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.
For older patients in intensive care units (ICUs), COVID is more severe than bacterial or viral pneumonia, suggests new research published in the Journal of the American Geriatrics Society.
Among 11 525 patients aged 70 years and older who were admitted to Dutch ICUs, ICU-mortality and hospital-mortality rates of patients admitted with COVID were 39.7% and 47.6%, respectively. These rates were higher than the mortality of patients admitted because of pneumonia from causes other than COVID. (ICU- and hospital-mortality rates of patients admitted with bacterial pneumonia were 19.1% and 28.8%, respectively, and with viral pneumonia were 22.7% and 31.8%, respectively). Differences persisted after adjusting for several clinical characteristics and intensive care unit occupancy rate.
“In ICU-patients aged 70 years and older, COVID is more severe – with approximately double mortality rates – compared with bacterial or viral pneumonia. Nevertheless, more than half of these older patients admitted to Dutch ICUs with COVID survived the hospital,” said corresponding author Lenneke E. M. Haas, MD, PhD, of Diakonessenhuis, in the Netherlands. “Our findings provide important additional data to include in informed goals-of-care discussions.”
SARS-CoV-2 virus. Source: Fusion Medical Animation on Unsplash
In an interview about new Omicron subvariants, leading vaccinologist Prof Shabir Madhi said that “we don’t need to be concerned” about any current threat they may pose to South Africa. However, he stressed that it can still be lethal, particularly in those without underlying T cell immunity. He also noted that boosters are also important for high-risk populations, while some sort of seasonality needs to be observed for COVID for it to make boosters worthwhile for those at low risk due to the way vaccination protection wanes.
The XBB 1.5 SARS-CoV-2 subvariant, nicknamed ‘Kraken’ by researchers, is now accounting for more than half of cases in the United States, and appears much more transmissible and antibody-evasive than the original Omicron variant which evolved in Southern Africa. Prof Pravin Manga, editor of the Wits Journal of Clicnical Medicine interviewed Prof Madhi and asked him what the emergence of Omicron subvariants meant for South Africa.
Prof Madhi, who is the Dean of the Faculty of Health Sciences at Wits University, noted that before this new XBB.1.5 variant, there were BA4 and BA5, which created a “mini surge” in the middle of last year when they arrived in SA. There were concerns that these strains seemed more antibody-resistant than previous ones, stoking fears that they would result in increased hospitalisations and deaths.
In light of the current situation, he says that “the short answer is that we don’t need to be concerned.”
One important aspect of immunity which was becoming apparent was that, although neutralising antibodies were important in protecting against contracting and transmitting the virus, “what seems to be playing a greater role in protecting against severe disease is the T cell immunity, the Natural Killer cell immunity.” This immunity is much more diverse than that from antibodies, instead of merely targeting the Spike protein is rather “multi-epitopic”, targeting the N-protein as well.
“Now this T cell immunity appears to be holding strong. It appears to be less affected by all these mutations. In fact, close to 75 to 80% of vaccine-induced T cell immunity is conserved despite the multiple mutations have arisen in Omicron and its subvariants.”
Differing impacts across countries
With regard to the impact of the virus, Prof Madhi noted that China had pursued its ‘zero COVID’ policy, along with “suboptimal” coverage of vaccines (especially among ages 60+) that were “probably not the best”, meaning that large portions of the population were essentially naïve to the virus.
SA meanwhile, had 90% of the population infected at least once with COVID, and coupled with vaccination, meant that many will have highly robust immunity, which appears to last for 9–12 months compared to vaccine-only immunity where protection starts wanes after 4–6 months.
“What is unlikely to materialise in a country such as South Africa is large numbers of hospitalisations,” he says.
Protecting at-risk populations and the need for new vaccines
At present, he says there is not a strong case for boosters, but people at greater risk, such as those over 60, people with underlying medical conditions, and compromised immune systems, hybrid immunity is likely not enough protection. In these cases probably at least four doses of vaccination. From a public health standpoint, the population under 45 without underlying conditions would require a huge effort for only a nominal benefit as they are no longer at high risk of severe disease.
Timing is also important, due to the waning of vaccine protection, as the best time to get a booster is “probably around two or three weeks before the start of the next resurgence.” Otherwise, it’s useless to get a booster now if the next resurgence is in six months and antibodies will have waned – an obvious logistical challenge for little benefit. Therefore, in order for boosters to be useful, the virus will have to settle into some sort of predictable seasonality such as with influenza.
