Research led by the University of Bristol has found that long COVID is not caused by an immune inflammatory reaction to COVID. Emerging data shows that immune activation may persist for months after contracting COVID. In this new study, published in eLife, researchers wanted to find out whether persistent immune activation and ongoing inflammation response could be the underlying cause of long COVID.
To investigate this, the Bristol team collected and analysed immune responses in blood samples from 63 patients hospitalised with mild, moderate or severe COVID at the start of the pandemic and before vaccines were available. The team then tested patients’ immune responses at three months and again at eight and 12 months post hospital admission. Of these patients, 79% (82%, 75%, and 86% of mild, moderate, and severe patients, respectively) reported at least one ongoing symptom with breathlessness and excessive fatigue being the most common.
Dr Laura Rivino, the study’s lead author, explained: “Long Covid occurs in one out of ten COVID cases, but we still don’t understand what causes it. Several theories proposed include whether it might be triggered by an inflammatory immune response towards the virus that is still persisting in our body, sending our immune system into overdrive or the reactivation of latent viruses such as human cytomegalovirus (CMV) and Epstein Barr virus (EBV).”
The team found patients’ immune responses at three months with severe symptoms displayed significant dysfunction in their T-cell profiles indicating that inflammation may persist for months even after they have recovered from the virus. Reassuringly, results showed that even in severe cases inflammation in these patients resolved in time. At 12 months, both the immune profiles and inflammatory levels of patients with severe disease were similar to those of mild and moderate patients.
Patients with severe COVID were found to display a higher number of long Covid symptoms compared to mild and moderate patients. However, further analysis by the team revealed no direct association between long COVID symptoms and immune inflammatory responses, for the markers that were measured, in any of the patients after adjusting for age, sex and disease severity.
Importantly, there was no rapid increase in immune cells targeting SARS-CoV-2 at three months, but T-cells targeting the persistent and dormant Cytomegalovirus (CMV) – a common virus that is usually harmless but can stay in your body for life once infected with it – did show an increase at low levels. This indicates that the prolonged T-cell activation observed at three months in severe patients may not be driven by SARS-CoV-2 but instead may be “bystander driven” ie driven by cytokines.
Dr Rivino added: “Our findings suggest that prolonged immune activation and Long COVID may correlate independently with severe COVID. Larger studies should be conducted looking at both a larger number of patients, including if possible vaccinated and non-vaccinated COVID patients, and measuring a larger range of markers and cytokines.
“Understanding whether inflammation and immune activation associate with Long COVID would allow us to understand whether targeting these factors may be a useful therapy for this debilitating condition.”
Patients who had heart attacks during the first COVID lockdown in the UK and Spain are predicted to live 1.5 and 2 years less, respectively, than their pre-COVID counterparts. That’s the finding of a study just published in European Heart Journal – Quality of Care and Clinical Outcomes.
“Restrictions to treatment of life-threatening conditions have immediate and long-term negative consequences for individuals and society as a whole,” said study author Professor William Wijns of the Lambe Institute for Translational Medicine, University of Galway, Ireland. “Back-up plans must be in place so that emergency services can be retained even during natural or health catastrophes.”
Research has shown that during the first wave of the pandemic, about 40% fewer heart attack patients went to hospital as governments told people to stay at home, fear of catching the virus, and the stopping of some routine emergency care. Compared to receiving timely treatment, heart attack patients who stayed at home were more than twice as likely to die, while those who delayed going to the hospital were nearly twice as likely to have serious complications that could have been avoided.
Heart attacks require urgent treatment with stents (called percutaneous coronary intervention or PCI) to open the blocked artery and restore blood flow. Delays, and the resulting lack of oxygen, lead to irreversible damage of the heart muscle and can cause heart failure or other complications. When a large amount of heart tissue is damaged, potentially fatal cardiac arrest results.
This study estimated the long-term clinical and economic implications of reduced heart attack treatment during the pandemic in the UK and Spain. The researchers compared the predicted life expectancy of patients who had a heart attack during the first lockdown with those who had a heart attack at the same time in the previous year. The study focused on ST-elevation myocardial infarction (STEMI), where a coronary artery is completely blocked. The researchers also compared the cost of STEMIs during lockdown with the equivalent period the year before.
