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1.
J Am Coll Emerg Physicians Open ; 1(2): 95-101, 2020 Apr.
Article in English | MEDLINE | ID: covidwho-1898665

ABSTRACT

The COVID-19 pandemic is creating unique strains on the healthcare system. While only a small percentage of patients require mechanical ventilation and ICU care, the enormous size of the populations affected means that these critical resources may become limited. A number of non-invasive options exist to avert mechanical ventilation and ICU admission. This is a clinical review of these options and their applicability in adult COVID-19 patients. Summary recommendations include: (1) Avoid nebulized therapies. Consider metered dose inhaler alternatives. (2) Provide supplemental oxygen following usual treatment principles for hypoxic respiratory failure. Maintain awareness of the aerosol-generating potential of all devices, including nasal cannulas, simple face masks, and venturi masks. Use non-rebreather masks when possible. Be attentive to aerosol generation and the use of personal protective equipment. (3) High flow nasal oxygen is preferred for patients with higher oxygen support requirements. Non-invasive positive pressure ventilation may be associated with higher risk of nosocomial transmission. If used, measures special precautions should be used reduce aerosol formation. (4) Early intubation/mechanical ventilation may be prudent for patients deemed likely to progress to critical illness, multi-organ failure, or acute respiratory distress syndrome (ARDS).

2.
CJC Open ; 3(3): 311-317, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1385284

ABSTRACT

BACKGROUND: In this study, we aimed to report clinical characteristics and outcomes of patients with and without SARS-CoV-2 infection who were referred for acute coronary syndrome (ACS) during the peak of the pandemic in France. METHODS: We included all consecutive patients referred for ST-elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) during the first 3 weeks of April 2020 in 5 university hospitals (Paris, south, and north of France), all performing primary percutaneous coronary intervention. RESULTS: The study included 237 patients (67 ± 14 years old; 69% male), 116 (49%) with STEMI and 121 (51%) with NSTEMI. The prevalence of SARS-CoV-2-associated ACS was 11% (n = 26) and 11 patients had severe hypoxemia on presentation (mechanical ventilation or nasal oxygen > 6 L/min). Patients were comparable regarding medical history and risk factors, except a higher prevalence of diabetes mellitus in SARS-CoV-2 patients (53.8% vs 25.6%; P = 0.003). In SARS-CoV-2 patients, cardiac arrest on admission was more frequent (26.9% vs 6.6%; P < 0.001). The presence of significant coronary artery disease and culprit artery occlusion in SARS-CoV-2 patients respectively, was 92% and 69.4% for those with STEMI, and 50% and 15.5% for those with NSTEMI. Percutaneous coronary intervention was performed in the same percentage of STEMI (84.6%) and NSTEMI (84.8%) patients, regardless of SARS-CoV-2 infection, but no-reflow (19.2% vs 3.3%; P < 0.001) was greater in SARS-CoV-2 patients. In-hospital death occurred in 7 SARS-CoV-2 patients (5 from cardiac cause) and was higher compared with noninfected patients (26.9% vs 6.2%; P < 0.001). CONCLUSIONS: In this registry, ACS in SARS-CoV-2 patients presented with high a percentage of cardiac arrest on admission, high incidence of no-reflow, and high in-hospital mortality.


CONTEXTE: Notre étude avait pour but d'établir les caractéristiques cliniques et les résultats de patients infectés ou non par le SRAS-CoV-2 qui ont été orientés en raison d'un syndrome coronarien aigu (SCA) pendant la phase aiguë de la pandémie en France. MÉTHODOLOGIE: Nous avons inclus dans l'étude tous les patients consécutifs qui ont présenté un infarctus du myocarde avec sus-décalage du segment ST (STEMI) ou sans sus-décalage du segment ST (NSTEMI) au cours des 3 premières semaines d'avril 2020 et qui ont été orientés vers 5 hôpitaux universitaires (situés à Paris, ainsi que dans le sud et le nord de la France), tous en mesure de réaliser des interventions co-ronariennes percutanées primaires. RÉSULTATS: L'étude comprenait 237 patients (âge : 67 ± 14 ans; proportion d'hommes : 69 %); 116 (49 %) présentaient un STEMI et 121 (51 %), un NSTEMI. La prévalence d'un SCA associé à une infection par le SRAS-CoV-2 s'établissait à 11 % (n = 26), et 11 patients étaient en hypoxémie grave (nécessitant une ventilation artificielle ou l'administration d'oxygène par voie nasale à un débit de plus de 6 l/min) à leur arrivée. Les patients présentaient des antécédents médicaux et des facteurs de risque comparables, à l'exception du fait que la prévalence du diabète était plus élevée chez les patients infectés par le SRAS-CoV-2 (53,8 % vs 25,6 %; p = 0,003). Ces derniers avaient plus souvent subi un arrêt cardiaque à leur admission (26,9 % vs 6,6 %; p < 0,001). Chez les patients infectés par le SRAS-CoV-2, une coronaropathie importante et une occlusion de l'artère coupable ont été observées chez respectivement 92 % et 69,4 % des patients présentant un STEMI, et chez 50 % et 15,5 % des patients présentant un NSTEMI. Une intervention coronarienne percutanée a été effectuée dans les mêmes proportions chez les patients subissant un STEMI (84,6 %) que chez ceux présentant un NSTEMI (84,8 %), sans égard à la présence ou à l'absence d'une infection par le SRAS-CoV-2, mais les cas de non-reperfusion (no-reflow) ont été plus fréquents chez les patients infectés que chez les autres patients (19,2 % et 3,3 %, respectivement; p < 0,001). Sept patients infectés par le SRAS-CoV-2 sont morts à l'hôpital (5 de cause cardiaque), ce qui représente un taux de mortalité plus élevé que chez les patients non infectés (26,9 % vs 6,2 %; p < 0,001). CONCLUSIONS: Dans le cadre de cette étude, le SCA survenu chez les patients infectés par le SRAS-CoV-2 était associé à un fort pourcentage d'arrêt cardiaque à l'admission, à une fréquence élevée de cas de non-reperfusion et à un taux élevé de mortalité hospitalière.

