Covid-19: a remote assessment in primary care
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m1182 (Published 25 March 2020) Cite this as: BMJ 2020;368:m1182Read our latest coverage of the coronavirus outbreak
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Dear Editor
In their comment about the role of lipids in the Covid-19 epidemic, Dr. D´Erasmo and colleagues wonder whether high lipids are bystanders or players (1).
It is not an easy question. For instance, in the study by Graselli et al. (2) D´Erasmo and colleagues mention that hypercholesterolemia was the third most common comorbidity. However, according to the authors the patients´ cholesterol was a “baseline measure”, which means that many of them may have been on statin treatment when they fell ill. The same may explain the findings in the study by Mehran et al. (3) because the patients´ lipid values were from “a history of hypercholesterolemia”. According to D´Erasmo and colleagues, hyperlipidemia was found in 25% of the hospitalized patients reported by Petrelli et al. (4), but according to their paper the difference between the number of those with critical and non-critical illness was minimal (26.6 vs. 24.1%) and there was no information about the type of hyperlipidemia.
Was it a high level of LDL-cholesterol or a high level of triglycerides? An important question because, as I mentioned in my previous Rapid Response (5), high levels of the former are beneficial because the cholesterol-carrier LDL participates in the immune system, whereas high levels of the latter may be a marker of the metabolic syndrome.
1. D´Erasmo L et al. Plasma lipids in COVID-19: bystanders or players? www.bmj.com/content/368/bmj.m1182/rr-20
2. Grasselli G, Zangrillo A, Zanella A et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323(16):1574–1581. doi:10.1001/jama.2020.5394.
3. Mehra MR, Desai SS, Kuy S, et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. 2020 May 1. doi: 10.1056/NEJMoa2007621
4. Petrilli C, Jones S, Yang J, et al. Factors associated with hospitalization and critical illness among 4,103 patients with Covid-19 disease in New York City. Available at MedRxiv: doi: 10.1101/2020.04.08.20057794.
5. Ravnskov U. Cholesterol-lowering treatment may be a major cause of serious Covid-19 infections. www.bmj.com/content/368/bmj.m1182/rr-21
Competing interests: No competing interests
Dear Editor
Most researchers consider the association between low cholesterol and infection as reverse causality, meaning that it is the microorganisms or the inflammation which lower cholesterol. However, there is much evidence that the explanation is that low cholesterol predisposes to infection because, as I have mentioned in a previous comment (1), there is solid evidence that LDL partakes in the immune system by adhering to and inactivating almost all kinds of microorganisms and their toxic products (2). In accordance is a study of hospitalized patients with various types of infectious diseases, where those with the lowest LDL-C measured previously had the largest risk of developing sepsis and where the risk was highest among those on statin treatment (3).
As mentioned by Matteo Pirro (4) the authors of several studies have claimed that patients who have been prescribed statin treatment have a lower risk of infectious diseases. However, these studies have a serious bias, because the authors have not investigated whether the patients have continued the treatment. Therefore, the benefit may instead have been due to their high cholesterol because several studies have found that 40-80% of all statin-treated patients stop their treatment by themselves probably because statin treatment may cause many serious side effects (6,7). Thus, in the papers mentioned by Pirro the authors have compared people who may have had high cholesterol most of their life with untreated people, most of whom may have had normal or low cholesterol.
As mentioned by Pirro as well, no one has studied whether people with familial hypercholesterolemia (FH) are protected against infections. However, in a review of eight preliminary cholesterol-lowering trials using a PCSK9-inhibitor as treatment of hypercholesterolemic people, many of whom had FH, common adverse events were nasopharyngitis, upper respiratory tract infections and influenza (8).
That high cholesterol may be protective is evident because in a meta-analysis of 19 studies where the authors had followed more than 68,000 elderly people for several years, most of those with the highest LDL-cholesterol lived the longest. None of the studies found the opposite and after the publication of this analysis, at least eight studies including almost 700,000 individuals have come up with the same result (10-17).
There are therefore good reasons to stop statin treatment of patients with severe Covid-9 infection, also because at least 20 statin trials have been unable to lower mortality with statistical significance (7) and because more than 20% of statin-treated people suffer from serious side effects (6,7).
1. Ravnskov U. Cholesterol-lowering treatment may worsen the outcome of a Covid-19 infection. BMJ 2020;368:m1182. https://www.bmj.com/content/368/bmj.m1182/rr-10
2. Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci 2012;344:391-4. doi: 10.1097/MAJ.0b013e31824ba6e0
3. Guirgis FW, Donnelly JP, Dodani S et al. Cholesterol levels and long-term rates of community-acquired sepsis. Crit Care. 2016;20:408
4. Pirro M. Cholesterol and cholesterol-lowering in COVID-19: why we should not let our guard down. https://www.bmj.com/content/368/bmj.m1182/rr-18
5. Diamond DM, de Lorgeril M, Kendrick M, Ravnskov U, Rosch PJ. Formal comment on “Systematic review of the predictors of statin adherence for the primary prevention of cardiovascular disease”. PLoS ONE 2019;14: e0205138. https://doi.org/10.1371/journal. pone.0205138.
