Issue #13: Hot and cold, wet and dry and the problem of confounding variables

Setting it Straight - Issue #13

Written by Nobel Laureate Professor Peter Doherty

As Shakespeare’s Richard III has it: ‘Now is the winter of our discontent, Made glorious summer...’ But is the summer experience of COVID-19 in the hard-hit northern hemisphere looking any less inglorious than the preceding, grim days of late winter and autumn? We’re used to the idea that colds and flu are more of a problem in winter, and many would like to believe that should also true for SARS-CoV-2 infection. But COVID-19 is a new disease and we’ve only lived with it for a very short time. While New York City and London were hard hit in the colder months, hot places like India, Texas, Florida and Indonesia are currently experiencing a surge in cases. Is there really a summer lull?

Why is the summer versus winter equation for COVID-19 hard to sort out? The besetting problem is what all research scientists understand, confounding variables. Though disease prevalence and mortality rates have fallen in the ‘Big Apple’, how much of that is due to social distancing? Is the incidence of severe disease and death decreasing because treatments are improving? The antiviral drug, Remdesivir, which does seem to have some inhibitory effect on SARS-CoV-2 replication, is progressively more available in the US. Has the realisation that COVID-19 is as much a vascular as a respiratory disease led to the broader use of anticoagulant therapy (medicines that help prevent blood clots) and improved outcomes for those who are severely ill? As time goes by, of course, we will learn the answer to those questions, but it is still early days.

While our thinking is conditioned by what normally happens with influenza, one of the many features that makes COVID-19 different from the flu is the degree of involvement of children. Influenza can be lethal for the very young, and it’s well established from excellent studies done in both Hong Kong and England, that kids are a major ‘introducer’ of flu viruses into households. With the 2009 H1N1 influenza pandemic in Britain, for example, there was a dramatic drop in incidence that coincided pretty much with the long, summer school vacation. For COVID-19, on the other hand, we see little evidence that children are particularly involved, either from the aspect of spread or when it comes to the need for hospitalisation. Some children have died but, fortunately, there are few such cases.

Why should SARS-CoV-2, or any respiratory virus, cause more infections in winter? When we set aside issues that relate to human behaviour, like social distancing and hand washing, the first line of defence against the many different viruses that cause colds and flu is the 7.0 μm (7,000 nanometre) thick layer of slimy to sticky mucus (see Slime, rhyme, snot) that bathes the surface epithelium of the upper airways. All these tiny viruses, which range in size from 30-250 nanometres, are inert particles that have no mechanism for moving themselves about. Some, though, have a protein on their surface that cleaves the sugar sialic acid from its attached mucin protein and helps the virus penetrate the protective mucus layer to access the vulnerable cells below. That enzymatic, or neuraminidase function, is characteristic of the influenza viruses and the paramyxoviruses that cause the deeper infections of the lung we associate with persistent coughing, pneumonia, or croup.

Like the common cold viruses, SARS-CoV-2 lacks a neuraminidase and grows well in the nose and sinuses where the effectiveness of the mucus layer is, perhaps, more readily compromised by local environmental conditions. Winter in the colder regions of the planet means that the outside air is dryer, windows are shut tight and the central heating is on. If our heating system does not have an associated humidifier, the net result is that we dry out too. Even so, when it comes to summer in the tropics, air-conditioners are also dehumidifiers. Prosperous households, at least, may have their window shut tight! And, if we do see an obvious difference in COVID-19 susceptibility for rich and poor in the equatorial summer, there’ll be a whole load of confounding variables.     

There’s a clear winter/summer divide for some virus infections. With pathogens like the yellow fever and dengue viruses that are transmitted by mosquitoes, it’s obvious that there’s no problem when it’s cold, as there are no insects around. When a disease is named ‘Russian spring/summer encephalitis’, the lack of any climate confusion is obvious. Caused by a virus that’s related to many carried by mosquitoes, this is a tick-borne infection that those living in the far north of the world contract when, released from the confines of apartment living through a freezing winter, they are bitten by an infected tick as they relax, warmed by the sun, at a picnic in grassy parkland.

Otherwise, while we can do well-controlled clinical trials to minimise the influence of confounding variables when testing this or that ‘off the shelf wonder drug’, that’s an impossible ask when it comes to the question of weather and respiratory virus infections. We shall have to wait and see whether, as time goes by, some pattern emerges re COVID-19 and seasonal variation. Operationally, it would be unwise to formulate policy based on the idea that there is a summer lull for COVID-19.