Virus World

Coronavirus Disease 2019 (COVID-19) vaccination has resulted in excellent protection against fatal disease, including in older adults. However, risk factors for post-vaccination fatal COVID-19 are largely unknown. We comprehensively studied three large nursing home outbreaks (20–35% fatal cases among residents) by combining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) aerosol monitoring, whole-genome phylogenetic analysis and immunovirological profiling of nasal mucosa by digital nCounter transcriptomics. Phylogenetic investigations indicated that each outbreak stemmed from a single introduction event, although with different variants (Delta, Gamma and Mu). SARS-CoV-2 was detected in aerosol samples up to 52 d after the initial infection.

Combining demographic, immune and viral parameters, the best predictive models for mortality comprised IFNB1 or age, viral ORF7a and ACE2 receptor transcripts. Comparison with published pre-vaccine fatal COVID-19 transcriptomic and genomic signatures uncovered a unique IRF3 low/IRF7 high immune signature in post-vaccine fatal COVID-19 outbreaks. A multi-layered strategy, including environmental sampling, immunomonitoring and early antiviral therapy, should be considered to prevent post-vaccination COVID-19 mortality in nursing homes. Although vaccination drops COVID-19 mortality in older adults, post-vaccine fatal COVID-19 in nursing home outbreaks was linked to Delta, Gamma and Mu variants, persistently detected in aerosols. Mortality was predicted by IFNB1 or age, ORF7a and ACE2 mRNAs.

Published May 22, 2023: https://doi.org/10.1038/s43587-023-00421-1

More than two-thirds of fully vaccinated people in a Texas prison caught COVID-19 during an outbreak of the Delta variant in July, but vaccines protected against severe illness, a study from the Centers for Disease Control and Prevention found. Of 185 fully vaccinated prisoners at the unnamed prison, 129, or about 70%, caught the virus, data compiled by the CDC and the Federal Bureau of Prisons showed. This was a much lower rate than the unvaccinated prisoners, 39 of 42 of whom – or about 93% — caught COVID-19 during the outbreak, said the study, published Tuesday in the CDC's Morbidity and Mortality Weekly Report. Four people, three of whom were unvaccinated, needed treatment in a hospital, the study said. One unvaccinated person died, it said.

Most of the prisoners were white men, and many had received Pfizer's vaccine at least four months before the outbreak, the data showed.  The study adds to growing evidence that COVID-19 vaccines cut the risk of severe disease and hospitalization. Prisons tend to have higher rates of COVID-19 and deaths because of cramped living conditions and underlying health conditions, the CDC said. Another CDC study from this month found that unvaccinated Americans were 11 times as likely to die of COVID-19 as vaccinated people. About 45% of people in the US are unvaccinated, according to the CDC. The latest CDC study showed that the Delta variant can spread among both vaccinated and unvaccinated people. "Infectious virus was cultured from vaccinated and unvaccinated infected persons," the study said. Measures like masks and regular testing are "critical" where physical distancing is "challenging," even if vaccination rates are high, the CDC said.

Men aged 50 years or older had a 60% higher mortality risk than women aged 50 years or older, in part due to smoking and CVD rates, a worldwide study published in the Canadian Medical Association Journal showed. “Many studies have examined the potential impact of social, behavioral and biological factors on sex differences in mortality, but few have been able to investigate potential variation across countries,” Yu-Tzu Wu, PhD, a research associate at King’s College London, and colleagues wrote. In general, women have longer life expectancies but higher rates of disability and morbidity than men, according to the researchers. “Few studies have identified factors that explain higher mortality in men,” they wrote. To help fill this research gap, Wu and colleagues analyzed data from 179,044 adults who were enrolled in 12 cohorts within the Ageing Trajectories of Health: Longitudinal Opportunities and Synergies (ATHLOS) project. The cohorts are from 28 countries, including the United States and countries in South America, Europe, Asia and Australia. Most cohorts in ATHLOS were established after 2000. The median age of the adults in the study was 63 years, nearly 55% were women and 14.7% died by the end of study follow-up (median follow-up period, 4 years).

Wu and colleagues reported that men had a 60% higher mortality risk than women (HR = 1.6; 95% CI, 1.51-1.7). They also noted that heterogeneity across all the studied countries varied greatly. For example, the HR ranged from:

• 1.07 (95% CI, 0.81-1.4) in Mexico;
• 1.43 (95% CI, 1.38-2.48) in the U.S.;
• 1.46 (95% CI, 1.35-1.57) in the United Kingdom; and
• 2.44 (95% CI, 1.54-3.85) in Japan.