A model was developed to estimate long-term survival, quality of life and costs related to STEMI. The UK analysis compared the period 23 March (when lockdown began) to 22 April 2020 with the equivalent time in 2019. The Spanish analysis compared March 2019 with March 2020 (lockdown began on 14 March 2020). Survival projections considered age, hospitalisation status and time to treatment using published data for each country. For example, using published data, it was estimated that 77% of STEMI patients in the UK were hospitalised prior to the pandemic compared with 44% during lockdown. The equivalent rates for Spain were 74% and 57%. The researchers also compared how many years in perfect health were lost for patients with a STEMI before versus during the pandemic.
The analysis predicted that patients who had a STEMI during the first UK lockdown would lose an average of 1.55 years of life compared to patients presenting with a STEMI before the pandemic. In addition, while alive, those with a STEMI during lockdown were predicted to lose approximately one year and two months of life in perfect health. The equivalent figures for Spain were 2.03 years of life lost and around one year and seven months of life in perfect health lost.
The cost analysis focused on initial hospitalisation and treatment, follow-up treatment, management of heart failure and productivity loss in patients unable to return to work. For example, the cost applied to a STEMI admission with PCI was £2837 in the UK and €8780 in Spain. Heart failure costs were estimated at £6086 in year one and £3882 in all subsequent years for the UK. The equivalent figures for Spain were €3815 (year one) and €2930 (each subsequent year).
Professor Wijns said: “The findings illustrate the repercussions of delayed or missed care. Patients and societies will pay the price of reduced heart attack treatment during just one month of lockdown for years to come. Health services need a list of lifesaving therapies that should always be delivered, and resilient healthcare systems must be established that can switch to emergency plans without delay. Public awareness campaigns should emphasise the benefits of timely care, even during a pandemic or other crisis.”
South African scientists – notably, the team headed by Professor Tulio de Oliveira – were thrown into the global spotlight through their pivotal role in detecting and monitoring the emergence of new variants of SARS-CoV-2 – the Beta variant in 2020 and Omicron in 2021. De Oliveira is now at the University of Stellenbosch, but for much of the pandemic headed the KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP).
The country’s advanced genomic sequencing capabilities and proactive surveillance efforts allowed for the early identification of the variants and the discoveries played a crucial role in alerting the global scientific community to the potential for viral mutations and the need for enhanced monitoring.
Now, scientists worldwide believe it is critical to continue investing in genomics to support disease control in public health in South Africa and the broader continent.
What is genomics?
The World Health Organization (WHO) defines genomic surveillance as “the process of constantly monitoring pathogens and analysing their genetic similarities and differences”. It is done through a method known as whole genome sequencing, which determines the entire genetic makeup of specific organisms or cell types. This method is also able to detect changes in areas of genomes, which can help scientists to establish how specific diseases form. The results of genomic sequencing can also be used in diagnosing and treating diseases.
Genomic sequencing enables scientists to read the DNA and RNA of pathogens and understand what they are and how they spread between people – and to develop vaccines and other measures to deal with them.
The US Centers for Disease Control (CDC) explains, “All organisms (bacteria, vegetable, mammal) have a unique genetic code, or genome that is composed of nucleotide bases (A, T, C, and G). If you know the sequence of the bases in an organism, you have identified its unique DNA fingerprint or pattern. Determining the order of bases is called sequencing. Whole genome sequencing is a laboratory procedure that determines the order of bases in the genome of an organism in one process.
“Scientists conduct whole genome sequencing by following these four main steps:
DNA shearing: Scientists begin by using molecular scissors to cut the DNA, which is composed of millions of bases (A’s, C’s, T’s, and G’s), into pieces that are small enough for the sequencing machine to read.
DNA barcoding: Scientists add small pieces of DNA tags, or bar codes, to identify which piece of sheared DNA belongs to which bacteria. This is similar to how a bar code identifies a product at a grocery store.
DNA sequencing: The bar-coded DNA from multiple bacteria is combined and put in a DNA sequencer. The sequencer identifies the A’s, C’s, T’s, and G’s, or bases, that make up each bacterial sequence. The sequencer uses the bar code to keep track of which bases belong to which bacteria.
Data analysis: Scientists use computer analysis tools to compare sequences from multiple bacteria and identify differences. The number of differences can tell the scientists how closely related the bacteria are, and how likely it is that they are part of the same outbreak…”
Time to expand
At a recent conference held at Stellenbosch University’s new state-of-the-art Biomedical Medical Research Institute, de Oliveira stressed that African and other experts should now build on their success in COVID-19 genomics to expand to other pathogens such as influenza, H5N1, and climate-amplified pathogens.
