Females far likelier to suffer with Long COVID

 A new study published today in the peer-reviewed journal Current Medical Research and Opinion, reveals that females are "significantly" more likely to suffer from Long COVID than males and will experience substantially different symptoms.

Long COVID is a syndrome in which complications persist more than four weeks after the initial infection of COVID-19, sometimes for many months.

Researchers from the Johnson & Johnson Office of the Chief Medical Officer Health of Women Team, who carried out the analysis of data from around 1.3 million patients, observed females with Long COVID are presenting with a variety of symptoms including ear, nose, and throat issues; mood, neurological, skin, gastrointestinal and rheumatological disorders; as well as fatigue.

Male patients, however, were more likely to experience endocrine disorders such as diabetes and kidney disorders.

"Knowledge about fundamental sex differences underpinning the clinical manifestations, disease progression, and health outcomes of COVID-19 is crucial for the identification and rational design of effective therapies and public health interventions that are inclusive of and sensitive to the potential differential treatment needs of both sexes," the authors explain.

"Differences in immune system function between females and males could be an important driver of sex differences in Long COVID syndrome. Females mount more rapid and robust innate and adaptive immune responses, which can protect them from initial infection and severity. However, this same difference can render females more vulnerable to prolonged autoimmune-related diseases."

As part of the review, researchers restricted their search of academic papers to those published between December 2019-August 2020 for COVID-19 and to January 2020-June 2021 for Long COVID syndrome. The total sample size spanning articles reviewed amounted to 1,393,355 unique individuals.

While the number of participants sounds large, only 35 of the 640,634 total articles in the literature provided sex disaggregated data in sufficient details about symptoms and sequalae of COVID-19 disease to understand how females and males experience the disease differently.

When looking at the early onset of COVID-19, findings show that female patients were far more likely to experience mood disorders such as depression, ear, nose, and throat symptoms, musculoskeletal pain, and respiratory symptoms. Male patients, on the other hand, were more likely to suffer from renal disorders -- those that affect the kidneys.

The authors note that this synthesis of the available literature is among the few to break down the specific health conditions that occur as a result of COVID-related illness by sex. Plenty of studies have examined sex differences in hospitalization, ICU admission, ventilation support, and mortality. But the research on the specific conditions that are caused by the virus, and its long-term damage to the body, have been understudied when it comes to sex.

"Sex differences in outcomes have been reported during previous coronavirus outbreaks," authors add. "Therefore, differences in outcomes between females and males infected with SARS-CoV-2 could have been anticipated. Unfortunately, most studies did not evaluate or report granular data by sex, which limited sex-specific clinical insights that may be impacting treatment." Ideally, sex disaggregated data should be made available even if it was not the researcher's primary objective, so other interested researchers can use the data to explore important differences between the sexes.

The paper also notes complicating factors worthy of additional study. Notably, women may be at greater risk of exposure to the virus in certain professions, such as nursing and education. Further, "there may be disparities in access to care based on gender that could affect the natural history of the disease, leading to more complications and sequela."

The latter serves as a rallying cry: availability of sex disaggregated data and intentional analysis is imperative if we are to ensure that disparate outcomes in disease course are addressed. No research is complete unless the data is made available to people who want to answer the question: does sex and gender matter?

Story Source:

Materials provided by Taylor & Francis Group. Note: Content may be edited for style and length.

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Journal Reference:

1. Shirley V. Sylvester, Rada Rusu, Biankha Chan, Martha Bellows, Carly O’Keefe, Susan Nicholson. Sex differences in sequelae from COVID-19 infection and in long COVID syndrome: a review. Current Medical Research and Opinion, 2022; 1 DOI: 10.1080/03007995.2022.2081454

https://www.sciencedaily.com/releases/2022/06/220621091420.htm

Where do COVID-19 variants come from?

 Patients with weakened immune system are at risk for chronic infection and develop highly mutated virus variants

 

•  New study finds that immunocompromised patients tend to develop chronic coronavirus infections, leading to highly mutated variants that bear multiple antibody-resistant mutations.

