Virus World

Background: As Omicron became the dominant variant in South Africa, little is known about the severity of its clinical presentation. We describe the clinical severity of patients hospitalised with SARS-CoV-2 infection during the first four weeks of the Omicron-dominated fourth wave and compare this to the first four weeks of the Betadominated second and Delta-dominated third waves in Gauteng Province.

Methods: Polymerase chain reaction and antigen positive SARS-CoV-2 case data were collated daily from laboratory reports. Data on hospital admissions were collected through an active surveillance programme established specifically for COVID-19. In addition to descriptive statistics, post-imputation random effect multivariable logistic regression models were used to compare disease severity in the three wave periods. Severe disease was defined as one or more of acute respiratory distress, supplemental oxygen, mechanical ventilation, high/intensive care or death.

Results: There were 41,046, 33,423, and 133,551 SARS-CoV-2 cases in the second, third and fourth waves respectively. About 4.9% of cases were admitted to hospital during the fourth wave compared to 18.9% and 13.7% during the second and third waves (p<0.001). During the fourth wave, 28.8% of admissions were severe disease compared to 60.1% and 66.9% in the second and third waves (p<0.001). Admitted patients in the omicron-dominated fourth wave were 73% less likely to have severe disease than patients admitted during the delta-dominated third wave (adjusted odds ratio [aOR] 0.27, 95% confidence interval [CI] 0.25-0.31).

Conclusion: The proportion of cases admitted was lower and those admitted were less severe during the first four weeks of the Omicron-dominated fourth wave in Gauteng province of South Africa. Since any combination of a less-virulent virus, comorbidities, high immunity from prior infection(s) or vaccination may be important contributors to this clinical presentation, care should be taken in extrapolating this to other populations with different co-morbidity profiles, prevalence of prior infection and vaccination coverage.

Preprint to be published in The Lancet available (Dec. 29, 2021):

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3996320

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.

Cells taken from patients at the time of diagnosis who later developed severe COVID-19 show a muted antiviral response, study finds. 

• Researchers studied cells collected by nasal swabs at the moment of diagnosis for both mild and severe COVID-19 patients
• Cells taken from patients who went on to develop severe disease had a muted antiviral response compared to those who went on to develop mild disease
• This suggests that it may be possible to develop early interventions that prevent severe COVID-19 from developing
• The team also identified infected host cells and pathways associated with protection against infection that may enable new therapeutic strategies for COVID-19 and other respiratory viral infections

Over the past 18 months, researchers have learned much about COVID-19 and its viral cause, SARS-CoV-2. They know how the virus enters the body, coming in through the nose and mouth and beginning its infection in the mucus layers of the nasal passageway. They know that infections that remain in the upper airway are likely to be mild or asymptomatic, while infections that progress down the airway to the lungs are much more severe and can lead to fatal disease. And they have identified common risk factors for severe disease, like age, gender, and obesity. But there are still many unanswered questions — such as when, and where, the course of severe COVID-19 is determined. Does the pathway to severe disease begin only after the body has failed to control mild disease, or could it start much earlier than that? Researchers at the Ragon Institute of MGH, MIT, and Harvard; the Broad Institute of MIT and Harvard; Boston Children’s Hospital (BCH); MIT; and the University of Mississippi Medical Center (UMMC) wondered whether this path towards severe disease could start much earlier than expected — perhaps even within the initial response created when the virus enters the nose.

