Evaluation of diseases complicating long COVID: A retrospective chart review (preprint)

Purpose Evidence for the pathogenesis and treatment of post-acute coronavirus disease 2019 (COVID-19) (long COVID) is lacking. As long COVID symptoms are predicted to have an impact on the global economy, clarification of the pathogenesis is urgently needed. Our experiences indicated that some symptoms were complicated by diseases established before the COVID-19 pandemic.Methods Using a retrospective, cross-sectional study, we aimed to evaluate the diseases complicating long COVID. Using the medical records of patients with confirmed severe acute respiratory syndrome coronavirus 2 infection exhibiting residual symptoms lasting ≥ 60 days post-infection who visited our clinic in January 2021–February 2023, we investigated the symptoms and diseases observed. We identified diseases that occurred after COVID-19 infection and excluded those that were exacerbations of existing diseases. Results: During the first visit, the most common symptoms reported in a total of 798 patients were fatigue (523 patients), anxiety (349 patients), and lack of motivation (344 patients). Complicating diseases were observed in 452 patients (57%). There were 115, 65, and 60 patients with postural tachycardia syndrome, postural syndrome without tachycardia, and mood disorders, respectively. Some diseases requiring immediate treatment included pulmonary thromboembolism, purulent shoulder arthritis, cerebellopontine angle tumors, myasthenia gravis, and cervical myelopathy.Conclusion All symptoms that occur after COVID-19 infection should not be treated as long COVID. Similar to normal medical treatment, a list of differential diagnoses should be maintained based on symptoms to obtain definitive diagnoses.

COVID-19 Coinfection with Malaria and Its Presentation with Bilateral Pleural Effusion: A Case Report and Literature Review (preprint)

Background There could be misdiagnosis of COVID 19 for malaria and vice versa because of their similar presentation, particularly when clinician relies mainly on symptoms. Coinfection with COVID-19 and malaria is associated with increased all-cause in-hospital mortality compared to isolated infection with SARS-CoV-2. Presentation with pleural effusion adds another challenge in the diagnosis of COVID-19.Case summary: This is a 57-year-old woman who presented with symptoms of acute febrile illness associated with shortness of breath and cough. Physical examination was remarkable for fever, hypotension, tachycardia, tachypnea, desaturation, decreased air entry and dullness over bilateral lower 1/3rd of the chest. Upon investigations, she was found to have ring-form trophozoites of plasmodium falciparum and bilateral ground glass opacities, bilateral consolidations and bilateral pleural effusions. She was managed with supportive treatments, antimalarial agents and antibiotics. COVID-19 was diagnosed late due to the initial high diagnostic inertia.Conclusion Clinicians should be aware of the possibility of COVID-19 in any patient who presents with acute febrile illness or respiratory complaints like shortness of breath and cough. In patients with symptoms such as fever, fatigue, and headache, both malaria and COVID-19 tests should always be performed. Though pleural effusion is rarely reported in COVID-19 patients, viral etiologies like COVID-19 should be considered if alternative diagnoses are lacking.

The COVID-19 mRNA vaccine Comirnaty induces anaphylactic shock in an anti-PEG hyperimmune large animal model: Role of complement in cardiovascular, hematological, and inflammatory mediator changes (preprint)

