Management of Hematologic Malignancies in the Era of COVID-19 Pandemic: Pathogenetic Mechanisms, Impact of Obesity, Perspectives, and Challenges.

The COVID-19 pandemic brought about an unprecedented societal and healthcare system crisis, considerably affecting healthcare workers and patients, particularly those with chronic diseases. Patients with hematologic malignancies faced a variety of challenges, pertinent to the nature of an underlying hematologic disorder itself as well as its therapy as a risk factor for severe SARS-CoV-2 infection, suboptimal vaccine efficacy and the need for uninterrupted medical observation and continued therapy. Obesity constitutes another factor which was acknowledged since the early days of the pandemic that predisposed people to severe COVID-19, and shares a likely causal link with the pathogenesis of a broad spectrum of hematologic cancers. We review here the epidemiologic and pathogenetic features that obesity and hematologic malignancies share, as well as potential mutual pathophysiological links predisposing people to a more severe SARS-CoV-2 course. Additionally, we attempt to present the existing evidence on the multi-faceted crucial challenges that had to be overcome in this diverse patient group and discuss further unresolved questions and future challenges for the management of hematologic malignancies in the era of COVID-19.

Breakthrough infections after COVID-19 vaccination: Insights, perspectives and challenges.

Vaccination programs against SARS-CoV-2 constitute the mainstay of public health interventions against the global COVID-19 pandemic. Currently available vaccines have shown 90% or better rates of protection against severe disease and mortality. Barely a year after vaccines became available, the Omicron variant and its unprecedented speed of transmission has posed a new challenge. Overall, Omicron presents increased immune escape, transmissibility, and decreased pathogenicity. Vaccines do not offer a full protection against SARS-CoV-2 acquisition, since "breakthrough" infections may occur in fully vaccinated individuals, who may in turn spread the virus to others. Breakthrough infections may be causally related to the viral profile (viral variant and load, incubation period, transmissibility, pathogenicity, immune evasion), immunity characteristics (mucosal versus systemic immunity, duration of immunity, etc.), host determinants (age, comorbidities, immune status, immunosuppressive drugs) and vaccination properties (platform, antigen dose, dose number, dose interval, route of administration). Determining the rate of breakthrough infections may be challenging and necessitates the conduction of population-based studies regarding vaccine effectiveness as well as neutralizing antibody testing, a surrogate of immune protection. In this review, we analyze the causes of breakthrough infections, their clinical consequences (severity of infection and transmission), methods of determining their incidence as well as challenges and perspectives. Long COVID as well as multi-inflammatory syndrome in adolescents may be significantly reduced in breakthrough infections. The need for universal pancoranavirus vaccines that would aim at protecting against a plethora of SARS-CoV-2 variants as well as emerging variants is discussed. Finally, novel vaccine strategies, such as nasal vaccines, may confer robust mucosal and systemic protection, reducing efficiently transmission.

Herpes zoster following COVID-19 vaccination in an immunocompetent and vaccinated for herpes zoster adult: A two-vaccine related event?

Reactivation of varicella-zoster virus (VZV) has been reported after the administration of different vaccine platforms against SARS-CoV-2, also among individuals without known immunosuppressive states. Herein, we describe for the first time a case of herpes zoster after mRNA vaccination against SARS-CoV-2 in a 53-year-old immunocompetent adult without any known comorbidities, who was previously vaccinated with a live attenuated zoster vaccine. The fact that the patient had no history of varicella and had been tested seronegative for VZV prior to immunization with the live attenuated zoster vaccine further contribute to the challenge of this unusual case. This advocates for a high level of vigilance on the part of clinicians regarding this rare complication among receivers of COVID-19 vaccines.

SARS-CoV-2 adipose tissue infection and hyperglycemia: A further step towards the understanding of severe COVID-19.