To test this, they studied cells taken from nasal swabs of patients at the time of their initial COVID-19 diagnosis, comparing patients who went on to develop mild COVID-19 to those who progressed into more severe disease and eventually required respiratory support. Their results showed that patients who went on to develop severe COVID-19 exhibited a much more muted antiviral response in the cells collected from those early swabs, compared to patients who had a mild course of disease. The paper appears in the journal Cell.  “We wanted to understand if there were pronounced differences in samples taken early in the course of disease that were associated with different severities of COVID-19 as the disease progressed,” said co-senior author José Ordovás-Montañés, an associate member in the Klarman Cell Observatory at Broad and assistant professor at BCH and Harvard Medical School. “Our findings suggest that the course of severe COVID-19 may be determined by the body’s intrinsic antiviral response to initial infection, opening up new avenues for early interventions that could prevent severe disease.” To understand the early response to infection, Sarah Glover of the Division of Digestive Diseases at UMMC and her laboratory collected nasal swabs from 58 people. Thirty-five swabs came from COVID-19 patients, taken at the time of diagnosis, representing a variety of disease states from mild to severe. Seventeen swabs came from healthy volunteers and six came from patients with respiratory failure due to other causes. The team isolated individual cells from each sample and sequenced them, looking for RNA that would indicate what kind of proteins the cells were making — a proxy for understanding what a given cell is doing at the moment of collection. Cells use RNA as instructions to make proteins — tools, machinery, and building blocks used within and by the cell to perform different functions and respond to its environment. By studying the collection of RNA in a cell — its transcriptome — researchers understand how a cell is responding, at that particular moment in time, to environmental changes such as a viral infection. Researchers can even use the transcriptome to see if individual cells are infected by an RNA virus like SARS-CoV-2.

Alex Shalek, co-senior author on the study, a member of the Ragon Institute of MGH, MIT, and Harvard, and institute member at Broad, specializes in studying the transcriptomes of individual cells. His lab has helped develop innovative approaches to sequence thousands of single cells from low-input clinical samples, like the nasal swab of COVID-19 patients, and uses the resulting data to create high-resolution pictures of the body’s orchestrated response to infection at the sample site. “Our single-cell sequencing approaches allow us to comprehensively study the body’s response to disease at a specific moment in time,” said Shalek, who is also an associate professor at MIT in the Institute for Medical Engineering & Science, the Department of Chemistry, and the Koch Institute for Integrative Cancer Research. “This gives us the ability to systematically explore features that differentiate one course of disease from another as well as cells that are infected from those that are not. We can then leverage this information to guide the development of more effective preventions and cures for COVID-19 and other viral infections.”

Ordovás-Montañés’s lab studies inflammatory responses and their memory, specializing in those found in epithelial cells — the top layer of cells, like those that line your nasal passageways and are collected by nasal swabs. Working with the Shalek lab and that of Bruce Horwitz, a senior associate physician in the BCH Division of Emergency Medicine, the researchers interrogated how both epithelial and immune cells were responding to early COVID-19 infection from the single-cell transcriptome data. First, the team found that the antiviral response, driven by a family of proteins called interferons, was much more muted in patients who went on to develop severe COVID-19. Second, patients with severe COVID-19 had higher amounts of highly inflammatory macrophages, immune cells that contribute to high amounts of inflammation, often found in severe or fatal COVID-19. Since these samples were taken well before COVID-19 had reached its peak state of disease in the patients, both these findings indicate that the course of COVID-19 may be determined by the initial or very early response of the nasal epithelial and immune cells to the virus. The lack of strong initial antiviral response may allow the virus to spread more rapidly, increasing the chances that it can move from the upper to lower airways, while the recruitment of inflammatory immune cells could help drive the dangerous inflammation in severe disease. Finally, the team also identified infected host cells and pathways associated with protection against infection — cells and responses unique to patients that went on to develop a mild disease. These findings may allow researchers to discover new therapeutic strategies for COVID-19 and other respiratory viral infections. If, as the team’s evidence suggests, the early stages of infection can determine disease, it opens a path for scientists to develop early interventions that can help prevent severe COVID-19 from developing. The team’s work even identified potential markers of severe disease, genes that were expressed in mild COVID-19 but not in severe COVID-19.  “Nearly all our severe COVID-19 samples lacked expression of several genes we would typically expect to see in an antiviral response,” said Carly Ziegler, a graduate student in the Health Science and Technology program at MIT and Harvard and one of the study’s co-first authors. “If further studies support our findings, we could use the same nasal swabs we use to diagnose COVID-19 to identity potentially severe cases before severe disease develops, creating an opportunity for effective early intervention.”