As for people who are at risk, at least four doses are probably required, though the case for a fifth is thin. Annual boosters are a likely option, and there is a need for a second generation of vaccines. These vaccines would need to be resilient against further mutations that may arise.
Novavax, monoclonal antibodies and Paxlovid
Regarding Novavax, Prof Madhi said that it had been licensed for use in South Africa, but their bivalent vaccine was not yet available. It would not be procured by government but rather by a private company – a situation which needs to change in terms of who is allowed to bring in vaccines. Another issue is whether the no fault compensation used by the government for public sector vaccinations would be used in the private sector as well.
Prof Manga also asked about whether there had been any success with monoclonal antibody treatment, to which Prof Madhi answered that there had been some limited use in the country but overall, monoclonal antibodies were “spectacularly unsuccessful” as they were highly specific and generally unable to keep up with mutations.
In general, antivirals hold much better promise, particularly Paxlovid which is unfortunately not available in South Africa. It was disappointing that it was not available in the country,
Benefits to both pregnant mothers and babies
Regarding pregnant women and children, Prof Madhi said that their own study shows that a substantial amount of transmission takes place between mothers and children. Infants with COVID under six months are often hospitalised, especially in the first month of life. Vaccination reduces the risk of hospitalisation and protects the baby as well, with research showing that babies born to vaccinated mothers were 80% less likely to develop COVID, “which is really a huge benefit,” he noted. This is likely a little reduced with Omicron because the only thing that babies get from the mother is antibodies, not T cell immunity.
Vaccination also reduces the risk of adverse pregnancy outcomes such as stillbirth, and safety “is simply not an issue” as supported by the data. He says there is case for vaccinating pregnant women, even under 45, in the second trimester of the pregnancy so that more antibodies are transferred to the foetus.
The year 2022 finally saw the COVID pandemic petering out, largely through the less-lethal but still highly contagious Omicron variant. Significant strides were made in cancer and Alzheimer’s research, although not without controversy. Amid growing public healthcare challenges in South Africa, the NHI Bill advanced closer to reality.
As Omicron displayed greatly reduced severity compared to prior strains, South African medical experts were some of the first to justify no longer being at ‘code red’. This brought an end to the cycles of lockdowns and travel restrictions characterised by the two previous years.
A number of key medical advances were made during the year for a variety of conditions. Studies showed that administering steroids after COVID hospitalisation with severe inflammation reduced mortality up to one year post-infection.
COVID was found to be linked to a spate of new-onset Type 1 diabetes, but this may just have been due to medical checkups as a result of developing COVID. The rheumatoid arthritis drug auranofin was found to relieve diabetes symptoms. And research suggested a possible way to deliver insulin and cancer drugs orally, by adding a ‘tag’ that lets them enter the bloodstream through the intestines.
The fields of cancer and Alzheimer’s research was rocked by findings of numerous red flags. This controversy did not stop real progress: the first new drug that had any real effectiveness against Alzheimer’s disease was confirmed in a historic trial. Fortunately, the flu jab also seems to protect against developing the disease. Indeed, serious infections appear to increase the risk of both Alzheimer’s and Parkinson’s.
In advanced ER-positive, HER-2 negative breast cancers, the new drug capivasertib halved the rate of progression.
Despite lessons learned in the COVID pandemic, South Africa saw the progression of systemic problems in healthcare such as a critical shortage of nurses. Dr Tim de Maayer’s open letter on appalling conditions at Rahima Moosa exposed deep-seated problems in Gauteng’s public healthcare system. This was followed by the shock resignation of top cancer surgeon Professor Carol-Ann Benn. The appointment of Nomantu Nkomo-Ralehoko as Gauteng Health MEC should hopefully change the province’s situation.
COVID infection often causes adipose atrophy, weight loss and cachexia, which significantly contribute to poor quality of life and mortality. Now, researchers at Karolinska Institutet have discovered that SARS-CoV-2 infection fuels blood vessel formation in fat tissues, thus revving up the body’s thermogenic metabolism. Blocking this process with an existing drug curbed weight loss in mice and hamsters that were infected with the virus, according to the study published in the journal Nature Metabolism.
