Coronavirus disease 2019 (COVID‐19), triggered by the betacoronavirus SARS‐CoV‐2, has become one of the worst pandemics of our time that has already caused more than 250,000 deaths (JHU ...data‐05/06/2020, https://coronavirus.jhu.edu/). Effective therapeutic approaches are urgently needed to reduce the spread of the virus and its death toll. Here, we assess the possibility of using interferon‐lambda (IFNλ), a third type of interferon sharing low homology with type I IFNs and IL‐10, for treating COVID‐19 patients. We discuss the unique role of IFNλ in fine‐tuning antiviral immunity in the respiratory tract to achieve optimal protection and minimal host damage and review early evidence that SARS‐CoV‐2 may impair IFNλ induction, leading to a delayed type I IFN‐dominated response that triggers hyperinflammation and severe disease. We also consider the potential windows of opportunity for therapeutic intervention with IFNλ and potential safety considerations. We conclude that IFNλ constitutes a promising therapeutic agent for reducing viral presence and hyperinflammation in a single shot to prevent the devastating consequences of COVID‐19 such as pneumonia and acute respiratory distress syndrome (ARDS).
Can we treat COVID‐19 with IFNλ? E. Andreakos and S. Tsiodras discuss how SARS‐CoV‐2 may impair IFNλ induction, leading to a delayed type I IFN‐dominated response that triggers hyperinflammation and severe disease.
A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage
. Here, we report that ...for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-λ and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.
Accumulating evidence points toward a very high prevalence of prolonged neurological symptoms among coronavirus disease 2019 (COVID-19) survivors. To date, there are no solidified criteria for ...‘long-COVID’ diagnosis. Nevertheless, ‘long-COVID’ is conceptualized as a multi-organ disorder with a wide spectrum of clinical manifestations that may be indicative of underlying pulmonary, cardiovascular, endocrine, hematologic, renal, gastrointestinal, dermatologic, immunological, psychiatric, or neurological disease. Involvement of the central or peripheral nervous system is noted in more than one-third of patients with antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data. The most frequent neurological manifestations of ‘long-COVID’ encompass fatigue; ‘brain fog’; headache; cognitive impairment; sleep, mood, smell, or taste disorders; myalgias; sensorimotor deficits; and dysautonomia. Although very limited evidence exists to date on the pathophysiological mechanisms implicated in the manifestation of ‘long-COVID’, neuroinflammatory and oxidative stress processes are thought to prevail in propagating neurological ‘long-COVID’ sequelae. In this narrative review, we sought to present a comprehensive overview of our current understanding of clinical features, risk factors, and pathophysiological processes of neurological ‘long-COVID’ sequelae. Moreover, we propose diagnostic and therapeutic algorithms that may aid in the prompt recognition and management of underlying causes of neurological symptoms that persist beyond the resolution of acute COVID-19. Furthermore, as causal treatments for ‘long-COVID’ are currently unavailable, we propose therapeutic approaches for symptom-oriented management of neurological ‘long-COVID’ symptoms. In addition, we emphasize that collaborative research initiatives are urgently needed to expedite the development of preventive and therapeutic strategies for neurological ‘long-COVID’ sequelae.
Greece imposed a nationwide lockdown in March 2020 to mitigate transmission of severe acute respiratory syndrome coronavirus 2 during the first epidemic wave. We conducted a survey on age-specific ...social contact patterns to assess effects of physical distancing measures and used a susceptible-exposed-infectious-recovered model to simulate the epidemic. Because multiple distancing measures were implemented simultaneously, we assessed their overall effects and the contribution of each measure. Before measures were implemented, the estimated basic reproduction number (R
) was 2.38 (95% CI 2.01-2.80). During lockdown, daily contacts decreased by 86.9% and R
decreased by 81.0% (95% credible interval CrI 71.8%-86.0%); each distancing measure decreased R
by 10%-24%. By April 26, the attack rate in Greece was 0.12% (95% CrI 0.06%-0.26%), one of the lowest in Europe, and the infection fatality ratio was 1.12% (95% CrI 0.55%-2.31%). Multiple social distancing measures contained the first epidemic wave in Greece.
