Virus World

The Omicron variant of the SARS-CoV2 virus is intrinsically as severe as previous variants, , according to a preprint version of a large U.S. study that counters assumptions in other studies that it was more transmissible but less severe. The findings, which estimated Omicron's severity after accounting for the impact of vaccines, should reinforce the importance of inoculations and booster shots, experts said. Vaccines helped keep hospitalizations and deaths relatively low during the Omicron surge compared with previous variants.  The study, which is undergoing peer review at Nature Portfolio, was posted on Research Square on May 2. The authors, from Massachusetts General Hospital, Minerva University and Harvard Medical School, declined to comment until peer review is completed. "We found that the risks of hospitalization and mortality were nearly identical" between the Omicron era and times in the past two years when different variants were dominant, the researchers said in their report. The new study, based on records of 130,000 COVID patients in Massachusetts, is unique and "pretty strong," said Dr. Arjun Venkatesh of Yale School of Medicine and the Yale Center for Outcomes Research and Evaluation, who was not involved in the research.

Rather than just looking at numbers of deaths and hospitalizations, as earlier studies have done, it accounted for patients' vaccination status and medical risk factors and compared similar groups of people, Venkatesh said. The authors cited potential limitations in their report, including the possibility that the analysis underestimated the number of vaccinated patients in more recent COVID waves, and the total number of infections, because it excluded patients who performed at-home rapid tests.  The study did not account for treatments patients may have received, such as monoclonal antibodies or antiviral drugs "that are known to reduce hospitalizations," Venkatesh noted. "It's possible that if we didn't have these treatments available today, Omicron would be even worse." Countries around the world have found that a significant percentage of their citizens were unwilling to get a COVID vaccine, even during surges of apparently deadlier variants. When the Omicron variant was first identified late in 2021, public health officials said it caused much milder symptoms in the vast majority of infected people. That may have encouraged the vaccine hesitant that they were less in need of a shot. But Venkatesh said the new preprint adds to evidence that vaccines helped spare people from the worst impacts of Omicron. "Don't make the mistake" of thinking vaccines and boosters are not important, he said.

Preprint of the research (May 2, 2022):

https://www.researchsquare.com/article/rs-1601788/v1 

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

• 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

British scientists analysing data from a widely-used COVID-19 symptom-tracking app have found there are six distinct types of the disease, each distinguished by a cluster of symptoms. A King’s College London team found that the six types also correlated with levels of severity of infection, and with the likelihood of a patient needing help with breathing - such as oxygen or ventilator treatment - if they are hospitalised. The findings could help doctors to predict which COVID-19 patients are most at risk and likely to need hospital care in future waves of the epidemic.

“If you can predict who these people are at Day Five, you have time to give them support and early interventions such as monitoring blood oxygen and sugar levels, and ensuring they are properly hydrated,” said Claire Steves, a doctor who co-led the study. Besides cough, fever and loss of smell - often highlighted as three key symptoms of COVID-19 - the app data showed others including headaches, muscle pains, fatigue, diarrhoea, confusion, loss of appetite and shortness of breath. The outcomes also varied significantly; some got mild, flu-like symptoms or a rash and others suffered acute symptoms or died. The study, released online on June 16 but not peer-reviewed by independent scientists, described the six COVID-19 types as:

1 ‘Flu-like’ with no fever: Headache, loss of smell, muscle pains, cough, sore throat, chest pain, no fever.

2 ‘Flu-like’ with fever: Headache, loss of smell, cough, sore throat, hoarseness, fever, loss of appetite.

