̽��ֱ�� of Cambridge - Andrew Conway Morris

Underactive immune response may explain obesity link to COVID-19 severity

cjb250 — Mon, 20 Mar 2023 12:00:14 +0000

Scientists at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) and Wellcome Sanger Institute showed that following SARS-CoV-2 infection, cells in the lining of the lungs, nasal cells, and immune cells in the blood show a blunted inflammatory response in obese patients, producing suboptimal levels of molecules needed to fight the infection.

Since the start of the pandemic, there have been almost 760 million confirmed cases of SARS-CoV-2 infection, with almost 6.9 million deaths. While some people have very mild – or even no – symptoms, others have much more severe symptoms, including acute respiratory distress syndrome requiring ventilator support.

One of the major risk factors for severe COVID-19 is obesity, which is defined as a body mass index (BMI) of over 30. More than 40% of US adults and 28% of adults in England are classed as obese.

While this link has been shown in numerous epidemiological studies, until now, it has not been clear why obesity should increase an individual’s risk of severe COVID-19. One possible explanation was thought to be that obesity is linked to inflammation: studies have shown that people who are obese already have higher levels of key molecules associated with inflammation in their blood. Could an overactive inflammatory response explain the connection?

Professor Menna Clatworthy is a clinician scientist at the ̽��ֱ�� of Cambridge, studying tissue immune cells at CITIID alongside caring for patients at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust. She said: “During the pandemic, the majority of younger patients I saw on the COVID wards were obese. Given what we know about obesity, if you’d asked me why this was the case, I would have said that it was most likely due to excessive inflammation. What we found was the absolute opposite.”

Clatworthy and her team analysed blood and lung samples taken from 13 obese patients with severe COVID-19 requiring mechanical ventilation and intensive care treatment, and 20 controls (non-obese COVID-19 patients and ventilated non-COVID-19 patients). These included patients admitted to the Intensive Care Unit at Addenbrooke’s Hospital.

Her team used a technique known as transcriptomics, which looks at RNA molecules produced by our DNA, to study activity of cells in these key tissues. Their results are published in the American Journal of Respiratory and Critical Care Medicine.

Contrary to expectations, the researchers found that the obese patients had underactive immune and inflammatory responses in their lungs. In particular, when compared to non-obese patients, cells in the lining of their lungs and some of their immune cells had lower levels of activity among genes responsible for the production of two molecules known as interferons (INF) – interferon-alpha and interferon-gamma – which help control the response of the immune system, and of tumour necrosis factor (TNF), which causes inflammation.

When they looked at immune cells in the blood of 42 adults from an independent cohort, they found a similar, but less marked, reduction in the activity of interferon-producing genes as well as lower levels of IFN-alpha in the blood.

Professor Clatworthy said: “This was really surprising and unexpected. Across every cell type we looked at, we found that that the genes responsible for the classical antiviral response were less active. They were completely muted.”

̽��ֱ��team was able to replicate its findings in nasal immune cells taken from obese children with COVID-19, where they again found lower levels of activity among the genes that produce IFN-alpha and IFN-gamma. This is important because the nose is one of the entry points for the virus – a robust immune response there could prevent the infection spreading further into the body, while a poorer response would be less effective.

One possible explanation for the finding involves leptin, a hormone produced in fat cells that controls appetite. Leptin also plays a role in the immune response: in individuals who are normal weight, levels of the hormone increase in response to infection and it directly stimulates immune cells. But obese people already have chronically higher levels of leptin, and Clatworthy says it is possible that they no longer produce sufficient additional leptin in response to infection, or are insensitive to it, leading to inadequate stimulation of their immune cells.

̽��ֱ��findings could have important implications both for the treatment of COVID-19 and in the design of clinical trials to test new treatments.

Because an overactive immune and inflammatory response can be associated with severe COVID-19 in some patients, doctors have turned to anti-inflammatory drugs to dampen this response. But anti-inflammatory drugs may not be appropriate for obese patients.