The researchers also reported that among all participants, more than 40% refrained from drinking alcohol, 36.3% had a primary education or less and 20.7% were current smokers. Of four diseases that the researchers studied — CVD, diabetes, hypertension and depression —hypertension (40.4%) was most common, while diabetes (12.7%) was least common. Overall, 17.5% adults lived alone and 28.3% did not have a spouse.

“The strength of association between sex and mortality did not decrease when we adjusted for most socioeconomic, lifestyle, social or health factors,” Wu and colleagues wrote. “Sex differences in mortality became wider when we accounted for education, wealth, alcohol consumption, depression and no spouse.” The researchers found that CVD (HR = 1.56; 95% CI, 1.46-1.66) and smoking (HR = 1.47; 95% CI, 1.39-1.55) were the only factors that “slightly attenuated” sex differences in mortality, prompting them to stratify age-adjusted HRs by smoking and smoking and CVD. This lowered the overall sex differences in nonsmokers (HR = 1.4; 95% CI 1.32-1.49) and former smokers (HR = 1.43; 95% CI, 1.32-1.56). The adjustment for smoking and CVD “further attenuated” the data (HR = 1.44; 95% CI, 1.36-1.52). The HR for overall sex difference dropped to 1.34 (95% CI, 1.25-1.44) in nonsmokers who did not have CVD.

Findings published in CMAJ (March 15, 2021):

https://doi.org/10.1503/cmaj.200484

Compared with nasal swabs, saliva tests may better reflect infection deep in the lungs.  To the known risk factors for developing severe COVID-19—age, male sex, or any of a series of underlying conditions—a new study adds one more: high levels of the virus in your saliva. Standard COVID-19 tests sample the nasal passage. But several new tests look for SARS-CoV-2, the pandemic coronavirus, in saliva, and the new work finds a striking correlation between high virus levels there and later hospitalization or death. If the results are confirmed, saliva tests could help doctors prioritize which patients in the early stages of the disease should receive medicines that drive down levels of the virus. “I thought it was pretty striking,” says Shane Crotty, a virologist at the La Jolla Institute for Immunology, who was not involved with the research. Crotty notes the results suggest virus levels in saliva reflect viral load deep in the lungs, where the disease does much of its damage in severe cases. “That is a fundamentally valuable insight,” Crotty says. The new work isn’t the first to link the body’s coronavirus load and disease outcome. Several research groups have found a correlation between high viral levels in the nasal passages at the time of a patient’s hospital admission and ultimate disease severity. But other groups have failed to find that same link. The standard test to detect SARS-CoV-2 samples nasal mucus using nasopharyngeal (NP) swabs. The procedure is unpleasant, but it is the customary way to sample respiratory pathogens. In recent months, however, several research groups have developed and received emergency use authorization from the U.S. Food and Drug Administration for tests detecting SARS-CoV-2 in saliva. Yale University researchers were among the first, and the university’s hospitals have been using both saliva and NP swab tests. In both cases, labs analyze the samples using quantitative reverse transcription polymerase chain reaction tests, which can detect genetic material from SARS-CoV-2 and quantify the number of viral particles in each milliliter of sample.

Researchers led by Akiko Iwasaki, an immunologist at Yale, compared viral loads in saliva and NP swabs from 154 patients and 109 people without the virus. They divided the patients into groups that had low, medium, and high viral loads as determined by both types of test. Then they compared those results with the severity of symptoms the patients developed later. They found that patients who developed severe disease, were hospitalized, or died were more likely to have had high virus loads in their saliva tests, but not in their NP swabs. Viral load in both saliva and nasal mucus declined over time in patients who recovered, but not in those who died. When Iwasaki and her colleagues reviewed patients’ electronic medical records for markers of disease in the blood, they found that high saliva viral loads correlated with high levels of immune signals such as cytokines and chemokines, nonspecific molecules that ramp up in response to viral infections and have been linked to tissue damage. People with more virus in their saliva also gradually lost certain cells that mount an immune response against viral targets, had lower levels of antibodies targeting the spike protein that the virus uses to enter cells, and were slower to develop the strong immune response needed to knock down the virus in cases where they recovered. The team’s results appeared on 10 January in a preprint that has not been peer reviewed.

