Mauritius - When the effects of saturated fat replacement failed to conform to the modelling, no-one cared.

There may be no country in the world in which a suggested limit on saturated fat has not been followed by a relatively rapid increase in the incidence of diabetes and obesity.

Of course this is a matter of observation not experiment, but so is most of the evidence that various dietary guidelines organizations have relied on over the years.

 

A particularly egregious case seems to have occurred in Mauritius, after the Mauritian Government changed the fat content of ration oil, a cheap cooking oil used by most of the population, by decree. In 1987 it had been 75-100% (median 87.5%) palm oil, with (by then) some soybean oil – overnight this was changed to 100% soybean oil. This change was based on predictions from the research of Ancel Keys into heart disease, in particular the 7 Countries study and the intervention in East Finland.

This took PUFA intakes (almost all linoleic acid) to 8.6%E for men and 8.8%E for women, and lowered SFA intakes to 7%E and 7.5%E respectively. These were, as reported, not high fat diets, and it may be relevant that Mauritius is a sugar-producing nation.[1,2]

 5 years later, in 1992, researchers, including experts from Finland and the WHO, measured the changes in fat intake and cholesterol in the Mauritian population, focusing on Hindu Indians.

 

"In the 5-year survey of lipids and other biomarkers, mean population serum total cholesterol concentration fell appreciably from 5.55 mmol/l to 4.7 mmol/l (P<0.001). The prevalence of overweight or obesity increased, and the rates of glucose intolerance changed little."[1]

 

However, in a letter to the BMJ, N Chandrasekharan, a consultant chemical pathologist and Kalyana Sundram, senior research officer of the Palm Oil Research Institute of Malaysia disputed these findings -

 "On the purported fall in serum cholesterol concentration from 5.7 mmol/l in 1987 to 4.6 mmol/l in 1992, it is not evident whether the samples were from the same subjects.

The data for 1992 on the per caput fat intake of 56.2 g per day based on a 24 hour dietary recall is a far cry from the 73.7 g reported by the Food and Agriculture Organisation. The figures for edible oil intake seem erroneous. In 1987 palm oil accounted for only 27.5% of the edible oils consumed and its saturated fatty acids contributed 1.89% of the total energy intake and this fell to 0.33% in 1992."[3]

 

However, we have previously found FAO fat consumption estimates to be unreliable, overestimating NZ butter consumption in recent years by a factor of 4. And Chandrasekharan and Sundram’s letter contains this statement:

 "Although we are also concerned about the need to reduce the prevalence of non­communicable diseases in Mauritius, we disagree on the kind of simplistic thinking and draconian measures advocated."[3]

 

In other words, whatever the effect on fat intakes or cholesterol, the change was a radical one. It put more linoleic acid into the Mauritian food supply, and as in other places, the change in mandated fats would have been accompanied by voluntary changes along the same lines. We may doubt whether cholesterol levels changed, but not that people began to consume more soybean oil.

 So what happened? The 1987 intervention included several good ideas – exercise more, smoke less, drink less – as well as less certain ones – eat less salt, eat less saturated fat and more soybean oil.

 However, it seems unlikely that CVD went down – circulatory mortality as a percentage of mortality increased after 1987. [4]

 "Over 1981–2004 the proportion of circulatory disease mortality rose from 44% to 49% in males, and from 46% to 57% in females."

 

Mauritius is now #2 in the world for diabetes mortality. However, a coding change in 2004 meant that much of what had been recorded as circulatory disease mortality was shifted to diabetes mortality. What we do know is that diabetes prevalence increased, as has incidence of pre-diabetes.

 "The prevalence of Type 2 diabetes increased significantly during the period studied, from 12.8% in 1987, to 15.2% in 1992, and 17.9% in 1998."[5]

 

Note that this contradicts the 1992 claim – by some of the same authors – that “the rates of glucose intolerance changed little” between 1987 and 1992, a discordance not mentioned in the 2002 paper.[1]

 "The age-standardized prevalence of diabetes in 2009 was 22.3% (95% CI 20.0–24.6) among men and 20.2% (18.3–22.3) among women, representing an increase since 1987 of 64 and 62% among men and women, respectively".[6]

 

The Mauritius fat change paper has been cited just 17 times in 25 years, and not one of the citing papers includes any follow up on the consequences of the change there. For example, an AHA paper mentions the Mauritius change in glowing terms without following up whether benefit or harm ensued, beyond the claimed 5-year drop in cholesterol.[7] Palm oil reduction was modelled for India in 2013, and a doubled palm oil tax has been implemented in Fiji since, all in papers citing the 1987-1992 Mauritius cholesterol drop.[8, 9]
But none follows that citation up with any hard outcomes.

 Conversely, none of the papers on health in Mauritius since 1992, charting worsening trends, and in which the Finns still feature as authors, mentions the oil change of 1987. However, the earlier paper had contained a warning:[2]

 "Whether the replacement of palm oil by soya bean oil, rich in n-6 polyunsaturated fatty acids, is the optimal dietary change may be questioned... the consumption of fats high in polyunsaturated fatty acids may lead to increased concentrations of free radicals and oxidised low-density lipoprotein, which may promote the progression of atherosclerosis. Therefore, notwithstanding the apparent success of the intervention in Mauritius, an oil high in monounsaturated fatty acids, such as olive oil or rapeseed oil, might be preferable if such an oil substitution were currently being planned."

 

It appears now that both saturated fat in the diet, and a low intake of omega 6 linoleic acid,  are beneficial in terms of the incorporation of the omega 3 fatty acids EPA and DHA into circulating lipids and cells.[10, 11, 12, 13] EPA in particular is anti-inflammatory, and is an approved drug for the prevention of CVD.[14]

 "These observations indicate that the efficacy of n-3 fatty acids in reducing arachidonic acid level is dependent on the linoleic acid to saturated fatty acid ratio of the diet consumed."[11]

 "The results suggest that dietary substitution of SFA with n-6PUFA, despite maintaining low levels of circulating cholesterol, hinders n-3PUFA incorporation into plasma and tissue lipids."[13]

 

The conversion of linoleic acid to arachidonic acid, and the peroxidation of arachidonic acid to aldehydes which interfere with insulin signaling, as well as its conversion to cannabinoids which increase adipocyte growth, in a context of decreased omega 3 availability from high LA and low SFA diet, are pathways that may explain the eventual adverse outcomes in Mauritius, especially in a population with high sugar availability.[15,16]

 "Our recent finding that sucrose and other high glycemic index carbohydrates abrogate the antiobesity effect of n-3 PUFAs might, at least in part, provide an explanation to the apparent discrepancy between human and rodent intervention studies, and the lack of effect in some human trials. In addition to the amount and type of carbohydrates, the levels of n-6 PUFAs, linoleic acid in particular, in the background diet might influence the antiobesogenic effect of n-3 PUFAs."[15]

 

It seems that, in the matter of diet, public health experts cannot be relied on to investigate the possibility that they have made a mistake. They control the narrative so that a (questionable) historical change in cholesterol within a 5-year period is considered evidence that a lifetime intervention is valuable, yet a nation-wide worsening of hard endpoints after that intervention can be ignored. Certainly the diabetes disaster in Mauritius can have had many causes, but the possibility that the soya bean oil intervention was one of them has not even registered in the medical literature over a 30 year period, let alone been tested.

 H/T Louise Stephen @LouiseStephen9 author of  'Eating Ourselves Sick' for bringing this intervention to my attention.

