Red cell volume measurement: using technetium as a replacement for chromium.

Whether or not otherwise healthy cigarette smokers are less likely to become infected with coronavirus disease (COVID-19) is controversial. The findings in several studies that have reported a lower prevalence of smoking in hospitalised patients compared with the general population [1-4] have been criticised on the grounds that hospitalised patients tend to be older and that older patients tend not to smoke. However, at least one study controlled for age and gender [4]. That smokers, once hospitalised, have a poorer outcome than nonsmokers [5] is not surprising, but what is not clear is the proportion of smokers in subjects undergoing ‘test and trace’ who test positive for COVID-19 but who are not necessarily symptomatic. In a recent scientific brief, the WHO reported that no such studies have yet been undertaken [5]. However, from the perspective of protection from infection in the first place, these subjects, rather than smoking patients hospitalized and with poor outcomes, form the most important group.

We speculate that otherwise healthy smokers may be protected from COVID-19 infection as the result of upregulation of bronchopulmonary expression of ABC cassette transporter (multi-drug resistance) proteins. These membrane-linked proteins, the best known of which is P-glycoprotein (P-gp), have been likened to rotating doors that inhibit the entrance of or extrude a wide range of foreign substances from cells. In general, they furnish parts of the body that interface with the outside world, such as bronchopulmonary, gastrointestinal and renal tubular epithelia, and bile canaliculi, ‘pumping’ towards the exterior. They are also present in blood–brain barrier, protecting the brain.

In previous work using dynamic gamma camera scintigraphy, we measured the disappearance rate from the lungs of Tc-99m-labelled methoxyisobutyl-isonitrile (MIBI), administered as an inhaled radioaerosol. This compound, widely used in nuclear medicine, especially for myocardial perfusion imaging, is an multi-drug resistance (MDR) substrate. Interestingly, healthy cigarette smokers showed a striking reduction in clearance rate compared with nonsmokers, the opposite to the clearance rates of Tc-99m-diethylenetriaminepentaacetic acid. Cigarette smoke is full of xenobiotics, raising the strong possibility that bronchopulmonary MDR proteins are upregulated by cigarette smoke and suggesting that the rate of clearance of the tracer across the pulmonary blood-gas barrier could be a quantitative marker of bronchopulmonary MDR protein expression [6], especially P-gp. We subsequently showed, however, that the Tc-99m-MIBI clearance rate strongly correlated with the pulmonary immunohistological expression of MRP1, rather than P-gp, and that expression was increased in smokers [7].

The question, therefore, arises as to whether such upregulation could hinder the cellular entry of viruses. It has been shown that P-gp in T-lymphocytes is capable of extruding hydrophobic peptides essential for the fusion of HIV-1 [8]. Other than HIV-1, however, it is difficult to find publications in the literature relating MDR to the infectivity of viruses.

If the above speculation turns out to be correct, then the administration of ingredients of cigarette smoke, such as nicotine which has been suggested as the mediator of protection in smokers [1], are likely to be ineffective in showing protection if administered via routes other than inhalation. Starting to smoke would potentially be harmful as substrates are initially MDR blockers, with upregulation following later.

Caveats to the above speculation are that in nonsmokers, we found first, no difference in clearance rate between men and women, and second, a trend for clearance to be delayed, rather than accelerated, in older subjects [9]. However, as implied in the WHO scientific brief alluded to above, the known poorer clinical outcome in the elderly and in males is a separate statistic from infection rate itself.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.