Co-author Dr Andrew Conway Morris from the Department of Medicine at the ̽��ֱ�� of Cambridge and Honorary Consultant on the intensive care unit at Addenbrooke’s Hospital said: “What we’ve shown is that not all patients are the same, so we might need to tailor treatments. Obese subjects might need less anti-inflammatory treatments and potentially more help for their immune system.”

Clinical trials for potential new treatments would need to involve stratifying patients rather than including both severe and normal weight patients, whose immune responses differ.

̽��ֱ��research was largely supported by Wellcome, the Medical Research Council and the National Institute of Health and Care Research, including via the NIHR Cambridge Biomedical Research Centre.

Reference
Guo, SA, Bowyer, GS, Ferdinand, JR, Maes, M & Tuong, ZK et al. Obesity associated with attenuated tissue immune cell responses in COVID-19. Am J Resp Critical Care Med; 1 Mar 2023; DOI: 10.1164/rccm.202204-0751OC

Individuals who are obese may be more susceptible to severe COVID-19 because of a poorer inflammatory immune response, say Cambridge scientists.

During the pandemic, the majority of younger patients I saw on the COVID wards were obese... I would have said that it was most likely due to excessive inflammation. What we found was the absolute opposite

Menna Clatworthy

Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust

Intensive care unit at Addenbrooke's Hospital

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Air filter significantly reduces presence of airborne SARS-CoV-2 in COVID-19 wards

cjb250 — Tue, 16 Nov 2021 08:36:58 +0000

While the discovery could have implications for improving the safety of repurposed ‘surge wards’, the researchers say it also opens up the possibility of being able to set standards for cleaner air to reduce the risk of airborne transmission of infections.

Over the duration of the pandemic there has been a steady rise in the evidence that the SARS-CoV-2 virus can be transmitted through the air in small droplets (aerosols). But as hospitals have seen their capacity overwhelmed, they have been forced to manage many of their COVID-19 patients in repurposed ‘surge’ wards, which often lack the ability to change the air with a high frequency. While the use of appropriate personal protective equipment (PPE) protects staff and patients significantly reduces the risk of transmission, there are still reports of patient-to-healthcare worker transmission of the virus, potentially through the inhalation of viral particles.

A team at the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals (CUH) NHS Foundation Trust investigated whether portable air filtration/UV sterilisation devices could reduce airborne SARS- CoV-2 in general wards that had been repurposed as a COVID ward and a COVID Intensive Care Unit (ICU). ̽��ֱ��results are published in Clinical Infectious Diseases.

Dr Vilas Navapurkar, a Consultant in Intensive Care Medicine at CUH, who led the study, said: “Reducing airborne transmission of the coronavirus is extremely important for the safety of both patients and staff. Effective PPE has made a huge difference, but anything we can do to reduce the risk further is important.”

“Because of the numbers of patients being admitted with COVID-19, hospitals have had to use wards not designed for managing respiratory infections. During an intensely busy time, we were able to pull together a team from across the hospital and ̽��ֱ�� to test whether portable air filtration devices, which are relatively inexpensive, might remove airborne SARS-CoV-2 and make these wards safer.”

̽��ֱ��team performed their study in two repurposed COVID-19 units in Addenbrooke’s Hospital. One area was a surge ward managing patients who required simple oxygen treatment or no respiratory support; the second was a surge ICU managing patients who required ventilation either through non-invasive mask ventilation or invasive respiratory support, such as involving the use of an invasive tube and tracheostomy.

̽��ֱ��team installed a High Efficiency Particulate Air (HEPA) air filter/UV steriliser. HEPA filters are made up of thousands of fibres knitted together to form a material that filters out particles above a certain size. ̽��ֱ��machines were placed in fixed positions and operated continuously for seven days, filtering the full volume of air in each room between five and ten times per hour.

In the surge ward, during the first week prior to the air filter being activated, the researchers were able to detect SARS-CoV-2 on all sampling days. Once the air filter was switched on and run continuously, the team were unable to detect SARS-CoV-2 on any of the five testing days. They then switched off the machine and repeated the sampling – once again, they were able to detect SARS-CoV-2 on three of the five sampling days.

