We would like to thank Moril et al.1 for their interest in our paper and for prompting us to explore the topic further. The spike protein is responsible for facilitating the entry of SARS-CoV-2 into human cells and requires priming by protease TMPRSS2 to allow fusion of the viral and cellular membranes.2
The receptor used by the spike protein is the angiotensin-converting enzyme 2 (ACE2),2 which is expressed in different cell strains, as well as in the lung, where there is a gradient of ACE2 expression (higher expression in the upper respiratory tract [nasal epithelium] and lower in the alveolar pneumocytes).2
It has been suggested that a higher expression of ACE2 could contribute to increased SARS-CoV-2 viral infectivity.2 As Moril et al. mention,1 active smokers with chronic obstructive pulmonary disease have a higher level of expression of ACE2 than former smokers and former smokers have a higher level than never smokers,1, 2 while a decrease in ACE2 expression has been observed in the bronchial epithelial cells of former smokers compared with active smokers.1, 2
Not all authors have obtained the same results. Lee et al.3 did not identify any differences in ACE2 expression based on age, sex, or smoking status, and suggest that smoking is not a protective factor, but rather a risk factor for Covid-19 disease progression.
Voinsky et al.4 did not find higher ACE2 and TMPRSS2 expression in smokers or never smokers, but they did observe higher expression of TMPRSS4 (that encodes a protease for cell entry similar to TMPRSS2) in smokers compared to never smokers, suggesting that they may be at increased risk for Covid-19 infection.
Regarding the comment of Moril et al.1 on the possibility of a better prognosis in smokers, Takagi, in Japan,5 carried out a meta-regression that showed a positive association between the prevalence of smoking and Covid-19 infection independent of other co-variables, so the hypothesis that smokers have a better disease prognosis is not supported. In a new meta-analysis of our data,6 we classified patients as smokers or former smokers (only 5 articles differentiated former smokers) (Fig. 1).
Former smokers clearly showed similarly poor progression, while current smokers showed a clear tendency to worse progression but without statistical significance. The same results were obtained in the meta-analysis of Patanavanich et al.7 (only 8 articles divided smokers into categories).
Most of the studies included in the meta-analysis have significant limitations: they are mostly retrospective and have significant selection and data biases and lack a comparative group, making it difficult to establish causality.
We reaffirm that smokers and former smokers have a worse Covid-19 progression, including higher mortality, and that nicotine cannot be considered a protective factor in any way.