3.
J Autoimmun ; 121: 102662, 2021 07.
Article in English | MEDLINE | ID: covidwho-1385817

ABSTRACT

Herein, we consider venous immunothrombotic mechanisms in SARS-CoV-2 infection and anti-SARS-CoV-2 DNA vaccination. Primary SARS-CoV-2 infection with systemic viral RNA release (RNAaemia) contributes to innate immune coagulation cascade activation, with both pulmonary and systemic immunothrombosis - including venous territory strokes. However, anti-SARS-CoV-2 adenoviral-vectored-DNA vaccines -initially shown for the ChAdOx1 vaccine-may rarely exhibit autoimmunity with autoantibodies to Platelet Factor-4 (PF4) that is termed Vaccine-Induced Thrombotic Thrombocytopenia (VITT), an entity pathophysiologically similar to Heparin-Induced Thrombocytopenia (HIT). The PF4 autoantigen is a polyanion molecule capable of independent interactions with negatively charged bacterial cellular wall, heparin and DNA molecules, thus linking intravascular innate immunity to both bacterial cell walls and pathogen-derived DNA. Crucially, negatively charged extracellular DNA is a powerful adjuvant that can break tolerance to positively charged nuclear histone proteins in many experimental autoimmunity settings, including SLE and scleroderma. Analogous to DNA-histone interactons, positively charged PF4-DNA complexes stimulate strong interferon responses via Toll-Like Receptor (TLR) 9 engagement. A chain of events following intramuscular adenoviral-vectored-DNA vaccine inoculation including microvascular damage; microbleeding and platelet activation with PF4 release, adenovirus cargo dispersement with DNA-PF4 engagement may rarely break immune tolerance, leading to rare PF4-directed autoimmunity. The VITT cavernous sinus cerebral and intestinal venous territory immunothrombosis proclivity may pertain to venous drainage of shared microbiotal-rich areas of the nose and in intestines that initiates local endovascular venous immunity by PF4/microbiotal engagement with PF4 autoantibody driven immunothrombosis reminiscent of HIT. According to the proposed model, any adenovirus-vectored-DNA vaccine could drive autoimmune VITT in susceptible individuals and alternative mechanism based on molecular mimicry, vaccine protein contaminants, adenovirus vector proteins, EDTA buffers or immunity against the viral spike protein are secondary factors. Hence, electrochemical DNA-PF4 interactions and PF4-heparin interactions, but at different locations, represent the common denominator in HIT and VITT related autoimmune-mediated thrombosis.


Subject(s)
Autoantibodies/immunology , COVID-19/immunology , Purpura, Thrombocytopenic, Idiopathic/immunology , SARS-CoV-2/immunology , Thrombosis/immunology , Vaccines/adverse effects , COVID-19/pathology , COVID-19/prevention & control , Humans , Platelet Activation/immunology , Platelet Factor 4/immunology , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/pathology , Thrombosis/chemically induced , Thrombosis/pathology , Vaccines/immunology
4.
Nat Microbiol ; 6(1): 11-18, 2021 01.
Article in English | MEDLINE | ID: covidwho-1387364

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is having a catastrophic impact on human health1. Widespread community transmission has triggered stringent distancing measures with severe socio-economic consequences. Gaining control of the pandemic will depend on the interruption of transmission chains until vaccine-induced or naturally acquired protective herd immunity arises. However, approved antiviral treatments such as remdesivir and reconvalescent serum cannot be delivered orally2,3, making them poorly suitable for transmission control. We previously reported the development of an orally efficacious ribonucleoside analogue inhibitor of influenza viruses, MK-4482/EIDD-2801 (refs. 4,5), that was repurposed for use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently in phase II/III clinical trials (NCT04405570 and NCT04405739). Here, we explored the efficacy of therapeutically administered MK-4482/EIDD-2801 to mitigate SARS-CoV-2 infection and block transmission in the ferret model, given that ferrets and related members of the weasel genus transmit the virus efficiently with minimal clinical signs6-9, which resembles the spread in the human young-adult population. We demonstrate high SARS-CoV-2 burden in nasal tissues and secretions, which coincided with efficient transmission through direct contact. Therapeutic treatment of infected animals with MK-4482/EIDD-2801 twice a day significantly reduced the SARS-CoV-2 load in the upper respiratory tract and completely suppressed spread to untreated contact animals. This study identified oral MK-4482/EIDD-2801 as a promising antiviral countermeasure to break SARS-CoV-2 community transmission chains.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/prevention & control , COVID-19/transmission , Cytidine/analogs & derivatives , Hydroxylamines/pharmacology , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , COVID-19/immunology , Chlorocebus aethiops , Cytidine/pharmacology , Cytokines/immunology , Disease Models, Animal , Disease Transmission, Infectious/prevention & control , Female , Ferrets , Random Allocation , Vero Cells
6.
J Med Virol ; 93(9): 5328-5332, 2021 09.
Article in English | MEDLINE | ID: covidwho-1363671