Postscript: it will be obvious to students of evidence-based medicine that the quality of evidence used to create this argument has left much to be desired. With the exception of the date and intent of the intervention and the diabetes incidence data, nothing here tells us quite what we want to know. For example, circulatory disease as a percentage of mortality is a suggestive but imperfect measure, even before the coding change. So there will be those who read this article and feel justified in dismissing the need for it.
But I ask them to look at things another way - the data in this page is, to the best of my knowledge, the sum total of the published, peer-reviewed evidence on the subject. The Mauritius intervention - a legal disruption of the saturated fat supply to replace it with unsaturated fat within an entire community, in a way designed to target its most vulnerable members - has been the masturbation fantasy of a certain type of public health epidemiologist for as long as I can remember. There is a constant supply of peer-reviewed publications modelling the long-term effect of such an intervention on the putatively preventable causes of mortality, and there have been none directly investigating the impact on those causes in this case - where the long-planned intervention actually happened.
The reasons for this neglect are a matter for conjecture; we may hear future tales of suppressed data and publication bias as we did with the Sydney Heart Study and Minnesota Coronary Experiment studies (both of which also involved changes of fat products given to a population, rather than the less certain changes of mere advice given in most other diet-heart studies)[17] but the conclusion ought surely to be that the modelling should stop until the facts have been checked. 

References

[1]  Dowse GK, Gareebo H, Alberti KGMM, Zimmet P, Tuomilehto J, Purran A, et al. Changes in population cholesterol concentrations and other cardiovascular risk factor levels after five years of the non­communicable disease intervention programme in Mauritius. BMJ 1995;311:1225­9.

 

[2]  Uusitalo U, Feskens EJM, Tuomilehto J, Dowse G, Haw U, Fareed D, et al. Fall in total cholesterol concentration over five years in association with changes in fatty acid composition of cooking oil in Mauritius: cross sectional survey. BMJ 1996;313:1044­6.

 

[3]  Chandrasekharan N, Sundram K. Fall in cholesterol after changes in composition of cooking oil in Mauritius. BMJ. 1997;314(7079):516. doi:10.1136/bmj.314.7079.516

 

[4]  Morrell, S., Taylor, R., Nand, D. et al. Changes in proportional mortality from diabetes and circulatory disease in Mauritius and Fiji: possible effects of coding and certification. BMC Public Health 19, 481 (2019) doi:10.1186/s12889-019-6748-7

 

[5]  Söderberg S, Zimmet P, Tuomilehto J, de Courten M, Dowse GK, Chitson P, Gareeboo H, Alberti KG, Shaw JE. Increasing prevalence of Type 2 diabetes mellitus in all ethnic groups in Mauritius. Diabet Med. 2005 Jan;22(1):61-8.

 

[6]  Magliano DJ, Söderberg S, Zimmet PZ, et al. Explaining the increase of diabetes prevalence and plasma glucose in Mauritius. Diabetes Care. 2012;35(1):87–91. doi:10.2337/dc11-0886

 

[7]  Mozaffarian D, Afshin A, Benowitz NL, et al. Population approaches to improve diet, physical activity, and smoking habits: a scientific statement from the American Heart Association. Circulation. 2012;126(12):1514–1563. doi:10.1161/CIR.0b013e318260a20b

 

[8]  Basu S, Babiarz KS, Ebrahim S, Vellakkal S, Stuckler D, Goldhaber-Fiebert JD. Palm oil taxes and cardiovascular disease mortality in India: economic-epidemiologic model. BMJ. 2013;347:f6048. Published 2013 Oct 22. doi:10.1136/bmj.f6048

 

[9]  Coriakula J, Moodie M, Waqa G, Latu C, Snowdon W, Bell C. The development and implementation of a new import duty on palm oil to reduce non-communicable disease in Fiji. Global Health. 2018;14(1):91. Published 2018 Aug 29. doi:10.1186/s12992-018-0407-0

 

[10]  Gibson, Robert A. Musings about the role dietary fats after 40 years of fatty acid research. Prostaglandins, Leukotrienes and Essential Fatty Acids, Volume 131, 1 – 5

 

[11] Garg ML, Thomson ABR, and Clandinin M T. Interactions of saturated, n-6 and n-3 polyunsaturated fatty acids to modulate arachidonic acid metabolism.

The Journal of Lipid Research, February 1990 , 31, 271-277.

 

[12] Dabadie H, Motta C, Peuchant E, LeRuyet P, Mendy F. Variations in daily intakes of myristic and alpha-linolenic acids in sn-2 position modify lipid profile and red blood cell membrane fluidity. Br J Nutr. 2006 Aug;96(2):283-9.

 

[13] Dias Cintia B, Wood LG, and Garg Manohar L. Effects of dietary saturated and n-6 polyunsaturated fatty acids on the incorporation of long-chain n-3 polyunsaturated fatty acids into blood lipids. European Journal of Clinical Nutrition. 2016; 70: 812-818

 

[14] Budoff M, Brent Muhlestein J, Le VT, May HT, Roy S, Nelson JR. Effect of Vascepa (icosapent ethyl) on progression of coronary atherosclerosis in patients with elevated triglycerides (200-499 mg/dL) on statin therapy: Rationale and design of the EVAPORATE study. Clin Cardiol. 2018;41(1):13–19. doi:10.1002/clc.22856

 

[15] Madsen L, Kristiansen K. Of mice and men: Factors abrogating the antiobesity effect of omega-3 fatty acids. Adipocyte. 2012;1(3):173–176. doi:10.4161/adip.20689

 

[16] Clark TM, Jones JM, Hall AG, Tabner SA, Kmiec RL. Theoretical Explanation for Reduced Body Mass Index and Obesity Rates in Cannabis Users. Cannabis Cannabinoid Res. 2018;3(1):259-271. Published 2018 Dec 21. doi:10.1089/can.2018.0045


[17] Ramsden Christopher E, Zamora Daisy, Majchrzak-Hong Sharon, Faurot Keturah R, Broste Steven K, Frantz Robert P et al. Re-evaluation of the traditional diet-heart hypothesis: analysis of recovered data from Minnesota Coronary Experiment (1968-73) BMJ 2016; 353 :i1246
https://www.bmj.com/content/353/bmj.i1246

A Reading List, and I Shill for a New Cookbook

It's been a time for reading lists; in lockdown I enjoyed discovering the books of T.H. White (The Goshawk and The Age of Scandal) and Evan S. Connell (Mrs Bridges) and reading Hillary Mantel's memoir (Giving Up the Ghost).
Sam Kriss also has a great reading list in Damage magazine, which features some of the best political writing I've read in ages - kind of a Leftist Spectator, if you get my drift, i.e. an honest journal, in a time when honesty is a rare and dangerous thing.

This is a reading list I compiled for PreKure a while back, of books most worth reading if you're interested in the nutrition-and-health ideas this blog has covered over the years.


The Perfect Health Diet, Paul and Shou-Ching Jaminet, 2012

This was one of the first “Paleo” books I read and, in my opinion, still one of the best. There are all sorts of sensible ideas, lots of references, and it’s not exclusively low carb. Some of their theoretical objections to keto diets haven’t come to much, and can be taken with a grain of salt, but there’s so much of value here to compensate. As far as population health goes, this is a clever and coherent interpretation of the evidence.


The Daughter of Time, Josephine Tey, 1951

This amusing 1950’s British detective story is a “research thriller”. The action, such as it is, takes place in a hospital bed as an injured detective sends his friends to libraries in search of the evidence in the case of a well-known historical mystery. Tey’s genius, and the lasting appeal of this book (Christopher Hitchens called it one of the most important ever written) is to show us how the most cherished received beliefs can be based – if we look closely – on lies and hearsay, the suppression of evidence, and self-serving propaganda. (*cough* saturated fat *cough*) And when Tey’s detective comes around to her alternative hypothesis, he oversells it – we suspect the author’s bias by now, and already know the evidence is too corrupt to accept; so its very flaws help to make this book perfect. If you want to inoculate young adults against fake news without getting mired in any modern controversies, convince them to read The Daughter of Time.