•SARS-CoV-2 exhibits intra-host small- and large-scale genomic variability.•SNVs are collocalized with probes and primers used in molecular diagnostic assays.•SARS-CoV-2 Spike (S) gene host a ...potential recombination hot-spot.
In December 2019, an outbreak of atypical pneumonia (Coronavirus disease 2019 -COVID-19) associated with a novel coronavirus (SARS-CoV-2) was reported in Wuhan city, Hubei province, China. The outbreak was traced to a seafood wholesale market and human to human transmission was confirmed. The rapid spread and the death toll of the new epidemic warrants immediate intervention. The intra-host genomic variability of SARS-CoV-2 plays a pivotal role in the development of effective antiviral agents and vaccines, as well as in the design of accurate diagnostics.
We analyzed NGS data derived from clinical samples of three Chinese patients infected with SARS-CoV-2, in order to identify small- and large-scale intra-host variations in the viral genome. We identified tens of low- or higher- frequency single nucleotide variations (SNVs) with variable density across the viral genome, affecting 7 out of 10 protein-coding viral genes. The majority of these SNVs (72/104) corresponded to missense changes. The annotation of the identified SNVs but also of all currently circulating strain variations revealed colocalization of intra-host as well as strain specific SNVs with primers and probes currently used in molecular diagnostics assays. Moreover, we de-novo assembled the viral genome, in order to isolate and validate intra-host structural variations and recombination breakpoints. The bioinformatics analysis disclosed genomic rearrangements over poly-A / poly-U regions located in ORF1ab and spike (S) gene, including a potential recombination hot-spot within S gene.
Our results highlight the intra-host genomic diversity and plasticity of SARS-CoV-2, pointing out genomic regions that are prone to alterations. The isolated SNVs and genomic rearrangements reflect the intra-patient capacity of the polymorphic quasispecies, which may arise rapidly during the outbreak, allowing immunological escape of the virus, offering resistance to anti-viral drugs and affecting the sensitivity of the molecular diagnostics assays.
The oxazolidinone antibiotic linezolid has demonstrated potent antimicrobial activity against Gram-positive bacterial pathogens, including methicillin-resistant staphylococci. This article ...systematically reviews the published literature for reports of linezolid-resistant Staphylococcus (LRS) infections to identify epidemiological, microbiological and clinical features for these infections. Linezolid remains active against >98% of Staphylococcus, with resistance identified in 0.05% of Staphylococcus aureus and 1.4% of coagulase-negative Staphylococcus (CoNS). In all reported cases, patients were treated with linezolid prior to isolation of LRS, with mean times of 20.0 ± 47.0 months for S. aureus and 11.0 ± 8.0 days for CoNS. The most common mechanisms for linezolid resistance were mutation (G2576T) to the 23S rRNA (63.5% of LRSA and 60.2% of LRCoNS) or the presence of a transmissible cfr ribosomal methyltransferase (54.5% of LRSA and 15.9% of LRCoNS). The emergence of linezolid resistance in Staphylococcus poses significant challenges to the clinical treatment of infections caused by these organisms, and in particular CoNS.
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China and rapidly spread worldwide, with a vast majority of confirmed cases presenting with respiratory ...symptoms. Potential neurological manifestations and their pathophysiological mechanisms have not been thoroughly established. In this narrative review, we sought to present the neurological manifestations associated with coronavirus disease 2019 (COVID-19). Case reports, case series, editorials, reviews, case-control and cohort studies were evaluated, and relevant information was abstracted. Various reports of neurological manifestations of previous coronavirus epidemics provide a roadmap regarding potential neurological complications of COVID-19, due to many shared characteristics between these viruses and SARS-CoV-2. Studies from the current pandemic are accumulating and report COVID-19 patients presenting with dizziness, headache, myalgias, hypogeusia and hyposmia, but also with more serious manifestations including polyneuropathy, myositis, cerebrovascular diseases, encephalitis and encephalopathy. However, discrimination between causal relationship and incidental comorbidity is often difficult. Severe COVID-19 shares common risk factors with cerebrovascular diseases, and it is currently unclear whether the infection per se represents an independent stroke risk factor. Regardless of any direct or indirect neurological manifestations, the COVID-19 pandemic has a huge impact on the management of neurological patients, whether infected or not. In particular, the majority of stroke services worldwide have been negatively influenced in terms of care delivery and fear to access healthcare services. The effect on healthcare quality in the field of other neurological diseases is additionally evaluated.