ABSTRACT

Middle East respiratory syndrome coronavirus (MERS-CoV) is one of the recently identified zoonotic coronaviruses. The one-hump camels are believed to play important roles in the evolution and transmission of the virus. The animal-to-animal, as well as the animal-to-human transmission in the context of MERS-CoV infection, were reported. The camels shed the virus in some of their secretions, especially the nasal tract. However, there are many aspects of the transmission cycle of the virus from animals to humans that are still not fully understood. Rodents played important roles in the transmission of many pathogens, including viruses and bacteria. They have been implicated in the evolution of many human coronaviruses, especially HCoV-OC43 and HCoV-HKU1. However, the role of rodents in the transmission of MERS-CoV still requires more exploration. To achieve this goal, we identified MERS-CoV that naturally infected dromedary camel by molecular surveillance. We captured 15 of the common rodents (rats, mice, and jerboa) sharing the habitat with these animals. We collected both oral and rectal swabs from these animals and then tested them by the commercial MERS-CoV real-time-PCR kits using two targets. Despite the detection of the viral shedding in the nasal swabs of some of the dromedary camels, none of the rodents tested positive for the virus during the tenure of this study. We concluded that these species of rodents did not harbor the virus and are most unlikely to contribute to the transmission of the MERS-CoV. However, further large-scale studies are required to confirm the potential roles of rodents in the context of the MERS-CoV transmission cycle, if any.


Subject(s)
Camelus/virology , Coronavirus Infections/transmission , Coronavirus Infections/veterinary , Epidemiological Monitoring/veterinary , RNA, Viral/genetics , Animals , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Humans , Mice , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Nasal Cavity/virology , Rats , Real-Time Polymerase Chain Reaction , Rectum/virology , Rodentia/virology , Saudi Arabia/epidemiology
7.
Int J Infect Dis ; 108: 187-189, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1351682

ABSTRACT

OBJECTIVES: The present study compared the performance of the Lumipulse G Sars-CoV-2 Ag kit with the TaqPath COVID-19 RT-PCR CE IVD kit. METHODS: The study was conducted on 4266 naso-oropharyngeal swabs. Samples were subjected to antigen RT-PCR tests for the detection of Sars-CoV-2 and related variants. Statistical analyses were conducted in R software. RESULTS: We found 503 positives (including 138 H69-V70 deletion carriers) and 3763 negatives by RT-PCR, whereas 538 positives and 3728 negatives were obtained by antigen testing. We achieved empirical and binormal AU-ROCs of 0.920 and 0.990, accuracy of 0.960, sensitivity of 0.866, specificity of 0.973, positive and negative predictive values of 0.810 and 0.980. We obtained a positive correlation between viral loads and antigen levels (R2 = 0.81), finding a complete concordance for high viral loads (log10 copies/mL > 5.4). Antigen levels > 222 pg/mL were found to be reliable in assigning positive samples (p < 0.01). Concerning variant carriers, antigen test detected them with the same accuracy as other positive samples. CONCLUSIONS: Molecular and antigen tests should be evaluated regarding the prevalence of the area. In case of low prevalence, antigen testing can be employed as a first-line screening for the timely identification of affected individuals with high viral load, also if carriers of Sars-CoV-2 variants.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Sensitivity and Specificity , Viral Load
8.
J Clin Invest ; 131(13)2021 07 01.
Article in English | MEDLINE | ID: covidwho-1304352

ABSTRACT

The upper respiratory tract is compromised in the early period of COVID-19, but SARS-CoV-2 tropism at the cellular level is not fully defined. Unlike recent single-cell RNA-Seq analyses indicating uniformly low mRNA expression of SARS-CoV-2 entry-related host molecules in all nasal epithelial cells, we show that the protein levels are relatively high and that their localizations are restricted to the apical side of multiciliated epithelial cells. In addition, we provide evidence in patients with COVID-19 that SARS-CoV-2 is massively detected and replicated within the multiciliated cells. We observed these findings during the early stage of COVID-19, when infected ciliated cells were rapidly replaced by differentiating precursor cells. Moreover, our analyses revealed that SARS-CoV-2 cellular tropism was restricted to the nasal ciliated versus oral squamous epithelium. These results imply that targeting ciliated cells of the nasal epithelium during the early stage of COVID-19 could be an ideal strategy to prevent SARS-CoV-2 propagation.


