "social media". A few newspaper reports related to COVID-19 and psychosocial impacts have also been added as per context. RESULTS: Neurological and neuropsychiatric manifestations of COVID-19 are abundant. Clinical features of both central and peripheral nervous system involvement are evident. These have been categorically analyzed briefly with literature support. Most of the psychological effects are secondary to pandemic-associated regulatory, socioeconomic and psychosocial changes. CONCLUSION: Neurological and neuropsychiatric manifestations of this disease are only beginning to unravel. This demands a wide index of suspicion for prompt diagnosis of SARS-CoV-2 to prevent further complications and mortality.

Les impacts neurologiques et neuropsychiatriques d'une infection à la COVID-19. CONTEXTE: Bien qu'il s'agisse principalement d'une maladie des voies respiratoires, la maladie infectieuse à coronavirus apparue en 2019 (COVID-19) s'est avérée avoir un lien de causalité avec une pléthore d'impacts d'ordre neurologique, neuropsychiatrique et psychologique. Cette étude entend donc analyser ces impacts tout en discutant l'évolution des recommandations thérapeutiques se rapportant à cette maladie. MÉTHODES: Les bases de données PubMed et Google Scholar ont été interrogées entre les 1er janvier et 30 mai 2020. Les termes clés suivants ont été utilisés : « COVID-19 ¼, « SRAS ­ CoV-2 ¼, « Pandémie ¼, « Neuro ­ COVID ¼, « AVC ­ COVID ¼, « Épilepsie ­ COVID ¼, « COVID ­ encéphalopathie ¼, « SRAS ­ CoV-2 ­ encéphalite ¼, « SRAS ­ CoV-2 ­ rhabdomyolyse ¼, « COVID ­ maladie démyélinisante ¼, « Manifestations neurologiques ¼, « Manifestations psychosociales ¼, « Recommandations thérapeutiques ¼, « COVID-19 et changement thérapeutiques ¼, « Psychiatrie ¼, « Marginalisés ¼, « Télémédecine ¼, « Santé mentale ¼, « Quarantaine ¼, « Infodémique ¼ et « Médias sociaux ¼. De plus, quelques articles de journaux relatifs à la pandémie de COVID-19 et à ses impacts psychosociaux ont également été ajoutés en fonction du contexte. RÉSULTATS: Il appert que les manifestations neurologiques et neuropsychiatriques des infections à la COVID-19 sont nombreuses. Les caractéristiques cliniques d'une implication des systèmes nerveux central et périphérique sautent désormais aux yeux. Ces caractéristiques ont fait l'objet d'une brève analyse systématique à l'aide de publications scientifiques. En outre, la plupart des impacts d'ordre psychologique de cette pandémie se sont révélés moins apparents que les changements réglementaires, socioéconomiques et psychosociaux. CONCLUSION: Les manifestations neurologiques et neuropsychiatriques de cette maladie ne font que commencer à être élucidées. Cela exige donc une capacité accrue de vigilance en vue d'un diagnostic rapide, et ce, afin de prévenir des complications additionnelles et une mortalité accrue.

Immune-mediated necrotizing myopathy (NAM) related to SARS-Cov-2 infection: a case report.

BACKGROUND: There is a growing body of evidence that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or COVID-19 infection is associated with the development of autoimmune diseases. A recent systematic review reported that the new-onset autoimmune disorders during or after COVID-19 infection included inflammatory myopathies such as immune-mediated necrotizing myopathies. CASE PRESENTATION: We described a 60-year-old man diagnosed with COVID-19 infection and later presented with a two-week history of myalgia, progressive limb weakness, and dysphagia. He had a Creatinine Kinase (CK) level of more than 10,000 U/L, was strongly positive for anti-signal recognition particle (SRP) and anti-Ro52 antibody, and a muscle biopsy revealed a paucity-inflammation necrotizing myopathy with randomly distributed necrotic fibers, which was consistent with necrotizing autoimmune myositis (NAM). He responded well clinically and biochemically to intravenous immunoglobulin, steroids and immunosuppressant and he was able to resume to his baseline. CONCLUSION: SARS-CoV-2 may be associated with late-onset necrotizing myositis, mimicking autoimmune inflammatory myositis.