On the ICU, the team found limited evidence of airborne SARS-CoV-2 in the weeks when the machine was switched off and traces of the virus on one sampling day when the machine was active.

Additionally, the air filters significantly reduced levels of bacterial, fungal and other viral bioaerosols on the both the surge ward and the ICU, highlighting an added benefit of the system.

First author Dr Andrew Conway Morris, from the Department of Medicine at the ̽��ֱ�� of Cambridge, said: “We were really surprised by quite how effect air filters were at removing airborne SARS-CoV-2 on the wards. Although it was only a small study, it highlights their potential to improve the safety of wards, particularly in areas not designed for managing highly infectious diseases such as COVID-19.”

Crucially, the research team developed a robust technique for assessing the quality of air, involving placing air samplers at various points in the room and then testing the samples using PCR assays similar those used in the ‘gold standard’ COVID-19 tests.

Professor Stephen Baker, from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the ̽��ֱ�� of Cambridge, said: “Cleaner air will reduce the risk of airborne disease transmission, but it’s unlikely to be the case that just installing an air filter will be enough to guarantee the air is clean enough. Every room and every situation will be different. A key part of our work has been developing a robust way of measuring air quality.”

Dr Navapurkar added: “We’re all familiar with the idea of having standards for clean water and of hygiene standards for food. We need now to agree standards for what is acceptable air quality and how we meet and monitor those standards.”

̽��ֱ��research was supported by Wellcome, the Medical Research Council and the National Institute for Health Research Cambridge Biomedical Research Centre.

Reference
Conway Morris, A, et al. ̽��ֱ��removal of airborne SARS-CoV-2 and other microbial bioaerosols by air filtration on COVID-19 surge units. Clin Inf Dis; 30 Oct 2021; DOI: 10.1093/cid/ciab933

Image: Dr Vilas Navapurkar in ICU beside an air filter

When a team of doctors, scientists and engineers at Addenbrooke’s Hospital and the ̽��ֱ�� of Cambridge placed an air filtration machine in COVID-19 wards, they found that it removed almost all traces of airborne SARS-CoV-2.

Reducing airborne transmission of the coronavirus is extremely important for the safety of both patients and staff

Vilas Navapurkar

Medi2Go

Coronavirus

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DNA test can quickly identify pneumonia in patients with severe COVID-19, aiding faster treatment

sc604 — Fri, 15 Jan 2021 06:00:00 +0000

For patients with the most severe forms of COVID-19, mechanical ventilation is often the only way to keep them alive, as doctors use anti-inflammatory therapies to treat their inflamed lungs. However, these patients are susceptible to further infections from bacteria and fungi that they may acquire while in hospital – so called ‘ventilator-associated pneumonia’.

Now, a team of scientists and doctors at the ̽��ֱ�� of Cambridge and Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, led by Professor Gordon Dougan, Dr Vilas Navapurkar and Dr Andrew Conway Morris, have developed a simple DNA test to quickly identify these infections and target antibiotic treatment as needed.

̽��ֱ��test, developed at Addenbrooke’s hospital in collaboration with Public Health England, gives doctors the information they need to start treatment within hours rather than days, fine-tuning treatment as required and reducing the inappropriate use of antibiotics. This approach, based on higher throughput DNA testing, is being rolled out at Cambridge ̽��ֱ�� Hospitals and offers a route towards better treatments for infection more generally. ̽��ֱ��results are reported in the journal Critical Care.

Patients who need mechanical ventilation are at significant risk of developing secondary pneumonia while they are in intensive care. These infections are often caused by antibiotic-resistant bacteria, and are hard to diagnose and need targeted treatment.

