Updated: Jul 19
Type 1 interferon deficiency: Biomarker of patients at risk of severe COVID-19
Date: July 17, 2020
Source: INSERM (Institut national de la santé et de la recherche médicale)
Summary:Which patients are more likely to develop a severe form of COVID-19? In a new study, researchers describe a unique and unexpected immunological phenotype in severe and critical patients.
FULL STORY Which patients will develop a severe form of Covid-19? This is a key question that needs to be answered to improve the individual management and prognosis of patients. In a study published in Science on July 13, teams from AP-HP, Inserm, Université of Paris, Institut Pasteur and Institut Imagine describe a unique and unexpected immunological phenotype in severe and critical patients, consisting of a severely impaired response of interferon (IFN) type I, associated with a persistent blood viral load and an excessive inflammatory response. These data suggest that IFN type I deficiency in the blood could be a hallmark of severe forms of Covid-19. It also supports the potential value of therapeutic approaches that combine early administration of IFN, with appropriate anti-inflammatory therapy targeting IL-6 or TNF-α, in patients preventing severe disease forms.
Approximately 5% of people with Covid-19 progress to a severe or critical form, including the development of severe pneumonia that progresses to acute respiratory distress syndrome. While these forms sometimes occur early in the course of the disease, clinical observations generally describe a two-stage progression of the disease, beginning with a mild to moderate form, followed by respiratory aggravation 9 to 12 days after the onset of the first symptoms. This sudden progression suggests deregulation of the host inflammatory response.
A growing number of indications suggest that this aggravation is caused by a large increase in cytokines. This runaway inflammatory response is correlated with massive infiltration in the lungs of innate immune cells, namely neutrophils and monocytes, creating lung damage and acute respiratory distress syndrome.
By analogy with a genetic disease leading to a similar pulmonary pathology identified at Institut Imagine by the team of Inserm researcher Frédéric Rieux-Laucat, the initial hypothesis assumed excessive production of interferon (IFN) type I, a marker of the response to infections. However, in seriously ill patients, the teams of Darragh Duffy (Dendritic Cell Immunobiology Unit, Institut Pasteur/Inserm), Frédéric Rieux-Laucat (Laboratory of Immunogenetics of Pediatric Autoimmune Diseases at Institut Imagine -- Inserm/Université de Paris), Solen Kernéis (Mobile Infectiology Team, AP-HP. Centre -- Université of Paris) and Benjamin Terrier (Department of Internal Medicine, AP-HP. Centre -- Université of Paris) show that the production and activity of type-I IFN are strongly reduced in the most severe forms of Covid-19.
In addition, there is a persistent blood viral load, indicating poor control of viral replication by the patient's immune system which leads to an ineffective and pathological inflammatory response. The inflammation, caused by the transcription factor NF-kB, also leads to increased production and signaling of tumor necrosis factor (TNF)-alpha and the pro-inflammatory cytokine interleukin IL-6.
Distinct type-I IFN responses may be characteristic of each stage of the disease This low signature of type-I IFN differs from the response induced by other respiratory viruses such as human respiratory syncitial virus or influenza A virus, both of which are characterized by high production of type-I IFN.
The study also showed that low levels of type-I IFN in plasma precede clinical worsening and transfer to intensive care. Levels of circulating Type 1 IFN could even characterize each stage of disease, with the lowest levels observed in the most severe patients. These results suggest that in SARS-CoV-2 infection, the production of type-I IFN is inhibited in the infected host, which could explain the more frequent severe forms in individuals with low production of this cytokine, such as the elderly or those with co-morbidities. Therefore, type-I IFN deficiency could be a signature of severe forms of COVID-19 and could identify a high-risk population.
These results further suggest that the administration of IFN-alpha/Beta combined with anti-inflammatory therapy targeting IL-6 or TNF-α, or corticosteroids such as dexamethasone, in the most severe patients could be a therapeutic avenue to be evaluated for severe forms of COVID-19. Story Source: Materials provided by INSERM (Institut national de la santé et de la recherche médicale). Note: Content may be edited for style and length. Journal Reference:
Jérôme Hadjadj, Nader Yatim, Laura Barnabei, Aurélien Corneau, Jeremy Boussier, Nikaïa Smith, Hélène Péré, Bruno Charbit, Vincent Bondet, Camille Chenevier-Gobeaux, Paul Breillat, Nicolas Carlier, Rémy Gauzit, Caroline Morbieu, Frédéric Pène, Nathalie Marin, Nicolas Roche, Tali-Anne Szwebel, Sarah H Merkling, Jean-Marc Treluyer, David Veyer, Luc Mouthon, Catherine Blanc, Pierre-Louis Tharaux, Flore Rozenberg, Alain Fischer, Darragh Duffy, Frédéric Rieux-Laucat, Solen Kernéis, Benjamin Terrier. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science, 2020; eabc6027 DOI: 10.1126/science.abc6027
INSERM (Institut national de la santé et de la recherche médicale). "Type 1 interferon deficiency: Biomarker of patients at risk of severe COVID-19." ScienceDaily. ScienceDaily, 17 July 2020. <www.sciencedaily.com/releases/2020/07/200717101015.htm>.