Subject(s)
COVID-19/virology , Host Microbial Interactions , Nasal Mucosa/virology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/pathology , COVID-19/physiopathology , Cell Differentiation , Cilia/pathology , Cilia/physiology , Cilia/virology , Furin/genetics , Furin/metabolism , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Macaca , Models, Biological , Nasal Mucosa/pathology , Nasal Mucosa/physiopathology , Pandemics , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA-Seq , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Stem Cells/pathology , Stem Cells/virology , Virus Internalization , Virus Replication/genetics , Virus Replication/physiology
9.
Pharmacol Res Perspect ; 9(4): e00810, 2021 08.
Article in English | MEDLINE | ID: covidwho-1269137

ABSTRACT

In this individual patient data meta-analysis we examined datasets of two randomized placebo-controlled trials which investigated the effect of nasal carrageenan separately on children and adults. In both trials, iota-carrageenan was administered nasally three times per day for 7 days for patients with the common cold and follow-up lasted for 21 days. We used Cox regression to estimate the effect of carrageenan on recovery rate. We also used quantile regression to calculate the effect of carrageenan on colds of differing lengths. Nasal carrageenan increased the recovery rate from all colds by 54% (95% CI 15%-105%; p = .003). The increase in recovery rate was 139% for coronavirus infections, 119% for influenza A infections, and 70% for rhinovirus infections. The mean duration of all colds in the placebo groups of the first four quintiles were 4.0, 6.8, 8.8, and 13.7 days, respectively. The fifth quintile contained patients with censored data. The 13.7-day colds were shortened by 3.8 days (28% reduction), and 8.8-day colds by 1.3 days (15% reduction). Carrageenan had no meaningful effect on shorter colds. In the placebo group, 21 patients had colds lasting over 20 days, compared with six patients in the carrageenan group, which corresponds to a 71% (p = .003) reduction in the risk of longer colds. Given that carrageenan has an effect on diverse virus groups, and effects at the clinical level on two old coronaviruses, it seems plausible that carrageenan may have an effect on COVID-19. Further research on nasal iota-carrageenan is warranted.


Subject(s)
Antiviral Agents/administration & dosage , Carrageenan/administration & dosage , Common Cold/virology , Coronavirus Infections/drug therapy , Influenza, Human/drug therapy , Picornaviridae Infections/drug therapy , Administration, Intranasal , Adult , Antiviral Agents/therapeutic use , Carrageenan/pharmacology , Child, Preschool , Common Cold/drug therapy , Female , Humans , Male , Nasal Sprays , Randomized Controlled Trials as Topic , Regression Analysis , Survival Analysis , Time Factors , Treatment Outcome
10.
J Med Virol ; 93(7): 4392-4398, 2021 07.
Article in English | MEDLINE | ID: covidwho-1263103

ABSTRACT

With the arrival of coronavirus disease 2019 (COVID-19) in Brazil in February 2020, several preventive measures were taken by the population aiming to avoid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection including the use of masks, social distancing, and frequent hand washing then, these measures may have contributed to preventing infection also by other respiratory viruses. Our goal was to determine the frequencies of Influenza A and B viruses (FLUAV/FLUBV), human mastadenovirus C (HAdV-C), Enterovirus 68 (EV-68), and rhinovirus (RV) besides SARS-CoV-2 among hospitalized patients suspect of COVID-19 with cases of acute respiratory disease syndrome (ARDS) in the period of March to December 2020 and to detect possible coinfections among them. Nucleic acid detection was performed using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in respiratory samples using naso-oropharyngeal swabs and bronchoalveolar lavage. A total of 418 samples of the 987 analyzed (42.3%) were positive for SARS-CoV-2, 16 (1.62%) samples were positive for FLUAV, no sample was positive for FLUBV or EV-68, 67 (6.78%) samples were positive for HAdV-C, 55 samples were positive for RV 1/2 (26.3%) and 37 for RV 2/2 (13.6%). Coinfections were also detected, including a triple coinfection with SARS-CoV-2, FLUAV, and HAdV-C. In the present work, a very low frequency of FLUV was reported among hospitalized patients with ARDS compared to the past years, probably due to preventive measures taken to avoid COVID-19 and the high influenza vaccination coverage in the region in which this study was performed.


