Thank you for your Letter and concerns raised about delays to registration and failure to identify similar systematic review protocols in PROSPERO. PROSPERO, which provides registration free of charge, now receives over 47,000 submissions annually including both new submissions and resubmissions (from authors whose original submission required revision owing to low quality or incomplete information). With only 1.7 FTE administrative staff funded to manage PROSPERO, demand for registration outstrips capacity of staff to process requests.
Previous appeals to PROSPERO users to improve the quality of submission and thus reduce the need for query, feedback and resubmission and consequently demand on the register were unsuccessful. With the intention of reducing further delays, in 2020, a decision was made to automatically publish records waiting for more than 30 days from submission, providing they pass a series of automatic checks (assessing whether a record is submitted in English language and includes information about review methodology). This allowed us to focus efforts on supporting the research endeavour surrounding the global COVID-19 pandemic. We aim to publish reviews related to covid by the end of the next working day. As this has reduced the time to registration and been met with approval by the review community, we have decided to continue automatic publishing system. Future development plans involve exploring how a more detailed automatic checking process...
Thank you for your Letter and concerns raised about delays to registration and failure to identify similar systematic review protocols in PROSPERO. PROSPERO, which provides registration free of charge, now receives over 47,000 submissions annually including both new submissions and resubmissions (from authors whose original submission required revision owing to low quality or incomplete information). With only 1.7 FTE administrative staff funded to manage PROSPERO, demand for registration outstrips capacity of staff to process requests.
Previous appeals to PROSPERO users to improve the quality of submission and thus reduce the need for query, feedback and resubmission and consequently demand on the register were unsuccessful. With the intention of reducing further delays, in 2020, a decision was made to automatically publish records waiting for more than 30 days from submission, providing they pass a series of automatic checks (assessing whether a record is submitted in English language and includes information about review methodology). This allowed us to focus efforts on supporting the research endeavour surrounding the global COVID-19 pandemic. We aim to publish reviews related to covid by the end of the next working day. As this has reduced the time to registration and been met with approval by the review community, we have decided to continue automatic publishing system. Future development plans involve exploring how a more detailed automatic checking process can be implemented. Furthermore , we intend to reduce the time from receipt to automatic publication from 30 days to 10 days.
To maximise effective searching and prevent similar records being missed, PROSPERO is also exploring automatic identification of similar reviews pre-submission and a requirement for authors to explain how their proposed review is different and/or needed. This may help to reduce duplication and consequently, research waste. We hope these developments will also improve user experience and the quality of our service.
Yours sincerely,
Ruth Walker and Connor Evans on behalf of the PROSPERO team.
Pawlak1 critiqued our challenge to conventional dietary guidelines for people diagnosed with familial hypercholesterolaemia (FH)2. Indeed, his criticism was so incriminatory that he stated our recommendation “constitutes malpractice”. Considering the gravity of his claim, especially as it is levied against co-authors who are mostly MDs, it is important to disclose what we actually recommended, and to point out the flawed evidence Pawlak used to claim that we have committed malpractice.
First, Pawlak misunderstood the purpose of our paper. We did not question “the efficacy of low-saturated fat, low-cholesterol diet to reduce LDL cholesterol”, as he stated. We provided strong support for the hypothesis that factors other than LDL-C, such as smoking, hypercoagulation and hyperinsulinemia, have a potent influence on the incidence of coronary events in FH that dwarfs that of LDL-C3. For example, in our Figure 4 we illustrated the findings of Gaudet et al.4, who demonstrated that FH people without obesity or insulin resistance had no greater rate of coronary heart disease (CHD) than non-FH people. In contrast, obese, insulin-resistant FH people had over 7 times greater incidence of CHD than non-FH people. Moreover, in recent work we have elaborated on the extensive, but largely ignored, literature demonstrating that factors other than LDL-C, such as increased levels of coagulation factors, explain why only a subset of FH individuals develop premature CHD5. Finally, we in...
Pawlak1 critiqued our challenge to conventional dietary guidelines for people diagnosed with familial hypercholesterolaemia (FH)2. Indeed, his criticism was so incriminatory that he stated our recommendation “constitutes malpractice”. Considering the gravity of his claim, especially as it is levied against co-authors who are mostly MDs, it is important to disclose what we actually recommended, and to point out the flawed evidence Pawlak used to claim that we have committed malpractice.
First, Pawlak misunderstood the purpose of our paper. We did not question “the efficacy of low-saturated fat, low-cholesterol diet to reduce LDL cholesterol”, as he stated. We provided strong support for the hypothesis that factors other than LDL-C, such as smoking, hypercoagulation and hyperinsulinemia, have a potent influence on the incidence of coronary events in FH that dwarfs that of LDL-C3. For example, in our Figure 4 we illustrated the findings of Gaudet et al.4, who demonstrated that FH people without obesity or insulin resistance had no greater rate of coronary heart disease (CHD) than non-FH people. In contrast, obese, insulin-resistant FH people had over 7 times greater incidence of CHD than non-FH people. Moreover, in recent work we have elaborated on the extensive, but largely ignored, literature demonstrating that factors other than LDL-C, such as increased levels of coagulation factors, explain why only a subset of FH individuals develop premature CHD5. Finally, we included in our paper a review of the literature demonstrating that elderly people with the highest levels of LDL-C show either an equal or lower rate of mortality than people with the lowest LDL-C6. Other work, as well, has shown that FH people at 70 years of age have a significantly lower 10 year mortality rate compared to the general population7. Therefore, we find no reason to recommend that FH people reduce their LDL-C levels with diet or medication.