John Sillitoe, the Director of the Genomic Surveillance Unit at the Wellcome Sanger Institute in the United Kingdom, agreed.
“It is important now to focus on endemic diseases so we can improve our understanding and control of endemic diseases. We should also be looking at TB, particularly with the increased prevalence in drug resistance and reduced response to drugs. For other African countries, malaria should be a key focus area. We know that drug resistance now is spreading into Africa from South East Asia and understanding the right combination of drugs to use is something that is easily identifiable through genomic surveillance.”
But surveillance is also about being ready for the next pandemic.
“There’s that classic line that, ‘diseases take no notice of national borders’,” Sillitoe said in an interview. “So, it is really important that we can get as wide a picture of surveillance as possible to identify something new emerging as soon as possible.”
Marco Salemi, Professor of Experimental Pathology at the Department of Pathology, Immunology, and Laboratory Medicine at the University of Florida College of Medicine, said Africa and the world need to be “proactive, rather than reactive” in the battle against future epidemics. He said the world is currently focused on monitoring the COVID-19 pandemic. “But we forget this is this huge reservoir of pathogens out there which we know so little about and which can become more and more of a threat, especially because of climate change – so we need to understand more about all these pathogens in the wild, in animals, and their potential to jump to humans, especially with the rate of globalisation on the planet … Events of zoonotic transmissions will become more and more frequent. We need to face it.”
Building capacity
De Oliveira is of the view that Africa could, in the next few years, potentially, “leapfrog over the rest of the world” in genomic surveillance, thanks to its success in COVID-19 genomics and its experience in using genomics to monitor other pathogens over the past 20 years.
We won’t be starting from scratch.
The use of genomics in infectious diseases started in the mid-eighties during the HIV epidemic, when scientists realised HIV was a complex virus that existed in many different sub-types. Scientists around the world started using genomic tools to sequence the HIV virus, track its origin, and trace the way the virus disseminated.
Genomics has, however, changed dramatically since the 1980s.
“There have been many attempts… to use genomics for public health purposes, but the key factor that was always missing was the ability to generate DNA sequencing in real-time,” said Salemi. “Real-time means there is an epidemic, with cases happening today – and we need to generate sequences within one or two days and then to analyse the genomic data and then to have actionable information that can be immediately transmitted to the public health authorities so that they can act within a few days.”
“Now the technological and computational limitations of the past few years have been overcome, and, as was clearly shown during the COVID-19 pandemic, we have machines that can generate literally thousands of sequences, like coronavirus sequences, in less than one day, or even within a few hours. At the same time, we have high-performance computer clusters, and super calculators that are capable of analysing this data in a very short time,” he said.
These technical advances would, of course, be of little value without people to use them and develop them further.
“Investment has been made on the continent in infectious disease surveillance and genomics surveillance specifically, and so we have lots of experts on the continent who know a lot about infectious diseases and how viruses work, and why it’s important to look at the genomics to trace when there is going to be a new outbreak,” says Professor Zané Lombard, Principal Medical Scientist in the Division of Human Genetics at the University of the Witwatersrand. “South Africa’s role during COVID-19 showcased what can happen quickly and effectively for public health interventions if you have the right experts with the right platform and expertise and infrastructure in place to do that kind of surveillance.”
De Oliveira and his team have worked closely with the Africa Centres for Disease Control and Prevention (Africa CDC) to scale genomic surveillance on the continent and have actively collaborated with other African countries to share expertise, resources, and genetic data in a bid to foster a continent-wide approach to genomic surveillance.
They have also helped set up large genomics facilities in Zimbabwe, Mozambique, and Botswana.
The Africa CDC, through its Pathogen Genomics Initiative (Africa PGI), has, for the past few years, been building a continent-wide genomic disease surveillance network. In 2019, when the PGI started its work, only seven of the African Union’s 55 member states had public health institutions with the equipment and staff to do genetic sequencing. Today, 31 African nations are able to do genetic sequencing for surveillance of COVID, malaria, cholera, Ebola, and other diseases.
De Oliveira said the continent’s experience in genomic surveillance of pathogens in Africa evolved to “unheard-of” levels during COVID. “We’ve been trying to advance genomic surveillance in Africa for the past two decades, and when the pandemic came, we had the right expertise to deal with viruses and respiratory pathogens such as tuberculosis, so we were able to pivot for SARS-CoV-2. In the end, South Africa and Africa became an example to follow for the whole world.