Iwasaki and her colleagues argue that saliva may be a better predictor of disease outcome than nasal mucus because the latter comes from the upper respiratory tract, whereas severe disease is associated with damage deep in the lungs. “Saliva may better represent what is going on in the lower respiratory tract,” Iwasaki says, because cilia lining the respiratory tract naturally move mucus up from the lungs into the throat, where it mixes with saliva; coughs have the same effect. The results don’t have enough statistical power to reveal how much more likely a person with a high saliva viral load is to develop severe COVID-19, Iwasaki says. She is also eager for other groups to replicate the results, especially because efforts to link high NP swab viral loads with disease progression have had mixed results. If other research confirms the finding, “it would clear away a lot of the fog” around this disease, Crotty says. Monica Gandhi, an infectious disease expert at the University of California, San Francisco, adds that if saliva tests are predictive, they could help doctors identify patients to treat early with either antibodies to reduce viral load or steroids to tamp down overactive nonspecific immune responses. Saliva tests are cheaper and easier than NP tests, but much less widely available. So confirmation of the new results could bolster efforts to make saliva tests more readily available, says Sri Kosuri, CEO of Octant, Inc., a biotech company. “If this study happened in March, we’d be talking about whether we should be doing NP testing at all,” Kosuri says.

Preprint available in medRxiv  (Jan. 10, 2021):

https://doi.org/10.1101/2021.01.04.21249236 

Human medical trials have begun on severely ill COVID-19 patients using low-doses of radiation. The first results on a very small group at Emory University Hospital were published this week and the results were quite extraordinary. Researchers at Emory University Hospital, led by Dr. Mohammad Khan, Associate Professor of Radiation Oncology, treated five COVID-19 patients with severe pneumonia who were requiring supplemental oxygen and whose health was visibly deteriorating. Their mean age was 90 with a range from 64 to 94, four were female, four were African-American, and one was Caucasian. 

These patients were given a single low-dose of radiation (1.5 Gy) to both lungs, delivered by a front and back beam configuration. Patients were in an out of the Radiotherapy Department in 10 to 15 minutes. Within 24 hours, four of the patients showed rapid improvement in oxygenation and mental status (more awake, alert and talkative) and were being discharged from the hospital 12 days later. Blood tests and repeated imaging of the lungs confirmed that the radiation was safe and effective, and did not cause adverse effects – no acute skin, pulmonary, gastrointestinal or genitourinary toxicities.

The gray (Gy) is a dose unit of ionizing radiation defined as the absorption of one joule of radiation energy per kilogram of matter. The Gy replaces the older unit of the rad, and 1 Gy = 100 Rad. I should mention that medical doses are different than environmental doses as they are not whole body, but are targeted to a specific organ or tissue. So 1.5 Gy is quite low dose for medical uses. This treatment is critical because severe COVID-19 cases cause cytokine release syndrome, also known as a cytokine storm. Such a storm is a deadly uncontrolled systemic inflammatory response of the body’s immune system resulting from the release of great amounts of pro-inflammatory cytokines, which act as a major factor in producing acute respiratory distress syndrome, or ARDS, which is what kills....

Preprint of the origina, study available at medRxiv (June 8, 2020):

https://www.medrxiv.org/content/10.1101/2020.06.03.20116988v1

Immune genes could play a part in the risk of needing intensive care when infected with SARS-CoV-2. An analysis of DNA from more than 24,000 people who had COVID-19 and required treatment in intensive care has yielded more than a dozen new genetic links to the risk of developing extreme illness from the disease. The study, which was published on 17 May in Nature1 and has more than 2,000 authors, highlights the role of the immune system in fuelling the later stages of particularly severe COVID-19. The results could one day contribute to the development of therapies for COVID-19 — and potentially other diseases that cause acute respiratory distress or sepsis. “These are likely to be processes that are active in other conditions,” says Kenneth Baillie, an intensive-care specialist at the University of Edinburgh, UK, and lead author on the study. “Everything that we’ve done in COVID will, I think, be relevant to other groups of patients that we haven’t identified yet.”