Foods of the Foreign Born in Relation to Health, Bertha M. Wood, 1922

Wood was a US dietitian and wrote this book at a time when the US was receiving migrants and refugees from all over Europe, as well as Mexico and the Middle East; some had brought political terrorism with them, xenophobia was if anything more extreme than it is today, and in this climate Wood wanted to familiarise nursing and dietetic students with the variety of immigrant diets so that they could help these populations in what we would today call a culturally appropriate manner. Thanks to her research we can learn about the real Mediterranean diets of 100 years ago, and that Hungarians gave children whiskey instead of milk on their cereal. A feature of this book is that Wood tells us how to adapt each population’s diet for diabetics by removing the starchy carbs. Foods of the Foreign Born is available free online at https://archive.org/details/foodsforeignbor00woodgoog/page/n6


Biochemistry. Mathews, van Holde, Ahern. 3rd edition. 2000.

This is a second-hand biochemistry textbook. I recommend older editions like this, which you can sometimes find in op shops, because they give less space to the biochemistry of the genome, which isn’t useful information if you’re interested in nutrition, and thus have more nuts-and-bolts detail than whatever they’re selling today. It also says on page 841 that “Adult onset diabetes can often be controlled by dietary restriction of carbohydrate”. Only experts in biochemistry were allowed to tell us something that simple and true in 2000 - the rest of the world back then only cared about saturated fat and felt that the Mediterranean Diet was quite daring.
This book is, amongst other things, your essential guide to what functions vitamins and minerals really perform in the body. Disclaimer – I understand few of the many mathematical formulas in this book that are an essential part of a real biochemistry education, but enjoyed this book nonetheless, making especial use of the index.


The Meat Fix: How a Lifetime of Healthy Living Nearly Killed Me! John Nicholson, 2012

This is a light, funny read by a UK sports journalist who wrecked his gut and metabolic health by trying to be a good vegetarian. I recommend it as a consumer’s eye view of the path many are on today, and also an insight into what popular low-carb science looks like to an ordinary convert – a bit pseudoscientific from our perspective, but still thoroughly effective.


And, of course, The Big Fat Surprise (Nina Teicholz) and Why We Get Fat (Gary Taubes) – these are the books that best explain how we got to where we are today.


Now, I've never run advertising on this blog. I did try at one stage, when I ran out of money, but Google weren't interested. Their loss, my escape.

However, given a chance to sell out in a good cause, in a time when paid work ain't what it used to be, I've leapt at it.

Ally Houston from PaleoCanteen has written "Low Carb on a Budget" with chef John Meechan and this is the book I've long meant to write but never had time for.
Lower income people are most likely to suffer from the conditions for which low carb is the specific cure, from metabolic syndrome to obesity to type 2 diabetes to depression, anxiety and chronic pain.
Yet low-carb cookbooks are often written by foodies and include a wide variety of expensive, hard to find, and - not to put too fine a point on it - unnecessary - ingredients. Even without these, there is still some extra cost over white bread, sugar, margarine and processed meat, but nothing you won't soon make back from your dentist, doctor, pharmacy and snack bills.
Low Carb on a Budget gets high praise from those most worth listening to in the UK diet-and-public health debate; if you don't know the names of some of those praising it, check out their work.
Another great selling point is that I'll get a pound, whatever that is, for every copy sold through the link above, and the  Public Health Collaboration, a very effective lobby group in the UK, will get 50p.

My Letter to Cochrane on the Hooper 2020 saturated fat meta

I submitted this on the Cochrane form at
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011737.pub2/comment

Others will have points to add about study quality and other factors, I have stuck to what I know (not wanting to waste my life battling an opponent who can obviously be reanimated an unlimited number of times).


The introduction to this meta-analysis includes an error uncorrected from the 2015 version.
Oliver 1953 measured total cholesterol, not LDL cholesterol. Further, it is relevant that every subject in Oliver 1953 had been eating the same hospital diet for at least 5 weeks before the cholesterol samples were taken, which does not support a diet-heart interpretation of the results.[1] (The presence of FH in the sample, and/or survivorship bias, are probably more reasonable interpretations)

[1] The Plasma Lipids in Coronary Artery Disease. Oliver MF, Boyd GS. Br Heart J. 1953 Oct;15(4):387-92. 

The section headed "Agreements and disagreements with other studies or reviews" has not addressed any written after 2014, meaning that this section has not been updated. There are several analyses of the diet heart trials since 2015 that should have been addressed (indeed, that should have been read before the current Cochrane review was designed). Some are listed below.[2,3.4]

[2] Hamley, S. The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials. Nutr J 16, 30 (2017). https://doi.org/10.1186/s12937-017-0254-5

[3] Thornley S, Schofield G, Zinn C, Henderson G. How reliable is the statistical evidence for limiting saturated fat intake? A fresh look at the influential Hooper meta-analysis. Intern Med J. 2019;49(11):1418‐1424. doi:10.1111/imj.14325

[4] Jeffery L Heileson, Dietary saturated fat and heart disease: a narrative review, Nutrition Reviews, Volume 78, Issue 6, June 2020, Pages 474–485, https://doi.org/10.1093/nutrit/nuz091

The discussion of Siri-Tarino 2010 in "Agreements and disagreements with other studies or reviews" claims that adjustment for lipids has confounded its null result, however Siri-Tarino at al had already addressed this by isolating studies not adjusted for lipids with no difference in their null result. This is quite understandable as adjusting for lipids also means adjusting for TG and HDL, cardiometabolic risk markers which can be beneficially infuenced by saturated fat and worsened by carbohydrate.
Studies which do not adjust for lipids can be favourable to saturated fat, for example the Malmo DCS, a high-quality observational study using a 7-day food diary and more rigorous exclusion criteria than is usual, or the 2019 dose-response meta-analysis of observational studies by Zhe et al.[5,6]

[5] Leosdottir M, Nilsson PM, Nilsson JA, Månsson H, Berglund G. Dietary fat intake and early mortality patterns--data from The Malmö Diet and Cancer Study. J Intern Med. 2005;258(2):153‐165. doi:10.1111/j.1365-2796.2005.01520.x

[6] Zhu, Y., Bo, Y. & Liu, Y. Dietary total fat, fatty acids intake, and risk of cardiovascular disease: a dose-response meta-analysis of cohort studies. Lipids Health Dis 18, 91 (2019). https://doi.org/10.1186/s12944-019-1035-2

The claim that greater lowering of LDL in trials being associated with greater reduction of events supports the diet-heart hypothesis may be unsound. Persons in good metabolic health are at significantly lower risk of CVD events despite other risk factors.[7] Persons who are obese, have diabetes, or the metabolic syndrome do not usually experience drops in LDL cholesterol when fat in the diet is changed; the subjects in the feeding studies cited, who did experience such drops, were healthy volunteers.[8,9,10]

[7] Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Low triglycerides-high high-density lipoprotein cholesterol and risk of ischemic heart disease. Arch Intern Med. 2001;161(3):361‐366. doi:10.1001/archinte.161.3.361

[8] Flock MR, Green MH, Kris-Etherton PM; Effects of Adiposity on Plasma Lipid Response to Reductions in Dietary Saturated Fatty Acids and Cholesterol, Advances in Nutrition. 2011;2,(3):261–274, https://doi.org/10.3945/an.111.000422

[9] Benatar JR, Sidhu K, Stewart RAH. Effects of High and Low Fat Dairy Food on Cardio-Metabolic Risk Factors: A Meta-Analysis of Randomized Studies. Tu Y-K, ed. PLoS ONE. 2013;8(10):e76480. doi:10.1371/journal.pone.0076480.

[10] Lefevre M, Champagne CM, Tulley RT,et al. Individual variability in cardiovascular disease risk factor responses to low-fat and low-saturated-fat diets in men: body mass index, adiposity, and insulin resistance predict changes in LDL cholesterol. Am J Clin Nutr. 2001;82(5):957–963, https://doi.org/10.1093/ajcn/82.5.957

It is also relevant that from 2004 the Swedish population began to reject diet-heart advice, to such an extent that butter sales rose and margarine sales dropped; cholesterol levels also rose.[11] Yet as recently as 2018 mortality from, and incidence of, AMI was continuing to decline in Sweden. In fact incidence of AMI had stayed stable from 1987 to 2005, after which it began to drop from 42,263 PA to 25,789 PA in 2018.[12]


[11] Johansson I, Nilsson LM, Stegmayr B, Boman K, Hallmans G, Winkvist A. Associations among 25-year trends in diet, cholesterol and BMI from 140,000 observations in men and women in Northern Sweden. Nutr J. 2012;11:40.