Immunogenicity of SARS-CoV-2 mRNA intramuscular vaccination in patients with muscular disorders.

Backgrounds: Little clinical data is available on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with muscular disorders (MDs). The immunogenicity of SARS-CoV-2 vaccines against MDs, in particular, remains unknown. Thus, this study aimed to confirm the immunogenicity and safety of the SARS-CoV-2 vaccine against MDs. Methods: All participants were vaccinated with two doses of mRNA vaccines (BNT162b2, Pfizer-BioNTech). The serum samples were collected from each patient on the day of second dose of vaccination, and then, consecutively, after one month, three months, and six months. Anti-SARS-CoV-2 IgG levels were determined using the Abbott SARS-CoV-2 IgG II Quant assay. Results: We evaluated 75 individuals, including 42 patients with MDs and 33 patients with non-muscular disorders (non-MDs). Non-MD patients primarily include those with severe motor and intellectual disabilities. The median age of the patients was 32 years (range 12-64 years). After one and three months following the second immunization, patients with MDs had lower antibody responses. Furthermore, three months following the second immunization, the proportion of high responders among patients with MDs decreased significantly compared to that among patients without MDs (p-value of less than 0.01). No serious adverse events were observed in patients with or without MDs. Conclusion: Intensity and latency of antibody response were suppressed in patients with MDs. Although MDs may be a key contributor in predicting the antibody response to SARS-CoV-2 vaccination, SARS-CoV-2 immunization in MDs needs extensive research.

Molecular mechanisms in chloroquine-exposed muscle cells elucidated by combined proteomic and microscopic studies.

OBJECTIVES: Chloroquine (CQ) is an antimalarial drug with a growing number of applications as recently demonstrated in attempts to treat Covid-19. For decades, it has been well known that skeletal and cardiac muscle cells might display vulnerability against CQ exposure resulting in the clinical manifestation of a CQ-induced myopathy. In line with the known effect of CQ on inhibition of the lysosomal function and thus cellular protein clearance, the build-up of autophagic vacuoles along with protein aggregates is a histological hallmark of the disease. Given that protein targets of the perturbed proteostasis are still not fully discovered, we applied different proteomic and immunological-based studies to improve the current understanding of the biochemical nature of CQ-myopathy. METHODS: To gain a comprehensive understanding of the molecular pathogenesis of this acquired myopathy and to define proteins targets as well as pathophysiological processes beyond impaired proteolysis, utilising CQ-treated C2C12 cells and muscle biopsies derived from CQ-myopathy patients, we performed different proteomic approaches and Coherent Anti-Stokes Raman Scattering (CARS) microscopy, in addition to immunohistochemical studies. RESULTS: Our combined studies confirmed an impact of CQ-exposure on proper protein processing/folding and clearance, highlighted changes in the interactome of p62, a known aggregation marker and hereby identified the Rett syndrome protein MeCP2 as being affected. Moreover, our approach revealed-among others-a vulnerability of the extracellular matrix, cytoskeleton and lipid homeostasis. CONCLUSION: We demonstrated that CQ exposure (secondarily) impacts biological processes beyond lysosomal function and linked a variety of proteins with known roles in the manifestation of other neuromuscular diseases.