“All the investments we have made in genomic surveillance for COVID can now be leveraged and advanced to other areas of genomics in Africa… including for rare diseases, for cancer diagnostics, and human genomics. Finally, we have the tools and the equipment, as well as the support, to do advanced genomics in Africa, as we have dreamt of doing for the last twenty years.”
What it means in practical terms
Asked what it means, practically, to build capacity for genomics research, Lombard said one aspect is the establishment of strong laboratories. “Historically, if infrastructure was not available locally, researchers would partner with international labs and send their samples to have their sequencing done there. The problem with that was that expertise in using [that] technique was not being built locally,” she said. “It is really important to train the right people who know how to do the laboratory experiments but also to interpret the data correctly.
“It’s not only about building the infrastructure in the labs but also about training the individuals and making sure there are job opportunities locally for them,” she said.
Turning to the machines used in genomics, Lombard said, “The most popular machine these days is called a next-generation sequencer. These can read the whole DNA sequence of a virus.”
Salemi added, “Some of these sequencers are very large and some are even little portable boxes. Some can sequence thousands of samples at a time, while others are capable of sequencing a few dozen samples at a time. The samples, depending on the virus (or pathogen) being tested for, are taken from blood samples, nasal swabs, or sputum from patients, from faeces, urine, or from the skin.
“The BMRI (at Stellenbosch University) – which has the largest sample storage capacity in the southern hemisphere – can store five million samples at minus 80 degrees. If someone wants to build a lab that includes top-of-the-line computational capacity, it will cost anything from $40 million (over 700 million), but to start a small operation to do a few hundred sequences of a virus every week, $100 000 to $200 000 (roughly R17 million to R34 million) is enough, which has been done in many different African countries during the pandemic.”
Training is key
While all the scientists interviewed agreed that laboratories are important in building capacity for genomics research, they stressed that what is really needed is to train more individuals.
“More people need to be trained in genomics but also in bioinformatics, which is a really important component of this work. The technology component is becoming very smart and automated, but the data being generated is becoming more and more complex, with bigger data sets. Dealing with these,” Lombard said, “requires special data analysis skills and bioinformatics skills. The field of bioinformatics will need investment so that we can deal with the deluge of data that will come out.”
She said South African and other African universities are taking this skills need seriously, with many initiatives to offer undergraduate and post-graduate training programmes in these areas.
Salami agreed. “The most important part of building capacity is the human training. I find it naïve and sad when I hear politicians talking about building top-of-the-line laboratories, when, what they really need to do is to start building human capacity. Africa is an amazing reservoir (from which to build these skills) because 50 percent of the continent [are] people who are less than 30 years old. There are about 27 excellent laboratories all over Africa. We need to start creating a strong next generation of scientists.”
In support of this, de Oliveira is trying to raise 100 million dollars to implement real-time genomic research to enable the African continent to respond to new epidemics.
He said during COVID, the Network for Genomics Surveillance was founded and funded by the Department of Science and Innovation and the South African Medical Research Council (SAMRC). This funding was until 2021.
The Centre for Epidemic Response and Innovation, which is led by de Oliveira and forms part of the BMRI, is funded by the Africa CDC, the WHO, the Rockefeller Foundation, and the Elma Foundation. These funders support the work in South Africa and in other African countries, as well as the SA government. The BMRI was mostly funded by Stellenbosch University to the effect of R900 million, while the Department of Higher Education provided about R300 million. CERI occupies one floor of the BMRI.
In de Oliveira’s words, “This truly is the genome era for Africa.”
The ‘Phezulu: Looking Up’ podcast series launched today by UNICEF South Africa (https://www.UNICEF.org/SouthAfrica/) tells the stories of the impact of the COVID-19 years on children and young people and how, with the right support and opportunities, children and young people are determined to build a safer, fairer and better post pandemic South Africa.
The eight-part series delves into issues such as mental wellbeing, disrupted education and access to child healthcare; including routine childhood immunisations, through the voices of children and young people and experts working to mitigate the impact.