Research Cited Published in Cell:

https://www.cell.com/cell/pdf/S0092-8674(21)00882-5.pdf 

Evidence is growing that self-attacking ‘autoantibodies’ could be the key to understanding some of the worst cases of SARS-CoV-2 infection.   More than a year after COVID-19 emerged, many mysteries persist about the disease: why do some people get so much sicker than others? Why does lung damage sometimes continue to worsen well after the body seems to have cleared the SARS-CoV-2 virus? And what is behind the extended, multi-organ illness that lasts for months in people with ‘long COVID’? A growing number of studies suggest that some of these questions might be explained by the immune system mistakenly turning against the body — a phenomenon known as autoimmunity. “This is a rapidly evolving area, but all the evidence is converging,” says Aaron Ring, an immunologist at the Yale School of Medicine in New Haven, Connecticut.

Early in the pandemic, researchers suggested that some people have an overactive immune response to COVID infection. Immune-system signalling proteins called cytokines can ramp up to dangerous levels, leading to ‘cytokine storms’ and damage to the body’s own cells. Clinical trials have now shown that some drugs that broadly dampen immune activity seem to reduce death rates in critically ill people, if administered at the right time. But scientists studying COVID are increasingly also highlighting the role of autoantibodies: rogue antibodies that attack either elements of the body’s immune defences or specific proteins in organs such as the heart. In contrast to cytokine storms, which tend to cause systemic, short-duration problems, autoantibodies are thought to result in targeted, longer-term damage, says immunologist Akiko Iwasaki, a colleague of Ring’s at Yale.  Even healthy people make autoantibodies, but not generally in large amounts, and the molecules don’t usually seem to cause damage or attack the immune system. Yet researchers also have evidence that nefarious autoantibodies do have a role in many infectious diseases. There are several theories to explain how autoimmunity might emerge from COVID and other infections. Some people might be predisposed to producing autoantibodies that can then wreak havoc during an infection. Alternatively, infections could even trigger the production of autoantibodies. If researchers can establish the link, they might be able to come up with avenues for treatment, both for the repercussions of COVID and for other diseases caused by viruses.

Finding autoantibodies

In late September, a group led by Jean-Laurent Casanova at the Rockefeller University in New York City reported that more than 10% of 987 individuals with severe COVID-19 had antibodies that attacked and blocked the action of type 1 interferon molecules, which normally help to bolster the immune response against foreign pathogens1. That was a striking proportion, the researchers say, because people’s antibody repertoires are normally very dissimilar, and no one in a control group for the study had these antibodies. The researchers also saw the antibodies in people before their COVID-19 infection, so Casanova thinks that some people could be genetically predisposed to produce them. And the autoantibodies were more common in men than women — a possible factor in why COVID seems to hit men harder. The first evidence suggesting that autoantibodies against interferon might put people at higher risk of infectious disease was published in 1984, and evidence has accumulated since then, Casanova says. But now COVID is drawing more attention to the connection. “Now people understand the problem,” he says, “and all of a sudden they realize that what my lab has been doing for 25 years is actually pretty meaningful.” Casanova is now screening 40,000 people to see how many have pre-existing autoantibodies and determine whether their distribution by age, ancestry and gender matches that of severe COVID. Other research groups have supported Casanova’s autoantibody connection. Iwasaki, Ring and others screened 194 patients and hospital workers with varying severities of COVID for a wide range of autoantibodies. Their study, which was posted online in December and has not yet been peer reviewed, found a higher prevalence of autoantibodies against the immune system in infected individuals than in uninfected people. They found autoantibodies that attacked B cells, as well as some that attacked interferon.....

Published in Nature (Jan. 19, 2021):

https://doi.org/10.1038/d41586-021-00149-1

• 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

BACKGROUND

Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials.

METHODS

We randomly assigned hospitalized adult patients with severe Covid-19 pneumonia in a 2:1 ratio to receive convalescent plasma or placebo. The primary outcome was the patient’s clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death.