“Our study proposes a completely new concept for treating COVID associated weight loss by targeting the blood vessels in the fat tissues,” says corresponding author Yihai Cao, professor at Karolinska Institutet.
The researchers examined how different types of fat, including brown fat and visceral and subcutaneous white fat, reacted when exposed to SARS-CoV-2 and how it impacted weight in mice and hamsters. They found that the animals lost significant amounts of weight in four days and that this weight loss was preceded by the activation of brown fat and the browning of both types of white fat. These fat tissues also contained more microvessels and high levels of a signaling protein called vascular endothelial growth factor (VEGF), which promotes the growth of new blood vessels.
Similar mechanisms in humans
The researchers observed the same mechanisms in human tissue samples from four patients who died of COVID, suggesting the findings could be clinically relevant for humans.
When the animals were treated with an anti-VEGF drug, the animals recovered most of their lost weight and their fat tissues exhibited fewer microvessels.
“Antiangiogenic drugs are currently used in the clinic to treat various types of cancers,” Yihai Cao says. “It’s possible these drugs could also be helpful in treating COVID-related problems such as excessive weight loss and metabolic changes, thus improving the quality of life and survival for these patients. Of course, we will need more research to validate if our preclinical findings also hold up in human trials.”
After nearly three years of its harsh and extremely unpopular zero-COVID policy, the Chinese government announced on Wednesday the suspension of key parts of the contentious restrictions.
One of the ways some Chinese people expressed relief at the news was to go to the social media account of Dr Li Wenliang, the whistleblowing doctor who warned of the emerging coronavirus Wuhan and who was himself one of the virus’s early victims.
According to BBC News, they left messages “as if stopping by the graveside of a family elder” in which they shared their feelings.
“On the train, I suddenly remembered you and burst into tears. Dr Li, it’s over now, it’s dawn. Thank you,” read one message.
Another wrote: “I’ve come to see you and let you know – the dust has settled. We’re reopening.”
Chinese authorities punished the 33-year-old ophthalmologist for spreading “false statements”. He later died from COVID as he battled to save patients, prompting an outpouring of public grief and anger.
Xi Jinping’s campaign of zero-COVID aimed to completely eradicate the virus in China. The leadership hailed it as a success while other countries battled with surges of infections and deaths. Crucially, however, the policy made no use of Western-developed vaccines, mainly relying on the Chinese-developed and produced Sinovac.
Thus, with the lifting of the strictest parts of zero-COVID, people turned Dr Li’s page into a place to express their frustrations, hopes and grief. They also remembered his heroism in the face of authority.
“Those who blow the whistle are always worth remembering,” wrote one user. “I look forward to a more transparent society.”
China’s zero-COVID policy did appear to keep the country safe from the pandemic. There were 5200 deaths officially recorded in the pandemic while the US has recorded over one million.
The zero-COVID policy did not come without other costs. Sudden lockdowns saw people unable to get food. People testing positive for COVID were prevented from being with their families and were forced into centralised quarantine facilities. Gatherings and travel were subject to restriction.
Recently, workers broke out of a Foxconn factory which was supposed to be locked down for a quarantine. The event made international headlines as the authorities engaged in a manhunt for the escapees.
Some questioned whether the restrictions had been worth it.
“I took the subway this morning and for the first time did not have to look at the health code,” one user from Sichuan wrote.
“Some people say the epidemic has only started now after three years of hard work. So was it a waste of time? What of all those who paid a huge price, and even their lives for it?”
Others worried for China’s elderly population, many of whom are still unvaccinated.
“Dr Li, the real test of the three-year epidemic has begun. The epidemic is not as serious as yours, but I am exhausted,” one person wrote.
COVID patients hospitalised for acute respiratory distress syndrome (ARDS) are less likely to need endotracheal intubation with prone positioning, but evidence is inconclusive for other outcomes such as mortality, suggests an in-depth analysis of the latest evidence published by The BMJ.
Since the 1970s, prone positioning has been standard care for patients with severe ARDS as it encourages a larger part of the lung to expand, enabling bigger breaths.
Usually, it is done for critically ill patients who are sedated and intubated. But in February 2020, reports emerged of possible benefits from prone positioning of awake COVID and it was widely adopted.
Since then, several studies have examined its effectiveness in awake COVID patients , but results have been conflicting.
To try and resolve this uncertainty, researchers trawled databases for randomised trials comparing awake prone positioning to usual care for adult COVID patients with hypoxaemic respiratory failure.