6. Diamond DM, Ravnskov U. How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Exp Rev Clin Pharmacol. 2015;8:201–210. doi: 10.1586/17512433.2015.1012494
7. Ravnskov U, de Lorgeril M, Diamond DM et al. LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Exp Rev Clin Pharm. 2018;11:959–970. doi.org/10.1080/17512433.2018.1519391
8. Farnier M, Gaudet D, Valcheva V, Minini P, Miller K, Cariou B. Efficacy of alirocumab in high cardiovascular risk populations with or without heterozygous familial hypercholesterolemia: Pooled analysis of eight ODYSSEY Phase 3 clinical program trials. Int J Cardiol 2016;223:750-7. doi: 10.1016/j.ijcard.2016.08.273.
9. 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: e010401. doi:10.1136/ bmjopen-2015-010401
10. You S, Zhong C, Xu J et al. LDL-C/HDL-C ratio and risk of all-cause mortality in patients with intracerebral hemorrhage. Neurol Res. 2016;38:903-908. doi: 10.1080/01616412.2016.1204797
11. Park C H, Kang EW, Park JT et al. Association of serum lipid levels over time with survival in peritoneal dialysis patients. J Clin Lipidol. 2017;11(4):945-54. doi: 10.1016/j.jacl.2017.06.004.
12. Ahn C, Hwang Y, Park SK. Predictors of all-cause mortality among 514,866 participants from the Korean National Health Screening Cohort. PLoS One. 2017;12(9):e0185458. doi: 10.1371/journal.pone.0185458.
13. Zuliani G, Volpato S, Dugo M, Vigna GB, Morieri ML, Maggio M, et al. Combining LDL-C and HDL-C to predict survival in late life: The InChianti study. PLoS One. 2017;12(9): e0185307. https://doi.org/10.1371/journal.pone.0185307.
14. Orozco-Beltran D, Gil-Guillen VF, Redon J et al. Lipid profile, cardiovascular disease and mortality in a Mediterranean high-risk population: The ESCARVAL-RISK study. PLoS One. 2017;12:e0186196. doi: 10.1371/journal.pone.0186196. Berton 589
15. Wang M-C, Hu H-Y, Lin I-F, Chuang J-T. Plasma lipid concentrations and survival in
geriatric population. A retrospective cohort study. Medicine. 2019;98:49(e18154). http://dx.doi.org/10.1097/MD.0000000000018154
16. Yousufuddin M, Takahashi PY, Major B et al. Association between hyperlipidemia and mortality after incident acute myocardial infarction or acute decompensated heart failure: a propensity score matched cohort study and a meta-analysis. BMJ Open. 2019;9:e028638. doi:10.1136/bmjopen-2018-028638
17. Dégano IR, Ramos R, Garcia-Gil. Three-year events and mortality in cardiovascular disease patients without lipid-lowering treatment. Eur J Prev Cardiol. 2019 doi: 10.1177/2047487319862103
18. Ravnskov U, de Lorgeril M, Diamond DM et al. LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Exp Rev Clin Pharm. 2018;11:959–70. doi.org/10.1080/17512433.2018.1519391
Competing interests: No competing interests
Dear Editor,
Recently, a report on SSRN and a rapid response on bmj.com suggest the role of reduced plasma cholesterol in worsening COVID-19 prognosis (1, 2). Subsequently, Pirro et al (3) in a rapid response on bmj.com argued the possible benefit of reducing low-density lipoprotein cholesterol (LDL-C) in this condition, irrespective of the infection-related hypocholesterolaemia. Moreover, these authors further suggested the possible beneficial role of statins during COVID-19 disease considering the high burden of cardiovascular complications observed in these patients.
We would like to invite everyone to be more cautious in interpreting the relationships between plasma lipids and COVID-19 disease, because the available evidence, as it has been collected, does not allow to draw any definitive conclusions about the causal role, if any, of plasma lipids or its treatment in influencing COVID-19 outcomes.
Support for this belief comes from a review of the literature we conducted to investigate the association between plasma lipids and SARS-CoV-2 infection. To this aim, we have recently searched in different electronic databases (Pubmed, SSNR, MedRixv) for any article reporting data on plasma lipids or hyperlipidaemia in COVID-19 patients. Lei Y et al (4) showed that there were no differences in plasma levels of total cholesterol and triglycerides (TGs) between symptomatic and asymptomatic patients with COVID-19. Similarly, comparable levels of blood lipids have been found in the 55 COVID-19 patients admitted to the Fifth Medical Center of PLA General Hospital (5). Moreover, in the 97 patients reported by Nie et al (6), authors have found no differences in levels of LDL-C and TGs between patients with severe or mild disease. Interestingly, in this report it was noted that plasma levels of high-density lipoprotein cholesterol (HDL-C) were lower in patients with the severe as compared to those with the milder form of pneumonia. These data may support the hypothesis that HDL particles may exert some protection against SARS-CoV-2 due to their well-known anti-microbial and anti-inflammatory actions (7).
A different picture emerges if we consider the prevalence of hyperlipidaemia. Though defined according to variable criteria, this condition appears to be largely represented in patients diagnosed with COVID-19. In a report including 1591 Italian patients with SARS-CoV-2 infection (8), hypercholesterolemia was the third most common (18%) comorbidity, after hypertension (49%) and cardiovascular diseases (21%). In the study considering 4,103 COVID-19 patients evaluated in New York City (9), hyperlipidaemia was found in 25% of hospitalized patients. Finally, in the recently published work (10) describing clinical characteristics of 8,910 COVID-19 patients collected in the observational database from 169 hospitals in Asia, Europe, and North America, the prevalence of hyperlipidaemia reached-up 30.2% among survivors and 35% among non-survivors.
