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Juan Lama
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A quarter of COVID-19 survivors had impaired lung function 1 year after infection, and older patients, those with more than three chronic conditions, and those with severe cases improved slower than other patients over time, a Dutch study published yesterday in PLOS One reveals. A team led by University of Amsterdam researchers evaluated diffusing capacity for carbon monoxide (DLCO), spirometry results, and health-related quality of life (HRQL) in 301 COVID-19 survivors who underwent at least one lung-function test from May 2020 to December 2021. Median patient age was 51 years, and 56% were men. The study involved 349 patients total. Nearly half of patients hospitalized Of the 301 participants who had lung-function testing, 30% had mild, 44% had moderate, and 26% had severe or critical COVID-19. Older age, higher body mass index, more chronic conditions, and the presence of cardiovascular disease, diabetes, and chronic lung diseases other than asthma or chronic obstructive pulmonary disease (COPD) were more common among patients who had severe infections than among those with mild cases. A total of 47% of patients were hospitalized. On admission, 86 hospitalized patients received low-flow oxygen, 15 required high-flow oxygen, and 29 needed invasive mechanical ventilation. Thirty-nine patients were admitted to the intensive care unit and stayed for a median of 6 days. Overall, 70 participants received the corticosteroid dexamethasone, and 10% were given the anti-inflammatory drug tociluzimab. At 1 month of follow-up, a below-normal DLCO was seen in 26% participants with mild, 23% with moderate, and 74% with severe COVID-19. In the mildly ill group, no statistically significant improvement in single-breath diffusion capacity occurred up to 1 year after symptom onset..... Published in PLOS ONE (Sept. 11, 2023): https://doi.org/10.1371/journal.pone.0290893
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Juan Lama
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Compared with earlier variants, Omicron may cause less damage to the lungs, new animal research suggests. A spate of new studies on lab animals and human tissues are providing the first hints of why the Omicron variant causes milder disease than previous versions of the coronavirus. In studies on mice and hamsters, Omicron produced less damaging infections, often limited largely to the upper airway: the nose, throat and windpipe. The variant did much less harm to the lungs, where previous variants would often cause scarring and serious breathing difficulty. “It’s fair to say that the idea of a disease that manifests itself primarily in the upper respiratory system is emerging,” said Roland Eils, a computational biologist at the Berlin Institute of Health, who has studiedhow coronaviruses infect the airway. In November, when the first report on the Omicron variant came out of South Africa, scientists could only guess at how it might behave differently from earlier forms of the virus. All they knew was that it had a distinctive and alarming combination of more than 50 genetic mutations. Previous research had shown that some of these mutations enabled coronaviruses to grab onto cells more tightly. Others allowed the virus to evade antibodies, which serve as an early line of defense against infection. But how the new variant might behave inside of the body was a mystery. “You can’t predict the behavior of virus from just the mutations,” said Ravindra Gupta, a virologist at the University of Cambridge. Over the past month, more than a dozen research groups, including Dr. Gupta’s, have been observing the new pathogen in the lab, infecting cells in Petri dishes with Omicron and spraying the virus into the noses of animals. As they worked, Omicron surged across the planet, readily infecting even people who were vaccinated or had recovered from infections. But as cases skyrocketed, hospitalizations increased only modestly. Early studies of patients suggested that Omicron was less likely to cause severe illness than other variants, especially in vaccinated people. Still, those findings came with a lot of caveats. For one thing, the bulk of early Omicron infections were in young people, who are less likely to get seriously ill with all versions of the virus. And many of those early cases were happening in people with some immunity from previous infections or vaccines. It was unclear whether Omicron would also prove less severe in an unvaccinated older person, for example. Experiments on animals can help clear up these ambiguities, because scientists can test Omicron on identical animals living in identical conditions. More than half a dozen experiments made public in recent days all pointed to the same conclusion: Omicron is milder than Delta and other earlier versions of the virus. On Wednesday, a large consortium of Japanese and American scientists released a report on hamsters and mice that had been infected with either Omicron or one of several earlier variants. Those infected with Omicron had less lung damage, lost less weight and were less likely to die, the study found. Although the animals infected with Omicron on average experienced much milder symptoms, the scientists were particularly struck by the results in Syrian hamsters, a species known to get severely ill with all previous versions of the virus. “This was surprising, since every other variant has robustly infected these hamsters,” said Dr. Michael Diamond, a virologist at Washington University and a co-author of the study. Several other studies on mice and hamsters have reached the same conclusion. (Like most urgent Omicron research, these studies have been posted online but have not yet been published in scientific journals.) The reason that Omicron is milder may be