[12] Data accessed from Swedish Social Registry website 28/05/20 https://sdb.socialstyrelsen.se/if_hji/resultat.aspx

Probiotics for the prevention of Upper Respiratory Tract infections - a back-of-the-envelope Bradford Hill analysis

“With most people, disbelief in a thing is founded on a blind belief in something else" 
      G. C. Lichtenberg


The Cochrane Collaboration found low-quality evidence that probiotics prevent UTRIs, and moderate-quality evidence that probiotics reduce antibiotic prescriptions for UTRI.
Because the antibiotic finding is most robust (aside from bearing the higher-quality GRADE score, it's also not a self-reported outcome), we'll take this as our baseline and see if it is strengthened or weakened by a Bradford Hill analysis.

1) Strength of association: for antibiotic use, RR 0.65 (0.45 to 0.94), n=1184.[1]
The true association is subject to type 2 confounding by two factors - by intention-to-treat analysis, and potentially by the random consumption of yogurt and other fermented foods supplying similar effects.

2) Consistency of association: the association is consistent, with similar (but slightly larger) effect sizes for all other measures of URTI. The association is reasonably consistent between different trials (there is no major contradiction). The association is strongly consistent with the effects of probiotics on vaccination immunity (RCTs using independently measured serum makers so more robust than the UTRI trials). The association is consistent with results for sambucus (effect size 1.717) (see 9, "analogy").[1,2,3,4]

3) Specificity: Probiotics have had no consistent association with several other outcomes predicted for them. Probiotic treatment of mothers during pregnancy only results in better immunity after vaccine for mother, not infant, consistent with dendrite cell pathway for effect.[2]

4) Temporality: Implicit in trial design

5) Biological gradient: dose-reponse is seldom tested in probiotic experiments perhaps because of assumption that a living organism can replicate, however a dose-response for duration of treatment is seen in the vaccine studies.[3] The analogous effect of echinacae purpurea in zebrafish is strongly dose-dependent.[5]

6) Plausibility: effect of probiotic on immune tone is well-studied, insofar as the immune system is currently understood the effect is plausible. Increased innate immunity around infection improves the acquired immune response. "A significant property of these bacteria is their ability to mimic natural infections, while intrinsically possessing mucosal adjuvant properties".[6] Dendrite cell presentation provides plausible pathway.[7]

7) Coherence - laboratory and field work are strongly coherent, animal experiments support human, herbs with similar immune effects to probiotics in experiments tend to have similar associations with URTIs in RCTs.[4]

8) Experiment - the association is experimental, the mechanism holds across a wide range of experiment types, including those with lowest risk of confounding or placebo effect.

9) Analogy - herbal effects are analogous, as when plant polysaccharides mimic bacterial lipopolysaccharides. Vaccine adjuncts are also analogous. Probiotics and herbal antivirals are researched as adjuvants.

Bradford Hill analysis allows us to see an association within its complete scientific context, to test whether it is causal.
It was originally designed to test the low-quality evidence that arises from purely observational, non-interventional studies, but is also useful to test the results of experiments where one considers these inadequate by themselves.

Here's what I think is the parsimonious way to explain the association: In the vaccine research, probiotics double the odds of lasting immunity after vaccination. Many infections are "repeats" of infections we have had before but lost immunity to. If probiotics prevent "repeat" infections by maintaining antibody responses, this can account for the effect, even without a direct effect on immunity to any new pathogen (although this is also plausible).
Immunologists are currently worried that many exposed to COVID-19 have not had a sufficient or lasting antibody response and are at risk of re-infection. The less re-infectious COVID-19 is, the sooner we can safely end our current economic restrictions, which will also take a toll on human life if maintained indefinitely.



1] Cochrane Database of Systematic Reviews. Q Hao, RB Dong, T Wu.
Probiotics for preventing acute upper respiratory tract infections
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD006895.pub3/full

2] Zimmermann P, Curtis N. The influence of probiotics on vaccine responses - A systematic review.
Vaccine. 2018 Jan 4;36(2):207-213. doi: 10.1016/j.vaccine.2017.08.069. Epub 2017 Sep 18.
https://www.ncbi.nlm.nih.gov/pubmed/28923425

3] Lei WT, Shih PC, Liu SJ, Lin CY, Yeh TL. Effect of Probiotics and Prebiotics on Immune Response to Influenza Vaccination in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Nutrients. 2017;9(11):1175. Published 2017 Oct 27. doi:10.3390/nu9111175
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707647/

4] Hawkins J, Baker C, Cherry L, Dunne E. Black elderberry (Sambucus nigra) supplementation effectively treats upper respiratory symptoms: A meta-analysis of randomized, controlled clinical trials. Complement Ther Med. 2019 Feb;42:361-365. doi: 10.1016/j.ctim.2018.12.004. Epub 2018 Dec 18.

5] Guz L, Puk K, Walczak N, Oniszczuk T, Oniszczuk A.
Effect of dietary supplementation with Echinacea purpurea on vaccine efficacy against infection with Flavobacterium columnare in zebrafish (Danio rerio). Pol J Vet Sci. 2014;17(4):583-6.


6] Benef Microbes. 2020 Mar 27:1-14. doi: 10.3920/BM2019.0121. [Epub ahead of print]
Immune modulatory capacity of probiotic lactic acid bacteria and applications in vaccine development.
Mojgani N, Shahali Y, Dadar M.

7] Gallo PM, Gallucci S. The dendritic cell response to classic, emerging, and homeostatic danger signals. Implications for autoimmunity. Front Immunol. 2013;4:138. Published 2013 Jun 10. doi:10.3389/fimmu.2013.00138

You can't Boost your Immunity? or, Debunking the COVID-19 Skeptics.

Kate's elderberry concoction, photograph by Hayley Theyers

Is there anything as useless as the professional Skeptic community in a health  crisis? Some people are paid to be roadblocks, others are educated professionals going well outside their lanes after the witches they despise for getting in their lanes at other times, others are just the sort of people who get an existential thrill from negating what they don't understand, or journalists with a "tough" reputation to uphold and a grab-bag of empty rhetoric.
In the history of science no-one has been wrong more often than the skeptic. What we usually call scepticism in the scientific method is just BEING CAREFUL.
"The first principle is that you must not fool yourself and you are the easiest person to fool." Richard P. Feynman
This is nothing like rushing into print with a negative opinion and a few pejoratives on a subject you haven't studied until now so you're either linking to the first blog that agrees with you on an emotional level, instead of looking at the literature, or you're scanning the literature quickly for reasons to dismiss it.