RESULTS

A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo. The median time from the onset of symptoms to enrollment in the trial was 8 days (interquartile range, 5 to 10), and hypoxemia was the most frequent severity criterion for enrollment. The infused convalescent plasma had a median titer of 1:3200 of total SARS-CoV-2 antibodies (interquartile range, 1:800 to 1:3200]. No patients were lost to follow-up. At day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale (odds ratio, 0.83 (95% confidence interval [CI], 0.52 to 1.35; P=0.46). Overall mortality was 10.96% in the convalescent plasma group and 11.43% in the placebo group, for a risk difference of −0.46 percentage points (95% CI, −7.8 to 6.8). Total SARS-CoV-2 antibody titers tended to be higher in the convalescent plasma group at day 2 after the intervention. Adverse events and serious adverse events were similar in the two groups.

CONCLUSIONS

No significant differences were observed in clinical status or overall mortality between patients treated with convalescent plasma and those who received placebo. (PlasmAr ClinicalTrials.gov number, NCT04383535. opens in new tab.)

Published in NEJM (November 24, 2020):

https://doi.org/10.1056/NEJMoa2031304

New findings by scientists at the National Institutes of Health and their collaborators help explain why some people with COVID-19 develop severe disease. The findings also may provide the first molecular explanation for why more men than women die from COVID-19. The researchers found that more than 10% of people who develop severe COVID-19 have misguided antibodies―autoantibodies―that attack the immune system rather than the virus that causes the disease. Another 3.5% or more of people who develop severe COVID-19 carry a specific kind of genetic mutation that impacts immunity. Consequently, both groups lack effective immune responses that depend on type I interferon, a set of 17 proteins crucial for protecting cells and the body from viruses. Whether these proteins have been neutralized by autoantibodies or―because of a faulty gene―were produced in insufficient amounts or induced an inadequate antiviral response, their absence appears to be a commonality among a subgroup of people who suffer from life-threatening COVID-19 pneumonia.

These findings are the first published results from the COVID Human Genetic Effort(link is external), an international project spanning more than 50 genetic sequencing hubs and hundreds of hospitals. The effort is co-led by Helen Su, M.D., Ph.D., a senior investigator at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH; and Jean-Laurent Casanova, M.D., Ph.D., head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University in New York. Major contributions were made by Luigi Notarangelo, M.D., chief of the NIAID Laboratory of Clinical Immunology and Microbiology (LCIM); Steven Holland, M.D., director of the NIAID Division of Intramural Research and senior investigator in the NIAID LCIM; clinicians and investigators in hospitals in the Italian cities of Brescia, Monza and Pavia, which were heavily hit by COVID-19; and researchers at the Uniformed Services University of the Health Sciences in Bethesda, Maryland. The wide variation in the severity of disease caused by SARS-CoV-2, the virus behind COVID-19, has puzzled scientists and clinicians. SARS-CoV-2 can cause anything from a symptom-free infection to death, with many different outcomes in between. Since February 2020, Drs. Su and Casanova and their collaborators have enrolled thousands of COVID-19 patients to find out whether a genetic factor drives these disparate clinical outcomes.

The researchers discovered that among nearly 660 people with severe COVID-19, a significant number carried rare genetic variants in 13 genes known to be critical in the body’s defense against influenza virus, and more than 3.5% were completely missing a functioning gene. Further experiments showed that immune cells from those 3.5% did not produce any detectable type I interferons in response to SARS-CoV-2. Examining nearly 1,000 patients with life-threatening COVID-19 pneumonia, the researchers also found that more than 10% had autoantibodies against interferons at the onset of their infection, and 95% of those patients were men. Biochemical experiments confirmed that the autoantibodies block the activity of interferon type I.