 

• The good news: While many different variants are formed in immunocompromised patients, these variants are at low risk for spreading onwards

 

A new Tel Aviv University study reveals that the many SARS-CoV-2 variants are likely formed in chronic COVID-19 patients who suffer from immunosuppression. The researchers suggest that a weakened antibody response, particular in the lower airways of these chronic patients, may prevent full recovery from the virus and drive the virus to mutate many times during a lengthy infection. In other words, the researchers explain that the virus’ ability to survive and reproduce in the immunosuppressed patient’s body without restriction leads to the evolution of many variants. Furthermore, the variants found among those chronically ill with COVID-19 bear many of the same mutations in their evolution as those present in variants-of-concern for severe illness, particularly those mutations associated with evading disease-killing antibodies. The new findings indicate that while rapidly-spreading variants are rare among the many strains borne from immunosuppressed patients, the likelihood increases and they do arise when global infection rates boom.

 

The study was led by Prof. Adi Stern and Ph.D. student Sheri Harari of the Shmunis School of Biomedicine and Cancer Research at the Wise Faculty of Life Sciences at Tel Aviv University, in collaboration with Dr. Yael Paran and Dr. Suzy Meijer of Tel Aviv Sourasky Medical Center (Ichilov). It was published in the prestigious journal  Nature Medicine.

 

Prof. Stern explains that since the outbreak of COVID-19, the rate at which the virus evolves has been somewhat puzzling. During the first year of the pandemic, a relatively slow but constant rate of mutations were observed. However, since the end of 2020, the world has witnessed the emergence of variants that are characterized by a large number of mutations, far exceeding the rate observed during the first year. Various scientific hypotheses about the link between chronic COVID-19 patients and the rate of the accumulation of mutations have surfaced, but nothing definitive has been proven yet. In this new study, Prof. Stern and team shed light on some pieces of this complex puzzle and try to answer the question of how variants are formed.

 

Prof. Stern explains: “The coronavirus is characterized by the fact that in every population, there are people who become chronically infected. In the case of these patients, the virus remains in their body for a lengthy period of time, and they are at high risk for recurrent infection. In all of the cases observed so far, these were immunocompromised patients – part of their immune system is damaged and unable to function. In biological evolutionary terms, these patients constitute an ‘incubator’ for viruses and mutations – the virus persists in their body for a long time and succeeds in adapting to the immune system, by accumulating various mutations.”

 

The study involved an examination of chronic COVID-19 patients at the Tel Aviv Sourasky Medical Center (“Ichilov Hospital”). According to Prof. Stern, the results reveal a complex picture; on the one hand, no direct connection was found between anti-COVID-19 drug treatment and the development of variants. On the other hand, the research discovered that it is likely the  weakened immune system of immunocompromised patients that creates pressure for the virus to mutate. In fact, the researchers found that there were chronic patients who showed a pattern of apparent recovery, followed by recurring viral infection. In all of these patients, a mutated form of the virus emerged, suggesting that recovery had not been achieved; this is partially reminiscent of the modus operandi of HIV following inadequate drug treatment.

 

Upon closer examination of some patients, the researchers found that when such a pattern of apparent recovery is observed (based on negative nasopharyngeal swabs), the virus continues to thrive in the lungs of the patients. The researchers therefore suggest that the virus accumulates mutations in the lungs, and then traverses back to the upper respiratory tract.

 

Prof. Stern concludes: “The complexity of coronavirus evolution is still being revealed, and this poses many challenges to the scientific community. I believe that our research has succeeded in peeling back a missing layer of the big picture, and has opened the door for further research efforts to discover the origins of the various variants. This study highlights the importance of protecting immunocompromised individuals, who are at high risk for the virus, yet may also be an incubator for the formation of the next variant, posing a risk to all of us.”

 

Link to the article:

https://www.nature.com/articles/s41591-022-01882-4

 

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JOURNAL

Nature Medicine

DOI

10.1038/s41591-022-01882-4 

ARTICLE TITLE

Drivers of adaptive evolution during chronic SARS-CoV-2 infections

ARTICLE PUBLICATION DATE

20-Jun-2022

https://www.eurekalert.org/news-releases/956584

Erectile dysfunction drugs could help in the treatment of esophageal cancer

 A group of drugs commonly used to treat erectile dysfunction may be able to boost the effect of chemotherapy in oesophageal cancer, according to new research funded by Cancer Research UK and the Medical Research Council.