The primary purpose of our paper was to point out that low cholesterol, low saturated fat diets have been recommended to FH individuals for over 80 years, without any evidence of benefit. Indeed, we stated in our paper that diets that are low in fat are therefore high in carbohydrates, which may promote an atherogenic biomarker profile. What we did recommend was that FH individuals with components of the metabolic syndrome, e.g., excess weight, hypertension, hyperinsulinemia or hyperglycemia, would benefit from a diet low in carbohydrates. Support for this recommendation is based in the vast literature on clinical trials utilizing the low carbohydrate diet (LCD), which has shown its effectiveness in improving CHD-sensitive biomarkers, at a level equal to or superior to low fat diets8. The well-established benefits of an LCD in improving CHD-sensitive biomarkers supported our recommendation that a clinical trial should be performed with LCD only in FH individuals with components of the metabolic syndrome or excess hypercoagulation markers.
Second, based on the findings of 3 publications, two of them conducted on non-FH rodents and one in non-FH people, Pawlak claimed that our recommendation of the LCD for FH would “exacerbate atherosclerosis”. It is therefore important to assess whether the findings of these three papers justify his concern that the LCD is inherently atherogenic.
Two studies Pawlak cited were conducted on genetically manipulated mice designed to model human atherosclerosis9 10. Research on a rodent model of a human disease should be scrutinized closely to satisfy criteria in which the methods and biomarker outcomes are comparable to the human condition. These two studies do not satisfy these criteria. The diets of the animals are unlike a typical diet a human would consume, in general, and certainly do not match the diet of someone on an LCD. In the Foo et al.,9 study, the food was composed of sugar (8.4%), corn starch (3.6%), casein protein (45%) and milkfat (43%). This diet has no relevance to human nutrition, with one of numerous flaws being that an LCD is typically composed of 20-25% protein, 60-70% fat and 10-15% carbohydrates. Indeed, a diet that contains more protein than fat is likely to make a person ill. The second study by Kostogrys et al.,10 as well, contained a diet for the rodents with a dietary composition that no human should consume; it contained 52% protein, 12% sugar, 5% corn starch, 21% fat (butter), and the remainder as cellulose and minerals. Confirmation that these findings are unrelated to human research on LCD is that in both studies the mice developed hypertriglyceridemia, an effect that does not happen in people on LCD8. These rodent studies, therefore, have no translational value toward understanding LCD effects on CHD.
Animal research that is more relevant to mechanisms underlying premature CHD in FH individuals is provided by the Watanabe rabbit model of FH, which has high cholesterol, elevated coagulation factors (Factor VIII and fibrinogen) and develops human-like atherosclerosis.11 12 It is of value that the development of atherosclerosis in the Watanable rabbit was prevented by probucol, a medication which also reduces cardiovascular events in FH people.13 Most importantly, probucol reduced coagulation factor levels without lowering their high cholesterol.12
Pawlak cited a 20 year old clinical study that he asserted documented “the progression and the severity of CAD” (coronary artery disease) in people on an LCD. The problems with this cited study are so extensive they could fill a textbook on flawed scientific methods. First, the repeated blood work and cardiac imaging in this year-long intervention study would have had a very high cost, but no funding source was mentioned in the paper. Second, subjects were given dietary guidance, but the study did not include a registered dietician. Third, it is stated that each individual was questioned regarding dietary habits, but there is no record of what the subjects consumed. Specifically, there is no quantification of the categories, macronutrients or amount of food the subjects in the two groups ate. Fourth, there is a vague, unsubstantiated statement that a subset of patients adopted a ‘high-protein diet’, which, in theory, is equivalent to an LCD. However, there is no confirmation as to whether the ‘high-protein diet’ as described by Fleming was an LCD. Fifth, this author published related work with the same dietary program that demonstrated an increase in triglycerides in subjects on a high fat diet. The finding that people on the high fat diet developed hypertriglyceridemia is inconsistent with every other study on LCD effects on triglycerides. Overall, the work by Fleming is flawed at every level of analysis, and his findings have not been replicated by any LCD study.
The fact that Pawlak has depended on three fatally flawed studies to justify his claims that an LCD is harmful provides strong support for our contention that there is no high caliber research that demonstrates the LCD is harmful. A relevant year-long study conducted at Stanford University demonstrated that the LCD was equal or superior to other diets, including a low saturated fat (Ornish) diet, in terms of cardiovascular biomarker risk outcomes.14
Finally, Pawlak praised the effects of a low-fat, vegetarian diet in improving cardiovascular health, citing work by Ornish et al.15 However, the Ornish work was not solely a diet study. It involved an experimental group that was prescribed an intensive lifestyle intervention that included a low fat, vegetarian diet, as well as aerobic exercise sessions, stress management training, smoking cessation, group psychosocial support, and they were told to avoid sugar consumption. Control subjects were given no interventions other than to follow routine advice from their personal physicians. The multi-factorial nature of the intervention group does not permit the conclusion that any one factor, such as diet, was causally related to the outcomes of the study. It should be noted, as well, that despite the intensive lifestyle intervention in the experimental group, there was no difference in hard cardiovascular outcomes, such as the incidence of myocardial infarctions, coronary artery bypass grafts or death, between the two groups.