Skin and soft tissue infections (SSTIs) are among the most common infections in outpatients and the most frequent infectious cause of referrals to emergency departments in developed world, ...contributing to significant morbidity and healthcare expenditures. We sought to review recent literature covering epidemiology of SSTIs.
Staphylococcus aureus and streptococci predominate and methicillin-resistant S. aureus (MRSA) poses additional challenges; community-acquired-MRSA in some areas is superseding methicillin-susceptible S. aureus and multidrug resistance is evolving. Incidence data of SSTIs from United States show a decreasing trend, whereas trends of hospitalization rates were increasing. Despite low mortality associated with SSTIs, high rates of treatment failure and relapses are of concern. Diagnosis and management decisions in the emergency department (ED) lack validated tools for prediction of clinical response particularly among elderly, immunocompromised, obese, and patients with comorbidities. A variety of modifiable and nonmodifiable risk factors of the host and data from local epidemiology should be considered to prevent recurrence and treatment failure.
An evolving epidemiology of SSTIs make microbiologic documentation and surveillance of local data imperative. New assessment algorithms with potential use in the ED are a priority. The universal applicability of international guidelines is questioned in this setting.
Objective
Emerging data indicate an increased risk of cerebrovascular events with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and highlight the potential impact of coronavirus ...disease (COVID‐19) on the management and outcomes of acute stroke. We conducted a systematic review and meta‐analysis to evaluate the aforementioned considerations.
Methods
We performed a meta‐analysis of observational cohort studies reporting on the occurrence and/or outcomes of patients with cerebrovascular events in association with their SARS‐CoV‐2 infection status. We used a random‐effects model. Summary estimates were reported as odds ratios (ORs) and corresponding 95% confidence intervals (CIs).
Results
We identified 18 cohort studies including 67,845 patients. Among patients with SARS‐CoV‐2, 1.3% (95% CI = 0.9–1.6%, I2 = 87%) were hospitalized for cerebrovascular events, 1.1% (95% CI = 0.8–1.3%, I2 = 85%) for ischemic stroke, and 0.2% (95% CI = 0.1–0.3%, I2 = 64%) for hemorrhagic stroke. Compared to noninfected contemporary or historical controls, patients with SARS‐CoV‐2 infection had increased odds of ischemic stroke (OR = 3.58, 95% CI = 1.43–8.92, I2 = 43%) and cryptogenic stroke (OR = 3.98, 95% CI = 1.62–9.77, I2 = 0%). Diabetes mellitus was found to be more prevalent among SARS‐CoV‐2 stroke patients compared to noninfected historical controls (OR = 1.39, 95% CI = 1.00–1.94, I2 = 0%). SARS‐CoV‐2 infection status was not associated with the likelihood of receiving intravenous thrombolysis (OR = 1.42, 95% CI = 0.65–3.10, I2 = 0%) or endovascular thrombectomy (OR = 0.78, 95% CI = 0.35–1.74, I2 = 0%) among hospitalized ischemic stroke patients during the COVID‐19 pandemic. Odds of in‐hospital mortality were higher among SARS‐CoV‐2 stroke patients compared to noninfected contemporary or historical stroke patients (OR = 5.60, 95% CI = 3.19–9.80, I2 = 45%).
Interpretation
SARS‐CoV‐2 appears to be associated with an increased risk of ischemic stroke, and potentially cryptogenic stroke in particular. It may also be related to an increased mortality risk. ANN NEUROL 2021;89:380–388
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