Subject(s)
Adenoviridae Infections/epidemiology , COVID-19/epidemiology , Common Cold/epidemiology , Enterovirus Infections/epidemiology , Influenza, Human/epidemiology , Physical Distancing , Adenoviridae Infections/prevention & control , Adolescent , Adult , Aged , Aged, 80 and over , Brazil/epidemiology , COVID-19/prevention & control , Child , Child, Preschool , Coinfection/epidemiology , Coinfection/virology , Common Cold/prevention & control , Enterovirus D, Human/genetics , Enterovirus D, Human/isolation & purification , Enterovirus Infections/prevention & control , Female , Humans , Infant , Influenza A virus/genetics , Influenza A virus/isolation & purification , Influenza B virus/genetics , Influenza B virus/isolation & purification , Influenza, Human/prevention & control , Male , Masks , Mastadenovirus/genetics , Mastadenovirus/isolation & purification , Middle Aged , Nucleic Acid Amplification Techniques/methods , Reverse Transcriptase Polymerase Chain Reaction/methods , Rhinovirus/genetics , Rhinovirus/isolation & purification , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Young Adult
11.
Int J Comput Assist Radiol Surg ; 16(8): 1403-1412, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1258242

ABSTRACT

PURPOSE: During the COVID-19 pandemic, a threatening bottleneck of medical staff arose due to a shortage of trained caregivers, who became infected while working with infectious patients. While telemedicine is rapidly evolving in the fields of teleconsultation and telesurgery, proper telediagnostic systems are not yet available, although the demand for contactless patient-doctor interaction is increasing. METHODS: In this project, the current limitations were addressed by developing a comprehensive telediagnostic system. Therefore, medical examinations have been assessed in collaboration with medical experts. Subsequently, a framework was developed, satisfying the relevant constraints of medical-, technical-, and hygienic- aspects in order to transform in-person examinations into a contactless procedure. Diagnostic steps were classified into three groups: assisted procedures carried out by the patient, teleoperated examination methods, and adoptions of conventional methods. RESULTS: The Telemedical Diagnostic Framework was implemented, resulting in a functional proof of concept, where potentially infectious patients could undergo a full medical examination. The system comprises, e.g., a naso-pharyngeal swab, an inspection of the oral cavity, auscultation, percussion, and palpation, based on robotic end-effectors. The physician is thereby connected using a newly developed user-interface and a lead robot, with force feedback control, that enables precise movements with the follower robot on the patient's side. CONCLUSION: Our concept proves the feasibility of a fully telediagnostic system, that consolidates available technology and new developments to an efficient solution enabling safe patient-doctor interaction. Besides infectious situations, this solution can also be applied to remote areas.


Subject(s)
COVID-19 , Remote Consultation , Telemedicine , Humans , Pandemics , SARS-CoV-2
12.
J Clin Med ; 10(11)2021 May 24.
Article in English | MEDLINE | ID: covidwho-1244047

ABSTRACT

BACKGROUND: During the lockdown period caused by the SARS-CoV-2 pandemic, we monitored via online survey the trend of allergic symptoms and the therapeutic compliance in patients followed at our center. MATERIAL AND METHODS: In June 2020, we selected children followed at the Allergy and Immunology Service of Umberto I Hospital, aged between 6 and 16 years old, diagnosed with asthma and/or rhinitis and sensitized to grass pollen or dust mite. We sent an email with 12 multiple-choice questions investigating several areas: type of disease and sensitization, recurrence of symptoms, medication use during lockdown compared to the same period of the previous year. RESULTS: The results of 82 questionnaires showed that 17.8% of patients suffered from asthma, 24.4% from rhinitis, and 57.8% from both. Within the group of asthmatic children, most of them presented an improvement of their symptoms. Likewise, with regard to allergic rhinitis, most of them reported better clinical conditions. Regarding treatment, we observed a global decrease in the use of on-demand therapies (salbutamol, nasal corticosteroid, and antihistamine) for both pathologies. In addition, there was a reduction in the use of basal therapy for asthma and rhinitis from 2019 (23.3%) to 2020 (15.5%). CONCLUSIONS: Our data show a general trend of clinical improvement and a reduction in the use of on-demand and basal therapy in allergic children during the lockdown.

13.
J Med Invest ; 68(1.2): 192-195, 2021.
Article in English | MEDLINE | ID: covidwho-1231288

ABSTRACT

This report presents a case of a 74-year-old man who showed dramatic therapeutic response to treatment of coronavirus infectious disease-19 (COVID-19) pneumonia. He reported four-day history of sustained fever and acute progressive dyspnea. He developed severe respiratory failure, underwent urgent endotracheal intubation and showed marked elevation of inflammatory and coagulation markers such as c-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH) and D-dimer. Chest computed tomography (CT) demonstrated diffuse consolidation and ground glass opacity (GGO). We diagnosed critical COVID-19 pneumonia with detailed sick contact history and naso-pharyngeal swab of a reverse-transcriptase-polymerase-chain reaction (RT-PCR) assay testing. He received anti-viral drug, anti-interleukin (IL-6) receptor antagonist and intravenous methylprednisolone. After commencing combined intensive therapy, he showed dramatic improvement of clinical condition, serum biomarkers and radiological findings. Early diagnosis and rapid critical care management may provide meaningful clinical benefit even if severe case. J. Med. Invest. 68 : 192-195, February, 2021.