In conclusion, Pawlak has failed to justify his charge that we have committed malpractice by recommending that FH individuals with components of metabolic syndrome should follow a carbohydrate restricted diet.
1. Pawlak R. Low carbohydrate diets should NOT be recommended for patients with familiar hypercholesterolaemia. BMJ-Evidence Based Medicine 2020.
2. Diamond DM, Alabdulgader AA, de Lorgeril M, et al. Dietary Recommendations for Familial Hypercholesterolaemia: an Evidence-Free Zone. BMJ Evid Based Med 2020.
3. Ravnskov U, de Lorgeril M, Diamond DM, et al. LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Expert Rev Clin Pharmacol 2018;11(10):959-70.
4. Gaudet D, Vohl MC, Perron P, et al. Relationships of abdominal obesity and hyperinsulinemia to angiographically assessed coronary artery disease in men with known mutations in the LDL receptor gene. Circulation 1998;97(9):871-77.
5. Ravnskov U, de Lorgeril M, Kendrick M, et al. Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia. Med Hypotheses 2018;121:60-63.
6. Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. Bmj Open 2016;6(6).
7. Mundal L, Sarancic M, Ose L, et al. Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992-2010. J Am Heart Assoc 2014;3(6):e001236.
8. Diamond DM, O'Neill BJ, Volek JS. Low carbohydrate diet: are concerns with saturated fat, lipids, and cardiovascular disease risk justified? Curr Opin Endocrinol Diabetes Obes 2020;27(5):291-300.
9. Foo SY, Heller ER, Wykrzykowska J, et al. Vascular effects of a low-carbohydrate high-protein diet. Proc Natl Acad Sci U S A 2009;106(36):15418-23.
10. Kostogrys RB, Franczyk-Zarow M, Maslak E, et al. Low carbohydrate, high protein diet promotes atherosclerosis in apolipoprotein E/low-density lipoprotein receptor double knockout mice (apoE/LDLR(-/-)). Atherosclerosis 2012;223(2):327-31.
11. Watanabe Y. Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit). Atherosclerosis 1980;36(2):261-8.
12. Mori Y, Wada H, Nagano Y, et al. Hypercoagulable state in the Watanabe heritable hyperlipidemic rabbit, an animal model for the progression of atherosclerosis. Effect of probucol on coagulation. Thromb Haemost 1989;61(1):140-3.
13. Yamashita S, Hbujo H, Arai H, et al. Long-term probucol treatment prevents secondary cardiovascular events: a cohort study of patients with heterozygous familial hypercholesterolemia in Japan. J Atheroscler Thromb 2008;15(6):292-303.
14. Gardner CD, Kiazand A, Alhassan S, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women. Jama-Journal of the American Medical Association 2007;297(9):969-77.
15. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998;280(23):2001-7.
In a systematic review of cholesterol reduction clinical trials, DuBroff et al claimed that “the evidence presented challenges cardiovascular disease prevention through targeted reductions of LDL-cholesterol”. However, it should be noted that the concept authors claim to challenge has never been proved, nor properly tested (1). This raises the question of whether there is a need to disprove an unproven concept. In science, the burden is on the proof.
Nevertheless, if it was to disprove, we must recognize the limitations of the present study. Regarding testing "the target paradigm", the authors first categorized the trials as to whether they did or did not meet average LDL-cholesterol reduction recommended by AHA/ACC 2018 guidelines (2) for individuals. Then, they intended to test the association between reaching this arbitrary target (suggested by one specific guideline) with the trial being positive or negative regarding death or cardiovascular events. However, no statistical inference was performed for this main analysis and no significance level was presented for the interaction between reaching the target and having clinical benefit. Instead, in this systematic review that intended to test a hypothesis that implied interaction phenomenon, the authors "intentionally did not perform a meta-analysis" under the justification that trials “involved three different drug classes”.
Finally, as the authors noted, it was a systematic review of s...
In a systematic review of cholesterol reduction clinical trials, DuBroff et al claimed that “the evidence presented challenges cardiovascular disease prevention through targeted reductions of LDL-cholesterol”. However, it should be noted that the concept authors claim to challenge has never been proved, nor properly tested (1). This raises the question of whether there is a need to disprove an unproven concept. In science, the burden is on the proof.
Nevertheless, if it was to disprove, we must recognize the limitations of the present study. Regarding testing "the target paradigm", the authors first categorized the trials as to whether they did or did not meet average LDL-cholesterol reduction recommended by AHA/ACC 2018 guidelines (2) for individuals. Then, they intended to test the association between reaching this arbitrary target (suggested by one specific guideline) with the trial being positive or negative regarding death or cardiovascular events. However, no statistical inference was performed for this main analysis and no significance level was presented for the interaction between reaching the target and having clinical benefit. Instead, in this systematic review that intended to test a hypothesis that implied interaction phenomenon, the authors "intentionally did not perform a meta-analysis" under the justification that trials “involved three different drug classes”.
Finally, as the authors noted, it was a systematic review of studies not suited to test the paradigm of targets. The primary test for this hypothesis should be the randomization of patients to have drug doses adjusted to a target goal or to have a fixed dose.
In fact, a proper conclusion of a systematic review that aimed to “test the validity of this [target] paradigm” would be for absence of evidence, instead of claiming evidence of absence by very limited data analysis against a unproven concept.