Despite the increased prevalence of history of hyperlipidaemia in COVID-19 patients, its impact on disease prognosis appears weak. In 124 patients suffering with COVID-19, Simmonet et al (11) found that hyperlipidaemia was not able to predict the necessity of invasive mechanical ventilation. Similar results were reported by Zhang et al (12) who detected no association between hyperlipidaemia and severity of the disease. In the previously mentioned US study (9), authors found that hyperlipidaemia was a risk factor for hospitalization but not for critical illness (defined as a composite of care in the intensive care unit, use of mechanical ventilation, discharge to hospice, or death) and, finally, in the largest cohort of COVID-19 patients reported so far (10), the presence of hyperlipidaemia was not able to independently predict in hospital death.
A possible interpretation that might be helpful in clarifying this somewhat confusing picture is that plasma lipid levels or hyperlipidaemia should be considered as bystanders (or risk markers) rather than players directly involved in the pathogenesis of complications caused by SARS-CoV-2 infection. Indeed, it is well known that there is a strong link between plasma lipids or hyperlipidaemia and other comorbidities such as cardiovascular diseases, diabetes mellitus or obesity, which have been recognised to worsen the prognosis of COVID-19 (12). Similarly, the better chance of survival observed in SARS-CoV2 infected patients who reported previous use of statins (12,13), the most commonly used lipid-lowering medication, should be interpreted considering that statin use may be a proxy of increased cardio metabolic risk. On the other side, the low cholesterol levels observed in COVID patients with worst prognosis (1,2) can be well explained as the consequence of malnutrition that may occur in these patients (3,14) as well as the direct consequence of the more severe inflammation occurring in COVID-19 patients with poorest outcomes.
In summary, we are in favour of the idea that plasma lipids or hyperlipidaemia might have a neutral effect on COVID-19, but they can describe the metabolic status of patients, which may have a direct impact on disease’s prognosis. In this context, hyperlipidaemia may be eventually used as a clinical hallmark in identifying patients that may require more intensive care. However, further studies, including randomized clinical trials, are needed before any conclusion can be reached regarding a potential, direct role of lipids or its treatment in SARS-CoV-2 infection. We hope that these studies will focus mainly on evaluating those lipid fractions, e.g. TGs and HDL, which have the closest link with the immune system/meta-inflammation networking.
References
1. Hu X, Chen D, Wu L et al. Low Serum Cholesterol level among patients with COVID-19 infection in Wenzhou, China (February 21, 2020). Available at SSRN: https://ssrn.com/abstract=3544826.
2. Ravnskow U. Cholesterol-lowering treatment may worsen the outcome of a Covid-19 infection. https://www.bmj.com/content/368/bmj.m1182/rr-10
3. Pirro M, Bianconi V. Cholesterol and cholesterol-lowering in COVID-19: why we should not let our guard down (May 1, 2020). https://www.bmj.com/content/368/bmj.m1182/rr-18
4. Lei Y，Huang X, Lang B et al. Clinical features of imported cases of coronavirus disease 2019 in Tibetan patients in the Plateau area. Available at MedRxiv: doi:10.1101/2020.03.09.20033126.
5. Yang P, Ding Y, Xu Z, et al. Epidemiological and clinical features of COVID-19 patients with and without pneumonia in Beijing, China. Available at MedRxiv: doi:10.1101/2020.02.28.20028068.
6. Nie S, Zhao X, Zhao K, et al. Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study. Available at MedRxiv: doi:10.1101/2020.03.24.20042283.
7. Pirillo A, Catapano AL, Norata GD. HDL in infectious diseases and sepsis. Handb Exp Pharmacol. 2015;224:483-508. doi:10.1007/978-3-319-09665-0_15.
8. Grasselli G, Zangrillo A, Zanella A et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020;323(16):1574–1581. doi:10.1001/jama.2020.5394.
9. Petrilli C, Jones S, Yang J, et al. Factors associated with hospitalization and critical illness among 4,103 patients with Covid-19 disease in New York City. Available at MedRxiv: doi: 10.1101/2020.04.08.20057794.
10. Mehra MR, Desai SS, Kuy S, et al. Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19. N Engl J Med. 2020 May 1. doi: 10.1056/NEJMoa2007621
11. Simonnet A, Chetboun M, Poissy J, et al. Lille Intensive Care COVID-19 and Obesity study group. High prevalence of obesity in severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) requiring invasive mechanical ventilation. Obesity (Silver Spring). 2020 Apr 9. doi: 10.1002/oby.22831.
12. Zhang JJ, Dong X, Cao YY, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy. 2020 Feb 19. doi: 10.1111/all.14238
13. Castiglione V, Chiriacò M, Emdin M, et al. Statin therapy in COVID-19 infection, European Heart Journal - Cardiovascular Pharmacotherapy. doi: 10.1093/ehjcvp/pvaa042
14. Laviano A, Koverech A, Zanetti M. Nutrition support in the time of SARS-CoV-2 (COVID-19). Nutrition. 2020 Apr 2:110834. doi: 10.1016/j.nut.2020.110834.