Background: Comirnaty, Pfizer-BioNTech's polyethylene-glycol (PEG)-containing Covid-19 vaccine, can cause hypersensitivity reactions (HSRs) in a small fraction of immunized people which can, very rarely, culminate in life-threatening anaphylaxis. A role of anti-PEG antibodies (Abs) has been proposed, but causality has not yet been proven in an animal model. This study aimed to provide such evidence using anti-PEG hyperimmune pigs (i.e., pigs displaying very high levels of anti-PEG Abs). We also sought to find evidence for the role of complement (C) activation and thromboxane A2 (TXA2) release in blood as contributing effects to anaphylaxis. Methods: Pigs (n=6) were immunized with 0.1 mg/kg PEGylated liposome (Doxebo) i.v. the rise of anti-PEG IgG and IgM was measured in serial blood samples with ELISA. After 2-3 weeks, during the height of seroconversion, the animals were injected i.v. with 1/3 human vaccine dose (HVD) of Comirnaty, and the hemodynamic (PAP, SAP), cardiopulmonary (HR, EtCO2,), hematological parameters (WBC, granulocyte, lymphocyte, and platelet counts) and blood immune mediators (anti-PEG IgM and IgG Abs, C3a and TXA2) were measured as endpoints of HSRs. Results: A week after immunization of 6 pigs with Doxebo, the level of anti-PEG IgM and IgG rose 5-10-thousands-fold in all animals, and they all developed anaphylactic shock to i.v. injection of 1/3 HVD of Comirnaty. The reaction, starting within 1 min, led to the abrupt decline of SAP along with maximal pulmonary hypertension, decreased pulse pressure amplitude, tachycardia, granulo- and thrombocytopenia, and paralleling rises of plasma C3a and TXB2 levels. These vaccine effects were not observed in non-immunized pigs. Conclusions: Consistent with previous studies with PEGylated nano-liposomes, these data show a causal role of anti-PEG Abs in the anaphylaxis to Comirnaty. The reaction involves C activation, and, hence, it represents C activation-related pseudo-allergy (CARPA). The setup provides the first large-animal model for mRNA-vaccine-induced anaphylaxis in humans.

Patient-Centered Paradigm for Managing Autonomic Long COVID Symptoms During Sports and Exercise.

ABSTRACT: This report highlights a new, patient-centered paradigm for managing post-COVID-19 dysautonomia symptoms during sports and exercise. The patient was a healthcare worker exposed before vaccination. She experienced postural orthostatic tachycardia plus exertional tachycardia, with postexertional fatigue, beginning a few weeks after testing positive for COVID-19. Stress test, echo, and an extensive dysautonomia evaluation were negative. Recommended nonpharmacological and pharmacological interventions were poorly tolerated. Prescription of a novel regimen of "basal-dose" ivabradine, plus very low-dose metoprolol according to an exertional "sliding scale" managed symptoms to an acceptable level for work and recreation.

Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study) (preprint)

Background: Significant clinical similarities have been observed between the recently described Long-Haul COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, brain-fog, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design: A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.

Comparative Cohort Study of Post-Acute Covid-19 Infection with a Nested, Randomized Controlled Trial of Ivabradine for Those With Postural Orthostatic Tachycardia Syndrome (The COVIVA Study) (preprint)

Background:  Significant clinical similarities have been observed between the recently described ‘Long-Haul’ COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog”, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design:  A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction.  A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction.  Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade. Trial registration:ClinicalTrials.gov, ID:NCT05481177 Registered on 29 July 2022.

Targeted Treatment of Inappropriate Sinoatrial Node Tachycardia Based on Electrophysiological and Structural Mechanisms.

The purpose of this review is to determine the causal mechanisms and treatment of inappropriate sinoatrial tachycardia (IST), defined as a non-physiological elevation in resting heart rate. IST is defined as a resting daytime sinus rate >100 beats/minute and an average 24-hour heart rate >90 beats/minute. Potential causal mechanisms include sympathetic receptor hypersensitivity, blunted parasympathetic tone, or enhanced intrinsic automaticity within the sinoatrial node (SAN) pacemaker-conduction complex. These anomalies may coexist in the same patient. Recent ex-vivo near-infrared transmural optical imaging of the SAN in human and animal hearts provides important insights into the functional and molecular features of this complex structure. In particular, it reveals the existence of preferential sinoatrial conduction pathways that ensure robust SAN activation with electrical conduction. The mechanism of IST is debated because even high-resolution electroanatomical mapping approaches cannot reveal intramural conduction in the 3-dimensional SAN complex. It may be secondary to enhanced automaticity, intranodal re-entry, or sinoatrial conduction pathway re-entry. Different pharmacological approaches can target these mechanisms. Long-acting ß blockers in IST can act on both primarily increased automaticity and dysregulated autonomic system. Ivabradine targets sources of increased SAN automaticity. Conventional or hybrid ablation may target all the described abnormalities. This review provides a state-of-the-art overview of putative IST mechanisms. In conclusion, based on current knowledge, pharmacological and ablation approaches for IST, including the novel hybrid SAN sparing ablation, are discussed.