This research, published today (Tuesday) in Cell Reports Medicine, found that the drugs, known as PDE5 inhibitors can reverse chemotherapy resistance by targeting cells called cancer-associated fibroblasts (CAFs) residing in the area surrounding the tumour.

Although this is early discovery research, PDE5 inhibitors combined with chemotherapy may be able to shrink some oesophageal tumours more than chemotherapy could alone, tackling chemotherapy resistance, which is one of the major challenges in treating oesophageal cancer. 

Oesophageal cancer affects the food pipe that connects your mouth to your stomach, and while it is a relatively rare cancer, the UK has one of the higher rates in the world, with 9,300* new oesophageal cancer cases in the UK every year**. 

Currently this disease has much poorer outcomes*** and treatment options compared to other cancers, with around just 1 in 10 patients surviving their disease for 10 years or more. Part of the reason for this is that, in many cases, it can be resistant to chemotherapy, with around 80% of people not responding****.

Resistance to chemotherapy in oesophageal cancer is influenced by the tumour microenvironment, the area that sounds the tumour. This is made up of molecules, blood vessels, and cells such as cancer associated fibroblasts (CAFs), which are important for tumour growth. It feeds the tumour and can act as a protective cloak, preventing treatments like chemotherapy from having an effect. 

The team of researchers led by Professor Tim Underwood at the University of Southampton wanted to identify the cells in the tumour microenvironment which protects the tumour from treatment so they could target them.

The researchers found that levels of PDE5, an enzyme originally found in the wall of blood vessels are higher in oesophageal adenocarcinoma compared with healthy oesophageal tissue. High levels of PDE5 were found in CAFs within the tumour microenvironment. They also found that high expression of PDE5 is associated with worse overall survival, suggesting that PDE5 would be an effective target for treatment.

Following this, the researchers tested a PDE5 inhibitor*****, PDE5i, on CAFs from oesophageal tumours. They found that PDE5i were able to suppress CAF activity and make them look more like normal fibroblasts. 

Next, collaborating researchers at the University of Nottingham took samples of tumour cells from 15 tissue biopsies from eight patients, and used them to create lab-grown artificial tumours. They tested a combination of PDE5i and standard chemotherapy on the tumours. Of the 12 samples from patients whose tumours developed a poor response to chemotherapy in the clinic, 9 were made sensitive to standard chemotherapy by targeting CAFs with PDE5i.

The researchers also tested the treatment on mice implanted with chemotherapy resistant oesophageal tumours and found that there were no adverse side effects to the treatment, and that chemotherapy combined with PDE5i shrunk the tumours more than chemotherapy alone. 

An added benefit of using PDE5 inhibitors is that they are already proven to be a safe and well tolerated class of drug that’s given to patients world-wide, even in the high doses that would be required for this treatment. The researchers also say that giving PDE5 inhibitors to people with oesophageal cancer would be extremely unlikely to cause erections without the appropriate stimulation.

Professor Tim Underwood, lead author of the study and a professor of gastrointestinal surgery at the University of Southampton, said, “The chemotherapy resistant properties of oesophageal tumours mean that many patients undergo intensive chemotherapy that won’t work for them. Finding a drug, which is already safely prescribed to people every day, could be a great step forward in tackling this hard-to-treat disease.”

With the proven safety of these drugs and the positive results from this research, the researchers next step is a phase I/II clinical trial testing a PDE5 inhibitor in combination with chemotherapy in patients with advanced oesophageal cancer. 

If successful, this treatment could be helping a significant proportion of the around 9300 people a year diagnosed with oesophageal cancer within the next 5 to 10 years. The study could pave the way for the use of PDE5 inhibitors in other cancer types.