It's far more useful to point to what we DO know. And the first thing to be said, quite clearly, is that you CAN boost your immune system. See the evidence below. And a fast-acting, broad-spectrum immune response is how we get on top of new pathogens.
Straight up, it needs to be stated that COVID-19 is a new virus, with some specific features. Not everything that applies to previous colds, flus, or pneumonial diseases may apply.  So all older evidence needs to be evaluated carefully. But it's not completely new, this isn't smallpox in the New World, it's a nasty variation on the cold viruses we've seen before and the healthiest immune systems can usually react appropriately, as we see when we consider the high rate of mild cases and the low symptom load in the very young. The pattern so far is characteristic of other pandemics; people with no or light symptoms seem to have had a strong initial immune response and are producing antibodies to COVID-19. Here is a COVID-19 immunological case study of a mild infection, which concludes:
“our study indicates that robust multi-factorial immune responses can be elicited to the newly emerged virus SARS-CoV-2 and, similar to the avian H7N9 disease, early adaptive immune responses might correlate with better clinical outcomes.“
https://www.nature.com/articles/s41591-020-0819-2.pdf

In humans, we can test whether a compound (or organism) improves the recognition of new pathogens by giving it with a vaccine.
Consistently, acetaminophen (tylenol, paracetamol) suppresses this function in infants.
https://www.ncbi.nlm.nih.gov/pubmed/19837254Effects are dose- and drug-dependent - low-dose aspirin doesn't impair immunity in elderly given flu vaccine, ibuprofen doesn't impair it compared with paracetamol in infants.
Probiotics enhance it.
https://www.sciencedirect.com/science/article/pii/S0264410X17311672

We know that probiotics enhance the immune response in vaccinated infants, but we can't take those infants and then expose them to the disease to learn how significant this is - herd immunity means that the risk is low in a vaccinated population even for people whose vaccines didn't work. We can however do this in animals.
Here's an experiment where zebrafish were vaccinated against a bacterial pathogen, Flavobacterium columnare, then bathed in said pathogen, with varying amounts of echinacea purpurea in their diets.
It's a tough test with, you might think, little possibility of a placebo effect.
The first point is that this vaccine doesn't really work. Only 5% of vaccinated fish are surviving exposure to Flavobacterium columnare. But add the echinacea to their feed, and we see survival climb dose-dependently. 5g echinacea per Kg is the same as none - 5% survival. 10g/Kg = 6%. 20g/Kg = 30%. 30g/Kg = 36%.
https://www.ncbi.nlm.nih.gov/pubmed/25638970
That link is down at sci-hub, so here is a similar study by the same team - without the vaccine.
https://www.researchgate.net/publication/230257632_Effect_of_Echinacea_purpurea_on_growth_and_survival_of_guppy_Poecilia_reticulata_challenged_with_Aeromonas_bestiarum

You're not going to get ethics approval to try this in humans, so make of this what you can. Firstly, why echinacea? The active ingredient is a polysaccharide, and it likely activates a variety of TLR and NOD receptors much as pathogen lipopolysaccharides do.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140398/
Similarly with probiotic cell wall lysates. A company I worked for tested a lysate from a lactobacillus rhamnosus strain many years ago and found it had ligand activity at TLRs 2,4,7,9, and NOD2, which latter is a gamma-interferon pathway.
This is going to enhance the response to a pathogen, which relies on you recognising quickly that it IS a pathogen via PAMPs and DAMPs (q.v.), a signal which compounds with such activity are amplifying.
This is well-known in human vaccine research - such compounds are called adjuvants and play a poorly-understood role in establishing immunodominance (the identification and proliferation of the "right" antibody-producing (B, Th2) immune cell).

Another commonly used herbal supplement, andrographis, has similar adjuvant effects given with vaccines in animal experiments
https://www.ncbi.nlm.nih.gov/pubmed/17321475.

Elderberry has AFAIK not been tested as an adjuvant but has direct antiviral effects in mice exposed to human influenza A.
https://pdfs.semanticscholar.org/8850/575f0665e98360dc6386ad828e66f573d270.pdf

So what is the human evidence? Elderberry (sambucus) is effective for seasonal URT infections in a meta-analysis. The studies only add up to n=180, but the effect is large and consistent (you don't need a high-powered study when something has a decent effect - we're not counting crumbs here, there's a loaf on the table).
https://www.ncbi.nlm.nih.gov/pubmed/30670267

This is likely due to cytokine effects, and some people might ask "what about cytokine storm?"
https://pubmed.ncbi.nlm.nih.gov/11399518/

Cytokines early in infection are the immune system's alert response. If viral levels are controlled early, there is a lower risk of cytokine storm.
The analogy here is the phase one insulin response, which, if inadequate to manage glucose levels, may be followed by an exaggerated and hyperinsulinaemic phase 2 response.
There is some question as to whether COVID-19 mortality is really due to cytokine storm, as in SARS or swine flu, or due to a direct effect of the virus on the lung, where cells producing pulmonary surfactant (Type II alveolar epithelial cells) are damaged by the virus and reduce normal lung function.

Andrographis is effective for reducing cough.
https://www.karger.com/Article/FullText/442111
It has an opposite effect on TNF-alpha from sambucus, so if you are worried that sambucus is too inflammatory use a combined supplement, in my experience these are effective enough for easing the misery and shortening the course of the usual cold and flu.
https://www.ncbi.nlm.nih.gov/pubmed/22026410

An AI-type analysis of data found that andrographis suppressed ACE2 expression most; sambucus and the TCM staple astragalus (another adjuvant) were also on the list.
https://www.preprints.org/manuscript/202002.0047/v1

Now, you may not want ACE2 suppressed if you are in extremis. It is a normal feature of lung function, and vitamin D supplementation (25 ug/Kg) increases ACE2 expression but prevents LPS-induced lung injury in this Wistar rat example.
https://www.researchgate.net/publication/316630691_Effect_of_Vitamin_D_on_ACE2_and_Vitamin_D_receptor_expression_in_rats_with_LPS-induced_acute_lung_injury
The jury is very much still out on ACE inhibitors (which may increase ACE2 expression) and risk.
https://jamanetwork.com/journals/jama/fullarticle/2763803

However - if you use these medicines, the idea is to use them around exposure, or PRN for symptoms, as advised. If they work, the disease will be less serious, if they don't and you do experience pneumonia you're not going to be taking them in the ICU.
Never keep taking something that makes you feel worse.

Interestingly, echinacea, which is a star in the animal studies, has only weak effects in human trials.
https://www.ncbi.nlm.nih.gov/pubmed/24554461
Yet these studies were just as small and had the same potential for bias as the elderberry and andrographis trials. That quite distinct effects or strength of effect appears consistently when different compounds are tested answers the specificity test of a Bradford Hill analysis of the "immune boosting" question. In fact every Bradford Hill criteria is being well-met, whatever the limitations of the human research.

The weak effects of echinacea may be due to its relative fragility and variation as an extract, inadequate dosage, or to the timing of its use as a prophylactic. I use these extracts only when I am either obviously exposed, "coming down with something", or actually sick. My opinion, not necessarily what the science says and just the voice of experience, is that echinacea and elderberry, if good extracts in adequate doses, both work if taken soon enough (elderberry was very effective taken within 24 hours in the swine flu but had no effect when given more than 48 hours after symptoms started). Perhaps echinacea is better for colds and sambucus for flus, but even if that were true COVID-19 is not necessarily playing by all rules. I also use Sanderson's Viramax, a mixed supplement of sambucus, andrographis, echinacea and olive leaf extract when I'm sick for PRN symptom relief, on the basis of past satisfaction with its effects. There is some evidence for olive leaf extract, but the active ingredient seems to be found in extra virgin olive oil.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412187/

Apart from herbs and probiotics, what else is there evidence for?

Malnutrition impairs antibody production, obviously, so eat a sensible diet that includes minimally processed animal products, including meat, if you're skeptical about supplements.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033455/

Apart from that, it's well worth supplementing selenium (by Brazil nuts or supplements). A pre-2019 coronavirus encoded for 60 selenocysteine residues per core protein. This is a common viral adaptation and protects the stability of the viral genome (a good thing) while depressing host immunity (a bad thing).
https://www.sciencedaily.com/releases/2001/06/010608081506.htm
Wuhan, Northern Italy, the UK and NZ are all low-selenium areas where deficiency is common. Check the data for your region or county, which is usually available online.

The jury's still out on supplementary vitamin C, and I seemed to stop responding to it when my metabolic health improved, but it's cheap and can't hurt.
Update: high dose vitamin C is being used in New York hospitals.
https://www.dailymail.co.uk/news/article-8149191/New-York-hospitals-treating-corona-patients-6000-milligrams-VITAMIN-C.html
It's the end of winter in the Northern hemisphere so I'd be supplementing vitamin D3 if I lived there.
Inorganic zinc lozenges (especially zinc acetate) seem to have a role to play here, but may be a lot of trouble to maintain for the duration. It might be worth it depending on your level of risk, as the effect is strong enough.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418896/

The spread and virulence of viral infections is in large part a numbers game. Needlestick exposures to HCV had a higher clearance rate than exposures to contaminated blood transfusions. Every line of defense matters, and every proven or even just most-likely barrier to the pathogen establishing dominance over the immune system can be worth investment.