a matter of anatomy. Dr. Diamond and his colleagues found that the level of Omicron in the noses of the hamsters was the same as in animals infected with an earlier form of the coronavirus. But Omicron levels in the lungs were one-tenth or less of the level of other variants. A similar finding came from researchers at the University of Hong Kong who studied bits of tissue taken from human airways during surgery. In 12 lung samples, the researchers found that Omicron grew more slowly than Delta and other variants did. The researchers also infected tissue from the bronchi, the tubes in the upper chest that deliver air from the windpipe to the lungs. And inside of those bronchial cells, in the first two days after an infection, Omicron grew faster than Delta or the original coronavirus did. These findings will have to be followed up with further studies, such as experiments with monkeys or examination of the airways of people infected with Omicron. If the results hold up to scrutiny, they might explain why people infected with Omicron seem less likely to be hospitalized than those with Delta. Coronavirus infections start in the nose or possibly the mouth and spread down the throat. Mild infections don’t get much further than that. But when the coronavirus reaches the lungs, it can do serious damage. Immune cells in the lungs can overreact, killing off not just infected cells but uninfected ones. They can produce runaway inflammation, scarring the lung’s delicate walls. What’s more, the viruses can escape from the damaged lungs into the bloodstream, triggering clots and ravaging other organs. Dr. Gupta suspects that his team’s new data give a molecular explanation for why Omicron doesn’t fare so well in the lungs. Many cells in the lung carry a protein called TMPRSS2 on their surface that can inadvertently help passing viruses gain entry to the cell. But Dr. Gupta’s team found that this protein doesn’t grab on to Omicron very well. As a result, Omicron does a worse job of infecting cells in this manner than Delta does. A team at the University of Glasgow independently came to the same conclusion. Through an alternative route, coronaviruses can also slip into cells that don’t make TMPRSS2. Higher in the airway, cells tend not to carry the protein, which might explain the evidence that Omicron is found there more often than the lungs. Dr. Gupta speculated that Omicron evolved into an upper-airway specialist, thriving in the throat and nose. If that’s true, the virus might have a better chance of getting expelled in tiny drops into the surrounding air and encountering new hosts. “It’s all about what happens in the upper airway for it to transmit, right?” he said. “It’s not really what happens down below in the lungs, where the severe disease stuff happens. So you can understand why the virus has evolved in this way.” While these studies clearly help explain why Omicron causes milder disease, they don’t yet answer why the variant is so good at spreading from one person to another. The United States logged more than 580,000 cases on Thursday alone, the majority of which are thought to be Omicron. “These studies address the question about what may happen in the lungs but don’t really address the question of transmissibility,” said Sara Cherry, a virologist at the Perelman School of Medicine at the University of Pennsylvania. Dr. Diamond said he wanted to wait for more studies to be carried out, especially in people instead of animals, before endorsing the hypothesis that TMPRSS2 is the key to understanding Omicron. “I think it is still premature on this,” he said. Scientists know that part of Omicron’s contagiousness comes from its ability to evade antibodies, allowing it to easily get into cells of vaccinated people far more easily than other variants. But they suspect that Omicron has some other biological advantages as well. Last week, researchers reported that the variant carries a mutation that may weaken so-called innate immunity, a molecular alarm that rapidly activates our immune system at the first sign of an invasion in the nose. But it will take more experiments to see if this is indeed one of Omicron’s secrets to success. “It could be as simple as, this is a lot more virus in people’s saliva and nasal passages,” Dr. Cherry said. But there could be other explanations for its efficient spread: It could be more stable in the air, or better infect new hosts. “I think it’s really an important question,” she said.
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Juan Lama
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Human medical trials have begun on severely ill COVID-19 patients using low-doses of radiation. The first results on a very small group at Emory University Hospital were published this week and the results were quite extraordinary. Researchers at Emory University Hospital, led by Dr. Mohammad Khan, Associate Professor of Radiation Oncology, treated five COVID-19 patients with severe pneumonia who were requiring supplemental oxygen and whose health was visibly deteriorating. Their mean age was 90 with a range from 64 to 94, four were female, four were African-American, and one was Caucasian. These patients were given a single low-dose of radiation (1.5 Gy) to both lungs, delivered by a front and back beam configuration. Patients were in an out of the Radiotherapy Department in 10 to 15 minutes. Within 24 hours, four of the patients showed rapid improvement in oxygenation and mental status (more awake, alert and talkative) and were being discharged from the hospital 12 days later. Blood tests and repeated imaging of the lungs confirmed that the radiation was safe and effective, and did not cause adverse effects – no acute skin, pulmonary, gastrointestinal or genitourinary toxicities. The gray (Gy) is a dose unit of ionizing radiation defined as the absorption of one joule of radiation energy per kilogram of matter. The Gy replaces the older unit of the rad, and 1 Gy = 100 Rad. I should mention that medical doses are different than environmental doses as they are not whole body, but are targeted to a specific organ or tissue. So 1.5 Gy is quite low dose for medical uses. This treatment is critical because severe COVID-19 cases cause cytokine release syndrome, also known as a cytokine storm. Such a storm is a deadly uncontrolled systemic inflammatory response of the body’s immune system resulting from the release of great amounts of pro-inflammatory cytokines, which act as a major factor in producing acute respiratory distress syndrome, or ARDS, which is what kills.... Preprint of the origina, study available at medRxiv (June 8, 2020): https://www.medrxiv.org/content/10.1101/2020.06.03.20116988v1