Numerous studies have highlighted the prognostic significance of hyperglycemia in the outcomes of SARS-CoV-2 infection. A number of mechanisms have been proposed as potential drivers of this association, which were, however, up until recently based rather on speculation than on investigational evidence. It has been recently come to light that the development of insulin resistance in the frame of COVID-19 is likely the driving force behind the development of overt hyperglycemia. This results through the infectious insult of the adipose tissue, and is observed in conjunction with aberrant adipokine secretion by host adipocytes, such as decreased adiponectin, as well as a switch towards an antiviral immune secretory profile. These data could have a considerable relevance not only for the management of hyperglycemia in the course of the infection but also for the overall understanding of the pathogenesis of severe COVID-19.

Potential implications of lipid nanoparticles in the pathogenesis of myocarditis associated with the use of mRNA vaccines against SARS-CoV-2.

Although mRNA-based vaccines BNT162b2 and mRNA-1273 exhibit a remarkable efficacy and effectiveness in preventing particularly severe Covid-19 with an overall favorable adverse event profile, their use has been associated with rare cases of acute myocarditis. These occur most commonly after the second dose, with the highest incidence among young male recipients. This complication has not been frequently observed among adenoviral vector vaccine receivers, and its clinical, laboratory and imaging features resemble those of other common causes of acute myocarditis. The pathogenesis of mRNA-vaccine associated myocarditis has not yet been elucidated, although a number of mechanisms have been proposed, typically implicating the administered S-protein mRNA and likely mediated through an autoimmune mechanism. Nonetheless, other mechanisms may be implicated given the fact that myocarditis cases are very rarely observed among recipients of non mRNA vaccines. The recent observation of a similar adverse event in a recipient of the non-mRNA, peptide-based NVX-CoV2373 in the frame of a phase III clinical trial with 7020 participants in the active treatment arm raises the question whether the lipid nanoparticle sheath, which is a common structural component of these platforms could be implicated in the pathogenesis of vaccine-induced myocarditis.

Could inhaled corticosteroids be the game changers in the prevention of severe COVID-19? A review of current evidence.

As the Coronavirus 2019 disease (COVID-19) pandemic is going through its second year, the world is counting more than 4.9 million lives lost. Many repurposed immunomodulatory drugs have been tried and failed to treat COVID-19. The only successful treatments that improve survival are systemic corticosteroids and tocilizumab, by targeting the systemic inflammatory cascade. An intriguing observation that patients with chronic respiratory disease seem to be less prone to COVID-19 gave ground to the hypothesis that inhaled corticosteroids (ICS) may protect them from SARS-CoV-2 infection. In this review, we summarize current evidence regarding the therapeutic role of inhaled and systemic corticosteroids in COVID-19, and we present experimental data on the potential actions of ICS against SARS-CoV-2 infection. We also discuss safety issues as well as therapeutic considerations and clinical implications of the use of ICS in COVID-19. Four randomized controlled trials (RCT) with more than 3000 participants suggest that ICS may lead to earlier clinical improvement and lower rate of hospitalization in patients with mild COVID-19, while 9 ongoing RCTs are anticipated to provide more evidence for the use of ICS in COVID-19. Recent evidence has shown promise that ICS could provide tangible benefits to patients suffering from COVID-19.

Vaccine induced thrombotic thrombocytopenia: The shady chapter of a success story.

The recognition of the rare but serious and potentially lethal complication of vaccine induced thrombotic thrombocytopenia (VITT) raised concerns regarding the safety of COVID-19 vaccines and led to the reconsideration of vaccination strategies in many countries. Following the description of VITT among recipients of adenoviral vector ChAdOx1 vaccine, a review of similar cases after Ad26.COV2·S vaccination gave rise to the question whether this entity may constitute a potential class effect of all adenoviral vector vaccines. Most cases are females, typically younger than 60 years who present shortly (range: 5-30 days) following vaccination with thrombocytopenia and thrombotic manifestations, occasionally in multiple sites. Following initial incertitude, concrete recommendations to guide the diagnosis (clinical suspicion, initial laboratory screening, PF4-polyanion-antibody ELISA) and management of VITT (non-heparin anticoagulants, corticosteroids, intravenous immunoglobulin) have been issued. The mechanisms behind this rare syndrome are currently a subject of active research and include the following: 1) production of PF4-polyanion autoantibodies; 2) adenoviral vector entry in megacaryocytes and subsequent expression of spike protein on platelet surface; 3) direct platelet and endothelial cell binding and activation by the adenoviral vector; 4) activation of endothelial and inflammatory cells by the PF4-polyanion autoantibodies; 5) the presence of an inflammatory co-signal; and 6) the abundance of circulating soluble spike protein variants following vaccination. Apart from the analysis of potential underlying mechanisms, this review aims to synopsize the clinical and epidemiologic features of VITT, to present the current evidence-based recommendations on diagnostic and therapeutic work-up of VITT and to discuss new dilemmas and perspectives that emerged after the description of this entity.