“Children and adolescents were affected by every aspect of the COVID-19 pandemic and this podcast series tells their stories of resilience,” said Muriel Mafico, UNICEF South Africa Deputy Representative. “Importantly, the episodes also reflect on the response to share learnings, including how the roll-out of the COVID-19 vaccine saved countless lives and re-opened our world,”
The podcast series features expert analysis and voices, including contributions from academics, all of whom continue to play a critical role in the ongoing recovery for every child. The series not only highlights the indirect impact of COVID-19 on children and youth, but also how COVID-19 vaccinations changed the trajectory of the crisis by enabling children and adolescents to resume their childhoods.
The series will be available on a weekly basis, on all major podcast platforms from 23rd May 2023. Listeners can now subscribe and join the conversation. This production was made possible thanks to the generous support of the German Federal Foreign Office and other partners.
A study that used data for 1.1 million children in Bavaria found that SARS-CoV-2 infection was linked to an increased risk of a diagnosis of type 1 diabetes. The findings, which are published in JAMA, also point to a direct effect of COVID on the development of type 1 diabetes.
Different studies have documented an increased incidence of type 1 diabetes during the COVID pandemic. However, none of the studies distinguishes between children with and without SARS-CoV-2 infection.
Researchers at Helmholtz Munich and TU Dresden, in cooperation with the Kassenärztliche Vereinigung Bayern (KVB) used a database to make an analysis of the temporal relationship between a COVID diagnosis and the diagnosis of type 1 diabetes. Amongst the analysed children without type 1 diabetes diagnosis before the start of the pandemic, 16.6% had a diagnosis of COVID between January 2020 and December 2021.
SARS-CoV-2 infection associated with an increased risk of type 1 diabetes in children
The researchers’ initial findings were consistent with data from Germany and other countries: the incidence rate of type 1 diabetes in children between the ages of two and 12 years was around 50% higher in the years 2020 to 2021 as compared to the incidence rate in 2018 to 2019. Important and novel, they found that the development of type 1 diabetes in 2020 to 2021 was higher in the children with COVID. The likelihood to develop type 1 diabetes was increased by 57% in children who had a confirmed SARS-CoV-2 infection compared to non-infected children. The increase in type 1 diabetes incidence occurred in the same quarter as the COVID diagnosis and also in later quarters.
The new data point to a direct effect of SARS-CoV-2 infection on the development of type 1 diabetes
“We are cautious in our interpretation, but the findings suggest that the virus could either promote initiation of the underlying autoimmunity in type 1 diabetes or accelerate the progression of the disease in children with existing autoimmunity,” says Ezio Bonifacio, last author of the study. Further studies will be needed, to elucidate the exact mechanism driving the increased incidence of type 1 diabetes during the COVID pandemic in young children.
Further studies planned
The team of researchers also has access to cohorts of prospectively followed children from the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) and the Fr1da Study. “We want to look into these cohorts to see whether the development of islet autoantibodies and/or type 1 diabetes was increased in the children after SARS-CoV-2 infection,” says Anette-Gabriele Ziegler, Director of the Helmholtz Munich Institute of Diabetes Research and GPPAD researcher. The findings of these studies will help to determine whether vaccination against COVID should be considered in children at risk for type 1 diabetes.
Millions of doses of the Pfizer-BioNtech COVID-19 vaccine procured by the South African government have expired and the shot is largely unavailable to people in the country.
Several people who have contacted Spotlight have expressed “frustration” and “dismay” that despite government having announced in February that it was sitting on a massive stockpile of almost 30 million vaccines, they are struggling to access the Pfizer shot.
Explaining the vast quantity of unused vaccines, the Health Department at the time said vaccine uptake has been low due to decreasing cases, people’s erroneous perception that the pandemic is over, and hesitancy affected by vaccine disinformation.
Expired but not expired?
National Department of Health spokesperson Foster Mohale confirmed that seven million Pfizer doses had expired but they would not be disposed of. Instead, the vaccine manufacturers would test the vaccines to ensure continued safety and efficacy. The South African Health Products Regulatory Authority (SAHPRA) will review the test results and, if satisfied that the vaccine will still work as well as data showed before, they will approve an extended shelf life.
The remaining estimated 23 million Johnson and Johnson (J&J) vaccine doses in South Africa are due to expire in 2024 and 2025.
“The expiry of a vaccine is not the same as the expiry date of food which cannot be extended,” Mohale says, adding that the Pfizer vaccine has a short shelf life and that the vaccine’s expiry date has been extended twice in the past. He says the testing should be done by June and the Pfizer shots would become available in July.