Team effort

Much of the data were collected from people who were infected with SARS-CoV-2 during the first waves of the pandemic in the United Kingdom. At that time, many intensive-care staff members were terrified of spending time on the ward, says Baillie. A coronavirus outbreak in 2003 caused by the related virus SARS-CoV had a mortality rate of about 10% and had hit health-care workers particularly hard. “We were nervous,” says Baillie. “Certainly, in the first wave of the pandemic, and for some people in subsequent waves, it seemed like a considerable personal risk.” Despite their fear and the frenzy of providing care at the onset of the pandemic, scores of health-care workers took on the added burden of enrolling participants in studies that investigate how genetics might have contributed to disease severity. Many of the participants were on ventilators, and enrolling them meant long discussions with relatives who were going through some of the most difficult times of their lives, says Baillie. The result was an effort called GenOMICC, which researchers hope will help to improve treatment options for COVID-19 and other conditions in future pandemics. Baillie and his colleagues analysed data from more than 24,000 people and combined this information with data sets from around the world. They found 49 DNA sequences that are associated with becoming critically ill from COVID-19. Sixteen of these had not been reported previously. Among these sequences are some that could affect the activity of genes and proteins involved in the immune system. Raging immune cells have long been implicated in causing some of the tissue damage seen in late-stage, severe cases of COVID-19. Baillie and his colleagues found genetic links to inflammatory responses and the activation of immune cells — processes that can damage the lungs and reduce their capacity to send oxygen to the body’s tissues. “It definitely expands our understanding of the genetic determinants of severe COVID,” says Brent Richards, a human geneticist at McGill University in Montreal, Canada. Richards is an investigator on another project called the COVID-19 Host Genetics Initiative, a global effort in which scientists from more than 54 countries share data. The diversity of that effort will provide a crucial counterpart to the GenOMICC study, which is predominantly drawn from participants of European descent, says Richards.

Reliable results

In addition to the new findings, it is important that the UK study has replicated many of the findings by other groups, says Alexander Hoischen, a geneticist at Radboud University Medical Center in Nijmegen, the Netherlands. Replication of results across different data sets is crucial when trying to tease apart the possible contribution of common genetic variants to disease. Even so, it will take a great deal of work to show that these variants contribute directly to critical illness — a necessary step to turn these initial findings into new therapies. “That is still a long trajectory,” says Hoischen. But putting together these large consortia of investigators and taking the first steps are considerable triumphs, he adds. In the early days of the pandemic, it was unclear how participation in such large endeavours would benefit the careers of individual scientists. “Many of them acted as purely human beings,” he says, instead of worrying about their careers. “It illustrates the degree of solidarity that we really witnessed in COVID times.”

Cited research published in Nature (May 17, 2023):

https://doi.org/10.1038/s41586-023-06034-3 

Sage says majority were likely infected shortly before or soon after jab, before immunity had time to develop.  One in 25 people hospitalised with Covid-19 since December have had at least one dose of vaccine, with the majority infected shortly before or soon after vaccination – before immunity would have had time to develop. However, few of those who developed symptoms, did so more than 2 weeks after receiving a first dose – indicating that the vaccines do help to prevent serious disease once they’ve had time to take effect. The data, presented to the government’s Scientific Advisory Group for Emergencies (Sage), could be a further indication that people are dropping their guard once they’ve received a jab, wrongly assuming that they are immediately protected. Alternative explanations include the possibility that they were infected shortly before vaccination, during the vaccine appointment itself, or that vaccination triggered symptoms in infected people who were previously asymptomatic. In minutes from its 83rd meeting on 11 March Sage said:“The observation that a significant number of people developing symptoms within a few days of a first dose may suggest some behaviour change following vaccination. It is important therefore that communications around vaccination reinforce the need for safe behaviours to be maintained.” Almost 29 million people in the UK have received at least one dose of a coronavirus vaccine so far, with some degree of immune protection thought to develop around two weeks after receiving the first jab – although a second dose is needed to achieve the highest levels of protection.

According to data submitted to Sage by the Covid-19 Clinical Information Network (CO-CIN), there were 1,802 recorded cases of vaccinated patients hospitalised with Covid-19 in the UK as of 5 March. This accounted for 4.2% (1,802/42,788) of all Covid-related hospital admissions since 8 December – the date when the first people in the UK were vaccinated. The median time between vaccination and symptom onset for these patients was five days, indicating that most of them were infected shortly before or around the time of vaccination, with the remainder infected after vaccination but before immunity had developed. “Elderly and vulnerable people who had been shielding, may have inadvertently been exposed and infected either through the end-to-end process of vaccination, or shortly after vaccination through behavioural changes where they wrongly assume they are immune,” the CO-CIN report said.  Data from previous vaccine rollouts, national surveys and evidence from Israel have also indicated that people may be less likely to abide by social distancing rules once they’ve been vaccinated. In its 11 March meeting, Sage emphasised the need for better government communication about how long it takes for the jab to work, and that although the Covid-19 vaccines in use in the UK are highly effective, no vaccine is 100% effective. Minutes from the meeting said: “Some people will be hospitalised with Covid-19 even after completing their full vaccination schedule. It will be particularly important to monitor the prevalence of different variants present in this group by sequencing to understand any potential immune escape. This is under way by Public Health England.” A separate document released by Sage on Friday suggested there has been a four-fold increase in confirmed cases of the Brazilian P1 variant during the fortnight of 10 March to 24 March from 5 to 21, while cases of the South African variant have increased from 190 to 305.