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Juan Lama
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Exposure to the spike protein or receptor-binding domain (S-RBD) of SARS-CoV-2 significantly influences endothelial cells and induces pulmonary vascular endotheliopathy. In this study, angiotensin-converting enzyme 2 humanized inbred (hACE2 Tg) mice and cultured pulmonary vascular endothelial cells were used to investigate how spike protein/S-RBD impacts pulmonary vascular endothelium. Results show that S-RBD leads to acute-to-prolonged induction of the intracellular free calcium concentration ([Ca2+]i) via acute activation of TRPV4, and prolonged upregulation of mechanosensitive channel Piezo1 and store-operated calcium channel (SOCC) key component Orai1 in cultured human pulmonary arterial endothelial cells (PAECs). In mechanism, S-RBD interacts with ACE2 to induce formation of clusters involving Orai1, Piezo1 and TRPC1, facilitate the channel activation of Piezo1 and SOCC, and lead to elevated apoptosis. These effects are blocked by Kobophenol A, which inhibits the binding between S-RBD and ACE2, or intracellular calcium chelator, BAPTA-AM. Blockade of Piezo1 and SOCC by GsMTx4 effectively protects the S-RBD-induced pulmonary microvascular endothelial damage in hACE2 Tg mice via normalizing the elevated [Ca2+]i. Comparing to prototypic strain, Omicron variants (BA.5.2 and XBB) of S-RBD induces significantly less severe cell apoptosis. Transcriptomic analysis indicates that prototypic S-RBD confers more severe acute impacts than Delta or Lambda S-RBD. In summary, this study provides compelling evidence that S-RBD could induce persistent pulmonary vascular endothelial damage by binding to ACE2 and triggering [Ca2+]i through upregulation of Piezo1 and Orai1. Targeted inhibition of ACE2-Piezo1/SOCC-[Ca2+]i axis proves a powerful strategy to treat S-RBD-induced pulmonary vascular diseases. Published (Julay 14, 2023) in Sig Transduct Target Ther. : https://doi.org/10.1038/s41392-023-01556-8
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Juan Lama
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Some of the severe respiratory symptoms of COVID-19 seem to result from the activity of specific immune cells, which can cause long-term inflammation of the lungs. Alexander Misharin at Northwestern University in Evanston, Illinois, and his colleagues examined fluid from the lungs of 88 people with severe pneumonia caused by SARS-CoV-2 infection (R. A. Grant et al. Nature https://doi.org/fqds; 2021). Most of these individuals had high numbers of a certain type of T cell, a class of immune cells, in their lungs. The researchers also found that nearly 70% of alveolar macrophages, a type of immune cell that is located in the tiny air sacs of the lungs, contained SARS-CoV-2. The cells harbouring the virus showed relatively high expression of genes involved in inflammation. The findings suggest that, once the virus reaches the lungs, it can infect macrophages, which respond by producing inflammatory molecules that attract T cells. T cells, in turn, produce a protein that stimulates macrophages to make more inflammatory molecules. This persistent lung inflammation could lead to some of the life-threatening consequences of SARS-CoV-2 infection. Findings Published in Nature (Jan. 11, 2021): https://doi.org/10.1038/s41586-020-03148-w
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Juan Lama
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Antibiotics can leave the lung vulnerable to flu viruses, leading to significantly worse infections and symptoms, finds a new study in mice. The research discovered that signals from gut bacteria help to maintain a first line of defence in the lining of the lung. When mice with healthy gut bacteria were infected with the flu, around 80% of them survived. However, only a third survived if they were given antibiotics before being infected. "We found that antibiotics can wipe out early flu resistance, adding further evidence that they should not be taken or prescribed lightly," explains Dr Andreas Wack, who led the research at the Francis Crick Institute. "Inappropriate use not only promotes antibiotic resistance and kills helpful gut bacteria, but may also leave us more vulnerable to viruses. This could be relevant not only in humans but also livestock animals, as many farms around the world use antibiotics prophylactically. Further research in these environments is urgently needed to see whether this makes them more susceptible to viral infections." To test whether the protective effect was related to gut bacteria rather than local processes in the lung, the researchers treated mice with antibiotics and then repopulated their gut bacteria through faecal transplant. This restored interferon signalling and associated flu resistance, suggesting that gut bacteria play a crucial role in maintaining defences. These studies were published in Cell Reports: https://doi.org/10.1016/j.celrep.2019.05.105
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