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.

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