Magnitude of SARS-CoV-2 virus exposure may contribute to symptom severity. In a sample of seropositive adults (n=1101), we found that individuals who lived with a known COVID-19 case exhibited greater symptom severity and IgG concentrations compared to individuals who were seropositive but did not live with a known case (P<0.0001).

Notably, working in close proximity to others, which has received substantial attention as a risk factor for COVID-19,20 did not exhibit statistically significant associations with symptom severity or IgG antibody concentrations. Our results suggest that high virus exposure levels, which may often occur when exposed to a cohabitant with COVID-19, contribute to greater disease severity and stronger antibody responses. Regardless of which individual in the household was exposed first, our results suggest that preventing transmission within households should be a critical area of focus for public health efforts designed to reduce rates of symptomatic COVID-19. Policies and interventions that apply only to public places (e.g., mask mandates, business capacity limits) may be insufficient unless they are combined with measures that also reduce transmission within households (e.g., intensive testing, contact tracing, and isolation programs).

Preprint available in merRxiv (March 12, 2021):

https://doi.org/10.1101/2021.03.11.21253421

• Five genes seem to be associated with life-threatening cases of COVID-19, a new study found.
• The finding offers a potential explanation for why some patients get severely sick while others don't
• Two of these genes are linked to the innate immune response, while three are tied to inflammation and lung damage.
• The study offers a direction for more research into certain potential COVID-19 treatments.

A growing body of research is highlighting a select set of genes that may explain why some people develop more severe COVID-19 cases than others. Certain genes, for instance, instruct the body to make more ACE2 receptors, which the coronavirus uses to invade our cells. Studies show that people whose bodies naturally code for more of these receptors could be at higher risk of severe infection. On Friday, researchers at the University of Edinburgh announced that they'd identified five genes that may be associated with life-threatening cases of COVID-19. The genes are, perhaps unsurprisingly, associated with a weaker innate immune response and more aggressive inflammation. The new study compared more than 2,200 coronavirus patients in UK intensive-care units to patients of similar ancestry who hadn't tested positive for COVID-19.  The critically ill COVID-19 patients were found to have a lower expression of IFNAR2, a gene that helps code for proteins called interferons. These act as an emergency flare to warn the immune system of an intruder. The patients also displayed a variation in a cluster of genes called OAS, which normally helps prevent a virus from replicating.  What's more, the critically ill patients had higher expressions of the genes TYK2 and CCR2, which can drive inflammation and potentially lead to lung injury. And they displayed a variation in the gene DPP9, which scientists have linked to pulmonary fibrosis (damaged or scarred lung tissue).

A weak immune system is at risk of collapse

Typically, when our immune system senses a foreign invader, it dispatches white blood cells to destroy the threat. But in some patients, that innate immune response isn't strong enough to vanquish the coronavirus right away. This can trigger aggressive inflammation that damages healthy tissue or leads to organ failure. Dr. Panagis Galiatsatos, a pulmonary physician at Johns Hopkins Bayview Medical Center, compared that process to an earthquake — generally, it's the falling buildings that kill someone, not the quake itself. "Your infection is a rattling of your immune system," he previously told Business Insider. "If your immune system is just not well structured, it's just going to collapse." That means genetic signals that inhibit the body's natural defenses or encourage inflammation might set off a chain reaction that ultimately leads to critical respiratory failure. Other factors, including age and underlying health conditions, play a role in severe COVID-19 cases as well.

Implications for COVID-19 treatments

In unlocking some of the mysteries surrounding severe COVID-19, the Edinburgh researchers also found clues about how to treat patients. "Our results immediately highlight which drugs should be at the top of the list for clinical testing," Kenneth Baillie, an academic consultant in critical-care medicine who co-led the research, told Reuters.   Drugs that boost the expression of INFAR2, for instance, might help patients fight the virus before it wreaks havoc in the body. One potential treatment, a multiple sclerosis drug called Rebif, is attempting a similar approach by giving patients a boost of interferon. Merck, the company behind the drug, hopes the therapy might prevent the coronavirus from replicating. The Edinburgh study also suggests that drugs targeting inflammation could play a key role in halting the disease's progression. In particular, the researchers point to a class of anti-inflammatory drugs called Janus kinase (JAK) inhibitors, which are already used to treat rheumatoid arthritis.  One such arthritis drug, Eli Lilly's baricitinib, was recently authorized by the FDA for use in combination with remdesivir....