Competing interests: No competing interests
Dear Editor,
The article by Greenalgh, Koh and Car is excellent and very useful for those of us volunteering for the COVID-19 Clinical Advisory Service, but I disagree on two points that are important to highlight.(1)
Firstly, the article regards the combination of a pulse of 110 bpm *with* the onset of new confusion as an important clinical indicator of severity that should drive admission to hospital. I would regard new confusion as an alarming symptom that may drive admission regardless of whether the pulse is above or below 100 bpm. I could not trace the provenance of this criterion, that appears in the infographic and the text, further back than the Centre for Evidence-Based Medicine "Rapid diagnosis strategy of community-acquired pneumonia for clinicians" (2), and certainly both the National Early Warning Score-2 (NEWS2) (3) and the NICE guidance on managing suspected COVID-19 pneumonia in the community (4) consider tachycardia and new confusion as independently important clinical signs when deciding on admission. I worry that some people with COVID-19 and new onset confusion may not be admitted to hospital on the basis that their pulse is below 100 bpm as a result.
The second point regards the Roth score. This article recognises a lack of consistency in how a straw-poll of 50 clinicians regard its value, but the corresponding question response on the CEBM web-site is more forthright in its rejection, going so far as to say "No" to the question "Should the Roth score be used in the remote assessment of patients with possible COVID-19?". "No" would be the right answer to the question "Should the Roth Score be used as a sole criterion for determining admission to hospital in suspected COVID-19". However, the answer to the question "Could the Roth score ever provide information that an experienced clinician might find useful in making their decision to direct a patient towards admission?" then the answer would be "Yes". It seems illogical to dismiss a piece of information as being so unreliable that it must not be used on the basis that it has a significant false positive and negative rate and has not been validated in the context of COVID-19, and to replace it with information about which we have no idea at all about the sensitivity and specificity in any context. There would not be much information we would be allowed to use in medicine if this was a logic that was widely applied.
I understand that the Roth score has been over-valued and inappropriately applied by some -with potentially negative consequences. There is a need to take account of its limitations if it is used, but it would be wrong to dismiss it entirely just because it would not often be helpful. In the context of the grave uncertainties and constraints faced in managing suspected COVID-19 remotely, all of our information is imperfect. In these circumstances different items of imperfect information can be used for triangulation. If the evidence from the narrative questioning recommended in the text, what is heard subjectively when talking to the patient, and the Roth score are all concordant, then that can increase confidence in a particular course of action. However, should the evidence be discordant, then that should prompt a search for additional sources of information and the allowance of a wider margin of potential error in our assessment. There is no need to routinely collect the Roth score, and it will not often yield useful information, but it may be one of those items of information where judicious use can be of value.
Yours sincerely,
Dr Chris Martin,
Director of Modelling at Crystallise Ltd, Honorary Researcher at CHIME, UCL and volunteer for the COVID-19 Clinical Advisory Service.
1. Greenhalgh, T., G. C. H. Koh, and J. Car. 2020. “Covid-19: a remote assessment in primary care.” BMJ 368.
2. Pluddemann, Annette, Richard Hobbs, Kamal R. Mahtani, and Carl Heneghan. 2020. Rapid Diagnosis Strategy of Community-Acquired Pneumonia for Clinicians. Oxford.
3. National Institute for Health and Care Excellence. 2020. “COVID-19 Rapid Guideline : Managing Suspected or Confirmed Pneumonia in Adults in the Community.” (April):1–14.
4. Royal College of Physicians. 2017. “National Early Warning Score (NEWS) 2.” Retrieved May 2, 2020 (https://www.rcplondon.ac.uk/projects/outputs/national-early-warning-scor...).
Competing interests: No competing interests
Dear Editor,
A response in the BMJ states that reduced plasma cholesterol levels might be the cause instead of the consequence of COVID-19 (1,2). The acute cholesterol-lowering impact of infections is largely documented in prospective observations (3) and recently also in COVID-19 (1). Malnutrition-inflammation-cachexia may explain such an effect. Thus, reverse causality (i.e., infections cause cholesterol reduction) instead of causality should be considered in interpreting the association between cholesterol and infections.
The proposed ability of LDLs to inactivate and protect rats from bacterial toxins is intriguing (2); however, it should be weighed against additional evidence. PCSK9 loss-of-function mutations are associated with significant LDL cholesterol reductions, but not with infection risk (4,5); they improve, instead, survival in patients with septic shock (6). Also, no reduced risk of infections is reported in patients with severe familial hypercholesterolemia.
The inverse association between total cholesterol and mortality discussed by Dr. Ravnskov should be interpreted with caution in the light of the limitations declared by the Authors of the original papers (7,8) (e.g., design of the study, ecological nature of some associations, no data on cholesterol subfractions, single cholesterol measurement, lack of adjustment for important confounders). In particular, chronic wasting diseases may distort even the long-term association between cholesterol and survival. Also, the epidemiological findings need to distinguish different lipoproteins, particularly HDLs, which possess antimicrobial and immune-modulatory properties. Therefore, the net reduction in plasma total cholesterol, which commonly involves HDL cholesterol, might reflect reduced anti-microbial actions of HDLs predisposing to infectious diseases (9).