They found 17 suitable trials, 12 with no bias risk, involving 2931 non-intubated patients who were able to breathe unassisted and who spent an average of 2.8 hours per day lying prone.
The primary outcome was endotracheal intubation, and secondary outcomes included mortality, ventilator-free days, intensive care unit (ICU) and hospital length of stay, change in oxygenation and respiratory rate, and adverse events.
High certainty evidence from a pooled analysis of 14 trials showed that awake prone positioning reduced the risk of endotracheal intubation compared with usual care (24.2% with awake prone positioning vs 29.8% with usual care). On average, awake prone positioning resulted in 55 fewer intubations per 1000 patients.
However, high certainty evidence from a pooled analysis of 13 trials evaluating mortality did not show a significant difference in mortality between the two groups (15.6% with awake prone positioning vs 17.2% with usual care), but the study may have lacked statistical power to detect a difference.
Awake prone positioning did not significantly affect other secondary outcomes either, including, ventilator-free days, ICU or hospital length of stay, based on low and moderate certainty evidence.
Limitations included lack of individual patient data, differences between the targeted and achieved duration of awake prone positioning, and variation in the definition and reporting of certain outcomes across studies.
But further sensitivity analysis supported these results, suggesting a high probability of benefit for the endotracheal intubation outcome and a low probability of benefit for mortality.
As such, the researchers conclude: “Awake prone positioning compared with usual care reduces the risk of endotracheal intubation in adults with hypoxemic respiratory failure due to covid-19 but probably has little to no effect on mortality or other outcomes.”
In a linked editorial, researchers point out that the benefits of prone positioning in COVID patients may be confined to those with more severe hypoxaemia and longer duration of prone positioning, so say it may be wise to focus efforts on these particular groups.
Several unanswered questions remain, including the ideal daily duration of treatment, the level of hypoxaemia that should prompt prone positioning, and how best to improve patient comfort and encourage adherence, they write.
These questions may never be answered definitively in COVID patients as, fortunately, far fewer are experiencing hypoxaemic respiratory failure or critical illness, they explain.
“The pandemic should, however, renew interest and encourage further evaluation of awake prone positioning – an intervention that may benefit a wide range of patients with hypoxaemia,” they conclude.
A major UK-wide trial has found that the the oral anticoagulant apixaban does not help patients recovering from moderate and severe COVID compared to standard care – despite this approach being offered to patients.
To date, more than a thousand NHS patients hospitalised with COVID have taken part in HEAL-COVID, a platform trial that is aiming to find treatments to reduce the number who die or are readmitted following their time in hospital.
The trial’s preliminary results have shown that prescribing the oral anticoagulant Apixaban does not affect subsequent mortality or rehospitalisation of COVID over the following year (apixaban 29.1%, versus standard care 30.8%).
As well as being ineffective, anticoagulant therapy has known serious side effects, and these were experienced by participants in the trial with a small number of the 402 participants receiving apixaban discontinuing due to bleeding events.
There was also no benefit from Apixaban in terms of the number of days alive and out of hospital at day 60 after randomisation (apixaban 59 days, versus standard care 59 days).
Following these results, the trial will continue to test atorvastatin, which acts on other mechanisms of disease that are thought to be important in COVID.
Chief Investigator for the trial Professor Charlotte Summers is an intensive care specialist at Addenbrooke’s Hospital and the University of Cambridge. She said: “These first findings from HEAL-COVID show us that a blood thinning drug, commonly thought to be a useful intervention in the post-hospital phase is actually ineffective at stopping people dying or being readmitted to hospital. This finding is important because it will prevent unnecessary harm occurring to people for no benefit. It also means we must continue our search for therapies that improve longer term recovery for this devastating disease.”
HEAL-COVID enrols patients when they are discharged from hospital, following their first admission for COVID. They are randomised to a treatment and their progress tracked.
According to a study published in JAMA Pediatrics, cases of young people seeking care for eating disorders greatly increased in the months of the pandemic.
Eating disorders (EDs), such as anorexia nervosa and bulimia nervosa, impact a wide range of individuals. In the developmental stages of adolescent and young adulthood, EDs – especially restrictive ones – can have particularly negative impacts. Furthermore, EDs commonly co-occur with other mental health conditions which can influence the trajectory of illness. Individuals with EDs have greater mortality rates, partly due to increased suicidality.