Anti-viral treatment for SARS-CoV-2 infection: A race against time amidst the ongoing pandemic.

Remdesivir (GS-5734), a drug initially developed to treat hepatitis C and Ebola virus disease, was the first approved treatment for severe coronavirus disease 2019 (COVID-19). However, apart from remdesivir, there is a paucity of other specific anti-viral agents against SARS-CoV-2 infection. In 2017, researchers had documented the anti-coronavirus potential of remdesivir in animal models. At the same time, trials performed during two Ebola outbreaks in Africa showed that the drug was safe. Although vaccines against SARS-CoV-2 infection have emerged at an enormously high speed, equivalent results from efforts towards the development of anti-viral drugs, which could have played a truly life-saving role in the current stage of the pandemic, have been stagnating. In this review, we will focus on the current treatment options for COVID-19 which mainly consist of repurposed agents or treatments conferring passive immunity (convalescent plasma or monoclonal antibodies). Additionally, potential specific anti-viral therapies under development will be reviewed, such as the decoy miniprotein CTC-445.2d, protease inhibitors, mainly against the Main protein Mpro, nucleoside analogs, such as molnupiravir and compounds blocking the replication transcription complex proteins, such as zotatifin and plitidepsin. These anti-viral agents seem to be very promising but still require meticulous clinical trial testing in order to establish their efficacy and safety. The continuous emergence of viral variants may pose a real challenge to the scientific community towards that end. In this context, the advent of nanobodies together with the potential administration of a combination of anti-viral drugs could serve as useful tools in the armamentarium against COVID-19.

Providing evidence on the ongoing health care workers' mask debate.

The scarcity of facemasks, particularly N95 respirators, combined with the lack of solid data to address the suitability of each mask type for adequate health care worker (HCW) protection have caused turmoil among HCWs. Current recommendations suggest mask usage solely during HCW contact with Covid-19 patients, namely plain medical mask for low-risk contacts and N95 for aerosol generating procedures. The distinction regarding the escalation of mask complexity depending on contact type is nevertheless based on plausible theoretical assumptions rather than hard evidence of a clear benefit. Conversely, we suggest that at least a plain mask should be used during all HCWs' contacts in healthcare facilities which constitute a highly probable but often overlooked means of SARS-CoV-2 transmission among HCWs.

In Vitro Data of Current Therapies for SARS-CoV-2.

BACKGROUND: In December 2019, a new coronavirus, named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), emerged from China, causing pneumonia outbreaks first in the Wuhan region and then spread worldwide. Due to a lack of efficient and specific treatments and the need to contain the epidemic, drug repurposing appears to be the most efficient tool to find a therapeutic solution. OBJECTIVES: The aim of this study was to summarize in vitro data of current agents used for the management of SARS-CoV-2 all over the world. METHODS: A literature search of articles from January 2000 until April 2020 was performed using MEDLINE, EMBASE and the Cochrane Library to assess in vitro data of current or putative therapies for SARS-CoV-2. RESULTS: Although in vitro studies are scarce, data regarding chloroquine, hydroxychloroquine, remdesivir, nitazoxanide, teicoplanin, ivermectin, lopinavir, homoharringtonine, and emetine seem promising. CONCLUSION: Scientists all over the world should work together and increase their efforts in order to find feasible and efficient solutions against this new global viral threat.