Subject(s)
COVID-19/drug therapy , Pneumonia, Viral/drug therapy , SARS-CoV-2 , Aged , Amides/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antiviral Agents/administration & dosage , COVID-19/diagnostic imaging , Critical Illness , Drug Therapy, Combination , Glucocorticoids/administration & dosage , Humans , Lung/diagnostic imaging , Male , Methylprednisolone/administration & dosage , Pneumonia, Viral/diagnostic imaging , Pyrazines/administration & dosage , Receptors, Interleukin-6/antagonists & inhibitors , Tomography, X-Ray Computed , Treatment Outcome
14.
Int J Pharm ; 603: 120686, 2021 Jun 15.
Article in English | MEDLINE | ID: covidwho-1220091

ABSTRACT

It is striking that all marketed SARS-CoV-2 vaccines are developed for intramuscular administration designed to produce humoral and cell mediated immune responses, preventing viremia and the COVID-19 syndrome. They have a high degree of efficacy in humans (70-95%) depending on the type of vaccine. However, little protection is provided against viral replication and shedding in the upper airways due to the lack of a local sIgA immune response, indicating a risk of transmission of virus from vaccinated individuals. A range of novel nasal COVID-19 vaccines are in development and preclinical results in non-human primates have shown a promising prevention of replication and shedding of virus due to the induction of mucosal immune response (sIgA) in upper and lower respiratory tracts as well as robust systemic and humoral immune responses. Whether these results will translate to humans remains to be clarified. An IM prime followed by an IN booster vaccination would likely result in a better well-rounded immune response, including prevention (or strong reduction) in viral replication in the upper and lower respiratory tracts.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Viral , COVID-19 Vaccines , Humans , Immunity, Humoral , Vaccination
15.
ACS Appl Mater Interfaces ; 13(21): 24477-24486, 2021 Jun 02.
Article in English | MEDLINE | ID: covidwho-1219585

ABSTRACT

The pseudovirus strategy makes studies of highly pathogenic viruses feasible without the restriction of high-level biosafety facility, thus greatly contributing to virology and is used in the research studies of SARS-CoV-2. Here, we generated a dual-color pseudo-SARS-CoV-2 virus using a human immunodeficiency virus-1 pseudovirus production system and the SARS-CoV-2 spike (S) glycoprotein, of which the membrane was labeled with a lipophilic dye (DiO) and the genomic RNA-related viral protein R (Vpr) of the viral core was fused with mCherry. With this dual-color labeling strategy, not only the movement of the whole virus but also the fate of the labeled components can be traced. The pseudovirions were applied to track the viral entry at a single-particle level in four types of the human respiratory cells: nasal epithelial cells (HNEpC), pulmonary alveolar epithelial cells (HPAEpiC), bronchial epithelial cells (BEP-2D), and oral epithelial cells (HOEC). Pseudo-SARS-CoV-2 entered into the host cell and released the viral core into the cytoplasm, which clearly indicates that the host entry mainly occurred through endocytosis. The infection efficiency was found to be correlated with the expression of the known receptor of SARS-CoV-2, angiotensin-converting 2 (ACE2) on the host cell surface. We believe that the dual-color fluorescently labeled pseudovirus system created in this study can be applied as a useful tool for many purposes in SARS-CoV-2/COVID-19.


Subject(s)
Fluorescent Dyes/chemistry , Pulmonary Alveoli/virology , SARS-CoV-2/physiology , Virus Internalization , Angiotensin-Converting Enzyme 2/metabolism , Endocytosis , Epithelial Cells/virology , Fluorescence , HEK293 Cells , HIV-1/genetics , Humans , Nasal Mucosa/virology , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism
16.
J Biol Chem ; 296: 100701, 2021.
Article in English | MEDLINE | ID: covidwho-1198856

ABSTRACT

The acid sphingomyelinase/ceramide system has been shown to be important for cellular infection with at least some viruses, for instance, rhinovirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Functional inhibition of the acid sphingomyelinase using tricyclic antidepressants prevented infection of epithelial cells, for instance with SARS-CoV-2. The structure of ambroxol, that is, trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol, a mucolytic drug applied by inhalation, suggests that the drug might inhibit the acid sphingomyelinase and thereby infection with SARS-CoV-2. To test this, we used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. Viral uptake and formation of ceramide localization were determined by fluorescence microscopy, activity of the acid sphingomyelinase by consumption of [14C]sphingomyelin and ceramide was quantified by a kinase method. We found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, events that were all prevented by pretreatment with ambroxol. We also obtained nasal epithelial cells from human volunteers prior to and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spike-induced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo. The addition of purified acid sphingomyelinase or C16 ceramide restored entry of pp-VSV-SARS-CoV-2 spike into ambroxol-treated epithelial cells. We propose that ambroxol might be suitable for clinical studies to prevent coronavirus disease 2019.