The protective role of cholesterol-lowering cannot be disclaimed. Statins reduce cholesterol and cardiovascular risk (10) without negatively affecting prognosis in septic patients (11). Statins improve prognosis in patients with bacterial and viral infections (12-14) and reduce viral load in patients with chronic hepatitis C (15). Finally, statins increase the expression of ACE2, the entry receptor for SARS-CoV-2 (16), whose cell surface expression is supposed to be reduced after viral binding. Reduced ACE2 expression upon SARS-CoV-2 binding should increase levels of the pro-inflammatory/pro-fibrotic angiotensin II, potentially exacerbating tissue inflammation and damage. Thus, statins may protect tissues from the deleterious impact of angiotensin II. This is additional to the reported efficacy of statins in mitigating myocarditis and thrombotic events, which are lethal features of COVID-19 (17,18).
In our opinion, available data do not allow us to affirm that low plasma cholesterol levels and the use of cholesterol-lowering drugs may worsen the outcome of patients with COVID-19. Oppositely, a clinical benefit may derive from lowering LDL cholesterol in these conditions, irrespective of the infection-related hypocholesterolemia. The rational for the use of statins is particularly emphasized if we consider the high burden of cardiovascular complications of COVID-19 (19). As in other critical situations, attention should be paid when using multi-drug regimens including statins, antibiotics and antiretroviral drugs.
References
1. Hu, X, Chen D, Wu L, He G, Ye W. Low Serum Cholesterol level among patients with COVID-19 infection in Wenzhou, China (February 21, 2020). Available at SSRN: https://ssrn.com/abstract=3544826.
2. Ravnskow U. Cholesterol-lowering treatment may worsen the outcome of a Covid-19 infection. BMJ 2020;368:m1182.
3. Feingold KR, Grunfeld C. The Effect of Inflammation and Infection on Lipids and Lipoproteins. [Updated 2019 Jan 8]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK326741/
4. Feng Q, Wei WQ, Chaugai S, Carranza Leon BG, Kawai V, Carranza Leon DA, Jiang L, Zhong X, Liu G, Ihegword A, Shaffer CM, Linton MF, Chung CP, Stein CM. A Genetic Approach to the Association Between PCSK9 and Sepsis. JAMA Netw Open. 2019 Sep 4;2(9):e1911130.
5. Mitchell KA, Moore JX, Rosenson RS, Irvin R, Guirgis FW, Shapiro N, Safford M, Wang HE. PCSK9 loss-of-function variants and risk of infection and sepsis in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. PLoS One. 2019 Feb 6;14(2):e0210808.
6. Momtazi AA, Banach M, Sahebkar A. PCSK9 inhibitors in sepsis: a new potential indication? Expert Opin Investig Drugs. 2017 Feb;26(2):137-139.
7. Jacobs D, Blackburn H, Higgins M, Reed D, Iso H, McMillan G, Neaton J, Nelson J, Potter J, Rifkind B. Report of the conference on low blood cholesterol: Mortality associations. Circulation 1992; 86:1046–60. https://doi.org/10.1161/01.cir.86.3.1046
8. Iribarren C, Jacobs DR Jr, Sidney S, Claxton AJ, Feingold KR. Cohort study of serum total cholesterol and in-hospital incidence of infectious diseases. Epidemiol Infect 1998; 121:335–47. https://doi.org/10.1017/s0950268898001435
9. Pirillo A., Catapano A.L., Norata G.D. (2015) HDL in Infectious Diseases and Sepsis. In: von Eckardstein A., Kardassis D. (eds) High Density Lipoproteins. Handbook of Experimental Pharmacology, vol 224. Springer, Cham
10. Johnston TP, Korolenko TA, Pirro M, Sahebkar A. Preventing cardiovascular heart disease: Promising nutraceutical and non-nutraceutical treatments for cholesterol management. Pharmacol Res. 2017 Jun;120:219-225.
11. Pertzov B, Eliakim-Raz N, Atamna H, Trestioreanu AZ, Yahav D, Leibovici L. Hydroxymethylglutaryl-CoA reductase inhibitors (statins) for the treatment of sepsis in adults - A systematic review and meta-analysis. Clin Microbiol Infect. 2019 Mar;25(3):280-289.
12. Wang ST, Sun XF. Role of Statins in Treatment and Prevention of Community-acquired Pneumonia:A Meta-analysis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2018 Feb 28;40(1):30-40.
13. Zheng YX, Zhou PC, Zhou RR, Fan XG. The benefit of statins in chronic hepatitis C patients: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2017 Jul;29(7):759-766.
14. Uthman OA, Nduka C, Watson SI, Mills EJ, Kengne AP, Jaffar SS, Clarke A, Moradi T, Ekström AM, Lilford R. Statin use and all-cause mortality in people living with HIV: a systematic review and meta-analysis. BMC Infect Dis. 2018 Jun 5;18(1):258.
15. Grammatikos G, Farnik H, Bon D, Böhlig A, Bader T, Berg T, Zeuzem S, Herrmann E. The impact of antihyperlipidemic drugs on the viral load of patients with chronic hepatitis C infection: a meta-analysis. J Viral Hepat. 2014 Aug;21(8):533-41.
16. South AM, Diz DI, Chappell MC. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol. 2020 May 1;318(5):H1084-H1090.
