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.
Might it be helpful to clarify in the title or abstract that the paper relates solely to estrogen containing contraceptives, and essentially the oral versions?
Editor,
I welcome this publication with it's focus on a potentially important cause of adverse pregnancy outcomes.
This study has several methodological faults that need to be declared and addressed.
The study's single author has written extensively on this topic over the last 29 years. He cites several of his own publications in the paper, As far as I can judge, they are all critical of caffeine in pregnancy. Surely this puts him at risk of bias.
The best way to address such bias is to conduct a systematic review with precise methodology. Also, at least one other author should be involved in assessing suitability of the papers, and minimising bias.
Only English language papers are studied.
Only PubMed and Google Scholar are searched. No reference is made to other important databases such as CDSR, Medline, EMBASE and CINAHL.. There does not appear to have been any pre-specified eligibility criteria in assessing whether or not studies should be included in the review e.g. community based populations or pre defined study methods.
There is no attempt made to assess the quality of the studies used in writing the paper.
The search strategy appears vague.
The results in table 1 give odds ratio but there is no quantification of this. What we need is absolute risk with numbers needed to harm. If this figure cannot be calculated then we should be told and given the reasons why.
Editor,
I welcome this publication with it's focus on a potentially important cause of adverse pregnancy outcomes.
This study has several methodological faults that need to be declared and addressed.
The study's single author has written extensively on this topic over the last 29 years. He cites several of his own publications in the paper, As far as I can judge, they are all critical of caffeine in pregnancy. Surely this puts him at risk of bias.
The best way to address such bias is to conduct a systematic review with precise methodology. Also, at least one other author should be involved in assessing suitability of the papers, and minimising bias.
Only English language papers are studied.
Only PubMed and Google Scholar are searched. No reference is made to other important databases such as CDSR, Medline, EMBASE and CINAHL.. There does not appear to have been any pre-specified eligibility criteria in assessing whether or not studies should be included in the review e.g. community based populations or pre defined study methods.
There is no attempt made to assess the quality of the studies used in writing the paper.
The search strategy appears vague.
The results in table 1 give odds ratio but there is no quantification of this. What we need is absolute risk with numbers needed to harm. If this figure cannot be calculated then we should be told and given the reasons why.
These limitations need to be acknowledged. For such an important topic potentially affecting so many vulnerable women, a more precise review and assessment of current evidence is warranted.
‘There is no safe level of caffeine intake in pregnancy’. That is the conclusion of this ‘narrative review’ of caffeine safety in pregnancy (BMJ Evidence Based Medicine, Open Access) which a patient brought to my attention very recently after hearing about it on the mainstream media. I felt that it requires clarification to avoid concern amongst the general public and those unable to analyse and critically appraise the literature.
The single author concluded that, after finding 48 studies (37 observational studies and 11 meta-analyses), caffeine intake in pregnancy significantly increases the risk of miscarriage, stillbirth, low birth weight, childhood leukaemia and childhood overweight/obesity. The author then goes on to recommend that all worldwide guidelines (including American, UK and Australian) stating the safety of caffeine in doses<200mg/day (approximately 2 cups of coffee) should be revised to say ‘there is no safe level of caffeine in pregnancy’.
However, there is no need to panic, which appears to be the response of the mainstream media and patients from the general population. Very soon after publication, this paper was picked up by several news outlets including CNN, The Guardian and also on a number of social media streams. Women were being told not to drink coffee in pregnancy the same way they were being told not to drink alochol.
This paper is far from as conclusive as it tries to make the reader believe, but serves as a good exampl...
‘There is no safe level of caffeine intake in pregnancy’. That is the conclusion of this ‘narrative review’ of caffeine safety in pregnancy (BMJ Evidence Based Medicine, Open Access) which a patient brought to my attention very recently after hearing about it on the mainstream media. I felt that it requires clarification to avoid concern amongst the general public and those unable to analyse and critically appraise the literature.
The single author concluded that, after finding 48 studies (37 observational studies and 11 meta-analyses), caffeine intake in pregnancy significantly increases the risk of miscarriage, stillbirth, low birth weight, childhood leukaemia and childhood overweight/obesity. The author then goes on to recommend that all worldwide guidelines (including American, UK and Australian) stating the safety of caffeine in doses<200mg/day (approximately 2 cups of coffee) should be revised to say ‘there is no safe level of caffeine in pregnancy’.
However, there is no need to panic, which appears to be the response of the mainstream media and patients from the general population. Very soon after publication, this paper was picked up by several news outlets including CNN, The Guardian and also on a number of social media streams. Women were being told not to drink coffee in pregnancy the same way they were being told not to drink alochol.
