COVID response in the obese calls for new approach say scientists

There are new warnings over COVID’s threat to the lives of those suffering from obesity as research has found lower levels of immune response.

Scientists at the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID) and the Wellcome Sanger Institute have found that following SARS-CoV-2 infection, cells in the lining of lungs and 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.

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

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 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.

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.

Professor Menna Clatworthy, a clinician scientist at the University of Cambridge studying tissue immune cells at CITIID alongside caring for patients at Addenbrooke’s, part of Cambridge University Hospitals NHS Foundation Trust (CUH), 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 requiring mechanical ventilation and intensive care treatment, and 20 controls (non-obese Covid patients and ventilated non-Covid patients). These included patients admitted to intensive care at CUH.

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.

Clatworthy added: “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.”

The team was able to replicate its findings in nasal immune cells taken from obese children with COVID, where they again found lower levels of activity among the genes that produce IFN-alpha and IFN-gamma.

The team said the findings were 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.

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

Because an overactive immune and inflammatory response can be associated with severe COVID 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 University of Cambridge and a consultant in intensive care at Addenbrooke’s 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.”

The team said 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.

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