17. Guan J, Sun X, Liang Y, Dong W, Zhang L, Zhu J, Wang G. Atorvastatin attenuates Coxsackie virus B3m-induced viral myocarditis in mice. J Cardiovasc Pharmacol. 2010 Nov;56(5):540-7.
18. Chaffey P, Thompson M, Pai AD, Tafreshi AR, Tafreshi J, Pai RG. Usefulness of Statins for Prevention of Venous Thromboembolism. Am J Cardiol. 2018 Jun 1;121(11):1436-1440.
19. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020 May;17(5):259-260.
Competing interests: No competing interests
Dear Editor,
According to Ravnskov (1), based on an observational study by Hu et al (2), cholesterol lowering treatment should be ceased in patients with a life-threatening Covid-19 infection. We argue that such advice should not be based on observational studies which have the inherent problem of several forms of bias and confounding that could explain the observed higher mortality from infectious diseases in subjects with low serum cholesterol.
Total and low-density have now (2) been shown to be significantly lower during severe Covid-19 infection, but as demonstrated previously low cholesterol levels are good markers of infectious disease severity (3). Importantly, this observation does not show causality, since low cholesterol levels may in fact be the result of (the severity of) the disease itself, as has been shown as early as 1952 by Dutch researchers (4).
The physical and emotional stress that accompany severe infection also influence cholesterol levels (5).
Taken together, since data from randomized clinical trials are lacking to support the conclusion of Ravnskov, the advice to cease cholesterol lowering therapy should be strongly discouraged, except in the setting of a well designed, controlled and preferably randomized study. More importantly, such strong recommendations could easily be misused by lay- and social media and result in discontinuation of cholesterol lowering therapies in high risk groups for cardiovascular events. We fear that this could worsen the outcome for this group of patients who already underuse the cardiovascular services due to COVID19-anxiety.
References:
1. Ravnskov, U. Cholesterol-lowering treatment may worsen the outcome of a Covid-19 infection. BMJ 2020;368:m1182
2. Hu, X, Chen D, Wu L, He G, Ye W. Low Serum Cholesterol level among patients with COVID-19 infection in Wenzhou, China (February 21, 2020). Available at SSRN: https://ssrn.com/abstract=3544826
3. Gustavo Lima, W, Alves Souza, N, Antunes Fernandes, SO, Nascimento Cardoso, V, Piassi Godói, I. Serum Lipid Profile as a Predictor of Dengue Severity: A Systematic Review and Meta-Analysis. Rev Med Virol . 2019 Sep;29(5):e2056. doi: 10.1002/rmv.2056. Epub 2019 Jun 6.
4. Groen, J., Tjiang, B. K., Kamminga, C. E., and Willebrands, A. F. (1952), Voeding, 13, 556
5. Gordon, H. The regulation of the human serum-cholesterol level. Postgrad Med J. 1959 Apr;35(402):186-96
Competing interests: No competing interests
Sir
Roth Score in Covid 19 Assessment - Throwing the baby out with the bath water
As one of the front line GPs assessing patients with Respiratory Issues, and a Public Health Physician, I am disappointed by the level of epidemiological and scientific rigour applied by the Centre for Evidence Medicine in their paper on the Roth Test.
As was stated in the article, there are no validated tests on assessing breathlessness in Primary Care but many of us elt that using the Roth Test as part of our holistic assessment was a useful way of trying to apply a bit more rigour to our the process.
The fact that some patients would be missed (False Negatives) is a feature or all screening tests, and is one that is appreciated by most of us working in General Practice.
Fortunately most of us in primary care will err on the side of caution and will also use multiple methods to confirm our initial assessment. The Roth Score we know will miss 1 in 5 cases. However in practice it was a useful adjunct to our other enquires. Our current sensitivity in COVID 19 antigen testing locally is 80% - much the same as the Roth test – should we stop using it?
When there is nothing else what do you do? You develop your own process. The Roth Test has now been replaced on many primary care guidelines with the ‘40m walk test’ or ‘room to room’ or ‘stair climbing test’; all with no validation whatsoever.
The fate of the test was decided by 50 ‘experts’’ opinions – those who according to the publication ‘regularly assess patients by phone’. However the paper goes on to say of this expert delphi group that - ‘Of (the) 50 experts, only 6 used the Roth score (most had never heard of it)’. An expert group indeed!!
And so we have in one fell swoop, on the basis on a group of so called experts, thrown the baby out with the bath water and deprived front line staff of a test that, for all its short comings, was better than anything that has now found common usage in the remote assessment of breathlessness.
For an organisation whose work I have in the past held in high esteem, this falls far short of the scientific rigour I have come to expect.