Subject(s)
Ambroxol/pharmacology , Antiviral Agents/pharmacology , SARS-CoV-2/drug effects , Sphingomyelin Phosphodiesterase/genetics , Vesiculovirus/drug effects , Virus Internalization/drug effects , Administration, Inhalation , Animals , Biological Transport , Ceramides/metabolism , Chlorocebus aethiops , Drug Repositioning , Epithelial Cells/drug effects , Epithelial Cells/enzymology , Epithelial Cells/virology , Expectorants , Gene Expression , Humans , Primary Cell Culture , Reassortant Viruses/drug effects , Reassortant Viruses/physiology , SARS-CoV-2/physiology , Sphingomyelin Phosphodiesterase/antagonists & inhibitors , Sphingomyelin Phosphodiesterase/metabolism , Sphingomyelins/metabolism , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Vesiculovirus/physiology
17.
Eur Respir J ; 57(4)2021 04.
Article in English | MEDLINE | ID: covidwho-1190024

ABSTRACT

INTRODUCTION: Hospitalised patients with coronavirus disease 2019 (COVID-19) as a result of SARS-CoV-2 infection have a high mortality rate and frequently require noninvasive respiratory support or invasive ventilation. Optimising and standardising management through evidence-based guidelines may improve quality of care and therefore patient outcomes. METHODS: A task force from the European Respiratory Society and endorsed by the Chinese Thoracic Society identified priority interventions (pharmacological and non-pharmacological) for the initial version of this "living guideline" using the PICO (population, intervention, comparator, outcome) format. The GRADE approach was used for assessing the quality of evidence and strength of recommendations. Systematic literature reviews were performed, and data pooled by meta-analysis where possible. Evidence tables were presented and evidence to decision frameworks were used to formulate recommendations. RESULTS: Based on the available evidence at the time of guideline development (20 February, 2021), the panel makes a strong recommendation in favour of the use of systemic corticosteroids in patients requiring supplementary oxygen or ventilatory support, and for the use of anticoagulation in hospitalised patients. The panel makes a conditional recommendation for interleukin (IL)-6 receptor antagonist monoclonal antibody treatment and high-flow nasal oxygen or continuous positive airway pressure in patients with hypoxaemic respiratory failure. The panel make strong recommendations against the use of hydroxychloroquine and lopinavir-ritonavir. Conditional recommendations are made against the use of azithromycin, hydroxychloroquine combined with azithromycin, colchicine, and remdesivir, in the latter case specifically in patients requiring invasive mechanical ventilation. No recommendation was made for remdesivir in patients requiring supplemental oxygen. Further recommendations for research are made. CONCLUSION: The evidence base for management of COVID-19 now supports strong recommendations in favour and against specific interventions. These guidelines will be regularly updated as further evidence becomes available.


Subject(s)
COVID-19/therapy , Hospitalization , Adrenal Cortex Hormones/therapeutic use , Adult , Humans , Meta-Analysis as Topic , Respiration, Artificial , Systematic Reviews as Topic
18.
Support Care Cancer ; 29(11): 6271-6278, 2021 Nov.
Article in English | MEDLINE | ID: covidwho-1182254

ABSTRACT

BACKGROUND: Immunocompromised cancer patients are presumed to be at high risk of developing COVID-19 infection. Predisposing factors to contracting COVID-19 and to severe outcomes have been described in registries but were not compared between solid tumors and hematological malignancies. METHOD: This retrospective single oncologic center study included adults with solid tumors or hematological malignancies referred to testing by naso-pharyngeal swab for a SARS-CoV-2 RT-PCR from March 10 to May 18, 2020. RESULTS: A total of 212 patients were included in the study. Forty-five (21%) were tested positive with SARS-CoV-2. The univariate analysis with positive SARS-CoV-2 PCR as a dependent variable reveals significant odds ratios (ORs) for age-with a mean of 62.5 years-(OR: 1.05, 95% CI: 1.02-1.08), performance status ≥2 (OR: 2.38, 95% CI: 1.22-4.70), inpatient status (OR: 2.36, 95%CI: 1.11-4.91), and hematological malignancies (OR: 2.48, 95% CI: 1.23-4.96). In contrast, OR for solid tumors reveals a negative association (OR: 0.40, 95% CI: 0.20-0.81). When integrating severe outcome (ICU admission or COVID-19-related death) as a dependent variable, the univariate logistic regression model shows significant ORs for pre-existing lymphopenia (OR: 4.0, 95% CI: 1.17-15.04), hematological malignancies (OR: 3.73, 95% CI: 1.09-13.80), and a negative association for solid tumors (OR: 0.27; 95% CI: 0.07-0.92). CONCLUSION: In patients referred for SARS-CoV-2 testing, hematological malignancies were associated with a higher risk of COVID-19 infection and severe outcomes. Other factors were age and inpatient status.


Subject(s)
COVID-19 , Hematologic Neoplasms , Neoplasms , Adult , COVID-19 Testing , Hematologic Neoplasms/epidemiology , Humans , Middle Aged , Neoplasms/epidemiology , Retrospective Studies , SARS-CoV-2
19.
Trials ; 22(1): 270, 2021 Apr 12.
Article in English | MEDLINE | ID: covidwho-1181120