Investigating Autonomic Nervous System Dysfunction among Patients with Post- Covid Condition and Prolonged Cardiovascular Symptoms (preprint)

The variability of heart rate (HR) and arterial pressure (AP), and their responses to head-up tilt test (HUTT) was investigated in post-Covid-19 syndrome (PCS) patients, reporting tachycardia and/or postural hypotension. PCS patients were tachycardic and showed attenuation of the following parameters: RMSSD; power of RR spectra at HF; occurrence of 2UV pattern of RR (symbolic analysis); and sample entropy. Basal AP and LF power of systolic AP were similar between PCS patients and control subjects; while 0V patterns of AP were exacerbated in PCS patients. Despite tachycardia and decrease in RMSSD, no parameter changed during HUTT in PCS patients. PCS patients reassessed after 6 months showed higher HF power of RR spectra and higher percentage of 2UV pattern of RR. Moreover, the reassessed PCS patients showed a lower occurrence of 0V patterns of AP, while the HUTT elicited HR and AP responses identical to control subjects. The HR and AP variability suggest an autonomic dysfunction with sympathetic predominance in PCS patients; while the lack of responses of HR and BP variability indices during HUTT indicates a marked impairment of autonomic control. However, the reassessment of PCS patients showed that the noxious effect of the PCS tended to fade over time.

Refractory Atrial Flutter, the Only Presentation of covid-19 Infection in a Neonate: a case report and review of literature (preprint)

Background The accurate incidence of different cardiovascular consequences of COVID-19 in pediatric population have been inadequately defined due to ongoing genotype changes in the virus. Although COVID-19 is known to increase inflammatory markers associated with atrial arrhythmias, the contemporary literature has poorly described new onset arrhythmias as a complication in previously healthy neonate with COVID-19 Case presentation Twenty-day-old female term neonate, born by caesarean section with immediate cry developed labored breathing, cyanosis and tachycardia after having close contact with a confirmed case of covid-19. She developed atrial flutter, which was refractory to cardioversion and drugs namely Amiodarone, Flecainide and Propranolol. The neonate was treated with IVIG. This is the first reported case of atrial flutter in neonatal period secondary to COVID-19. Conclusion Since the starting of SARS –COV2 pandemic all attentions and concerns has been mainly on respiratory manifestations and complications. The cardiovascular complications and treatment are neglected. This case reports tachyarrhythmia (Atrial Flutter) as unusual presentation of MISC in neonatal population and show role of IvIg in treatment of refractory arrhythmias.

Cardiac Arrhythmia after COVID-19 Vaccination versus Non-COVID-19 Vaccination: A Systematic Review and Meta-Analysis (preprint)

