To the Editor,We appreciate the interest and comments of Soriano and Ancochea1 regarding our papers 2. Further to the suggestion that “it would be of interest to repeat their statistics conducted during the first wave of COVID-19, again with the current estimates during the ongoing second wave, or later ones”, we would like to emphasize that our geographical observation was a type of anecdotal evidence that contributed to formulating a hypothesis. In a previous paper, we found that after adjusting for potentially relevant country-level confounders, there was a negative ecological association between COVID-19 mortality and the consumption of cabbage and cucumber in European countries 3. In this study, we acknowledged that “As in any ecological study, any inference from the observed association should be made at the country level, as the possibility of ecological fallacy precludes inferences at the individual level; and that further testing in properly designed individual studies would be of interest”. Indeed, what would be useful is testing the hypothesis in robust observational studies and/or clinical trials.Regarding our observation that COVID-19 could be considered as a disease of the Anthropocene 4 , other authors have recently provided a more complete description of the links between the disruption of the natural ecosystems that characterize the Anthropocene and the occurrence of zoonosis 5 6.1. Soriano J and Ancochea J. Saved by cabbage, killed by cabbage, and COVID-19. Allergy 2020; in press.2. Bousquet J, Anto JM, Czarlewski W, et al. Cabbage and fermented vegetables: from death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19. Allergy 2020. DOI: 10.1111/all.14549.3. Fonseca S, Rivas I, Romaguera D, et al. Association between consumption of vegetables and COVID-19 mortality at a country level in Europe. MedRix 2020; 10.1101/2020.07.17.201558464. O’Callaghan C and Anto J. COVID-19: The Disease of the Anthropocene.Env Res 2020; 187: 109683.doi: 109610.101016/j.envres.102020.109683. Epub 102020 May 109615.5. Morens DM and Fauci AS. Emerging Pandemic Diseases: How We Got to COVID-19. Cell 2020; 182: 1077-1092. 2020/08/28. DOI: 10.1016/j.cell.2020.08.021.6. Roche B, Garchitorena A, Guegan JF, et al. Was the COVID-19 pandemic avoidable? A call for a ”solution-oriented” approach in pathogen evolutionary ecology to prevent future outbreaks. Ecol Lett 2020 2020/09/02. DOI: 10.1111/ele.13586.JM AntoISGlobAL, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. IMIM (Hospital del Mar Research Institute), Barcelona, Spain. Universitat Pompeu Fabra (UPF), Barcelona, Spain. CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.J BousquetCharité, Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Comprehensive Allergy Center, Department of Dermatology and Allergy, Berlin, Germany. MACVIA-France, Montpellier, France.

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage were associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin converting enzyme 2 (ACE2). As a result of SARS-Cov-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT1R) axis associated with oxidative stress. This leads to insulin resistance, lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block the AT1R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects helpful in mitigating COVID-19 severity.

To the Editor, The fermentation process, born as a preservation method in the Neolithic age, enabled humans to eat not-so-fresh food and to survive.1 Fermented foods are “foods or beverages made via controlled microbial growth (including lactic acid bacteria (LAB)) and enzymatic conversions of food components.” 2 Not all fermented foods contain live cultures, as some undergo further processing after fermentation: pasteurization, smoking, baking, or filtration. These processes kill or remove the live microorganisms in foods such as soy sauces, bread, most beers and wines as well as chocolate. Live cultures can be found in fermented vegetables and fermented milk (fermented sour milk, yoghurt, probiotics, …). The westernized diet is lacking many traditional fermented foods.3The gut microbiota has an inter-individual variability due to genetic predisposition and diet 3. Some foods like cabbage can be fermented by the gut microbiota. 4 The westernized diet has been associated with changes in the gut microbiome.5In this Rostrum, we consider loss of food fermentation either as a reduction of fermented food consumption in the diet or as a change in the microbiome leading to a reduction of fermentation of foods in the gut. This paper is based on the hypothesis that diet may partly explain differences in COVID-19 death rates within and between countries.6

To the Editor, A COVID-19 epidemic started in China and then disseminated to other Asian countries before becoming a pandemic. It appears that the pandemic has so far resulted in proportionately fewer deaths in China and most Eastern Asian countries. Many reasons can explain this picture.1 One of them is the type of diet in the low mortality countries. 2This paper is the sixth of a series attempting to understand the role of diet in the differences of COVID-19 death rates between and within countries with the aim to identify potential preventive measures against COVID-19. The concept paper 2 was followed by two ecological studies comparing death rates in European countries and the consumption of vegetables or fermented foods. 3,4 We then proposed that sulforaphane from cruciferous vegetables1 and lactobacilli from fermented foods (submitted) were possibly involved in the reduction of insulin resistance in COVID-19.It is noteworthy that fermented foods are largely used in Asia.5,6 It is therefore important to check whether some commonly eaten fermented foods in these countries may explain geographic differences in COVID-19. Kimchi will be used as a model of fermented cabbage.

To the Editor, Sulforaphane [1-isothiocyanato-4-(methylsulfinyl)butane] is a clinically relevant nutraceutical compound present in cruciferous vegetables (Brassicaceae). It is used for the prevention and treatment of chronic diseases and may be involved in ageing.1Along with other natural nutrients, sulforaphane has been suggested to have a therapeutic value for the treatment of the coronavirus disease 2019 (COVID-19).2 Sulforaphane is an isothiocyanate stored in its inactive form glucoraphanin.3 The enzyme myrosinase, found in plant tissue and in the gut microbiome, is involved in the conversion of glucoraphanin to its active form sulforaphane.4

In December 2019, China reported the first cases of the coronavirus disease 2019 (COVID-19). This disease, caused by the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), has developed into a pandemic. To date it has resulted in ~5.6 million confirmed cases and caused 353,334 related deaths worldwide. Unequivocally, the COVID-19 pandemic is the gravest health and socio-economic crisis of our time. In this context, numerous questions have emerged in demand of basic scientific information and evidence-based medical advice on SARS-CoV-2 and COVID-19. Although the majority of the patients show a very mild, self-limiting viral respiratory disease, many clinical manifestations in severe patients are unique to COVID-19, such as severe lymphopenia and eosinopenia, extensive pneumonia, a “cytokine storm” leading to acute respiratory distress syndrome, endothelitis, thrombo-embolic complications and multiorgan failure. The epidemiologic features of COVID-19 are distinctive and have changed throughout the pandemic. Vaccine and drug development studies and clinical trials are rapidly growing at an unprecedented speed. However, basic and clinical research on COVID-19-related topics should be based on more coordinated high-quality studies. This paper answers pressing questions, formulated by young clinicians and scientists, on SARS-CoV-2, COVID-19 and allergy, focusing on the following topics: virology, immunology, diagnosis, management of patients with allergic disease and asthma, treatment, clinical trials, drug discovery, vaccine development and epidemiology. Over 140 questions were answered by experts in the field providing a comprehensive and practical overview of COVID-19 and allergic disease.