That being said, the value of using LDL-cholesterol targets has never been demonstrated, nor should be reinforced by guidelines.
2. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Circulation. 2019 Jun 18;139(25):e1182-e1186]. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
In this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
In order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking in...
In this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
In order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking into account studies that not official report it as ODYSSEY long Term and ODYSSEY COMBO I.
On the other hand, this article enlists essays in secondary prevention like FOURIER or IMPROVE-IT but it doesn’t include the HPS –with its huge statistical weight- or PROSPER –which achieves minor coronary death in elderly patients- or PROVE-IT or TNT. This situation looks like a whimsical selection without a solid support instead of a consistent piece of evidence.
I believe LDL central role in atherosclerosis is not quit questionable as the methodology used to calculate cardiovascular risk on primary prevention population or the residual risk in patients with prior heart disease. In my opinion, this would allow us to take the cardiovascular disease as the first cause of death of the world.
In this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
In order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking in...
In this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
In order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking into account studies that not official report it as ODYSSEY long Term and ODYSSEY COMBO I.
On the other hand, this article enlists essays in secondary prevention like FOURIER or IMPROVE-IT but it doesn’t include the HPS –with its huge statistical weight- or PROSPER –which achieves minor coronary death in elderly patients- or PROVE-IT or TNT. This situation looks like a whimsical selection without a solid support instead of a consistent piece of evidence.
I believe LDL central role in atherosclerosis is not quit questionable as the methodology used to calculate cardiovascular risk on primary prevention population or the residual risk in patients with prior heart disease. In my opinion, this would allow us to take the cardiovascular disease as the first cause of death of the world.
Dear Editor,
Recent literature suggested increased risk of severe COVID-19 in smokers which also got affirmation from World Health Organization (WHO) [1, 2]. However, original peer reviewed research which explained pathophysiological basis of the enhanced COVID-19 severity in smokers is currently scarce. Increased expression of SARS-CoV-2 cell entry receptor ACE2 in respiratory tract and lung tissue of smokers unraveled from analysis of gene expression data was used to predict higher chances of SARS-CoV-2 infection but that failed to explain enhanced COVID-19 severity [3]. Few authors have suggested that increased risk of severe complications and higher mortality rate in infected smokers may be due to host-specific factors like weakening of respiratory health and immunity caused by chronic smoking [4]. However, none of the virus-related factors which can be responsible for the COVID-19 severity in smokers has been reported until date. Based on the recent research updates on SARS-CoV-2 specific virulence in host cells, we propose a plausible mechanism which associates smoking with increased severity of COVID-19.
Apart from a cell surface entry receptor, coronaviruses require furin (a host protease) mediated cleavage of their spike (S) protein for successful invasion of the host cell. SARS-CoV-2, a member of the genus betacoronaviruses, has evolved a unique furin protease S1/S2 cleavage site, which is absent in other family members, including SARS-CoV-1 [5]. Rec...
Dear Editor,
Recent literature suggested increased risk of severe COVID-19 in smokers which also got affirmation from World Health Organization (WHO) [1, 2]. However, original peer reviewed research which explained pathophysiological basis of the enhanced COVID-19 severity in smokers is currently scarce. Increased expression of SARS-CoV-2 cell entry receptor ACE2 in respiratory tract and lung tissue of smokers unraveled from analysis of gene expression data was used to predict higher chances of SARS-CoV-2 infection but that failed to explain enhanced COVID-19 severity [3]. Few authors have suggested that increased risk of severe complications and higher mortality rate in infected smokers may be due to host-specific factors like weakening of respiratory health and immunity caused by chronic smoking [4]. However, none of the virus-related factors which can be responsible for the COVID-19 severity in smokers has been reported until date. Based on the recent research updates on SARS-CoV-2 specific virulence in host cells, we propose a plausible mechanism which associates smoking with increased severity of COVID-19.
Apart from a cell surface entry receptor, coronaviruses require furin (a host protease) mediated cleavage of their spike (S) protein for successful invasion of the host cell. SARS-CoV-2, a member of the genus betacoronaviruses, has evolved a unique furin protease S1/S2 cleavage site, which is absent in other family members, including SARS-CoV-1 [5]. Recently, Anand et al in a bioinformatics based analysis, showed that S1/S2 cleavage site of SARS-CoV-2 has striking similarity to the Furin-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). ENaC is present in the lung pneumocytes, where they have a physiological role in fluid clearance from the alveoli. ENaC has established roles in immune cell activation, and cytokine/chemokine mediated ARDS in inflammatory disorders [6, 7]. Furin is also required for proteolytic activation of ENaC by cleavage of extracellular domain of its α subunit [8]. SARS-CoV-2 in the infecting the pneumocytes can compete for Furin thus can inhibit proteolytic activation of ENaC, which will result in fluid accumulation inside the alveoli leading to pulmonary edema and acute respiratory distress syndrome (ARDS). Existing literature suggests that cigarette smoke condensate [9], more specifically its major ingredient Crotonaldehyde (CRO), can cause does-dependent inhibition of ENaC-α subunit expression in pneumocytes leading to edematous acute lung injury [10]. Reduced availability of active ENaC in smokers may get further exacerbated if they get infected with SARS-CoV-2 owing to virus mediated inactivation of this ion channel, making them vulnerable for developing severe COVID-19 symptoms (Fig. 1b). To note, the current smokers may be at increased risk of developing severe COVID-19 symptoms owing to the abundance of freshly released smoke condensates in their lungs leading to greater inhibition of ENaC in pneumocytes. Recent literature does suggest a higher risk of severe complications and a higher mortality rate among current smokers hospitalized with COVID-19 [2]. Our proposed mechanism is an effort to explain SARS-CoV-2 based etiology of increased disease severity in smokers, which was not discussed before and can have important implications for therapeutic management and health policy decisions for COVID-19.