Michelle Mitchell, chief executive of Cancer Research UK, said: "Developing new drugs for cancer is incredibly important, but doing so from scratch is a challenging process, and many fail along the way. We’ve also been keen to explore whether existing drugs, licensed for other diseases, can be effective in treating cancer. If these turn out to be successful treatments, they will also prove to be more affordable and become available to patients quicker.

"Progress in treatment for oesophageal cancer over the last 40 years has seen only limited improvement, which is why we’ve made it a research priority. We’re looking forward to seeing how the combined treatment of PDE5 inhibitors with chemotherapy performs in clinical trials.”

Nicola Packer, an HR manager from Basingstoke, was diagnosed with oesophageal cancer at age 53. She was being monitored due to her diagnosis of a condition called Barrett’s oesophagus, which can be a risk factor for oesophageal cancer “They found my tumour last February. They caught it at stage 2, which is unusual for oesophageal tumours as they often go undetected for a long time and are mostly diagnosed at stage 3 or 4.”

“Chemo generally doesn’t work that well on my kind of oesophageal tumour so I knew it couldn’t get rid of the tumour completely, that it could only shrink it with the hopes of making surgery more effective. The chemo was draining and each week they would tell me it was shrinking my tumour, but slowly. The anxiety you feel after going through chemotherapy and then having to wait through the weeks of recovery before you can have surgery, knowing that the chemo could only do so much is overwhelming.” 

“Research like this that could mean people like me can have a better response to chemotherapy is incredibly important.”

ENDS

JOURNAL

Cell Reports Medicine

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Cells

ARTICLE TITLE

Modulation of the tumor promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

ARTICLE PUBLICATION DATE

21-Jun-2022

https://www.eurekalert.org/news-releases/956599

How tumors make immune cells ‘go bad’

 Investigators from Cedars-Sinai Cancer have discovered that cancerous tumors called soft-tissue sarcomas produce a protein that switches immune cells from tumor-attacking to tumor-promoting. The study, published today in the peer-reviewed journal Cell Reports, could lead to improved treatments for soft-tissue sarcomas.

The researchers focused on the tumor microenvironment—an ecosystem of blood vessels and other cells recruited by tumors to supply them with nutrients and help them survive.

“Tumors also recruit immune cells,” said Jlenia Guarnerio, PhD, a research scientist with Cedars-Sinai Cancer, assistant professor of Radiation Oncology and Biomedical Sciences and senior author of the study. “These immune cells should be able to recognize and attack the tumor cells, but we found that the tumor cells secrete a protein that changes their biology, so instead of killing tumor cells they actually do the opposite.”

Soft-tissue sarcoma is a rare type of cancer that forms in the muscle, fat, blood vessels, nerves, tendons and joint lining. It most commonly occurs in the arms, legs and abdomen, and kills more than 5,000 people in the U.S. each year, according to the American Cancer Society.

In comparing samples of a variety of soft-tissue sarcomas in humans and laboratory mice, Guarnerio and her team noted that most of these tumors have an abundance of immune cells called myeloid cells in their microenvironment.

“It was striking that such a large percentage of the immune cells were myeloid cells, and we thought that since they obviously weren’t killing the tumor cells, they must be doing something to promote tumor growth,” said Stephen Shiao, MD, PhD, division director of the Division of Radiation Biology, co-leader of the Translational Oncology Program and a co-author of the study. “And indeed, our analysis of tumor samples showed that many of the myeloid cells had adopted a tumor-promoting function.”

To find out what was causing this change, investigators examined the proteins secreted by the tumor cells and the receptors on the surface of the myeloid cells—the elements cells use to communicate. “We examined the cross-talk between these two populations of cells,” Guarnerio said. “We found that the tumor cells expressed high levels of a protein called macrophage migration inhibitory factor [MIF], and that the myeloid cells had receptors to sense the MIF proteins. This makes them switch their biology and promote, rather than block, tumor growth.”

When the investigators generated tumors from cancer cells that didn’t express MIF, myeloid cells were able to penetrate the tumors and tumor growth was reduced.

“This means the myeloid cells might have attacked the tumors directly, or might have activated other immune cells, for example T cells, to attack the tumors,” Guarnerio said.