“Early on in the pandemic we noticed that COVID-19 patients appeared to be particularly at risk of developing secondary pneumonia, and started using a rapid diagnostic test that we had developed for just such a situation,” said co-author Dr Andrew Conway Morris from Cambridge’s Department of Medicine and an intensive care consultant. “Using this test, we found that patients with COVID-19 were twice as likely to develop secondary pneumonia as other patients in the same intensive care unit.”

COVID-19 patients are thought to be at increased risk of infection for several reasons. Due to the amount of lung damage, these severe COVID-19 cases tend to spend more time on a ventilator than patients without COVID-19. In addition, many of these patients also have a poorly-regulated immune system, where the immune cells damage the organs, but also have impaired anti-microbial functions, increasing the risk of infection.

Normally, confirming a pneumonia diagnosis is challenging, as bacterial samples from patients need to be cultured and grown in a lab, which is time-consuming. ̽��ֱ��Cambridge test takes an alternative approach by detecting the DNA of different pathogens, which allows for faster and more accurate testing.

̽��ֱ��test uses multiple polymerase chain reaction (PCR) which detects the DNA of the bacteria and can be done in around four hours, meaning there is no need to wait for the bacteria to grow. “Often, patients have already started to receive antobiotics before the bacteria have had time to grow in the lab,” said Morris. “This means that results from cultures are often negative, whereas PCR doesn’t need viable bacteria to detect – making this a more accurate test.”

̽��ֱ��test – which was developed with Dr Martin Curran, a specialist in PCR diagnostics from Public Health England’s Cambridge laboratory – runs multiple PCR reactions in parallel, and can simultaneously pick up 52 different pathogens, which often infect the lungs of patients in intensive care. At the same time, it can also test for antibiotic resistance.

“We found that although patients with COVID-19 were more likely to develop secondary pneumonia, the bacteria that caused these infections were similar to those in ICU patients without COVID-19,” said lead author Mailis Maes, also from the Department of Medicine. “This means that standard antibiotic protocols can be applied to COVID-19 patients.”

This is one of the first times that this technology has been used in routine clinical practice and has now been approved by the hospital. ̽��ֱ��researchers anticipate that similar approaches would benefit patients if used more broadly.

This study was funded by the National Institute for Health Research Cambridge Biomedical Research Centre.

Reference:
Mailis Maes et al. ‘Ventilator-associated pneumonia in critically ill patients with COVID-19.’ Critical Care (2021). DOI: 10.1186/s13054-021-03460-5

Researchers have developed a DNA test to quickly identify secondary infections in COVID-19 patients, who have double the risk of developing pneumonia while on ventilation than non-COVID-19 patients.

Using this test, we found that patients with COVID-19 were twice as likely to develop secondary pneumonia as other patients in the same intensive care unit

Andrew Conway Morris

Official U.S. Navy Page

Lt. Cmdr. Michael Heimes checks on a patient connected to a ventilator at Baton Rouge General Mid City campus

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Test can identify patients in intensive care at greatest risk of life-threatening infections

cjb250 — Wed, 13 Jun 2018 09:37:58 +0000

Infections in intensive care units (ICU) tend to be caused by organisms, such as multi-resistant gram-negative bacteria found in the gut, that are resistant to frontline antibiotics. Treating such infections means relying on broad spectrum antibiotics, which run the risk of breeding further drug-resistance, or antibiotics that have toxic side-effects.

Estimates of the proportion of patients in ICU who will develop a secondary infection range from one in three to one in two; around a half of these will be pneumonia. However, some people are more susceptible than others to such infections – evidence suggests that the key may lie in malfunction of the immune system.

In a study published in the journal Intensive Care Medicine, a team of researchers working across four sites in Edinburgh, Sunderland and London, has identified markers on three immune cells that correlate with an increased risk of secondary infection. ̽��ֱ��team was led by researchers at the Universities of Cambridge and Edinburgh and biotech company BD Bioscience.

“These markers help us create a ‘risk profile’ for an individual,” explains Dr Andrew Conway Morris from the Department of Medicine at the ̽��ֱ�� of Cambridge. “This tells us who is at greatest risk of developing a secondary infection.