Conflict of Interst
Authors declared no conflict of interest
References:
1. Smoking and COVID-19 [Internet]. [cited 2020 Jun 11].Available from: https://www.who.int/news-room/commentaries/detail/smoking-and-covid-19.
2. Alqahtani JS, Oyelade T, Aldhahir AM, Alghamdi SM, Almehmadi M, Alqahtani AS, Quaderi S, Mandal S, Hurst JR. Prevalence, Severity and Mortality associated with COPD and Smoking in patients with COVID-19: A Rapid Systematic Review and Meta-Analysis. Bhatt GC, editor. PLoS One; 2020; 15: e0233147Available from: https://dx.plos.org/10.1371/journal.pone.0233147.
3. Muus C, Luecken MD, Eraslan G, Waghray A, Heimberg G, Sikkema L, Kobayashi Y, Vaishnav ED, Subramanian A, Smilie C, Jagadeesh K, Duong ET, Fiskin E, Triglia ET, Ansari M, Cai P, Lin B, Buchanan J, Chen S, Shu J, Haber AL, Chung H, Montoro DT, Adams T, Aliee H, Samuel J, Andrusivova AZ, Angelidis I, Ashenberg O, Bassler K, et al. Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells. bioRxiv Cold Spring Harbor Laboratory; 2020; : 2020.04.19.049254.
4. van Zyl-Smit RN, Richards G, Leone FT. Tobacco smoking and COVID-19 infection. Lancet. Respir. Med. Elsevier; 2020;S2213-2600(20)30239-3. doi:10.1016/S2213-2600(20)30239-3.
5. Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E. The spike glycoprotein of the new coronavirus 2019-nCoV contains a Furin-like cleavage site absent in CoV of the same clade. Antiviral Res. Elsevier B.V.; 2020; 176: 104742.
6. Wynne BM, Zou L, Linck V, Hoover RS, Ma HP, Eaton DC. Regulation of lung epithelial sodium channels by cytokines and chemokines. Front. Immunol. Frontiers Media S.A.; 2017; 8.
7. Mutchler SM, Kleyman TR. New insights regarding epithelial Na+ channel regulation and its role in the kidney, immune system and vasculature. Curr. Opin. Nephrol. Hypertens. Lippincott Williams and Wilkins; 2019. p. 113–119.
8. Anand P, Puranik A, Aravamudan M, Venkatakrishnan AJ, Soundararajan V. SARS-CoV-2 strategically mimics proteolytic activation of human ENaC. Elife [Internet] 2020; 9:e58603. doi:10.7554/eLife.58603.
9. Xu H, Ferro TJ, Chu S. Cigarette smoke condensate inhibits ENaC α-subunit expression in lung epithelial cells. Eur. Respir. J. European Respiratory Society; 2007; 30: 633–642.
10. Li Y, Chang J, Cui Y, Zhao R, Ding Y, Hou Y, Zhou Z, Ji HL, Nie H. Novel mechanisms for crotonaldehyde-induced lung edema. Oncotarget Impact Journals LLC; 2017; 8: 83509–83522.
Figure Legends:
Figure 1 a. Normal pneumocytes maintain alveolar fluid resorption with the help of Furin proteolysis activated ENaC, b. Cigarette smoke condensate directly inhibits ENaC while SARS-CoV-2 competes for its Furin mediated proteolysis thus prevents its activation.
Usman et al (1) write that only one of the 18 studies of COVID-19 patients they included in their review of the Smoker's Paradox reported that "the prevalence of smokers resembles that of the general population."
But this study--by Richardson et al in New York City (2)--actually only reported the prevalence of "never smokers" at 84.4%. It did not distinguish between current and former smokers among the remaining 15.6%, however, so Usman et al should have marked this combined result with an asterisk in their Table 1. Far from resembling the general population, the 15.6% combined rate is less than half the 34% expected in USA, where approximately 14% are current and 20% former smokers. With this correction, all 18 studies support the Smoker’s Paradox, which belies the authors’ conclusion that a “protective effect should NOT be inferred” [emphasis added].
The protective effect is clearly real and further supported by the largest study of COVID-19 to date (n=7,162) with data on smoking status (3), which Usman et al did not include in their review. Current smokers in this CDC study comprised just 1.3% of all the COVID-19 patients seeking care from US hospitals in 50 states and Washington DC, 1.2% of those treated as outpatients, and 1.1% of those treated in intensive care units.
Usman et al also did not mention the compound most likely responsible for the protective effects of smoking against respiratory infections, which...
Usman et al (1) write that only one of the 18 studies of COVID-19 patients they included in their review of the Smoker's Paradox reported that "the prevalence of smokers resembles that of the general population."
But this study--by Richardson et al in New York City (2)--actually only reported the prevalence of "never smokers" at 84.4%. It did not distinguish between current and former smokers among the remaining 15.6%, however, so Usman et al should have marked this combined result with an asterisk in their Table 1. Far from resembling the general population, the 15.6% combined rate is less than half the 34% expected in USA, where approximately 14% are current and 20% former smokers. With this correction, all 18 studies support the Smoker’s Paradox, which belies the authors’ conclusion that a “protective effect should NOT be inferred” [emphasis added].