Original Studies Published  in Science  (Sept.  24, 2020):

https://doi.org/10.1126/science.abd4570

https://doi.org/10.1126/science.abd4585

Pregnant women with COVID-19 are at greater risk for hospitalization, ICU admission and receipt of mechanical ventilation compared with nonpregnant women of the same age, according to findings published in MMWR. In addition, Hispanic and non-Hispanic Black women who are pregnant are disproportionately impacted by SARS-CoV-2 infection during pregnancy, the findings demonstrate.

“During pregnancy, women experience immunologic and physiologic changes that could increase their risk for more severe illness from respiratory infections,” Sascha Ellington, PhD, of the CDC’s COVID-19 Emergency Response Team, and colleagues wrote. “To date, data to assess the prevalence and severity of COVID-19 among pregnant U.S. women and determine whether signs and symptoms differ among pregnant and nonpregnant women are limited.” Between Jan. 22 and June 7, CDC received reports of 326,335 women of reproductive age (15 to 44 years) who had positive test results for SARS-CoV-2. Of the 91,412 (28%) women with laboratory-confirmed infections for whom data on pregnancy status were available, 8,207 (9%) were pregnant. While symptomatic pregnant and nonpregnant women with COVID-19 reported comparable rates of cough (more than 50%) and shortness of breath (30%), pregnant women reported headache, muscle aches, fever, chills and diarrhea less often. Additionally, among women with COVID-19, 31.5% of pregnant women were reported to have been hospitalized compared with 5.8% of nonpregnant women. After adjusting for age, the presence of underlying medical conditions and race/ethnicity, pregnant women were significantly more likely to be admitted to the ICU (adjusted RR = 1.5, 95% CI, 1.2-1.8) and receive mechanical ventilation (aRR = 1.7, 95% CI, 1.2-2.4). According to the study results, 16 (0.2%) COVID-19-related deaths were reported among pregnant women aged 15 to 44 years and 208 (0.2%) such deaths were reported among nonpregnant women (aRR = 0.9, 95% CI, 0.5-1.5).

“Pregnant women might be at increased risk for severe COVID-19 illness,” the authors wrote. “To reduce severe COVID-19-associated illness, pregnant women should be aware of their potential risk for severe COVID-19 illness. Prevention of COVID-19 should be emphasized for pregnant women and potential barriers to adherence to these measures need to be addressed.”

A simple blood test may be able to help clinicians understand why one patient with COVID-19 may develop severe, life-threatening complications while another may show barely any symptoms at all. Researchers at the Charité university hospital in Berlin found several protein-based biomarkers that, when taken together, could be capable of predicting a person’s course of disease using laboratory equipment capable of running dozens of samples per day. Using mass spectrometry analysis, they found a set of 27 different proteins in blood samples from coronavirus patients being treated in the hospital—with different levels correlating with the severity of their disease, according to the World Health Organization's coding criteria for COVID-19.

"These results lay the foundations for two very different applications," said Markus Ralser, director of Charité's Institute of Biochemistry and a group leader at the Francis Crick Institute in London. "One possible future use would be for disease prognosis. An early blood test would enable the treating physician to predict whether or not a patient with COVID-19 will develop severe symptoms." "This could potentially save lives: the sooner physicians know which patients will require intensive care, the faster they can make use of the available treatment options," Ralser said. 

"Another possible future use would be as an in-hospital diagnostic test, which could provide clarity regarding a patient's condition—regardless of how they themselves describe it," he added. "In some cases, a patient's symptoms do not appear to provide an accurate picture of their true health status. An objective evaluation, based on their biomarker profile, could be extremely valuable in this regard." ..

Original Study Published in Cell Systems (June 2, 2020):

https://doi.org/10.1016/j.cels.2020.05.012

A South African study suggests reduced risks of hospitalisation and severe disease in people infected with the Omicron coronavirus variant versus the Delta one, though the authors say some of that is likely due to high population immunity.  Questions about Omicron's virulence are at the heart of scientific and political debate in many countries, as governments grapple with how to respond to the spread of the variant while researchers race to understand it. The study, which has not been peer-reviewed, found that people diagnosed with Omicron in South Africa between Oct. 1 and Nov. 30 were 80% less likely to be admitted to hospital than those diagnosed with another variant in the same period.  Among patients admitted in that period, those with Omicron had a similar chance of developing severe disease as those with other variants. However, the study found that people who were hospitalised with Omicron in October-November were 70% less likely to develop severe disease than those admitted with Delta between April and November.