The Official COVID-19 protocol from Shanghai, China, in English

This detailed protocol, which appeared online last week on an official Chinese Govt website, includes high-dose Vitamin C within the SOC drug recommendations. So far, when this has been pointed out to anyone in the "evidence-based medicine" community who has been busy online dismissing nutrient protocols for viral illnesses, they have pretended not to notice. Nor does there seem to be any reporting  or discussion in the western mainstream media.
What about prophylaxis? The blood concentrations of vitamin C from IV use are higher than we can get from oral dosing.
I think, if you read the Cochrane reviews of vitamin C for the common cold or pneumonia, there is a clinically significant advantage in high-risk subcategories (people stressed by cold or rigorous exercise for cold, seriously ill elderly for pneumonia). There is heterogeneity in exposure methods, some of which will replicate natural coronavirus exposure better than others. And the general advantages - reduced symptoms and duration - are reductions in COVID-19 transmission factors that could have a meaningful impact at a population level. Read them closely, don't just look for the first limitation that you think might allow you to dismiss a whole body of evidence.
https://www.ncbi.nlm.nih.gov/pubmed/23925826/
https://www.ncbi.nlm.nih.gov/pubmed/23440782
"Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them."

If you disagree that EBM, for a lot of proponents, stands for emotionally biased medicine, consider this: New Zealand has had to ration acetaminophen (Panadol, Tylenol) prescriptions due to a run on pharmacy stocks.
There is no human RCT of the safety of acetaminophen in pneumonia (we know vitamin C is safe from the Cochrane review), but antipyretics, including acetaminophen, cause a 37% increased risk of mortality in animal models.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951171/
Yet there is no EBM push online to warn about this and to mock the people buying or prescribing antipyretics.
EBM - it ought to be essential, it's lovely in theory, yet it seems to be toxic at the level of science communication.

I can't tell you what to do, but here's what I'm doing, besides all the washing and contact common sense stuff - I'm making sure I'm replete in selenium, zinc, retinol, and vitamin D. I'm taking 500mg vitamin C a day. If I start to get ill, I'll take a standardised elderberry extract and a standardised andrographis extract. I may increase the dose of vitamin C.



The Shanghai Protocol, from https://mp.weixin.qq.com/s/bF2YhJKiOfe1yimBc4XwOA


[Editor's note] 

On March 1st, the Chinese Journal of Infectious Diseases, which was hosted by the Shanghai Medical Association, pre-published the "Expert Consensus on Comprehensive Treatment of Coronavirus in Shanghai 2019" (http://rs.yiigle.com/m/yufabiao/1183266 .htm), which has attracted widespread attention in the industry. Shanghai TV also reported on the news last night. This consensus was reached by 30 experts representing the strongest medical force in the treatment of new-type coronavirus pneumonia in Shanghai. Through the research and summary of more than 300 clinical patients, and fully drawing on the treatment experience of colleagues at home and abroad, the "Shanghai Plan" was finally formed. At the end of the article, the list of 30 subject experts (18 writing experts and 12 consulting experts) from various medical institutions in Shanghai is attached.




Corona virus disease 2019 (COVID-19) was first reported on December 31, 2019 in Wuhan, Hubei Province. COVID-19, as a respiratory infectious disease, has been included in the Class B infectious diseases stipulated in the Law of the People's Republic of China on the Prevention and Control of Infectious Diseases and managed as a Class A infectious disease.

With the deepening of understanding of the disease, COVID-19 has accumulated a certain amount of experience in the prevention and control of COVID-19. The Shanghai New Coronary Virus Disease Clinical Treatment Expert Group follows the National New Coronary Virus Pneumonia Diagnosis and Treatment Program and fully draws on the treatment experience of colleagues at home and abroad to improve the success rate of clinical treatment and reduce the mortality rate of patients, prevent the progress of the disease, and gradually reduce the disease The proportion of patients with severe disease improves their clinical prognosis. Based on the continuous optimization and refinement of the treatment plan, expert consensus has been formed on the relevant clinical diagnosis and treatment.

I. Etiology and epidemiological characteristics

2019 novel coronavirus (2019-nCoV) is a new coronavirus belonging to the genus β. On February 11, 2020, the International Committee on Taxonomy of Viruses (ICTV) named the virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with COVID-19 and asymptomatic infection can transmit 2019-nCoV. Respiratory droplet transmission is the main route of transmission and can also be transmitted through contact. There is also the risk of aerosol transmission in confined enclosed spaces. COVID-19 patients can detect 2019-nCoV in stool, urine, and blood; some patients can still test positive for fecal pathogenic nucleic acid after the pathogenic nucleic acid test of respiratory specimens is negative. The crowd is generally susceptible. Children, infants, and young children also develop disease, but the condition is relatively mild.

Clinical characteristics and diagnosis

(A) clinical characteristics

The incubation period is 1 to 14 d, mostly 3 to 7 d, with an average of 6.4 d. Main symptoms are fever, fatigue, and dry cough. May be accompanied by runny nose, sore throat, chest tightness, vomiting and diarrhea. Some patients have mild symptoms, and a few patients have no symptoms or pneumonia.

The elderly and those suffering from basic diseases such as diabetes, hypertension, coronary atherosclerotic heart disease, and extreme obesity tend to develop severe illness after infection. Some patients develop symptoms such as dyspnea within 1 week after the onset of the disease. In severe cases, they can progress to acute respiratory distress syndrome (ARDS) and multiple organ dysfunction. The time to progression to severe illness was approximately 8.5 days. It is worth noting that in the course of severe and critically ill patients, there may be moderate to low fever, even without obvious fever. Most patients have a good prognosis, and deaths are more common in the elderly and those with chronic underlying disease.

The early CT examination showed multiple small patches or ground glass shadows, and the internal texture of the CT scans was thickened in the form of grid cables, which was obvious in the outer lung zone. A few days later, the lesions increased and the scope expanded, showing extensive lungs, multiple ground glass shadows, or infiltrating lesions, some of which showed consolidation of the lungs, often with bronchial inflation signs, and pleural effusions were rare. A small number of patients progressed rapidly, with imaging changes reaching a peak on days 7 to 10 of the course. Typical "white lung" performance is rare. After entering the recovery period, the lesions are reduced, the scope is narrowed, the exudative lesions are absorbed, part of the fiber cable shadow appears, and some patients' lesions can be completely absorbed.

In the early stage of the disease, the total number of white blood cells in the peripheral blood was normal or decreased, and the lymphocyte count was reduced. Some patients may have abnormal liver function, and the levels of lactate dehydrogenase, muscle enzyme, and myoglobin may increase; troponin levels may be increased. Most patients had elevated CRP and ESR levels and normal procalcitonin levels. In severe cases, D-dimer levels are elevated, other coagulation indicators are abnormal, lactic acid levels are elevated, peripheral blood lymphocytes and CD4 + T lymphocytes are progressively reduced, and electrolyte disorders and acid-base imbalances are caused by metabolic alkalosis See more. Elevated levels of inflammatory cytokines (such as IL-6, IL-8, etc.) may occur during the disease progression stage.

(Two) diagnostic criteria

1. Suspected case: Combined with the following epidemiological history and clinical manifestations. Suspected cases were diagnosed as having any one of epidemiological history and meeting any two of the clinical manifestations, or having no clear epidemiological history but meeting three of the clinical manifestations. ① Epidemiological history: travel history or residence history of Wuhan City and surrounding areas, or other communities with case reports within 14 days before the onset; history of contact with 2019-nCoV infection (positive nucleic acid test) within 14 days before the onset ; Patients with fever or respiratory symptoms from Wuhan and surrounding areas or from communities with case reports within 14 days before the onset of the disease; cluster onset. ② Clinical manifestations: fever and / or respiratory symptoms; with the above-mentioned imaging features of the new coronavirus pneumonia; the total number of white blood cells is normal or decreased in the early stage of onset, and the lymphocyte count is reduced.