3 Gastrointestinal: Headache, loss of smell, loss of appetite, diarrhoea, sore throat, chest pain, no cough.

4 Severe level one, fatigue: Headache, loss of smell, cough, fever, hoarseness, chest pain, fatigue.

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

Evidence suggests the variant that emerged in the UK may be more deadly as well as faster-spreading.  Early evidence suggests the variant of coronavirus that emerged in the UK may be more deadly, Prime Minister Boris Johnson said. However, there remains huge uncertainty around the numbers - and vaccines are still expected to work. The data comes from mathematicians comparing death rates in people infected with either the new or the old versions of the virus. The new more infectious variant has already spread widely across the UK. Mr Johnson told a Downing Street briefing: "In addition to spreading more quickly, it also now appears that there is some evidence that the new variant - the variant that was first identified in London and the south east - may be associated with a higher degree of mortality. "It's largely the impact of this new variant that means the NHS is under such intense pressure."

Public Health England, Imperial College London, the London School of Hygiene and Tropical Medicine and the University of Exeter have each been trying to assess how deadly the new variant is. Their evidence has been assessed by scientists on the New and Emerging Respiratory Virus Threats Advisory Group (Nervtag).  The group concluded there was a "realistic possibility" that the virus had become more deadly, but this is far from certain.Sir Patrick Vallance, the government's chief scientific adviser, described the data so far as "not yet strong".  He said: "I want to stress that there's a lot of uncertainty around these numbers and we need more work to get a precise handle on it, but it obviously is a concern that this has an increase in mortality as well as an increase in transmissibility."  Previous work suggests the new variant spreads between 30% and 70% faster than others, and there are hints it is about 30% more deadly.  For example, with 1,000 60-year-olds infected with the old variant, 10 of them might be expected to die. But this rises to about 13 with the new variant. This difference is found when looking at everyone testing positive for Covid, but analysing only hospital data has found no increase in the death rate. Hospital care has improved over the course of the pandemic as doctors get better at treating the disease.

Globally, the COVID-19 pandemic has had extreme consequences for the healthcare system and calls for diagnostic tools to monitor and understand the transmission, pathogenesis and epidemiology, as well as to evaluate future vaccination strategies.

Here we have developed novel flexible ELISA-based assays for specific detection of SARS-CoV-2 antibodies against the receptor-binding domain (RBD): An antigen sandwich-ELISA relevant for large population screening and three isotype-specific assays for in-depth diagnostics. Their performance was evaluated in a cohort of 350 convalescent participants with previous COVID-19 infection, ranging from asymptomatic to critical cases. We mapped the antibody responses to different areas on protein N and S and showed that the IgM, A and G antibody responses against RBD are significantly correlated to the disease severity. These assays-and the data generated from them-are highly relevant for diagnostics and prognostics and contribute to the understanding of long-term COVID-19 immunity.

Antibody (Ab) responses to SARS-CoV-2 can be detected in most infected individuals 10-15 days following the onset of COVID-19 symptoms. However, due to the recent emergence of this virus in the human population it is not yet known how long these Ab responses will be maintained or whether they will provide protection from re-infection. Using sequential serum samples collected up to 94 days post onset of symptoms (POS) from 65 RT-qPCR confirmed SARS-CoV-2-infected individuals, we show seroconversion in >95% of cases and neutralizing antibody (nAb) responses when sampled beyond 8 days POS.

We demonstrate that the magnitude of the nAb response is dependent upon the disease severity, but this does not affect the kinetics of the nAb response. Declining nAb titres were observed during the follow up period. Whilst some individuals with high peak ID50 (>10,000) maintained titres >1,000 at >60 days POS, some with lower peak ID50 had titres approaching baseline within the follow up period. A similar decline in nAb titres was also observed in a cohort of seropositive healthcare workers from Guy′s and St Thomas′ Hospitals. We suggest that this transient nAb response is a feature shared by both a SARS-CoV-2 infection that causes low disease severity and the circulating seasonal coronaviruses that are associated with common colds.

This study has important implications when considering widespread serological testing, Ab protection against re-infection with SARS-CoV-2 and the durability of vaccine protection.

Preprint available  at medRxiv  (July 11, 2020):

https://www.medrxiv.org/content/10.1101/2020.07.09.20148429v1