The investigators believe this information could be used to create novel therapies against soft-tissue sarcoma. A medication designed to stop cancer cells from expressing MIF could be tested in combination with existing therapies, for example, to see if it improves outcomes for patients.

“Recurrent and aggressive soft-tissue sarcoma has proved resistant to our existing therapies,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer. “Yet interventions aimed at targeting components of the tumor microenvironment, which have shown promise against many solid tumors, have been only marginally tested in soft-tissue sarcoma. This work may pave the way for much more effective interventions.”

Guarnerio plans to pursue these investigations, and to begin addressing many additional unanswered questions about soft-tissue sarcoma.

“The majority of studies in cancer biology and immunotherapy have been done on carcinoma, the most common type of cancer,” Guarnerio said. “Much work has been done to describe which types of immune cells infiltrate these tumors and how carcinoma cells interact with immune cells, but there is almost no research on sarcomas. We need to continue our investigation so that we understand the roles of many other cells—T cells and B cells, for example—and how all the players work together.”

The research was funded by National Institutes of Health grant numbers K99/R00, CA212200 and R01 CA258265; The Sarcoma Foundation of America grant number 2019 SFA 15-19; and by Cedars-Sinai Cancer.

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JOURNAL

Cell Reports

DOI

10.1016/j.celrep.2022.110977 

https://www.eurekalert.org/news-releases/956609

Plant virus plus immune cell-activating antibody clear colon cancer in mice

 A new combination therapy to combat cancer could one day consist of a plant virus and an antibody that activates the immune system’s “natural killer” cells, shows a study by researchers at the University of California San Diego.

In mouse models of colon cancer, the combination therapy eliminated all tumors and prevented their recurrence, which in turn resulted in 100% survival. The therapy also increased survival in mouse models of melanoma.

The work is reported in a paper published June 17 in Nano Letters.

The proof-of-concept therapy enhances the activity of cancer killing immune cells known as natural killer cells, which naturally reside in the body and in tumors. The job of natural killer cells is to target and destroy cancer cells—in doing so, they release molecules called antigens that the immune system can recognize and produce antibodies against.

The problem is that there are not enough natural killer cells in or near cancerous tumors to be effective. And those that are in the tumors cannot do their job because cancer cells can secrete molecules that bind to natural killer cells and suppress them.

The therapy overcomes these problems using two key ingredients: cowpea mosaic virus, which is a plant virus that infects legumes but is harmless to animals and humans, and an antibody called anti-4-1BB. Cowpea mosaic virus has a special ability to attract natural killer cells to the tumor microenvironment, while anti-4-1BB binds to receptors on these cells to snap them out of their immunosuppressed state. By joining forces, the plant virus and antibody not only draw a large enough crowd of natural killer cells to the tumors, but also fire them up for attack.

“With a combination therapy, we significantly improve cancer response,” said study senior author Nicole Steinmetz, professor of nanoengineering and director of the Center for NanoImmunoEngineering at the UC San Diego Jacobs School of Engineering. “Cancers work by manipulating the body through multiple pathways. When we hit on multiple pathways by combining different therapeutic agents (cowpea mosaic virus and anti-4-1BB), we get better results.”

“Nowadays, cancer is not treated with just one medication—it requires a multi-pronged approach. Our work takes advantage of different strategies to activate the innate immune system and destroy tumors. This can then initiate an adaptive immune response to help prevent tumor recurrence,” said first author Edward (Ted) Koellhoffer, a resident physician in radiology at UC San Diego Health who is a clinician-scientist in Steinmetz’s lab.

The researchers first tested their combination therapy on mouse models of colon cancer. The treatment regimen consisted of one weekly injection of cowpea mosaic virus and two weekly injections of anti-4-1BB. The injections were administered into the abdominal cavities of the mice for three weeks. All mice that were given the combination therapy experienced complete tumor elimination and survived for at least 90 days. When these mice were later rechallenged with colon cancer, any new tumors were also eliminated, and the mice all survived. The researchers also tested cowpea mosaic virus as a solo therapy and while it exhibited potency, the combination therapy demonstrated synergy and outperformed any controls.