Cited Research Published in Nature (Dec. 11, 2020):

https://doi.org/10.1038/s41586-020-03065-y

Increases in the levels of three cytokines are among the features linked to poor outcomes. study of COVID-19 patients at two London hospitals has identified blood-based immunological changes that are linked to the disease and, in some cases, to symptom severity. The results, reported in Nature Medicine on Monday (August 17) join a growing body of data on how the human immune system responds to SARS-CoV-2 that will hopefully lead to prognostic tools and potential treatments. “The study is a nice comprehensive characterization of the different trajectories of host response against SARS-CoV-2 [and] technically well performed,” Antonio Bertoletti an emerging infectious disease researcher at Duke-National University of Singapore who was not involved in the research, writes in an email to The Scientist. It provides “some specific findings, like the severe drop of dendritic cells and the inflammatory cytokine profile,” he adds, “[that] might predict the worsening of the disease.” Microbiologist and immunologist Stanley Perlman of the University of Iowa who also was not a part of the research team is less optimistic about the potential for prediction. “They came up with parameters that seem to define the different [severity] groups,” he says, “but for an individual [patient] it’s very hard” to make a prediction because “there is so much overlap” between the groups.  He nonetheless praises the efforts of the authors of the paper and similar endeavors, saying such studies provide “a sense for what seems to be happening in people who do worse, which in itself is useful, if not for prognosis . . . it can help you in management [of the disease].”

Since late 2019, the novel coronavirus SARS-CoV-2 has been relentlessly and rampantly spreading from person to person across the globe. While in many people the virus causes no ill effects, in others it ravages the lungs, leaving them hospitalized for weeks, and in some the infection is fatal. More than 780,000 people have died from the disease worldwide to date.  For a disease with such diversity of symptoms and outcomes, and in patients of different ages and sexes with different underlying conditions, finding a common immune signature for COVID-19—a set of immune proteins and cells that define the disease—may seem like an impossibility, but immunologist Adrian Hayday of King’s College London and the Francis Crick Institute was not discouraged by the odds. Despite “extraordinary heterogeneity” within patient populations, he says, “immune responses against potentially lethal pathogens can have very dominant effects that rise above the background and therefore provide you with an immune signature.” Discovering such a signature would be of great value, he explains. For one thing, “you might find things that are unique to COVID-19 and that might give you some very important things to target therapeutically,” he says. And, it might identify “changes that actually could give the doctors a very early indication of which way a patient was going to go.”

For Hayday and his colleagues’ study, the team collected blood samples from 63 patients with mild, moderate, and severe COVID-19 who were admitted to Guys and St. Thomas’s hospitals in London from March to May this year, and from 55 control individuals, including healthy people who had previously tested positive for coronavirus (and had had no or mild symptoms), people with other respiratory tract infections, and healthy individuals with no recent respiratory infections. The researchers performed flow cytometry experiments and protein assays on the blood samples to analyze the presence and characteristics of various immune cell types and to measure antibodies and other immune factors..

Research published in Nature Medicine (August 17, 2020):

https://doi.org/10.1038/s41591-020-1038-6

Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients. Methods. We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a meta-analysis of both case-control panels. Results. We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P<5x10-8) in the meta-analysis of both study panels, odds ratio [OR], 1.77; 95% confidence interval [CI], 1.48 to 2.11; P=1.14x10-10 and OR 1.32 (95% CI, 1.20 to 1.47; P=4.95x10-8), respectively. Among six genes at 3p21.31, SLC6A20 encodes a known interaction partner with angiotensin converting enzyme 2 (ACE2). 

The association signal at 9q34 was located at the ABO blood group locus and a blood-group-specific analysis showed higher risk for A-positive individuals (OR=1.45, 95% CI, 1.20 to 1.75, P=1.48x10-4) and a protective effect for blood group O (OR=0.65, 95% CI, 0.53 to 0.79, P=1.06x10-5). Conclusions. We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid-19 pathophysiology.

Preprint available at medRxiv (June 2, 2020):

https://doi.org/10.1101/2020.05.31.20114991