"Compellingly, together our data really suggest a positive story of a reduced severity of Omicron compared to other variants," said Professor Cheryl Cohen of the National Institute for Communicable Diseases (NICD), one of the study's authors. She said this was further reinforced by surveillance data showing significantly lower hospitalisations and deaths in South Africa's current Omicron-driven wave of infections than in previous waves, although case numbers were much higher.  Cohen said that the study's findings could likely be generalised to other countries in sub-Saharan Africa that also have very high levels of previous infection. "What is unclear is whether the picture will be similar in countries where there are high levels of vaccination but very low levels of previous infection," she said during a media briefing by a group of NICD scientists.  The study was carried out by a group of scientists from the NICD and major institutions including University of the Witwatersrand and University of KwaZulu-Natal. The authors included several caveats and cautioned against jumping to conclusions about Omicron's intrinsic characteristics.

"It is difficult to disentangle the relative contribution of high levels of previous population immunity versus intrinsic lower virulence to the observed lower disease severity," they wrote. An estimated 60% to 70% of people in South Africa have had a prior COVID-19 infection, Cohen said. Paul Hunter, a professor of medicine at Britain's University of East Anglia, described the South African study as important and said it was the first properly conducted study to appear in pre-print form on the issue of Omicron versus Delta severity. But Hunter said comparing Omicron data from one period with Delta data from an earlier period meant it was hard to determine whether the lower hospitalisation rates were due to Omicron being less virulent or to population immunity having risen. "To a certain extent this does not matter to the patient who only cares that they won't get very sick. But it is important to know to enable improved understanding of the likely pressures on health services," he said. Results of a major study by Imperial College London released last week showed there was no sign that Omicron was milder than Delta, although data on hospitalisations remains very limited. It has not been peer reviewed and published in a medical journal. read more

Research cited available at medRxiv (Dec. 21, 2021):

https://doi.org/10.1101/2021.12.21.21268116

Purpose: To develop a reliable tool that predicts which patients are most likely to be COVID-19 positive and which ones have an increased risk of hospitalization. Methods: From February 2020 to April 2021, trained nurses recorded age, gender, and symptoms in an outpatient COVID-19 testing center. All positive patients were followed up by phone for 14 days or until symptom-free. We calculated the symptoms odds ratio for positive results and hospitalization and proposed a random forest machine-learning model to predict positive testing. Results: A total of 8,998 patients over 16 years old underwent COVID-19 RT-PCR, with 1,914 (21.3%) positives. Fifty patients needed hospitalization (2.6% of positives), and three died (0.15%). Most common symptoms were: cough, headache, sore throat, coryza, fever, myalgia (57%, 51%, 44%, 36%, 35%, 27%, respectively). Cough, fever, and myalgia predicted positive COVID-19 test, while others behaved as protective factors. The best predictors of positivity were fever plus anosmia/ageusia (OR=6.31), and cough plus anosmia/ageusia (OR=5.82), both p<0.0001. Our random forest model had an ROC-AUC of 0.72 (specificity=0.70, sensitivity=0.61, PPV=0.38, NPV=0.86). Having steady fever during the first days of infection and persistent dyspnea increased the risk of hospitalization (OR=6.66, p<0.0001 and OR=3.13, p=0.003, respectively), while anosmia-ageusia (OR=0.36, p=0.009) and coryza (OR=0.31, p=0.014) were protective. Conclusion: Present study and algorithm may help identify patients at higher risk of having SARS-COV-2 (online calculator http://wdchealth.covid-map.com/shiny/calculator/), and also disease severity and hospitalization based on symptoms presence, pattern, and duration, which can help physicians and health care providers.