“In the long term, this will help us target therapies at those most at risk, but it will be immediately useful in helping identify individuals to take part in clinical trials of new treatments.”

Clinical trials for interventions to prevent secondary infections have met with mixed success, in part because it has been difficult to identify and recruit those patients who are most susceptible, say the researchers. Using this new test should help fine tune the selection of clinical trial participants and improve the trials’ chances of success.

̽��ֱ��markers identified are found on the surface of key immune cells: neutrophils (frontline immune cells that attack invading pathogens), T-cells (part of our adaptive immune system that seek and destroy previously-encountered pathogens), and monocytes (a type of white blood cell).

̽��ֱ��researchers tested the correlation of the presence of these markers with susceptibility to a number of bacterial and fungal infections. An individual who tests positive for all three markers would be at two to three times greater risk of secondary infection compared with someone who tests negative for the markers.

̽��ֱ��markers do not indicate which secondary infection an individual might get, but rather that they are more susceptible in general.

“As intensive care specialists, our priority is to prevent patients developing secondary infections and, if they do, to ensure they get the best treatment,” says Professor Tim Walsh from the ̽��ֱ�� of Edinburgh, senior author on the study.

̽��ֱ��Immune Failure in Critical Therapy (INFECT) Study examined data from 138 individuals in ICUs and replicated findings from a pilot study in 2013.

A key part of enabling this study was to standardise how the research could be carried out across multiple sites, say the researchers. They used an imaging technique known as flow cytometry, which involves labelling components of the cells with fluorescent markers and then shining a laser on them such that they give off light at different wavelengths. This has previously been difficult to standardise, but the researchers successfully developed a protocol for use, ensuring they could recruit patients from the four study sites.

̽��ֱ��study was funded by Innovate UK, BD Bioscience and the National Institute of Academic Anaesthesia.

Reference
Conway Morris, A et al. Cell surface signatures of immune dysfunction risk stratify critically ill patients: INFECT Study. Intensive Care Medicine; June 2018; DOI: 10.1007/s00134-018-5247-0

Patients in intensive care units are at significant risk of potentially life-threatening secondary infections, including from antibiotic-resistant bacteria such as MRSA and C. difficile. Now, a new test could identify those at greatest risk – and speed up the development of new therapies to help at-risk patients.

In the long term, this will help us target therapies at those most at risk, but it will be immediately useful in helping identify individuals to take part in clinical trials of new treatments

Andrew Conway Morris

MilitaryHealth

Intensive Care Unit

Researcher Profile: Dr Andrew Conway Morris

Dr Andrew Conway Morris is an intensive care specialist at Addenbrooke’s Hospital, part of Cambridge ̽��ֱ�� Hospitals. It was the hospital’s location on the Cambridge Biomedical Campus that attracted him back to the city where he had been born and raised.

“I moved to Cambridge in order to take advantage of the fantastic opportunities to work with some of the world’s leading scientists, as well as develop collaborations with the growing biotech and pharmaceutical cluster centred around Addenbrooke’s Hospital,” he says.

Conway Morris undertook his undergraduate medical education in Glasgow before moving to Edinburgh to train in Anaesthesia and Intensive Care Medicine. His PhD in Edinburgh was on dysfunction of immune cells known as neutrophils in critically ill patients and looking at the development of new diagnostic tests for secondary pneumonia.

He is now a Wellcome-funded Senior Research Associate in the John Farman Intensive Care Unit at Addenbrooke’s, where he is trying to find new ways to prevent and treat infections in hospitalised and critically-ill patients.

“I carry out my work using a combination of human cell models and animal models of pneumonia and aim to develop new therapies for infection that do not rely on antibiotics,” he says. “I also have a clinical project evaluating a new molecular diagnostic test for pneumonia, which aims to deliver more rapid and accurate tests for infection.”

Outside of work, it is his children that keep him occupied. “I have two boys who occupy most of my free time - both are football-mad - and I help run a local youth football team,” he adds.

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