Aims: Cardiac arrhythmia is a rare complication after vaccination. Recently, reports of arrhythmia after COVID-19 vaccination have increased. Whether the risk for cardiac arrhythmia is higher with COVID-19 vaccines than with non-COVID-19 vaccines remains controversial. This meta-analysis explored the incidence of arrhythmia after COVID-19 vaccination and compared it with the incidence of arrhythmia after non-COVID-19 vaccination. Methods: We searched the MEDLINE, Scopus, Cochrane Library, and Embase databases for English-language studies reporting the incidence of arrhythmia (the primary endpoint) after vaccination from January 1, 1947 to October 28, 2022. Secondary endpoints included incidence of tachyarrhythmia and all-cause mortality. Subgroup analyses were conducted to evaluate the incidence of arrhythmia by age (children [<18 years] versus adults [[≥]18 years]), vaccine type (mRNA COVID-19 vaccine versus non-mRNA COVID-19 vaccine; individual non-COVID-19 vaccines versus COVID-19 vaccine), and COVID-19 vaccine dose (first versus second versus third). Random-effects meta-analyses were performed, and the intrastudy risk for bias and the certainty of evidence were evaluated. This study was registered with PROSPERO (CRD42022365912). Results: The overall incidence of arrhythmia from 36 studies (1,528,459,662 vaccine doses) was 291.8 (95% CI 111.6-762.7) cases per million doses. The incidence of arrhythmia was significantly higher after COVID-19 vaccination (2263.4 [875.4-5839.2] cases per million doses; 830,585,553 doses, 23 studies) than after non-COVID-19 vaccination (9.9 [1.3-75.5] cases per million doses; 697,874,109 doses, 14 studies; P<0.01). Compared with COVID-19 vaccines, the influenza, pertussis, human papillomavirus, and acellular pertussis vaccines were associated with a significantly lower incidence of arrhythmia. The incidence of tachyarrhythmia was significantly higher after COVID-19 vaccination (4367.5 [1535.2-12,360.8] cases per million doses; 1,208,656 doses, 15 studies) than after non-COVID-19 vaccination (25.8 [4.5-149.4] cases per million doses; 179,822,553 doses, 11 studies; P<0.01). Arrhythmia was also more frequent after the third dose of COVID-19 vaccine (19,064.3 [5775.5-61,051.2] cases per million doses; 7968 doses, 3 studies) than after the first dose (3450.9 [988.2-11,977.6] cases per million doses; 41,714,762 doses, 12 studies; P=0.05) or second dose (2262.5 [2205.9-2320.7] cases per million doses; 34,540,749 doses, 10 studies; P<0.01). All-cause mortality was comparable between the COVID-19 and non-COVID-19 vaccination groups. Conclusions: The overall risk for arrhythmia after COVID-19 vaccination was relatively low, although it was higher in COVID-19 vaccine recipients than in non-COVID-19 vaccine recipients. This increased risk should be evaluated along with other important factors, such as the incidence of local outbreaks and the risk for arrhythmia due to COVID infection itself, when weighing the safety and efficacy of COVID-19 vaccines.

Zymosan-induced leukocyte and cytokine changes in pigs: a new model for streamlined drug testing against severe COVID-19 (preprint)

Injection of 0.1 mg/kg zymosan in pigs i.v. elicited transient hemodynamic disturbance within minutes, without major blood cell changes. In contrast, infusion of 1 mg/kg zymosan triggered maximal pulmonary hypertension with tachycardia, lasting for 30 min. This change was followed by a transient granulopenia with a trough at 1 h, and then, up to about 6 h, a major granulocytosis, resulting in a 3-4-fold increase of neutrophil-to-lymphocyte ratio (NLR). In parallel with the changes in WBC differential, qRT-PCR and ELISA analyses showed increased transcription and/or release of inflammatory cytokines and chemokines into blood, including IL-6, TNF-, CCL-2, CXCL-10, and IL-1RA. The expression of IL-6 peaked at already 1.5-2.5 h, and we observed significant correlation between lymphopenia and IL-6 gene expression. While these changes are consistent with zymosan's known stimulatory effect on both the humoral and cellular arms of the innate immune system, what gives novel clinical relevance to the co-manifestation of above hemodynamic, hematological, and immune changes is that they represent independent bad prognostic indicators in terminal COVID-19 and other diseases involving cytokine storm. Thus, within a 6 h experiment, the model enables consecutive reproduction of a symptom triad that is characteristic of late-stage COVID-19. Given the limitations of modeling cytokine storm in animals and effectively treating severe COVID-19, the presented relatively simple large animal model may advance the R&D of drugs against these conditions. One of these disease markers (NLR), obtained from a routine laboratory endpoint (WBC differential), may also enable streamlining the model for high throughput drug screening.