Photo by Mat Napo on Unsplash
A mother from East London, who is hoping to emigrate to the United States, told Spotlight that she was “frantically” trying to get shots for her 12-year-old son in time to leave. In South Africa, none of the currently available COVID-19 vaccines have been authorised for use in children under the age of 16. Elsewhere in the world, for example, in the United States, the Pfizer vaccine has been tested and authorised for use for children from the age of 12. “It is mandatory that he get the vaccine before entering the United States,” she says.
An intern responding to people’s questions on the Department of Health’s hotline says, “Many callers have phoned in stressing about travelling, emigrating, or getting vaccinated for the first time. We have been told that there are very few sites that still have some stock. If people have had two Pfizer doses, they can boost with a J&J dose. However, if they have only had one Pfizer, they will have to wait.”
The public exasperation expressed directly to Spotlight and on social media also relates to the health department’s vaccination website being outdated and it being hard to find places to get vaccinated. As GroundUp reported in January, getting a COVID-19 booster jab is not as easy as it should be.
‘The pandemic is not over’
Referring to the World Health Organization’s (WHO) lifting of the COVID-19 Public Health Emergency of International Concern(PHEIC) on May 5th, Mohale says, “The pandemic is not over and people, especially those who are at highest risk of severe disease and death should get vaccinated.” These included people with co-morbidities and the elderly. He says vaccination for COVID-19 has been integrated into routine primary healthcare facilities, which is where people should go for their jabs.
WHO director-general Tedros Ghebreyesus said it was the end of the emergency phase but not the end of the threat of COVID-19. In the week prior to the announcement, he said the disease claimed a life (globally) every three minutes, “and that’s just the deaths we know about”.
The decision to lift the emergency was based on the decreasing number of deaths and hospitalisations from COVID-19, the high levels of population immunity against SARS-CoV-2, and the widespread availability of COVID-19 vaccines and treatments.
Ghebreyesus warned that the COVID-19 pandemic is not over and that the virus could still pose a serious threat to public health. The WHO has urged countries to continue to monitor the situation closely and to maintain preparedness measures, such as surveillance, testing, and contact tracing.
Some experts have criticised the WHO’s decision to end the emergency phase, arguing that it is premature and could lead to a resurgence of the pandemic. Others have defended the decision, arguing that it is based on the best available evidence and that it is important to give countries the flexibility to manage the pandemic in a way that best suits their own circumstances.
‘Momentous’ announcement
Professor Salim Abdool Kariem, Director of CAPRISA, described the announcement as “momentous”. Writing in his regular COVID-19 updates blog, he says, “… we are still living in the midst of a pandemic with thousands of cases each day. Since SARS-CoV-2 is going to be with us for a long time, a pragmatic decision was needed as the COVID-19 pandemic emergency has been steadily receding and a new variant of concern has not emerged in the last 17 months. But the risk of a new variant of concern is ever-present, even if it is getting progressively smaller with time. The public is also tired of the pandemic and many have simply put it out of sight and out of mind.”
Kariem writes that globally there are currently far more COVID-19 cases, hospitalisations, and deaths each day than we had on the day (30 January 2020) that COVID-19 was initially declared a PHEIC. “So, it (the WHO decision) was not based on the situation getting to a point pre-PHEIC. Waiting to reach that point may take many years or may never happen and so ending the PHEIC is a judgement call, taking many factors into consideration.”
‘Still with us’
Speaking at a recent webinar, hosted by Internews, science writer David Quammen, who wrote a book on COVID-19 called ‘Breathless: The Scientific Race to Defeat a Deadly Virus’ and before that, ‘Spillover’, says, “The coronavirus is still with us, it’s circulating worldwide among humans, and circulating also among whitetail deer, feral mink, and probably other wild mammals.”
He says efforts currently need to be directed to approaching COVID-19 as a long-term cause of human illness, suffering, and death, not “a short-term catastrophe”.
He says laboratory techniques need to be improved as well as manufacturing capacity for updated COVID-19 vaccines. Inequitable access to vaccines will need to be solved. “We will need to dissolve vaccine reluctance and refusal – among the privileged but obdurate, and also among those historically ill-served by Western medicine – with better communication and education.” Diagnostic testing needs to be maintained and not reduced, as well as the sequencing of genomes from patient samples to detect and trace new and immune-evasive variants, he says.