Available as Preprint in medRxiv (August 10, 2021):

https://doi.org/10.1101/2021.08.09.21261729 

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

(Reuters) - A doctor in Boston with a shellfish allergy developed a severe allergic reaction after receiving Moderna’s coronavirus vaccine on Thursday, the New York Times reported on Friday, citing the doctor. Dr. Hossein Sadrzadeh, a geriatric oncology fellow at Boston Medical Center, said he had a severe reaction almost immediately after being vaccinated, feeling dizzy and with a racing heart, the NYT reported. It is the first severe reaction publicly linked to Moderna’s vaccine, which is in its first week of a nationwide rollout. David Kibbe, a spokesman at the Boston Medical Center, said in a statement on Friday that Dr. Sadrzadeh “felt he was developing an allergic reaction and was allowed to self-administer his personal epi-pen. He was taken to the Emergency Department, evaluated, treated, observed and discharged. He is doing well today.” A U.S. Food and Drug Administration official said last week that the FDA is investigating around five allergic reactions that occurred after people were administered Pfizer Inc and BioNTech SE’s COVID-19 vaccine in the United States.

An impaired count of natural killer immune cells and reduced ability to destroy infected cells are key characteristics of severe COVID-19 infection, according to a new study by Alberta researchers. A team of researchers at the University of Alberta and University of Calgary followed 12 patients with severe COVID-19 symptoms at hospitals in Edmonton. They found that the patients had a reduced number of NK cells and that cytokines—molecules that aid cell-to-cell communication in immune responses and stimulate the movement of cells toward sites of inflammation, infection and trauma—were also markedly reduced.  “This suggests there's something in particular about how this virus triggers the immune system, but also how it changes how the immune system can self-regulate,” said Mohamed Osman, a rheumatologist and immunologist and assistant professor of medicine in the U of A’s Faculty of Medicine & Dentistry. A substantial proportion of COVID-19 patients admitted to intensive care die of pneumonia due to a cytokine storm, where the body’s immune system goes into overdrive and attacks itself rather than fighting off the illness. NK cells are a key regulator of the immune response, controlling how active it becomes.

According to Osman, the findings of the study were confirmed with the help of Faisal Khan, director of the Hematology Translational Lab at the University of Calgary and associate professor at the Cumming School of Medicine. Since the initial publication of the findings, Osman said the team has also added data from an additional 18 patients showing similar results. The team is now working to get a better sense of whether the dampened NK cells are unique to the virus when it causes severe COVID-19. They are seeking to compare their findings with those from patients who have mild COVID-19 symptoms and others who have respiratory infections unrelated to COVID-19. If it is unique to severe COVID-19, the team hopes in future studies to identify genetic signatures that may exacerbate the problem and could be used as a biomarker to identify patients who may be at higher risk of developing severe symptoms. The team is also paying close attention to clinical trials of potential COVID-19 therapies that boost NK cell function, said Osman. One such ongoing trial is for the drug tocilizumab. “They’ve found that in those people who responded to tocilizumab, the NK cell function was restored,” said Osman. “That suggests this is a very nice biomarker that can be used to tell you whether the immune response to COVID-19 is actually resolving or not.”

Research cites published in Blood Advances (October 19, 2020):

Lancet’s translational research journal EBioMedicine.Test could inform doctors on best treatment options. Scientists have developed, for the first time, a score that can accurately predict which patients will develop a severe form of Covid-19. The study, led by researchers at RCSI University of Medicine and Health Sciences, is published in The Lancet’s translational research journal EBioMedicine. The measurement, called the Dublin-Boston score, is designed to enable clinicians to make more informed decisions when identifying patients who may benefit from therapies, such as steroids, and admission to intensive care units. Until this study, no Covid-19-specific prognostic scores were available to guide clinical decision-making. The Dublin-Boston score can now accurately predict how severe the infection will be on day seven after measuring the patient’s blood for the first four days.