Breakthrough blood test detects positive COVID-19 result in 20 minutes
Date: July 17, 2020
Source: Monash University
Summary: Researchers report a new method that detects positive COVID-19 cases using blood samples in about 20 minutes, and identifies whether someone has contracted the virus.
Researchers identify genetic factors that may influence COVID-19 susceptibility
Date:July 15, 2020
Summary: A new study has identified genetic factors that may influence susceptibility to COVID-19. The findings could guide personalized treatment for COVID-19.Share:
FULL STORY A new Cleveland Clinic study has identified genetic factors that may influence susceptibility to COVID-19. Published today in BMC Medicine, the study findings could guide personalized treatment for COVID-19.
While the majority of confirmed COVID-19 cases result in mild symptoms, the virus does pose a serious threat to certain individuals. Morbidity and mortality rates rise dramatically with age and co-existing health conditions, such as cancer and cardiovascular disease. However, even young and otherwise healthy individuals have unpredictably experienced severe illness and death. These clinical observations suggest that genetic factors may influence COVID-19 disease susceptibility, but these factors remain largely unknown. In this study, a team of researchers led by Feixiong Cheng, PhD, Genomic Medicine Institute, investigated genetic susceptibility to COVID-19 by examining DNA polymorphisms (variations in DNA sequences) in the ACE2 and TMPRSS2 genes. ACE2 and TMPRSS2 produce enzymes (ACE2 and TMPRSS2, respectively) that enable the virus to enter and infect human cells.
Looking at 81,000 human genomes from three genomic databases, they found 437 non-synonymous single-nucleotide variants in the protein-coding regions of ACE2 and TMPRSS2. They identified multiple potentially deleterious polymorphisms in both genes (63 in ACE2; 68 in TMPRSS2) that offer potential explanations for different genetic susceptibility to COVID-19 as well as for risk factors. Several ACE2 variants were found to be associated with cardiovascular and pulmonary conditions by potentially altering the angiotensinogen-ACE2. In addition, germline deleterious variants in the coding region of TMPRSS2, a key gene in prostate cancer, were found to occur in different cancer types, suggesting that oncogenic roles of TMPRSS2 may be linked to poor outcomes with COVID-19.
These findings demonstrate a possible association between ACE2 and TMPRSS2 polymorphisms and COVID-19 susceptibility, and indicate that a systematic investigation of the functional polymorphisms these variants among different populations could pave the way for precision medicine and personalized treatment strategies for COVID-19. However, all investigations in this study were performed in general populations, not with COVID-19 patient genetic data. Therefore, Dr. Cheng calls for a human genome initiative to validate his findings and to identify new clinically actionable variants to accelerate precision medicine for COVID-19.
"Because we currently have no approved drugs for COVID-19, repurposing already approved drugs could be an efficient and cost-effective approach to developing prevention and treatment strategies," Dr. Cheng said. "The more we know about the genetic factors influencing COVID-19 susceptibility, the better we will be able to determine the clinical efficacy of potential treatments."
This study was supported by the National Heart, Lung, and Blood Institute and the National Institute of Aging (both part of the National Institutes of Health) as well as Cleveland Clinic's VeloSano Pilot Program. make a difference: sponsored opportunity Story Source: Materials provided by Cleveland Clinic. Note: Content may be edited for style and length. Journal Reference:
Yuan Hou, Junfei Zhao, William Martin, Asha Kallianpur, Mina K. Chung, Lara Jehi, Nima Sharifi, Serpil Erzurum, Charis Eng, Feixiong Cheng. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Medicine, 2020; 18 (1) DOI: 10.1186/s12916-020-01673-z
Cleveland Clinic. "Researchers identify genetic factors that may influence COVID-19 susceptibility." ScienceDaily. ScienceDaily, 15 July 2020. <www.sciencedaily.com/releases/2020/07/200715123153.htm>.