Are there any evidence-based ways of assessing dyspnoea (breathlessness) by telephone or video
Trish Greenhalgh, Koot Kotze and Helene-Mari Van Der Westhuizen
On behalf of the Oxford COVID-19 Evidence Service Team, Nuffield Department of Primary Care Health Sciences, University of Oxford
02.04.2020 first published on 23.03.2020
Clinical Cardiology 04 October 2016
Assessment of Respiratory Distress by the Roth Score
Ehud Chorin Allison Padegimas Ofer Havakuk MD Edo Y. Birati Yacov Shacham Anat Milman MD Guy Topaz Nir Flint Gad Keren Pages: 636-639
Yours
Dr Peter Florida-James
MB ChB MRCGP MFPHM MFSEM DCH DRCOG DSEM DSM MBA
Competing interests: No competing interests
Dear Editor,
Thank you to Professor Greenhanlgn and her team for the write up of the excellent BMJ article “COVID-19: A remote assessment in Primary Care”
Firstly, the article is timely given how the primary care practitioners are facing the burden of management of patients with the associated risks. The helpful article and the infographic help many family care Practitioners focus on the management of patients remotely using telephone and if necessary video-based consultations. Although remote medicine practice using telephone and video tools have been around for a while, it is only recently after the WHO declared the coronavirus disease 2019 (COVID-19) a public health emergency of international concern. ¹ Many countries across the globe had to adopt quarantine measures for the population which resulted in many primary care practitioners to go adopt telephone or video-based consultations. However, the article does not address some key areas relating to the privacy of the patients.
Despite the relaxation of the privacy issues across North America, and Europe for primary care Practitioners to enable them to practice video-based encounters, some simple measures could be adopted. Many encounters with the patient in the real world are in a confidential environment, however, given the urgency of the COVID-19 situation, we must adopt some changes to the practice of medicine. The use of many internet standardized test-taking strategies using Webcam could be adopted. Asking the patient open-ended questions like if they are alone in the room, or if they could go into a private area of the house, could be one option. Also, the patient could scan the room around with their camera to ensure that privacy is maintained.
In the case of challenges to the assessment of breathing virtually, there are off the shelf wearables which measure the oxygen saturation but given the current situation with shortage of medical devices, it may be difficult to procure them rapidly. The microphone of the smartphone could be placed closer to the chest wall to listen to the breathing sounds. However, further research is needed to test the validity of these methods.
It must be noted that the surge in utilizing video visits could place a strain on the bandwidth², using standard telephone tools and text-based messaging³ could be adopted. The COVID 19 has shifted the paradigm of medical practice, and video-based encounters could be the standard mainstay in the practice of medicine in the upcoming years, as we move into the uncharted reorganization of the primary care health system.
Reference
1. World Health Organization. Coronavirus disease (COVID-19) outbreak (https://www.who.int.).
2. Reeves JJ, Hollandsworth HM, Torriani FJ, et al. Rapid Response to COVID-19: Health Informatics Support for Outbreak Management in an Academic Health System. Journal of the American Medical Informatics Association. March 2020. doi:10.1093/jamia/ocaa037
3. Grange ES, Neil EJ, Stoffel M, et al. Responding to COVID-19: The UW Medicine Information Technology Services Experience. Applied Clinical Informatics. 2020;11(02):265-275. doi:10.1055/s-0040-1709715
Competing interests: No competing interests
Dear Editor,
The Covid-19 outbreak was officially designated as a pandemic on March 11th by the WHO. It has rapidly spread to 190 counties across the world with 1,413,415 cases and 81,200 deaths as of April 7, 2020 [1]. The pandemic has accelerated in the West over the last two weeks, making it the new epicenter of the virus. Around Feb 13th, there were 15,000 newly diagnosed cases in China, increasing the total number of confirmed cases to 60,000. However, with the interventions of limiting the travel to and from the epidemic areas and expanding the capacity to triage patients with suspected infection, the number has decreased rapidly. Until March 30, the existing confirmed cases in China was 3199 and decreasing daily. Presently, the Covid-19 cases prevalent in China are the result of overseas travel. In a situation such as this, anti-epidemic issues require global cooperation, prevention and control, and global coordination and response.
Early detection and quick response in the initial period of disease spread is critical, which is easy to miss [2]. Europe and the United States are now becoming the new epicenter of the Covid-19 virus and are drawing global attention. It is possible that every major outbreak was a result of a lack of early vigilance against this disease, leading to a large amount of community transmission occurring in a short period of time, and a correspondingly costly public health response. There are lessons that can be learned by these countries, increasing their experience combatting epidemics.
The economic and psychological impact of the COVID-19 epidemic is believed to be enormous [3] despite extensive implementation of control measures. Nowadays, the disease is severe in developed countries (see top 10 countries of the newly-increasing cases daily), but that does not seem so in less developed countries, such as countries in Africa. As is known, Africa has the largest number of countries and the second largest population, accounting for more than 10 percent of the world's total population. Countries in the region have relatively vulnerable health systems and a low overall level of preparedness - regarding overall ability to prevent, detect and respond to public health emergencies timely [4]. However, the existing diagnosis cases and the cumulative number of diagnosed cases in Africa made up less than 1% of the global total until March 30. By April 7, the total number of cases in Africa reached over 10,000. At a population of 200 million people, only 238 individuals were diagnosed with COVID-19 in Nigeria. A similar pattern is found in other countries of Africa, including 52 cases in Ethiopia and 1322 cases in Egypt in a population of over 100 million.
Is it really such that there are so few cases in African countries with huge populations or is something else at play? How many were asymptomatic patients causing the disease continues to spread, was there adequate detection and were the criterion for testing applied homogeneously? With the limited information, we don’t know the exact reasons. However, a looming epidemic of COVID-19 in Africa presents a deadly threat. This is especially the case in densely populated urban areas with limited opportunities for social distancing, poor baseline systems to support hygiene and sanitation. It is believed that water scarcity in Africa contributes to lack of handwashing and hand hygiene [5].