Case report: Myositis causing isolated neck extensor myopathy (INEM) exacerbated after vaccination (preprint)

Background Myositis is a group of inflammatory skeletal muscle diseases that in some cases may be linked to vaccines.3 Case reports of new-onset myositis and other autoimmune events have previously been reported after administration of the COVID-19 vaccine. 4–13 Furthermore, three large surveys have described patients with a self-reported flare of myositis following COVID-19 vaccination 14–16 To our knowledge, no cases of flares of myositis causing isolated neck extensor myopathy (INEM) have previously been reported. Case presentation A female known with stable myositis causing isolated neck extensor myopathy (INEM) with minor sequela developed severe weakness of the extensor muscle of the neck three weeks following the Pfizer-BioNTech COVID-19 Vaccine. Until vaccine administration, the patient exhibited a good response to immunosuppressants (prednisolone followed by rituximab). On clinical examination, she had a forward drop of the head and neck extensor muscle strength was 3/5 on the MRC scale. She was initially treated with prednisone and a course of rituximab with no clinical improvement.  Subsequently, she was treated with intravenous immunoglobulins (IVIG). Within two weeks neck extensor weakness improved. She no longer had a head drop and neck extensor muscle strength was 4/5 on the MRC scale. The patient had a flare of myositis following immunization. The clinical course suggests that the vaccine may have triggered the flare, which could not be stabilized with previously effective treatment. Conclusions The time period between the COVID-19 vaccine and the exacerbation of myositis causing INEM suggests a link between the vaccine and the flare. The possible need for repeated vaccine boosters to maintain immunity against severe COVID-19 disease highlights the importance of acquiring more information on COVID-19 vaccine reactions in patients with pre-existing autoimmunity and on effective treatments vaccine related flares. Thus, clinicians should be aware of and report possible flares of autoimmune diseases following the vaccine. Nonetheless, the benefits of the COVID-19 vaccine outweigh the small risk of a myositis flare.

Benign Acute Children Myositis: Five Years’ Experience in a Tertiary Care Pediatric Hospital (preprint)

Purpose: Benign acute childhood myositis (BACM) is a self-limited childhood illness, and it is mainly caused by viral infections. Clinical and laboratory alterations usually normalize rapidly; generally, the only medical intervention required is supportive (hydration, analgesic medication). The low awareness about BACM often led to delayed diagnosis and unneeded ancillary investigations. This study aims to better characterize the clinical and laboratory features of BACM to improve the diagnostic process and inpatient and outpatient management.  Materials and methods: We conducted a retrospective study selecting all children admitted to Meyer's Children's Hospital-IRCCS (Florence, Italy) with a diagnosis of BACM over the last 5 years. Clinical, laboratory, and instrumental data were collected from electronic clinical records and analyzed.  Results: Sixteen patients were enrolled. The median age was 7.68 years (IQR 5.7-12.9). Male gender (62.5%) and Caucasian ethnicity (68.75%) were prevalent. Most of the patients were admitted during winter, and a second peak has been found in summer. All patients had bilateral calf pain at admission (87.5%), associated with asthenia, and refuse to walk (93.7%). Prodromal symptoms were fever (81.25%), cough (37.5%), coryza (43.5%), sore throat (50%), and vomiting (31.25%). The median value of CPK was 2,183.5 U/L (IQR 1,395.5-7,156.25) at peak. CPK median time to normalization was 7 days (IQR 7-8.5) from the nadir. Influenza B was the virus most frequently BACM associated, followed by influenza A; a novel association with Sars-CoV-2 has been detected. Two patients had pathogenic variants at the Next Generation Sequencing myopathies panel.  Conclusions: School-aged children admitted to the hospital with walking difficulty and myalgia generally after an upper respiratory tract infection with a moderate CPK elevation should remind at first of BACM. Rapid complaint resolution and biochemical markers normalization will prevent unnecessary tests and inappropriate therapies.

Polymyositis in a Patient with COVID-19 Infection with Colorectal Cancer: A Case Report (preprint)

Background: Association of idiopathic inflammatory myopathies (IIM) with malignancy has been well- recognized for a long time. However, its association with the novel corona virus (COVID-19) infection is extremely rare. Here we report a case of polymyositis in a patient with COVID-19 infection with underlying colorectal cancer. Case Presentation: Here we report a case of a 73-year-old male who was admitted for COVID-19 infection but developed persistent limb weakness which was finally diagnosed as polymyositis. He was given high dose steroid along with methotrexate to which he responded very well. Conclusions: Inflammatory myopathy should be suspected in elderly patients who present with generalized weakness especially in the background of malignancy. The association of COVID-19 infection with myositis needs further studies.