This paper is far from as conclusive as it tries to make the reader believe, but serves as a good example of how language can be used to persuade when evidence does not.
This ‘study’ is not a properly conducted systematic review or metanalysis and to publish it as an ''evidence synthesis'' is dangerous, as it implies a level of rigor which is not demonstrated. Literature from only PubMed and Google Scholar were searched. The search was not systematically or transparently documented and there was no reference to the PRISMA guidelines. This is important as it means that a significant number of studies will have been missed in the search, introducing significant reporting bias (studies with results showing caffeine is safe in pregnancy may not have been included).
The paper looks at both observational studies and meta-analyses and it is not clear whether non-independence has been accounted for – that is, some of the individual studies may have been included in the reported metanalyses. This would result in duplication of the data and an overestimation of the effect size. Because the review was not systematic, there is no detailed analysis of confounding factors (ie. Women who drank alcohol or smoked as well as drank coffee during their pregnancy which could also effect the outcomes). The variation between the studies have not been reported or investigated (therefore, cannot be compared or summed). This ‘heterogeneity’ has not been identified or reported. There is no consideration of publication bias (when only studies with positive results tend to get published), and even more importantly, no analysis of bias in each individual study (which is mandatory for any meta-analysis).
The author appears to try to make conclusions based on the ‘number of studies that found an effect’ instead of the ‘number of participants that were effected’. It also doesn't account for the quality or lack of quality of each study. Even if a lot of studies find an effect, if they are not well designed then the effect may not exist.
This paper seems to be written without any balance, making one concerned about the agenda of the author. The author states that the safety of caffeine may be supported by caffeine corporations (coffee and soft drink manufacturers). Indeed, a quick ‘Google’ search of the author’s name shows that he has written two books about the dangers of caffeine. While this does not mean that this report can be discounted, it does give some insight into the motives of the author.
Interestingly, one randomised controlled trial which found no effect of caffeine in pregnancy is briefly mentioned in the discussion of the study, but quickly ‘discredited’.
In short, this ''narrative review'' has probably gained far more media attention than was initially intended, however, the overarching and far-reaching consequences of this are significant when the evidence behind its recommendations is non-systematic and biased. Publication of such work should be discouraged, as the impact on the general population cannot be underestimated.
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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Might it be helpful to clarify in the title or abstract that the paper relates solely to estrogen containing contraceptives, and essentially the oral versions?
Editor,
I welcome this publication with it's focus on a potentially important cause of adverse pregnancy outcomes.
This study has several methodological faults that need to be declared and addressed.
The study's single author has written extensively on this topic over the last 29 years. He cites several of his own publications in the paper, As far as I can judge, they are all critical of caffeine in pregnancy. Surely this puts him at risk of bias.
The best way to address such bias is to conduct a systematic review with precise methodology. Also, at least one other author should be involved in assessing suitability of the papers, and minimising bias.
Only English language papers are studied.
Only PubMed and Google Scholar are searched. No reference is made to other important databases such as CDSR, Medline, EMBASE and CINAHL.. There does not appear to have been any pre-specified eligibility criteria in assessing whether or not studies should be included in the review e.g. community based populations or pre defined study methods.
There is no attempt made to assess the quality of the studies used in writing the paper.
The search strategy appears vague.
The results in table 1 give odds ratio but there is no quantification of this. What we need is absolute risk with numbers needed to harm. If this figure cannot be calculated then we should be told and given the reasons why.
These limitations need to be ackno...
Show More‘There is no safe level of caffeine intake in pregnancy’. That is the conclusion of this ‘narrative review’ of caffeine safety in pregnancy (BMJ Evidence Based Medicine, Open Access) which a patient brought to my attention very recently after hearing about it on the mainstream media. I felt that it requires clarification to avoid concern amongst the general public and those unable to analyse and critically appraise the literature.
The single author concluded that, after finding 48 studies (37 observational studies and 11 meta-analyses), caffeine intake in pregnancy significantly increases the risk of miscarriage, stillbirth, low birth weight, childhood leukaemia and childhood overweight/obesity. The author then goes on to recommend that all worldwide guidelines (including American, UK and Australian) stating the safety of caffeine in doses<200mg/day (approximately 2 cups of coffee) should be revised to say ‘there is no safe level of caffeine in pregnancy’.
However, there is no need to panic, which appears to be the response of the mainstream media and patients from the general population. Very soon after publication, this paper was picked up by several news outlets including CNN, The Guardian and also on a number of social media streams. Women were being told not to drink coffee in pregnancy the same way they were being told not to drink alochol.
This paper is far from as conclusive as it tries to make the reader believe, but serves as a good exampl...
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