And other detailed possible reasons are, 1) insufficient subjective attention about COVID-19 in some African countries, 2) lack of medical resources—one finds fewer than 4 hospital beds per capita in Sub-Saharan Africa [6], low surgical mask use, even in hospital wards [7] 4) insufficient detection strength, and 5) the neglect of the international community.
The international community will ignore the less developed countries in Africa, however viruses don't. This was apparent in 2013, when the international community implemented guidelines such as patient isolation, biosafety protocols, and PPE use among healthcare workers to prevent an Ebola pandemic [8]. In such a context of globalization, no country is immune and no country stands alone. For fighting the epidemic of COVID-19, international community should strengthen global cooperation to prevent a potentially catastrophic outbreak of Covid-19 in Africa and reduce the corresponding damage. Such Africa must be put on the map of the global fight against epidemic, even in poor and war-torn countries.
Here, we call on the less developed countries in Africa and international community to pay more attention to the Covid-19 disease in these countries and take full advantage of possible window periods. Means of “Four early” proposed by China including early screening, early detection, early diagnosis and early treatment could better prevent and control the COVID-19 pneumonia and it also applies for international community. We also call for the international organization to appreciate the distribution of health resources in low- and middle-income countries that have weak health-care systems from a global vision perspective.
We hope that you can appreciate the importance of our sentiment and that you would consider our response for printing in the weekly edition of BMJ.
Yanqing Fang, MD,PhD 1,2, Jack Ersbo 3, Bing Chen, MD,PhD 1,2, Yilai Shu, MD, PhD 1,2
1 ENT Institute and Otorhinolaryngology Department of the Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University. Shanghai, 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
2 NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai, 200031, PR China
3 Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, U.S.A.
Correspondence to: Dr. Yilai Shu (yilai_shu@fudan.edu.cn) and Bing Chen (chenbing@fudan.enu.cn), ENT Institute and Otorhinolaryngology Department of the Affiliated Eye and ENT Hospital, State Key Laboratory of Medical Neurobiology, Fudan University. Shanghai, 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
References
1. Coronavirus disease (COVID-19) outbreak. 2020 ]https://www.who.int/westernpacific/emergencies/covid-19
2. Hellewell J, Abbott S, Gimma A, Bosse NI, Jarvis CI, Russell TW, Munday JD, Kucharski AJ, Edmunds WJ, Sun F, Flasche S, Quilty BJ, Davies N, Liu Y, Clifford S, Klepac P, Jit M, Diamond C, Gibbs H, van Zandvoort K, Funk S, Eggo RM, Centre FTMM. Feasibility of controlling COVID-19 outbreaks by isolation of cases and contacts. The Lancet Global Health 2020, 8(4): e488-e496.
3. Lazzerini M, Putoto G. COVID-19 in Italy: momentous decisions and many uncertainties. The Lancet Global Health 2020.https://doi.org/10.1016/S2214-109X(20)30110-8
4. R HCBM. Africa is not starting from scratch on COVID-19. 2020 https://www.thinkglobalhealth.org/article/africa-not-starting-scratch-co...
5. Pickering A, Boehm A, Mwanjali M, Davis J. Efficacy of waterless hand hygiene compared with handwashing with soap: a field study in Dar es Salaam, Tanzania. Am J Trop Med Hyg. 2010. 82(2): 270-278.
6. Zere E. Hospital Efficiency in Sub-Saharan Africa. World Institute for Development Economics Research. June 2000.
7. Mehtar S. Lowbury Lecture 2007: infection prevention and control strategies for tuberculosis in developing countries--lessons learnt from Africa. Journal of Hospital Infection. 2008. 69, 321-327.
8. Briand S, Bertherat E, Cox P, Formenty P, Kieny M, Myhre J, Roth C, Chir B, Shindo N, Dye C. The international Ebola emergency. New England Journal of Medicine. 2014; 371:1180-1183.
Competing interests: No competing interests
Re: Covid-19: a remote assessment in primary care
Dear Editor
I read this article and also watched Prof Greenhalgh in Webinar presentation. I feel 10 min remote consultation can be very useful tool in assessing patients providing one has technology access to the patient or patient's carer at both ends . Technology access must be user friendly at both ends and must be readily understandable to the recipient i.e translated .
Remote consultation has to comply same format and discipline as in face to face consultation and any misunderstanding or incorrect advice can lad to adverse consequences . If technology access is available I will use remote consultation initially to my patients whom I have been seeing for a long time. I have on may occasions advised my regular patients on phone at no cost. For me technology access is the major challenge. Covid-19 pandemic is an example Remote advice in mass scale to millions of people -I am talking about India with1.3 billion population with more than 21 major languages suddenly imposed most rigid lockdown with barely 4 hours ' notice for coming to term with pandemic and leaving many millions of informal vital workforce without their only means sustaining their bare existence. If they any notice they could have used public transport to get back their villages. Remote consultation is used extensively all over the world and rapidly advancing its application . Covid-19 pandemic has povided a challenge to the world to perfect the art communication for health and well being all.
Scientists and public at large in the world are doing their best to come to term with pandemic but a lot more needs to be done to have technology to win hearts and minds of people across the nations in the world so that we can all live within our means within the bounds of nature.
Competing interests: No competing interests