EDs requires intensive specialist care, which is not often available in many settings. A rise in rates of anxiety and depression have been attributed to the COVID pandemic, as well as a worsening of ED. Possible reasons for this include uncertainty about the future, disruptions in daily routines, inconsistent access to food, more time spent in triggering environments, influence from the media, and changes in access to treatment.
Reports from hospitals indicated increasing numbers of diagnoses and hospital admissions for ED, but there was little geographically widespread data.
Therefore, the researchers set out to investigate trends in patient volume for inpatient medical hospitalisation as well as volume of patients seeking outpatient subspecialty care, both before and after the pandemic.
The researchers used an an observational case series design to compare changes in volume in inpatient and outpatient ED-related care at 15 sites between January 2018 and December 2021.
Before the COVID pandemic, the relative number of pooled inpatient ED admissions were increasing over time by 0.7% per month. After onset of the pandemic, there was a significant increase in admissions over time of 7.2% per month through April 2021, then a decrease of 3.6% per month through December 2021. Before the pandemic, relative outpatient ED assessment volume was stable over time, with an immediate 39.7% decline in April 2020. Thereafter, new assessments increased by 8.1% per month through April 2021, then decreased by 1.5% per month through December 2021. The nonhospital-based ED program did not demonstrate a significant increase in the absolute number of admissions after onset of the pandemic but did see a significant increase of 8.2 additional inquiries for care per month in the first year after onset of the pandemic.
“Given inadequate ED care availability prior to the pandemic, the increased postpandemic demand will likely outstrip available resources. Results highlight the need to address ED workforce and program capacity issues as well as improve ED prevention strategies.”
In pulmonary medicine, it has long been debated as to whether ventilator overstretches lung tissue, and now new research published in the American Journal of Respiratory and Critical Care Medicine has proven that they do in fact cause overstretching.
The University of California Riverside researchers showed that there were major differences between natural breathing versus the forced breathing from ventilators. These results are critical, particularly in context of the COVID pandemic and the rush to build ventilators.
“Using novel techniques, we observed that ventilators can overextend certain regions of the lungs,” said Mona Eskandari, assistant professor of mechanical engineering, who led the research. These results may explain why lung health declines for patients the longer they spend on the machines, especially in the case of disease.
Eskandari’s bMECH lab pioneered a technique to study lungs as they are made to breathe. On a custom-built ventilator designed in their lab, the researchers imitated both natural and artificial breathing. Then, they observed isolated lungs involved in both types of breathing using multiple cameras collecting fast, high-resolution images, a method called digital image correlation.
“Our setup allows us to imitate both physiological and artificial breathing on the same lung with the switch of a button,” Eskandari said. “The unique combination of our ventilator with digital image correlation gives us unprecedented insights into the way specific regions of the lungs work in concert with the whole.”
Using their innovative method to interface these two systems, UCR researchers collected evidence demonstrating that natural breathing stretches certain parts of the lung as little as 25% while those same regions stretch to as much as 60% when on a ventilator.
Scholars traditionally model the lungs like balloons, or what they refer to as thin-walled pressure vessels, where pushing air in and pulling air out are understood to be mechanically equivalent.
To explain what they observed in this study, the researchers propose moving away from thin-walled pressure vessel models and instead towards thick-walled models. Unlike thin-walled pressure vessels theory, a thick-walled model accounts for the differing levels of stress in airways resulting from ventilators pushing air in versus natural breathing, which pulls air in. This helps to explain how airways are more engaged and air is more evenly distributed in the lung during physiological breathing.
Iron lungs, the gigantic ventilators used during the late 1940s polio outbreak, acted more like a human chest cavity, expanding the lung as it naturally would. This creates a vacuum effect that pulls air into the lungs. Though this action is gentler for the lungs, these bulky systems prevented easy access to monitoring other organs in hospital care.
By contrast, modern ventilators are more portable and easier for caretakers to work with. However, they push air into the lungs that is not evenly distributed, overstretching some parts and causing a decline in lung health over time.
While it is unlikely that hospitals will return to the iron lung models, it is possible that modern machines can be altered to reduce injury.
“Now that we know about excessive strain when air is delivered to the lungs, the question for us becomes about how we can improve ventilation strategies by emulating natural breathing,” Eskandari said.