ABSTRACT

OBJECTIVES: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. TRIAL DESIGN: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. PARTICIPANTS: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease CRP ≥ 30mg/L at any time point Informed consent from patient or personal or professional representative Agreement to abstain from sexual intercourse or use contraception that is >99% effective for all participants of childbearing potential for 42 days after the last dose of study drug. For male participants, agreement to abstain from sperm donation for 42 days after the last dose of study drug. EXCLUSION: Requiring either invasive or non-invasive ventilation including CPAP or high flow nasal oxygen at any point after hospital admission but before baseline, not related to a pre-existing condition (e.g., obstructive sleep apnoea) Grade ≥ 5 severity on the modified WHO COVID-19 Ordinal Scale, i.e. SpO2 < 90% on ≥ 60% inspired oxygen by facemask at baseline; non-invasive ventilation; or invasive mechanical ventilation In the opinion of the investigator, progression to death is inevitable within the next 24 hours, irrespective of the provision of therapy Known severe allergic reactions to the investigational agents Child-Pugh B or C grade hepatic dysfunction Use of drugs within the preceding 14 days that are known to interact with any study treatment (FOS or RUX), as listed in the Summary of Product Characteristics Pregnant or breastfeeding Any medical condition or concomitant medication that in the opinion of the investigator would compromise subjects' safety or compliance with study procedures. Any medical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study Non-English speakers will be able to join the study. If participants are unable to understand verbal or written information in English, then hospital translation services will be requested at the participating site for the participant where possible. INTERVENTION AND COMPARATOR: RUXOLITINIB (RUX) (14 days): An oral selective and potent inhibitor of Janus Associated Kinases (JAK1 and JAK2) and cell proliferation (Verstovek, 2010). It is approved for the treatment of disease-related splenomegaly or constitutional symptoms in myelofibrosis, polycythaemia vera and graft-versus-host-disease. RUX will be administered orally 10mg bd Day 1-7 and 5mg bd Day 8-14. FOSTAMATINIB (FOS) (14 days): An oral spleen tyrosine kinase inhibitor approved for the treatment of thrombocytopenia in adult participants with chronic immune thrombocytopenia. FOS will be administered orally 150mg bd Day 1-7 and 100mg bd Day 8-14. Please see protocol for recommended dose modifications where required. COMPARATOR (Standard of Care, SOC): experimental arms will be compared to participants receiving standard of care. It is accepted that SOC may change during a rapidly evolving pandemic. Co-enrolment to other trials and rescue therapy, either pre- or post-randomisation, is permitted and will be accounted for in the statistical analysis. MAIN OUTCOMES: Pairwise comparison (RUX vs SOC and FOS vs SOC) of the proportion of participants diagnosed with severe COVID-19 pneumonia within 14 days. Severe COVID-19 pneumonia is defined by a score ≥ 5 on a modified WHO COVID-19 Ordinal Scale, comprising the following indicators of disease severity: Death OR Requirement for invasive ventilation OR Requirement for non-invasive ventilation including CPAP or high flow oxygen OR O2 saturation < 90% on ≥60% inspired oxygen RANDOMISATION: Participants will be allocated to interventions using a central web-based randomisation service that generates random sequences using random permuted blocks (1:1:1), with stratification by age (<65 and ≥65 years) and site. BLINDING (MASKING): No participants or caregivers are blinded to group assignment. Clinical outcomes will be compared blind to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): For an early informal dose examination by the Data Monitoring Committee a minimum of 30 participants will be recruited. For Stage 1 of this multi-arm multi-stage study, 171 participants will be randomised, with 57 participants in each arm. If at least one experimental intervention shows promise, then Stage 2 will recruit a further 95 participants per arm. Sample size calculations are given in the protocol. TRIAL STATUS: Recruitment is ongoing and started 2nd October 2020. We anticipate completion of Stage 1 by July 2021 and Stage 2 by April 2022. The current protocol version 2.0 of 11th February 2021 is appended. TRIAL REGISTRATION: EudraCT: 2020-001750-22 , 9th July 2020 ClinicalTrials.gov: NCT04581954 , 9th October 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
COVID-19/drug therapy , Oxazines/therapeutic use , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Adult , Aminopyridines , Humans , Morpholines , Nitriles , Pandemics , Pyrimidines , Randomized Controlled Trials as Topic , Respiration, Artificial , Treatment Outcome , Venous Thromboembolism/prevention & control
20.
IDCases ; 24: e01117, 2021.
Article in English | MEDLINE | ID: covidwho-1174265

ABSTRACT

A 41-year-old male with type 2 diabetes mellitus (T2DM) presented with complaints of recent onset limb weakness, diffuse body rash and fever. Computerized Tomography (CT) scan of the brain did not reveal a stroke but laboratory investigations of the patient portrayed multi-systemic involvement. Naso-pharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was taken which resulted as positive. Soon after, a biopsy of the skin lesions revealed histo-pathological features of leukocytoclastic vasculitis. The patient was further investigated for connective tissue disease and vasculitis only to yield a negative result for all relevant antibodies, with the exception of the anti-phospholipid antibody which was positive. The patient suffered through a complex and prolonged hospital stay that required the input of multiple sub-speciality teams. Although initially presenting with a normal chest X-ray the patient went on to have severe bilateral pneumonia and a progression of initial skin rash leading to severe necrosis of the left foot with dry gangrene of the left big toe. Due to these issues, coronavirus-disease-2019 (COVID-19) aimed therapy was started along with multiple skin debridements, antibiotics and eventual amputation of the patient's affected large toe. The following case-study details all the before-mentioned events with discussion of the possible reasons behind the patient's presentation and eventual outcome.

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