Management of Multisystem Inflammatory Syndrome in Children (MIS-C) in resource limited settings: The Kenyan Experience (preprint)

Background: Since the onset of the recent COVID-19 pandemic, there have been growing concerns regarding multisystem inflammatory syndrome in children (MIS-C). This study aims to describe the clinico-epidemiological profile and challenges in management of MIS-C in low-middle income countries by highlighting the Kenyan experience. Methods A retrospective study at the Aga Khan University Hospital Nairobi, Avenue Hospital Kisumu and Kapsabet County Referral Hospital was undertaken to identify cases of MIS-C. A detailed chart review using the World Health Organization (WHO) data collection tool was adapted to incorporate information on socio-demographic details and treatment regimens. Findings: Twenty children with MIS-C were identified across the three facilities. Seventy percent of the children were male (14 of 20). COVID-19 PCR testing was done for five children and only one was positive. The commonest clinical symptoms were fever (90%), tachycardia (80%), prolonged capillary refill (80%), oral mucosal changes (65%) and peripheral cutaneous inflammation (50%). Four children required admission into the critical care unit for ventilation support and inotropic support. Cardiac evaluation was available for six patients four of whom had myocardial dysfunction, three had valvulitis and one had pericarditis. Immunoglobulin therapy was availed to two children and systemic steroids provided for three children. There were no documented mortalities. Interpretation: We describe the first case series of MIS-C in East and Central Africa. Majority of suspected cases of MIS-C did not have access to timely COVID-19 PCR testing and other appropriate evaluations which highlights the iniquity in access to diagnostics and treatment.

The association of typical and atypical symptoms on in-hospital mortality of older adults with COVID-19: a multicentre cohort study (preprint)

Atypical disease presentations are common in older adults with COVID-19. The objective of this study was to determine the prevalence of atypical and typical symptoms in older adults with COVID-19 through progressive pandemic waves and the association of these symptoms with in-hospital mortality. This retrospective cohort study included consecutive adults aged over 65 years with confirmed COVID-19 infection who were admitted to seven hospitals in Toronto, Canada from March 1, 2020 to June 30, 2021. The median age for the 1786 patients was 78.0 years and 847 (47.5%) were female. Atypical symptoms (as defined by geriatric syndromes) occurred in 1187 patients (66.5%), but rarely occurred in the absence of other symptoms (n=106, 6.2%). The most common atypical symptoms were anorexia (n=598, 33.5%), weakness (n=519, 23.9%), and delirium (n=449, 25.1%). Dyspnea (adjusted odds ratio [aOR] 2.05, 95% confidence interval [CI] 1.62-2.62), tachycardia (aOR 1.87, 95% CI 1.14-3.04), and delirium (aOR 1.52, 95% CI 1.18-1.96) were independently associated with in-hospital mortality. In a cohort of older adults hospitalized with COVID-19 infection, atypical presentations frequently overlapped with typical symptoms. Further research should be directed at understanding the cause and clinical significance of atypical presentations in older adults.

Large tricuspid valve thrombus complicating COVID-19 pneumonia (preprint)

Background: Hemostatic disturbances with coronavirus disease 2019 (COVID-19) can predispose to tricuspid and right heart thrombi in very rare instances. Aim: We describe a 29-year-old female patient without previous cause of thrombosis who developed large tricuspid valve thrombus (TVT) and moderate-to-severe tricuspid regurgitation (TR) during the course of COVID-19 infection. Materials: and methods: Persistant fever and tachycardia with thrombocytopenia and high D-dimer increased the index of suspicion. The diagnosis was made by bedside transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR). Surgery was performed for thrombectomy and tricuspid valve replacement with a tissue valve. Discussion: and conclusion: Detection of TVT in COVID-19 patients on the basis of high index of suspicion, bedside TTE and non-invasive CMR helps early surgical treatment and subsequent reduction of mortality and hospital stay.