2. Confirmed cases: Those with one of the following etiology evidence are diagnosed as confirmed cases. ① Real-time fluorescent reverse transcription PCR detected 2019-nCoV nucleic acid positive. ② Viral gene sequencing revealed high homology with the known 2019-nCoV. ③ Except for nasopharyngeal swabs, take sputum as much as possible. Patients undergoing tracheal intubation can collect lower respiratory tract secretions and send viral nucleic acid test positive.

(Three) differential diagnosis

It is mainly distinguished from other known viral pneumonias such as influenza virus, parainfluenza virus, adenovirus, respiratory syncytial virus, rhinovirus, human metapneumovirus, severe acute respiratory syndrome (SARS) coronavirus, etc. , Different from Mycoplasma pneumoniae, Chlamydia pneumonia and bacterial pneumonia. In addition, it must be distinguished from non-infectious diseases such as pulmonary interstitial lesions and organizing pneumonia caused by connective tissue diseases such as vasculitis and dermatomyositis.

(Four) clinical classification

1. Mild: The clinical symptoms are slight, and no pneumonia manifestations on imaging examination.

2. Ordinary type: fever, respiratory tract symptoms, etc. Pneumonia manifestations on imaging examination.

Early warning of severe cases of common patients should be strengthened. Based on current clinical studies, elderly (aged> 65 years) with underlying diseases, CD4 + T lymphocyte count <250 2="" 3="" and="" blood="" days="" found="" il-6="" imaging="" increased="" lesions="" levels="" lung="" on="" progress="" significant="" significantly="" to="" were="">50 %, lactic dehydrogenase (LDH)> 2 times the upper limit of normal value, blood lactic acid ≥ 3 mmol / L, metabolic alkalosis, etc. are all early warning indicators of severe disease.

3. Heavy: Any one of the following. ① Shortness of breath, respiratory rate ≥ 30 times / min; ② In resting state, arterial oxygen saturation (SaO2) ≤ 93%; ③ arterial partial pressure of oxygen, PaO2) / fraction of inspired oxygen (FiO2) ≤ 300 mmHg (1 mmHg = 0.133 kPa). At high altitudes (above 1 000 m), PaO2 / FiO2 should be corrected according to the following formula: PaO2 / FiO2 × [Atmospheric Pressure (mmHg) / 760].

Pulmonary imaging examination showed that the lesions progressed significantly within 24 to 48 hours, and those with more than 50% of the lesions were managed as severe.

4. Dangerous: A person who meets any of the following conditions can be judged as critical. ① Respiratory failure occurs and requires mechanical ventilation; ② Shock occurs; ③ Combined with other organ failure, ICU monitoring and treatment is required.

(5) Clinical monitoring

The patient's clinical manifestations, vital signs, fluid volume, gastrointestinal function and mental state are monitored daily.

All patients were dynamically monitored for terminal blood oxygen saturation. For critically ill and critically ill patients, timely blood gas analysis is performed according to the changes in the condition; blood routine, electrolytes, CRP, procalcitonin, LDH, blood coagulation function indicators, blood lactic acid, etc. are tested at least once every 2 days; liver function, kidney function , ESR, IL-6, IL-8, lymphocyte subsets, at least once every 3 days; chest imaging examination, usually every 2 days. For patients with ARDS, routine ultrasound examination of the heart and lungs at the bedside is recommended to observe extravascular lung water and cardiac parameters. For monitoring of extracorporeal membrane oxygenation (ECMO) patients, refer to the implementation section of ECMO.

Treatment plan

(A) antiviral treatment

You can try hydroxychloroquine sulfate or chloroquine phosphate, or Abidol for oral administration, interferon nebulization and inhalation, interferon κ is preferred, and interferon α recommended by the national scheme can also be applied. It is not recommended to use 3 or more antivirals at the same time. The viral nucleic acid should be stopped in time after it becomes negative. The efficacy of all antiviral drugs remains to be evaluated in further clinical studies.

For patients with severe and critical viral nucleic acid positives, recovery patients can be tested for recovery plasma. For detailed operation and management of adverse reactions, please refer to the "Clinical Treatment Program for Recovery of New Coronary Pneumonia Patients During Recovery Period" (trial version 1). Infusion within 14 days of the onset may be more effective. If the viral nucleic acid is continuously detected at the later stage of the disease, the recovery period of plasma treatment can also be tried.

(Two) treatment of light and ordinary patients

Supportive treatment needs to be strengthened to ensure sufficient heat; pay attention to water and electrolyte balance to maintain internal environment stability; closely monitor patient vital signs and finger oxygen saturation. Give effective oxygen therapy in time. Antibacterials and glucocorticoids are not used in principle. The patient's condition needs to be closely monitored. If the disease progresses significantly and there is a risk of turning into severe, it is recommended to take comprehensive measures to prevent the disease from progressing to severe. Low-dose short-course glucocorticoids can be used with caution (see the application section of glucocorticoids for specific protocols) ). Heparin anticoagulation and high-dose vitamin C are recommended. Low-molecular-weight heparin 1 to 2 per day, continued until the patient's D-dimer level returned to normal. Once fibrinogen degradation product (FDP) ≥10 µg / mL and / or D-dimer ≥5 μg / mL, switch to unfractionated heparin. Vitamin C is administered at a dose of 50 to 100 mg / kg per day, and the continuous use time is aimed at a significant improvement in the oxygenation index. If lung lesions progress, it is recommended to apply a large-dose broad-spectrum protease inhibitor, ulinastatin, at 600 to 1 million units / day until the pulmonary imaging examination improves. In the event of a "cytokine storm", intermittent short veno-venuous hemofiltration (ISVVH) is recommended.

(III) Organ function supportive treatment for severe and critically ill patients

1. Protection and maintenance of circulatory function: implement the principle of early active controlled fluid replacement. It is recommended to evaluate the effective volume and initiate fluid therapy as soon as possible after admission. Severe patients can choose intravenous or transcolonic fluid resuscitation depending on the conditions. The preferred supplement is lactated Ringer's solution. Regarding vasoactive drugs, noradrenaline and dopamine are recommended to maintain vascular tone and increase cardiac output. For patients with shock, norepinephrine is the first choice. It is recommended to start low-dose vasoactive drugs at the same time as fluid resuscitation to maintain circulation stability and avoid excessive fluid infusion. Cardioprotective drugs are recommended for severe and critically ill patients, and sedative drugs that inhibit the heart are avoided as much as possible. For patients with sinus bradycardia, isoprenaline can be used. For patients with sinus rhythm, a heart rate of <50 80="" about="" and="" at="" beats="" dopamine="" font="" heart="" hemodynamic="" instability="" intravenous="" is="" isoproterenol="" low-dose="" maintain="" min.="" min="" of="" or="" pumping="" rate="" recommended="" the="" to="">

2. Reduce pulmonary interstitial inflammation: 2019-nCoV leads to severe pulmonary interstitial lesions that can cause pulmonary function deterioration. It is recommended to use a large dose of a broad-spectrum protease inhibitor ulinastatin.

3. Protection of renal function: Reasonable anticoagulant therapy and appropriate fluid therapy are recommended as soon as possible. See chapter "Cytokine storm" for prevention, protection and maintenance of circulatory function.

4. Protection of intestinal function: Prebiotics can be used to improve the intestinal microecology of patients. Use raw rhubarb (15-20 g plus 150 ml warm boiling water) or Dachengqi decoction for oral administration or enema.

5. Nutritional support: parenteral nutrition is preferred, via nasal feeding or via jejunum. The whole protein nutrient preparation is preferred, and the energy is 25 to 35 kcal / kg (1 kcal = 4.184 kJ) per day.