The protective effect is clearly real and further supported by the largest study of COVID-19 to date (n=7,162) with data on smoking status (3), which Usman et al did not include in their review. Current smokers in this CDC study comprised just 1.3% of all the COVID-19 patients seeking care from US hospitals in 50 states and Washington DC, 1.2% of those treated as outpatients, and 1.1% of those treated in intensive care units.
Usman et al also did not mention the compound most likely responsible for the protective effects of smoking against respiratory infections, which is not nicotine but carbon monoxide (CO). Several studies of using gaseous CO or CO releasing molecules as drugs to treat respiratory diseases have been published recently and more are registered at ClinicalTrials.gov.
Non-smokers seeking to ward off infection by SARS-COv2 need not start smoking, however. They can boost their endogenous production of CO simply by ingesting hemin, vitamin C, curcumin, or other supplements known to increase the expression and activity of heme oxygenase-1.(4) This releases equimolar amounts of CO, biliverdin that is converted to bilirubin, iron that is convert to ferritin, and three times as much water.
Too much CO exposure from any source causes tissue hypoxia, however, as CO binds more than aggressively than oxygen to cytochrome oxidase. This can be fatal if not detected and reversed before vital organs shut down. The risk of death correlates less with arterial or venous CO alone, however, than the difference between them, so I urge COVID-19 clinicians to start measuring both.(5)
References
1) Usman MS, Siddiqi TJ, Khan MS, et al. Is there a smoker’s paradox in COVID-19? BMJ Evidence-Based Medicine Published Online First: 11 August 2020. doi: 10.1136/bmjebm-2020-111492
2) Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020;323:2052–9
3) Chow N, Fleming-Dutra K, Gierke R, et al. [aka CDC COVID-19 Response Team] Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 — United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep 2020;69:382–386. DOI: http://dx.doi.org/10.15585/mmwr.mm6913e2
4) Barbagallo I, Galvano F, Frigiola A, et al. Potential therapeutic effects of natural heme oxygenase-1 inducers in cardiovascular diseases. Antioxid Redox Signaling 2013 Feb 10;18(5):507-21. doi: 10.1089/ars.2011.4360.
5) Donnay A. Toxicologist warns COVID-19 patients are dying of carbon monoxide poisoning that pulse oximeters cannot distinguish and both oxygen therapy and ventilators are making worse. Medium 2020; April 9. Available: https://medium.com/@albertdonnay_17627/toxicologist-warns-covid-19-patients-are-dying-of-carbon-monoxide-poisoning-that-pulse-oximeters-a2ac42d4c3a4 [Accessed 2 September 2020]
There is a hypothesis that nicotine may have a protective effect in COVID-19 (1). I present two recent reports on the association between smoking and COVID-19 infection/progression, and then presented reports regarding another mechanism of the association.
Paleiron et al. conducted a cross-sectional study to investigate the association between smoking and COVID-19 (2). The adjusted odds ratios (ORs) (95% confidence intervals [CIs]) of current smokers and subjects aged over 50 years for the risk of developing Covid-19 were 0.64 (0.49-0.84) and 2.6 (1.2-6.9), respectively. Smoking presented a protective effect on the developing COVID-19.
Farsalinos et al. conducted a meta-analysis to examine the effects of current smoking on adverse outcomes among hospitalized COVID-19 patients (3). Pooled OR (95% CI) of current smokers against non-current smokers and against former smokers for adverse outcomes was 1.53 (1.06-2.20) and 0.42 (0.27-0.74), respectively. Smoking relates to the progression of clinical outcomes in hospitalized COVID-19 patients, although the reason of poor clinical outcomes in former smokers should be explored by further studies.
There is another hypothesis that lithium will limit SARS-CoV2 infections. Rudd presented a hypothesis that the repurposing of low-cost inhibitors of glycogen synthase kinase-3 (GSK-3) such as lithium will limit SARS-CoV2 infections by both reducing viral replication and potentiating the immune response against the vi...
There is a hypothesis that nicotine may have a protective effect in COVID-19 (1). I present two recent reports on the association between smoking and COVID-19 infection/progression, and then presented reports regarding another mechanism of the association.
Paleiron et al. conducted a cross-sectional study to investigate the association between smoking and COVID-19 (2). The adjusted odds ratios (ORs) (95% confidence intervals [CIs]) of current smokers and subjects aged over 50 years for the risk of developing Covid-19 were 0.64 (0.49-0.84) and 2.6 (1.2-6.9), respectively. Smoking presented a protective effect on the developing COVID-19.
Farsalinos et al. conducted a meta-analysis to examine the effects of current smoking on adverse outcomes among hospitalized COVID-19 patients (3). Pooled OR (95% CI) of current smokers against non-current smokers and against former smokers for adverse outcomes was 1.53 (1.06-2.20) and 0.42 (0.27-0.74), respectively. Smoking relates to the progression of clinical outcomes in hospitalized COVID-19 patients, although the reason of poor clinical outcomes in former smokers should be explored by further studies.