Earlier lockdown restrictions linked to greater reduction in new COVID-19 cases
Findings should help inform policies as countries prepare to impose or lift restrictions
Date:July 15, 2020
Summary:Physical distancing measures, such as closing schools, workplaces, and public transport, and restricting mass gatherings, are associated with a meaningful reduction in new covid-19 cases, according to a new study.Share:
FULL STORY Physical distancing measures, such as closing schools, workplaces, and public transport, and restricting mass gatherings, are associated with a meaningful reduction in new covid-19 cases, finds a study published by The BMJ today. The data, gathered from 149 countries and regions, also show that implementing lockdown restrictions earlier was associated with a greater reduction in new cases. "These findings might support policy decisions as countries prepare to impose or lift physical distancing measures in current or future epidemic waves," say the researchers. Without evidence for effective treatments or a successful vaccine for covid-19, physical distancing has been recommended to minimise transmission, and thus reduce risk for the most vulnerable in society.
Physical distancing also therefore reduces pressure on public health and healthcare services, and allows time for the prevention and management of the disease. But 'real-life' data on the effectiveness of physical distancing measures are scarce.
To address this evidence gap, a team of UK and US researchers set out to compare the change in new cases (incidence) of covid-19 before and up to 30 days after implementation of physical distancing measures in the early stages of the pandemic. Their findings are based on daily reported cases of covid-19 for 149 countries or regions that implemented one or more of five physical distancing measures -- closures of schools, workplaces, and public transport, restrictions on mass gatherings and public events, and restrictions on people's movement within countries or regions ('lockdown') -- between 1 January and 30 May 2020.
On average, physical distancing measures were first implemented 9 days after the first reported case. However, some countries took longer to implement measures, including Thailand (58 days), Australia (51 days), Canada (46 days), Sri Lanka and the UK (45 days), Finland and Malaysia (42 days), and Cambodia, Sweden, and the US (40 days). On average, implementation of any physical distancing measure was associated with an overall reduction in covid-19 incidence of 13% over the study period.
In combination with school and workplace closure, restriction on mass gatherings seemed to be a key component associated with a decrease in covid-19 incidence. However, closure of public transport was not associated with any additional reduction in covid-19 incidence when the other four physical distancing measures were in place -- likely as a result of fewer people using public transport.
The data also show that earlier implementation of lockdown together with other physical distancing measures was associated with a larger reduction in the incidence of covid-19. This is an evaluation of natural experiments using observational methods, so is limited in its ability to establish cause. The researchers also point to some other limitations, such as being unable to assess compliance with physical distancing or take account of other measures (like use of face coverings by the public and mobile phone apps for contact tracing and isolation) that might have helped reduce transmission, due to lack of suitable data.
However, this is a large study with a robust analytical approach, and the results were similar after testing a range of alternative approaches to analyses, suggesting that the primary findings are robust to alternative analytic scenarios.
Further research is needed to provide more definitive answers about the extent, intensity, combinations, and timing of physical distancing measures, they write.
The researchers suggest that as the pandemic continues to evolve, "it will be crucial to repeat and extend this analysis to assess the impacts of interventions in the longer term, as well as to study combinations and sequencing of the lifting of physical distancing restrictions."
This study provides important preliminary evidence for the effectiveness of physical distancing measures in controlling the covid-19 pandemic, says Thomas May at Washington State University, in a linked editorial.
But he warns that failures in testing practices and data collection in many countries means that caution is needed when interpreting the findings.
"We must be careful not to mislead or overplay politically convenient findings and risk violating the public trust necessary for an effective pandemic response," he writes. He points out that calls for a coordinated, global public health infrastructure for a pandemic response have been growing for decades, and says "only by acknowledging our failures in systematic testing and data collection can we learn from our mistakes and avoid repeating them." Story Source: Materials provided by BMJ. Note: Content may be edited for style and length. Journal References:
Nazrul Islam, Stephen J Sharp, Gerardo Chowell, Sharmin Shabnam, Ichiro Kawachi, Ben Lacey, Joseph M Massaro, Ralph B D’Agostino, Martin White. Physical distancing interventions and incidence of coronavirus disease 2019: natural experiment in 149 countries. BMJ, 2020; m2743 DOI: 10.1136/bmj.m2743
Thomas May. Lockdown-type measures look effective against covid-19. BMJ, 2020; m2809 DOI: 10.1136/bmj.m2809
BMJ. "Earlier lockdown restrictions linked to greater reduction in new COVID-19 cases: Findings should help inform policies as countries prepare to impose or lift restrictions." ScienceDaily. ScienceDaily, 15 July 2020. <www.sciencedaily.com/releases/2020/07/200715190744.htm>.
Social distancing and COVID-19: A law of diminishing returns
Research finds distancing helps ease the burden on hospitals -- but only to a point
Date:July 15, 2020
Source:Washington University in St. Louis
Summary:New modeling shows how social distancing could have better been implemented. The key? Longer periods of distancing would have helped -- but only to a point. More needed to be done.Share:
FULL STORY The first case of the novel coronavirus, COVID-19, in the United States was in late January. By mid-March, "social distancing" had entered the public lexicon. People altered their routines and local jurisdictions suggested, urged, or required changes meant to slow the disease's spread.