The blood test works by measuring the levels of two molecules that send messages to the body’s immune system and control inflammation. One of these molecules, interleukin (IL)-6, is pro-inflammatory, and a different one, called IL-10, is anti-inflammatory. The levels of both are altered in severe Covid-19 patients. Based on the changes in the ratio of these two molecules over time, the researchers developed a point system where each 1-point increase was associated with a 5.6 times increased odds for a more severe outcome. “The Dublin-Boston score is easily calculated and can be applied to all hospitalised Covid-19 patients,” said RCSI Professor of Medicine Gerry McElvaney, the study’s senior author and a consultant in Beaumont Hospital. “More informed prognosis could help determine when to escalate or de-escalate care, a key component of the efficient allocation of resources during the current pandemic. The score may also have a role in evaluating whether new therapies designed to decrease inflammation in Covid-19 actually provide benefit.”

The Dublin-Boston score uses the ratio of IL-6 to IL-10 because it significantly outperformed measuring the change in IL-6 alone.  Despite high levels in blood, using only IL-6 measurements as a Covid-19 prognostic tool is hindered by several factors. IL-6 levels within the same patient vary over the course of any given day, and the magnitude of the IL-6 response to infection varies between different patients.

Published in EbioMedicine (Oct. 8, 2020):

https://doi.org/10.1016/j.ebiom.2020.103026

A study by U.S. researchers from Pennsylvania State University, Houston Methodist Hospital, Weill Cornell Medical College, and the CCDC Army Research laboratory in Austin, has investigated what’s the best time-window to collect plasma from COVID-19 convalescent patients. The researchers evaluated the changes with time in the levels of neutralizing antibodies (nAbs) against the virus in samples collected from 175 donors. The short answer: within the first 60 days after symptom onset. During this time, 80% of the individuals with any virus neutralization titer, display levels of neutralization above 160. This is the FDA-recommended value for use in COVID-19 convalescent plasma therapy. However, after this period, and during the next two months, the titers declined rapidly, and at some point only 20% of the individuals still maintain the recommended levels of neutralization.

The researchers also confirmed that neutralization titers are greater if the patients have undergone severe COVID-19 disease, and when the individuals are older. Just the presence of dyspnea (shortness of breath) in the patients, increases the titer of nAbs. Similarly, plasma from individuals in the age interval 20-30, as compared to older than 60-year old patients, are significantly less likely to have the recommended levels of neutralization after 60 days from symptoms start.

The study also confirmed the use of a simple ELISA assay to determine the levels of total antibodies against the receptor binding domain (RBD) of the viral spike protein, as an easy surrogate method to select plasma samples that will neutralize the virus. Virus neutralization assays are more time consuming, require several days, and need laboratory access to biosafety level 3 facilities.

The study is available as preprint in bioRxiv (August 21, 2020): https://doi.org/10.1101/2020.08.21.261909

A host of common health problems boost a person’s risk of becoming seriously ill if infected by the new coronavirus. Now an analysis reveals the extent of this vulnerable group: more than 20% of the world’s population has at least one underlying condition that raises the risk of severe disease.

Andrew Clark at the London School of Hygiene & Tropical Medicine and his colleagues examined the prevalence of diabetes, cardiovascular problems and other conditions that predispose people infected with SARS-CoV-2 to severe COVID-19 (A. Clark et al. Lancet Glob. Health http://doi.org/dzk9; 2020). Analysing data from 188 nations, the team estimates that 1.7 billion people worldwide have an elevated risk of ‘severe’ illness. The researchers also estimate that nearly 350 million people — some of whom do not have underlying conditions — would require hospitalization if infected. These findings can be used to assess how many high-risk people will need a vaccine once it is developed, the authors say.

Original Study Published in Lancet Global Health (June 15, 2020):

https://doi.org/10.1016/ S2214-109X(20)30264-3

Coronavirus disease 2019 (COVID-19) is a new pandemic disease. We previously reported that the viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) peaks within the first week of disease onset.1,2 Findings from Feb, 2020, indicated that the clinical spectrum of this disease can be very heterogeneous.3 Here, we report the viral RNA shedding patterns observed in patients with mild and severe COVID-19...