“We will need to prepare, not just for the next coming of SARS-CoV-2 (when it emerges from some infected human, or some deer or mink) but also for the next coronavirus or influenza virus (more than likely H1N1) or other highly adaptive animal-borne virus (there’s a whole rogue’s list of possibilities) that appears in humans, seemingly out of nowhere,” he says. “But they don’t come out of nowhere. They come from nature.”
The World Health Organization has announced that it was downgrading COVID from its previous status as a public health emergency of international concern, but noted that the pandemic is still not over. Recent spikes have occurred in Southeast Asia and the Middle East, and the agency warns that thousands of people a day are still dying from the virus. It also made a number of recommendations for national healthcare systems to maintain the gains made against the virus and for pandemic preparedness.
The WHO’s International Health Regulations (2005) (IHR) Emergency Committee had been following the decline in hospital and ICU missions along with the growth of immunity, and decided in its meeting on Thursday 4 May that it was time to recommend a transition to long-term management.
“It’s with great hope that I declare COVID-19 over as a global health emergency,” WHO Director-General Tedros Adhanom Ghebreyesus said, concurring the Committee’s advice.
“That does not mean COVID-19 is over as a global health threat,” he said, adding he wouldn’t hesitate to reconvene experts to reassess the situation should COVID-19 “put our world in peril.”
He also expressed concern that even though infections were down, COVID-19 surveillance was falling.
While various governments had been transitioning down for a while, this marks a major step for the WHO. The virus killed millions and sent the global economy into a nosedive, plunging millions more into poverty and reversing many decades of socioeconomic development.
While COVID was no longer considered to be an ongoing global threat, the WHO made number of recommendations for countries:
Sustain the national capacity gains and prepare for future events.
Integrate COVID-19 vaccination into life course vaccination programmes.
Bring together information from diverse respiratory pathogen surveillance data sources to allow for a comprehensive situational awareness.
Prepare for medical countermeasures to be authourisedwithin national regulatory frameworks to ensure long-term availability and supply.
Continue to work with communities and their leaders to achieve strong, resilient, and inclusive risk communications and community engagement (RCCE) and infodemic management programmes.
Continue to lift COVID-19 international travel related health measures
Secondary bacterial pneumonia was extremely common in patients with COVID-19, affecting almost half the patients who required support from mechanical ventilation. In a study published in the Journal of Clinical Investigation, researchers applied machine learning to medical record data and found that secondary bacterial pneumonia that does not resolve was a key driver of death in COVID patients.
Bacterial infections may even exceed death rates from the viral infection itself, according to the findings. The study’s researchers at Northwestern University Feinberg School of Medicine also found evidence that COVID does not cause a “cytokine storm,” so often believed to cause death.
“Our study highlights the importance of preventing, looking for and aggressively treating secondary bacterial pneumonia in critically ill patients with severe pneumonia, including those with COVID-19,” said senior author Benjamin Singer, MD, professor at Northwestern.
The investigators found nearly half of COVID patients develop a secondary ventilator-associated bacterial pneumonia.
“Those who were cured of their secondary pneumonia were likely to live, while those whose pneumonia did not resolve were more likely to die,” Singer said. “Our data suggested that the mortality related to the virus itself is relatively low, but other things that happen during the ICU stay, like secondary bacterial pneumonia, offset that.”
“The term ‘cytokine storm’ means an overwhelming inflammation that drives organ failure in your lungs, your kidneys, your brain and other organs,” Singer said. “If that were true, if cytokine storm were underlying the long length of stay we see in patients with COVID-19, we would expect to see frequent transitions to states that are characterised by multi-organ failure. That’s not what we saw.”
The study analysed 585 patients in the intensive care unit (ICU) at Northwestern Memorial Hospital with severe pneumonia and respiratory failure, 190 of whom had COVID. The scientists developed a new machine learning approach called CarpeDiem, which groups similar ICU patient-days into clinical states based on electronic health record data. This novel approach, which is based on the concept of daily rounds by the ICU team, allowed them to ask how complications like bacterial pneumonia impacted the course of the illness.
These patients or their surrogates consented to enrol in the Successful Clinical Response to Pneumonia Therapy (SCRIPT) study, an observational trial to identify new biomarkers and therapies for patients with severe pneumonia. As part of SCRIPT, an expert panel of ICU physicians used state-of-the-art analysis of lung samples collected as part of clinical care to diagnose and adjudicate the outcomes of secondary pneumonia events.
