Gareth Leng, the University of Edinburgh, @GarethLeng
It is now clear that, if you catch COVID-19, you are more likely to become seriously ill if you are overweight, and much more likely to become seriously ill if you are obese. It is important to know that obese individuals need special protection, but it’s more important to understand why they are more susceptible, because that might lead to life-saving treatments.
It’s not obvious. Among people who catch seasonal influenza, obesity does not increase the risk of death, nor the risk of needing artificial ventilation.
So how is infection with COVID-19 different from infection with the flu, and what consequences of COVID-19 might become more serious in obese individuals? It’s a puzzle that would be fun if it weren’t so grim. To answer it we need neither passion nor compassion, but cool analysis of the evidence, recognition of the limits of our understanding, and rigorous attempts to push back those limits.
Most patients who die with COVID-19 show notable signs of damage to the small blood vessels in the lung. There are extensive ‘microthrombi’ – clumps of red blood cells and platelets that may block the vessels. There are also extensive deposits of complement – proteins that contribute to the immune response to infection. In short, the lungs show the scars of a battle in which the defenders have caused as much damage as the invaders; the consequences of this appear to be that the lungs are left unable to provide enough oxygen to maintain life.
It appears that those who die with COVID-19 often do so because of “collateral damage” caused by a hyper-aggressive response of their own immune systems to the infection. But why might this be more likely in obese people?
Obesity is not a lifestyle choice nor a moral failing; it is a heritable disease with a multitude of defined genetic factors that interact with environmental stimuli and with each other in complex ways. It is a disease of multitudes; it affects multitudes of people in multitudes of ways, and is associated with many different adverse health outcomes. One of the most common is Type 2 diabetes, which is believed to develop when the capacity of adipocytes to store fat safely is overwhelmed. This leads to excess fat being stored ectopically in other tissues, such as the liver and muscle, where its presence leads to insulin resistance and thence to Type 2 diabetes.
This excess accumulation and inappropriate deposition of fat triggers inflammation. In biopsies from obese people, dead or damaged adipocytes are commonly observed, often accompanied by an infiltration of activated macrophages. These contribute to the production of a systemic pro-inflammatory state, characterised by increases in circulating levels of cytokines. If this contributes to alveolar damage, then, as Lockhart and O’Rahilly have noted, “this provides an obvious potential route whereby the metabolic risk factors could drive increased [Covid-19] mortality.” [1]
As Lockhart and Rahilly explain though, there are other plausible explanations – for example, in obesity there are lower levels of adiponectin, a hormone that has anti-inflammatory actions (1).
But while it may be tempting to seize onto one of these hypotheses and propose a novel treatment, without a sound mechanistic understanding, hasty action may be ill-advised. For example, in the lungs and other tissues of obese individuals there is increased expression of ACE2, an enzyme present on the surface of cells; the coronavirus binds to ACE2, and this helps it enter and infect the cell. It’s tempting to think that this might predispose individuals to a more invasive infection, and hence that they might benefit from treatments to reduce ACE2 expression. However, it’s not clear whether having more ACE2 contributes to worse covid-19 symptoms or whether the worst symptoms are the result of the virus binding to ACE2 and preventing its normal function.
Fundamental understanding is not gained overnight, but is a wealth accumulated from a century of public investment in science. It’s a wealth that accumulates with interest, for the more we know, the more value comes from every further advance. But it is a wealth that can be hard to realise. The knowledge and understanding that may be key to this particular puzzle is not held within any one community in science, but is distributed amongst many, and these different communities have to learn to talk to each other. Understanding what happens when people are infected with COVID-19 needs a fundamental understanding not just of the virus and the mechanisms of infection, but also of the causes and consequences of obesity, of the multiple defences engaged by the infected host, and of the consequences, both physiological and pathological, of both the infection itself and the host’s response to it.
References:
- Sam M. Lockhart and Stephen O’Rahilly (2020) When two pandemics meet: Why is obesity associated with increased COVID-19 mortality? https://www.mrl.ims.cam.ac.uk/wp-content/uploads/2020/06/When-two-pandemics-meet_MED_26Jun2020.pdf