How long is the long COVID? a retrospective analysis of football players in two major European Championships. (preprint)

Objectives, the goal of this study was to investigate the correlation between SARS-CoV-2 infection and muscle injuries among a large sample of professional soccer players. Methods, A retrospective cohort study was conducted on professional soccer players from the Serie A and LaLiga leagues during the 2019-2020 and 2020-2021 football seasons. The players were divided into two groups based on whether they contracted the Sars-CoV-2 infection (C+) or not (C-) during the 2020/2021 season. Data collection was conducted using the Transfermarkt24 site. Results, In the 2019-2020 both championships showed non-significant differences in the average number of muscular injuries between the C+ group and the C- group (Serie A: p=0.194; 95%CI: -0.044 to 0.215, LaLiga p=0.915; 95%CI: -0.123 to 0.137). In the 2020-2021 the C+ group had a significantly higher number of muscular injuries compared to the C- group in both championships (Serie A: p<0.001; 95%CI 0.731 to 1.038; LaLiga: p<0.001; 95%CI: 0.773 to 1.054). Multiple linear regression analysis confirmed that belonging to C+ in the season 2020/2021 was the variable that most strongly influenced the probability of having a muscle injury in both championships. Survival analysis revealed a hazard ratio of 3.73 (95%CI 3.018 to 4.628) and of 5.14 (95% CI 3.200 to 8.254) for Serie A and LaLiga respectively. Conclusions This retrospective cohort study revealed a significant association between SARS-CoV-2 infection and increased risk of muscle injury, emphasizing the importance of carefully considering the infection in the decision-making process for determining athletes' readiness to return to sport.

Characterization of Long COVID among U.S. Medicare Beneficiaries using Claims Data (preprint)

This retrospective study utilized healthcare claims data to investigate the incidence, patient demographics, and concurrent diagnoses associated with long COVID in the U.S. Medicare population. Nearly 194,000 (0.6%) beneficiaries had post-COVID condition diagnoses, with higher rates among nursing home residents. Of those medically attended for COVID-19, 3-5% were diagnosed with post-COVID conditions. We observed minimal demographic differences between those with and without long COVID. When comparing diagnoses concurrent with long COVID and COVID-19, certain codes (G72 and J84) for myopathies and interstitial pulmonary diseases were disproportionately present with long COVID.

Osteomalacic myopathy: A re-emerging scourge hiding in plain sight.

We present a cluster of patients with osteomalacic myopathy in the aftermath of the COVID-19 pandemic. We believe that the home confinement of these children may have contributed to the resurgence of this condition. This deficiency is eminently reversible.

Heart transplantation for COVID-19 myopathy in the United States.

Evidence on characteristics and outcomes of patients undergoing heart transplantation for coronavirus disease 2019 (COVID-19) associated cardiomyopathy is limited to case reports. Of all 6,332 patients aged ≥18 years undergoing heart transplantation from July 2020 through May 2022 in the United Network for Organ Sharing database, 12 (0.2%) patients had COVID-19 myocarditis and 98 (1.6%) patients with the same level of care had non-COVID-19 myocarditis. Their median age was 49 (range 19-74) years. All patients were hospitalized in the intensive care unit and 92.7% (n = 102) were on life support prior to transplantation. No patients with COVID-19 myocarditis required ventilation while waitlisted. Survival free from graft failure was 100% among COVID-19 patients and 88.5% among non-COVID-19 patients at a median of 257 (range 0-427) days post-transplant. These findings indicate that transplantation is rarely performed for COVID-19 related cardiomyopathy in the United States, yet early outcomes appear favorable in select patients.