“The application of machine learning and artificial intelligence to clinical data can be used to develop better ways to treat diseases like COVID and to assist ICU physicians managing these patients,” said study co-first author Catherine Gao, MD.
“The importance of bacterial superinfection of the lung as a contributor to death in patients with COVID-19 has been underappreciated, because most centres have not looked for it or only look at outcomes in terms of presence or absence of bacterial superinfection, not whether treatment is successful or not,” said study co-author Richard Wunderink, MD.
The next step in the research will be to use molecular data from the study samples and integrate it with machine learning approaches to understand why some patients go on to be cured of pneumonia and some don’t. Investigators also want to expand the technique to larger datasets and use the model to make predictions that can be brought back to the bedside to improve the care of critically ill patients.
Early in the COVID pandemic, it became clear that children infected with the coronavirus rarely developed serious disease. One hypothesis has been that children already have some immunity provided by memory T cells generated by common colds. Researchers at Karolinska Institutet are now able to show that OC43, one of the coronaviruses that cause common colds, boosts the immune response to COVID. The study, which is published in PNAS, could give rise to more tailored vaccine programmes for children and adults.
After studying unique blood samples from children taken before the pandemic, Karolinska Institutet researchers have now identified memory T cells that react to cells infected with SARS-CoV-2.
This new study reinforces this hypothesis and shows that T cells previously activated by the OC43 virus can cross-react against SARS-CoV-2.
Four coronaviruses cause common colds
One of the four coronaviruses causing seasonal common cold symptoms could stimulate an immune response with T cells able to also react to cells infected with SARS-CoV-2.
“These reactions are especially strong early in life and grow much weaker as we get older,” says the study’s corresponding author Annika Karlsson, research group leader at the Department of Laboratory Medicine, Karolinska Institutet. “Our findings show how the T-cell response develops and changes over time and can guide the future monitoring and development of vaccines.”
Strong immunity at the age of two
The results indicate that the memory T-cell response to coronaviruses develops as early as the age of two. The study was based on 48 blood samples from two- and six-year-old children, and 94 samples from adults between the ages of 26 and 83. The analysis also included blood samples from 58 people who had recently recovered from COVID-19.
“Next, we’d like to do analogous studies of younger and older children, teenagers and young adults to better track how the immune response to coronaviruses develops from childhood to adulthood,” says Marion Humbert, postdoctoral researcher currently at the Department of Medicine Huddinge, Karolinska Institutet, joint first author with Anna Olofsson, doctoral student at the Department of Laboratory Medicine.
Scientistshave made an important breakthrough in understanding failures during the progression of inflammatory diseases and in doing so unearthed a potential new therapeutic target. The scientists report in Nature that an enzyme called Fumarate Hydratase is repressed in macrophages. These immune cells are already implicated in a range of diseases including Lupus, arthritis, sepsis and COVID.
Lead author Luke O’Neill, Professor of Biochemistry at Trinity said: “No-one has made a link from Fumarate Hydratase to inflammatory macrophages before and we feel that this process might be targetable to treat debilitating diseases like Lupus, which is a nasty autoimmune disease that damages several parts of the body including the skin, kidneys and joints.”
Joint first-author Christian Peace added: “We have made an important link between Fumarate Hydratase and immune proteins called cytokines that mediate inflammatory diseases. We found that when Fumarate Hydratase is repressed, RNA is released from mitochondria which can bind to key proteins ‘MDA5’ and ‘TLR7’ and trigger the release of cytokines, thereby worsening inflammation. This process could potentially be targeted therapeutically.”
Fumarate Hydratase was shown to be repressed in a model of sepsis, an often-fatal systemic inflammatory condition that can happen during bacterial and viral infections. Similarly, in blood samples from patients with Lupus, Fumarate Hydratase was dramatically decreased.
“Restoring Fumarate Hydratase in these diseases or targeting MDA5 or TLR7 therefore presents an exciting prospect for badly needed new anti-inflammatory therapies,” said Prof O’Neill.
Excitingly, this newly published work is accompanied by another publication by a group led by Professor Christian Frezza, now at the University of Cologne, and Dr Julien Prudent at the MRC Mitochondrial Biology Unit (MBU), who have made similar findings in the context of kidney cancer.
“Because the system can go wrong in certain types of cancer, the scope of any potential therapeutic target could be widened beyond inflammation,” added Prof O’Neill.