“What’s remarkable is that the treated mice gain an immunological memory, meaning that their immune systems remember the tumor cells and can attack them on their own when the cancer reappears,” said Koellhoffer.

The researchers tested the same treatment regimen on mouse models of melanoma. Again, the combination therapy reduced tumor growth and protected the surviving mice from recurrence of the disease when rechallenged with melanoma.

“While the combination therapy was most impressive in the colon cancer model, improvement was also seen in the melanoma model,” said Steinmetz. “Based on the data, more research is needed to understand whether this therapy is effective against a broad range of cancers, or whether the real potential is for intraperitoneal disseminated disease.”

Steinmetz’s team plans to explore that further. The researchers hope that their combination therapy will lay the groundwork for an in situ cancer vaccine.

Paper: “Cowpea mosaic virus and Natural Killer Cell Agonism for In Situ Cancer Vaccination.”

This work was supported by the National Institutes of Health (R01 CA224605, R01 CA253615, U01 CA218292 and T32EB005970) and the Shaughnessy Family Fund for Nano-ImmunoEngineering at UC San Diego.

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JOURNAL

Nano Letters

DOI

10.1021/acs.nanolett.2c01328 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

Cowpea mosaic virus and natural killer cell agonism for in situ cancer vaccination

ARTICLE PUBLICATION DATE

17-Jun-2022

https://www.eurekalert.org/news-releases/956669

Some Omicron sub-variants escaping antibodies from Sinopharm shot -Chinese study

 

A small Chinese study detailed in The Lancet Infectious Diseases journal showed neutralising antibodies against some Omicron sub-variants were largely undetectable after two doses of a Sinopharm COVID-19 vaccine, with a booster shot only partly restoring them.

The study comes as China, which has approved only locally developed COVID shots including the Sinopharm vaccine, strives to improve vaccination rates, maintaining a "dynamic zero COVID" policy aimed at eradicate all outbreaks while many countries have adopted an approach of learning to live with the virus.

The vaccine, BBIBP-CorV, is one of the two Sinopharm COVID shots approved for use in China, and is also the main shot that the state-owned firm has exported.

Among 25 individuals who received two doses of BBIBP-CorV vaccine, the neutralising activity against sub-variants such as BA.2.12.1 and BA.4/BA.5 "was not or only minimally detectable", researchers said in correspondence published on Monday.

Neutralising activity against those sub-variants was observed in just 24-48% of subjects who received a BBIBP-CorV booster shot after the two-dose product, researchers said, citing results from a group of 25 participants.

The rate improved slightly, to 30-53%, for those who received a third shot made by a unit of Chongqing Zhifei Biological Products, another vaccine approved for use in China, according to data from another group of 30 subjects.

The study did not discuss the boosters' efficacy, a rate that reflects how well they could lower the risk of COVID disease or death, which is usually observed in large clinical trials.

https://www.marketscreener.com/quote/stock/CHONGQING-ZHIFEI-BIOLOGIC-9061134/news/Some-Omicron-sub-variants-escaping-antibodies-from-Sinopharm-shot-Chinese-study-40771067/

Xenon Pharmaceuticals Shares Rise After Positive FDA Meeting

 Xenon Pharmaceuticals Inc. shares were up 9% to $33.10 Tuesday after the biopharmaceutical company said it plans to continue its clinical program evaluating XEN1101 for the treatment of patients with focal onset seizures following the completion of an end-of-Phase 2 meeting with the Food and Drug Administration.

The outcome of the meeting supports the advancement of XEN1101 into Phase 3 clinical development, which Xenon plans to initiate in the second half of 2022, the company said.

Xenon said it plans to begin the Phase 3 program to support a new drug application for XEN1101.

The company plans to submit the application when the first XEN1101 Phase 3 study is completed, if the clinical trial is successful.

https://www.marketscreener.com/quote/stock/XENON-PHARMACEUTICALS-INC-18411162/news/Xenon-Pharmaceuticals-Shares-Rise-9-After-Positive-FDA-Meeting-40779128/