By the end of June, however, public health officials and news outlets were talking about a second wave. In July, many states were pausing or reversing their plans to reopen while, for the second time, hospital systems worried about running out of room. What could we have done better?
In an "editor's pick" paper published today in the journal Chaos of the American Institute of Physics, Washington University in St. Louis researchers in the lab of Rajan Chakrabarty, associate professor in the department of Energy, Environmental and Chemical Engineering at the McKelvey School of Engineering, modeled the interplay between the duration and intensity of social distancing. They found a law of diminishing returns, showing that longer periods of social distancing are not always more successful when it comes to slowing the spread, and that any strategy that involves social distancing requires other steps be taken in tandem.
"Conventional wisdom was, the more intense and long-term the social distancing, the more you will curb the disease spread," Chakrabarty said
"But that is true if you have social distancing implemented with contact tracing, isolation and testing. Without those, you will give rise to a second wave."
Added Payton Beeler, a second year doctoral student in Chakrabarty's lab, who also worked with Pai Liu, a postdoctoral fellow: "What we have found is that if social distancing is the only measure taken, it must be implemented extremely carefully in order for its benefits to be fully realized."
Their susceptible, exposed, infected, and recovered (SEIR) dynamics model used data gathered by Johns Hopkins University between March 18 and March 29, a period marked by a rapid surge in COVID-19 cases and the onset of social distancing in most US states. Calibrating their model using these datasets allowed the authors to analyze unbiased results that had not yet been affected by large-scale distancing in place. Unique to this project was the use of age stratification; the model included details on how much people of different age groups interact, and how that affects the spread of transmission.
No matter what strategy they looked at, one thing was clear, Chakrabarty said: "Had social distancing been implemented earlier, we probably would've done a better job." Researchers found that, over the short-term, more distancing and less hospital demand go hand in hand -- but only up to two weeks. After that, time spent distancing does not benefit hospital demand as much; society would have to increase social distancing time exponentially in order to see a linear decrease in hospital demand.
Thus the diminishing return: Society would see smaller and smaller benefits to hospital demand the longer it spent social distancing.
If social distancing "alone" is to be implemented longer than two weeks, a moderate shut down, say between 50-70%, could be more effective for the society than a stricter complete shut-down in yielding the largest reduction in medical demands.
Another strategy for flattening the curve involves acting intermittently, alternating between strict social distancing and no distancing to alleviate the strain on hospitals -- as well as some of the other strains on the economy and well-being imposed by longer-term distancing.
According to the model, the most efficient distancing- to- no-distancing ratio is 5 to 1; one day of no distancing for every five days at home. Had society acted in this way, hospital burden could have been reduced by 80%, Chakrabarty said. Exceeding this ratio, the model showed a diminishing return.
Critically, the researchers note that social distancing policy as a whole-of-government approach could not be successful without the implementation of wide-spread testing, contact tracing, and isolation of those found to be infected.
"And you have to do it aggressively," Chakrabarty said. "If you do not, what you're going to do, the moment you lift social distancing, is give rise to a second wave." That's because the people who are leaving their homes after distancing themselves are, ostensibly, all susceptible to COVID-19.
"Bending the curve using social distancing alone is analogous to slowing down the front of a raging wildfire without extinguishing the glowing embers," said Chakrabarty, whose other line of research focuses on the impacts of wildfires on climate and health. "They are waiting to start their own fires once the wind carries them away."
The model cannot inform strategies going forward because it used data collected in March, before any large-scale social distancing was implemented. But Chakrabarty said it may be able to inform our actions if we find ourselves in a similar situation in the future. "Next time, we must act faster, and be more aggressive when it comes to contact tracing and testing and isolation," Chakrabarty said. "Or else this work was for nothing." Story Source: Materials provided by Washington University in St. Louis. Original written by Brandie Jefferson. Note: Content may be edited for style and length. Journal Reference:
Pai Liu, Payton Beeler, Rajan K. Chakrabarty. Dynamic interplay between social distancing duration and intensity in reducing COVID-19 US hospitalizations: A “law of diminishing returns”. Chaos: An Interdisciplinary Journal of Nonlinear Science, 2020; 30 (7): 071102 DOI: 10.1063/5.0013871
Cite This Page:
Washington University in St. Louis. "Social distancing and COVID-19: A law of diminishing returns: Research finds distancing helps ease the burden on hospitals -- but only to a point." ScienceDaily. ScienceDaily, 15 July 2020. <www.sciencedaily.com/releases/2020/07/200715160005.htm>.