There is another hypothesis that lithium will limit SARS-CoV2 infections. Rudd presented a hypothesis that the repurposing of low-cost inhibitors of glycogen synthase kinase-3 (GSK-3) such as lithium will limit SARS-CoV2 infections by both reducing viral replication and potentiating the immune response against the virus (4). Murru et al. mentioned that lithium presented a clear antiviral activity demonstrated at preclinical level, which would remain the antiviral activity in clinical settings (5). Snitow et al. described that the molecular targets of lithium included the signaling kinase GSK-3 (6), and the therapeutic use of lithium by focusing on GSK-3 might be useful in patients with COVID-19 infections. In any case, clinical trials are needed for verifying the efficacy and safety of applying lithium.
References
1. Usman MS, Siddiqi TJ, Khan MS, Patel UK, Shahid I, Ahmed J, Kalra A, Michos ED. Is there a smoker's paradox in COVID-19? BMJ Evid Based Med. 2020 doi: 10.1136/bmjebm-2020-111492. [Epub ahead of print]
2. Paleiron N, Mayet A, Marbac V, Perisse A, Barazzutti H, Brocq FX, Janvier F, Bertrand D, Bylicki O. Impact of tobacco smoking on the risk of COVID-19.A large scale retrospective cohort study. Nicotine Tob Res 2021. doi: 10.1093/ntr/ntab004. [Epub ahead of print]
3. Farsalinos K, Barbouni A, Poulas K, Polosa R, Caponnetto P, Niaura R. Current smoking, former smoking, and adverse outcome among hospitalized COVID-19 patients: a systematic review and meta-analysis. Ther Adv Chronic Dis 2020;11:2040622320935765.
4. Rudd CE. GSK-3 Inhibition as a therapeutic approach against SARs CoV2: Dual benefit of inhibiting viral replication while potentiating the immune response. Front Immunol 2020;11:1638.
5. Murru A, Manchia M, Hajek T, Nielsen RE, Rybakowski JK, Sani G, Schulze TG, Tondo L, Bauer M; International Group for The Study of Lithium Treated Patients (IGSLi). Lithium's antiviral effects: a potential drug for CoViD-19 disease? Int J Bipolar Disord 2020;8(1):21.
6. Snitow ME, Bhansali RS, Klein PS. Lithium and therapeutic targeting of GSK-3. Cells 2021;10(2):255.
Thank you for your Letter and concerns raised about delays to registration and failure to identify similar systematic review protocols in PROSPERO. PROSPERO, which provides registration free of charge, now receives over 47,000 submissions annually including both new submissions and resubmissions (from authors whose original submission required revision owing to low quality or incomplete information). With only 1.7 FTE administrative staff funded to manage PROSPERO, demand for registration outstrips capacity of staff to process requests.
Previous appeals to PROSPERO users to improve the quality of submission and thus reduce the need for query, feedback and resubmission and consequently demand on the register were unsuccessful. With the intention of reducing further delays, in 2020, a decision was made to automatically publish records waiting for more than 30 days from submission, providing they pass a series of automatic checks (assessing whether a record is submitted in English language and includes information about review methodology). This allowed us to focus efforts on supporting the research endeavour surrounding the global COVID-19 pandemic. We aim to publish reviews related to covid by the end of the next working day. As this has reduced the time to registration and been met with approval by the review community, we have decided to continue automatic publishing system. Future development plans involve exploring how a more detailed automatic checking process...
Show MorePawlak1 critiqued our challenge to conventional dietary guidelines for people diagnosed with familial hypercholesterolaemia (FH)2. Indeed, his criticism was so incriminatory that he stated our recommendation “constitutes malpractice”. Considering the gravity of his claim, especially as it is levied against co-authors who are mostly MDs, it is important to disclose what we actually recommended, and to point out the flawed evidence Pawlak used to claim that we have committed malpractice.
First, Pawlak misunderstood the purpose of our paper. We did not question “the efficacy of low-saturated fat, low-cholesterol diet to reduce LDL cholesterol”, as he stated. We provided strong support for the hypothesis that factors other than LDL-C, such as smoking, hypercoagulation and hyperinsulinemia, have a potent influence on the incidence of coronary events in FH that dwarfs that of LDL-C3. For example, in our Figure 4 we illustrated the findings of Gaudet et al.4, who demonstrated that FH people without obesity or insulin resistance had no greater rate of coronary heart disease (CHD) than non-FH people. In contrast, obese, insulin-resistant FH people had over 7 times greater incidence of CHD than non-FH people. Moreover, in recent work we have elaborated on the extensive, but largely ignored, literature demonstrating that factors other than LDL-C, such as increased levels of coagulation factors, explain why only a subset of FH individuals develop premature CHD5. Finally, we in...
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In a systematic review of cholesterol reduction clinical trials, DuBroff et al claimed that “the evidence presented challenges cardiovascular disease prevention through targeted reductions of LDL-cholesterol”. However, it should be noted that the concept authors claim to challenge has never been proved, nor properly tested (1). This raises the question of whether there is a need to disprove an unproven concept. In science, the burden is on the proof.
Nevertheless, if it was to disprove, we must recognize the limitations of the present study. Regarding testing "the target paradigm", the authors first categorized the trials as to whether they did or did not meet average LDL-cholesterol reduction recommended by AHA/ACC 2018 guidelines (2) for individuals. Then, they intended to test the association between reaching this arbitrary target (suggested by one specific guideline) with the trial being positive or negative regarding death or cardiovascular events. However, no statistical inference was performed for this main analysis and no significance level was presented for the interaction between reaching the target and having clinical benefit. Instead, in this systematic review that intended to test a hypothesis that implied interaction phenomenon, the authors "intentionally did not perform a meta-analysis" under the justification that trials “involved three different drug classes”.
Finally, as the authors noted, it was a systematic review of s...
Show MoreIn this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
Show MoreIn order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking in...
In this article, the authors follow a very ambitious objective: to refute the LDL central role in atherosclerosis paradigm. There is an ironic statement that quotes: if you point to the King, be sure not to leave him alive. Here I’m afraid this article leaves the King alive because the methodology chose had inferior quality of evidence in relation to a well-done metanalisys like –for example- the one which was published by the Cholesterol Treatment Trialist (CTT).
Show MoreIn order to the studies included in this selection there were some inconsistencies. First of all, the WOSCOPS trial and the AFCAPS/TexCAPS trial were used to analyze the effect of a reduction at least of 30% in LDL but these two pivotal articles showed a reduction of 20% and 25%, respectively. In fact, in the pilots’ study there were only 157 deaths from 6605 patients randomized so the study hadn’t enough statistical power to analyze the mortality endpoint. In the same direction, the selection of the SEAS study was controversial because in spite of achieves a 61% reduction in LDL, the population included hadn’t a clear indication of statin treatment in relation of ethical considerations, affecting the results in order to MACE and mortality. Also it was very polemical to include trials as SHARP or AURORA with patients on dialysis because we know this kind of treatment actives a lot of mechanisms of morbidity and mortality with independence of the LDL level. Other weak point is to analyze mortality taking in...
Dear Editor,
Show MoreRecent literature suggested increased risk of severe COVID-19 in smokers which also got affirmation from World Health Organization (WHO) [1, 2]. However, original peer reviewed research which explained pathophysiological basis of the enhanced COVID-19 severity in smokers is currently scarce. Increased expression of SARS-CoV-2 cell entry receptor ACE2 in respiratory tract and lung tissue of smokers unraveled from analysis of gene expression data was used to predict higher chances of SARS-CoV-2 infection but that failed to explain enhanced COVID-19 severity [3]. Few authors have suggested that increased risk of severe complications and higher mortality rate in infected smokers may be due to host-specific factors like weakening of respiratory health and immunity caused by chronic smoking [4]. However, none of the virus-related factors which can be responsible for the COVID-19 severity in smokers has been reported until date. Based on the recent research updates on SARS-CoV-2 specific virulence in host cells, we propose a plausible mechanism which associates smoking with increased severity of COVID-19.
Apart from a cell surface entry receptor, coronaviruses require furin (a host protease) mediated cleavage of their spike (S) protein for successful invasion of the host cell. SARS-CoV-2, a member of the genus betacoronaviruses, has evolved a unique furin protease S1/S2 cleavage site, which is absent in other family members, including SARS-CoV-1 [5]. Rec...
Usman et al (1) write that only one of the 18 studies of COVID-19 patients they included in their review of the Smoker's Paradox reported that "the prevalence of smokers resembles that of the general population."
But this study--by Richardson et al in New York City (2)--actually only reported the prevalence of "never smokers" at 84.4%. It did not distinguish between current and former smokers among the remaining 15.6%, however, so Usman et al should have marked this combined result with an asterisk in their Table 1. Far from resembling the general population, the 15.6% combined rate is less than half the 34% expected in USA, where approximately 14% are current and 20% former smokers. With this correction, all 18 studies support the Smoker’s Paradox, which belies the authors’ conclusion that a “protective effect should NOT be inferred” [emphasis added].
The protective effect is clearly real and further supported by the largest study of COVID-19 to date (n=7,162) with data on smoking status (3), which Usman et al did not include in their review. Current smokers in this CDC study comprised just 1.3% of all the COVID-19 patients seeking care from US hospitals in 50 states and Washington DC, 1.2% of those treated as outpatients, and 1.1% of those treated in intensive care units.
Usman et al also did not mention the compound most likely responsible for the protective effects of smoking against respiratory infections, which...
Show MoreThere is a hypothesis that nicotine may have a protective effect in COVID-19 (1). I present two recent reports on the association between smoking and COVID-19 infection/progression, and then presented reports regarding another mechanism of the association.
Paleiron et al. conducted a cross-sectional study to investigate the association between smoking and COVID-19 (2). The adjusted odds ratios (ORs) (95% confidence intervals [CIs]) of current smokers and subjects aged over 50 years for the risk of developing Covid-19 were 0.64 (0.49-0.84) and 2.6 (1.2-6.9), respectively. Smoking presented a protective effect on the developing COVID-19.
Farsalinos et al. conducted a meta-analysis to examine the effects of current smoking on adverse outcomes among hospitalized COVID-19 patients (3). Pooled OR (95% CI) of current smokers against non-current smokers and against former smokers for adverse outcomes was 1.53 (1.06-2.20) and 0.42 (0.27-0.74), respectively. Smoking relates to the progression of clinical outcomes in hospitalized COVID-19 patients, although the reason of poor clinical outcomes in former smokers should be explored by further studies.
There is another hypothesis that lithium will limit SARS-CoV2 infections. Rudd presented a hypothesis that the repurposing of low-cost inhibitors of glycogen synthase kinase-3 (GSK-3) such as lithium will limit SARS-CoV2 infections by both reducing viral replication and potentiating the immune response against the vi...
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