6. Prevention and treatment of cytokine storm: It is recommended to use large doses of vitamin C and unfractionated heparin. Large doses of vitamin C are injected intravenously at a dose of 100 to 200 mg / kg per day. The duration of continuous use is to significantly improve the oxygenation index. It is recommended to use large doses. Dose of the broad-spectrum protease inhibitor ulinastatin, given 1.6 million units, once every 8 h, under mechanical ventilation, when the oxygenation index> 300 mmHg can be reduced to 1 million units / d. Anticoagulation The treatment protects endothelial cells and reduces the release of cytokines. When FDP ≥ 10 µg / mL and / or D-dimer ≥ 5 μg / mL, anticoagulation is given to unfractionated heparin (3 to 15 IU / kg per hour). Heparin is used for the first time. The patient's coagulation function and platelets must be re-examined 4 h later. ISVVH is used for 6 to 10 h every day.

7. Sedation and artificial hibernation: Patients undergoing mechanical ventilation or receiving ECMO need to be sedated on the basis of analgesia. For patients with severe man-machine confrontation during the establishment of an artificial airway, short-term application of low-dose muscle relaxants is recommended. Hibernation therapy is recommended for severe patients with oxygenation index < 200 mmHg. Artificial hibernation therapy can reduce the body's metabolism and oxygen consumption, and at the same time dilate the pulmonary blood vessels to significantly improve oxygenation. It is recommended to use continuous intravenous bolus medication, and the patient's blood pressure should be closely monitored. Use opioids and dexmedetomidine with caution. Because severely ill patients often have elevated IL-6 levels and easily cause abdominal distension, opioids should be avoided; 2019-nCoV can still inhibit sinus node function and cause sinus bradycardia, so it should be used with caution on Inhibitory sedatives. In order to prevent the occurrence and exacerbation of lung infections, and to avoid prolonged excessive sedation, try to withdraw muscle relaxants as soon as possible. It is recommended to monitor the depth of sedation closely.

8. Oxygen therapy and respiratory support: ① nasal cannula or mask oxygen therapy, SaO2 ≤93% under resting air condition, or SaO2 < 90% after activity, or oxygenation index (PaO2 / FiO2) 200-300 mmHg; With or without respiratory distress; continuous oxygen therapy is recommended. ② High-flow nasal cannula oxygen therapy (HFNC), receiving nasal cannula or mask oxygen therapy for 1-2 hours, oxygenation fails to meet treatment requirements, and respiratory distress does not improve; or hypoxemia during treatment And / or exacerbation of respiratory distress; or an oxygenation index of 150 to 200 mmHg; HFNC is recommended. ③ Noninvasive positive pressure ventilation (NPPV), receiving 1 to 2 h of HFNC oxygenation does not achieve the treatment effect, and there is no improvement in respiratory distress; or hypoxemia and / or exacerbation of respiratory distress during treatment; or When the oxygenation index is 150 ～ 200 mmHg; NPPV can be selected. ④ Invasive mechanical ventilation, HFNC or NPPV treatment does not meet the treatment requirements for 1 to 2 hours of oxygenation, and respiratory distress does not improve; or hypoxemia and / or exacerbation of respiratory distress during treatment; or oxygenation index <150 a="" are="" as="" be="" body="" considered.="" core="" font="" ideal="" invasive="" kg="" mass="" ml="" mmhg="" preferred.="" protective="" should="" small="" strategies="" the="" tidal="" ventilation="" volume="" with="">

9. Implementation of ECMO: Those who meet one of the following conditions may consider implementing ECMO. ① PaO2 / FiO2 < 50 mmHg for more than 1 h; ② PaO2 / FiO2 < 80 mmHg for more than 2 h; ③ Arterial blood pH < 7.25 with PaCO2 > 60 mmHg for more than 6 h. ECMO mode is preferred for intravenous-venous ECMO.

(4) Special problems and treatment in treatment

1. Application of glucocorticoids: Use glucocorticoids with caution. Imaging showed significant progress in pneumonia. Patients with SaO2 ≤ 93% or shortness of breath (respiratory frequency ≥ 30 breaths / min) or oxygenation index ≤ 300 mmHg in the state of no oxygen inhalation. Glucocorticoids can be added at the risk of intubation. Patients are advised to withdraw promptly from glucocorticoid use when intubation or ECMO support can maintain effective blood oxygen concentrations. For non-severe patients using methylprednisolone, the recommended dose is controlled at 20 to 40 mg / d, severe patients are controlled at 40 to 80 mg / d, and the course of treatment is generally 3 to 6 days. Can be increased or decreased according to the body weight.

2. Use of immunoregulatory drugs: Subcutaneous injection of thymosin 2 to 3 times per week has certain effects on improving patients' immune function, preventing the disease from becoming worse, and shortening the time of detoxification. Due to the lack of specific antibodies, high-dose intravenous immunoglobulin therapy is currently not supported. However, some patients have low levels of lymphocytes and the risk of co-infection with other viruses. Human immunoglobulin can be infused intravenously at 10 g / d for 3 to 5 days.

3. Accurate diagnosis and treatment of combined bacterial and fungal infections: clinical microbiological monitoring of all severe and critically ill patients. The sputum and urine of the patients are kept daily for culture, and the patients with high fever should be cultured in time. All patients with suspected sepsis who have indwelling vascular catheters should be sent for peripheral venous blood culture and catheter blood culture at the same time. All patients with suspected sepsis may consider collecting peripheral blood for molecular diagnostic tests for etiology, including PCR-based molecular biology testing and next-generation sequencing.

Elevated procalcitonin levels have implications for the diagnosis of sepsis / septic shock. When patients with new type of coronavirus pneumonia get worse, there is an increase in the level of CRP, which is not specific for the diagnosis of sepsis caused by bacterial and fungal infections.

Critically ill patients with open airways are often prone to bacterial and fungal infections at a later stage. If sepsis occurs, empirical anti-infective treatment should be given as soon as possible. For patients with septic shock, empirical antibacterial drugs can be used in combination before obtaining an etiological diagnosis, while covering the most common Enterobacteriaceae, Staphylococcus and Enterococcus infections. Patients with infection after hospitalization can choose β-lactamase inhibitor complex. If the treatment effect is not good, or the patient has severe septic shock, it can be replaced with carbapenem drugs. If considering enterococci and staphylococcal infections, glycopeptide drugs (vancomycin) can be added for empirical treatment. Daptomycin can be used for bloodstream infections, and linezolid can be used for lung infections. Attention should be paid to catheter-related infections in critically ill patients, and treatment should be empirically covered with methicillin-resistant staphylococci. Glycopeptide drugs (vancomycin) can be used for empirical treatment. Candida infection is also more common in critically ill patients. Candida should be covered empirically when necessary. Echinocin drugs can be added. With the length of hospitalization of critically ill patients, drug-resistant infections have gradually increased. At this time, the use of antibacterial drugs must be adjusted according to drug sensitivity tests.

4. Nosocomial infection prevention and control: ① In accordance with the Basic System for Infection Prevention and Control of Medical Institutions (Trial) of the National Health and Health Commission in 2019, actively implement evidence-based infection prevention and control clustering intervention strategies to effectively prevent ventilator-related pneumonia and intravascular Multidrug-resistant bacteria and fungal infections such as catheter-related bloodstream infections, catheter-related urinary tract infections, carbapenem-resistant gram-negative bacilli. ② Strictly follow the National Health and Health Commission's "Technical Guide for the Prevention and Control of New Coronavirus Infection in Medical Institutions (First Edition)", "Guidelines for the Use of Common Medical Protective Products in the Prevention and Control of Pneumonitis Due to New Coronavirus (Trial)" During the epidemic period, the technical guidelines for protection of medical personnel (trial implementation), strengthened process management, correctly selected and used personal protective equipment such as masks, gowns, protective clothing, eye masks, protective masks, gloves, and strict implementation of various disinfection and isolation measures Minimize the risk of nosocomial infections and prevent 2019-nCoV infections in hospitals by medical staff.

5. Treatment of infants and young children: Only mild symptomatic oral treatment is needed for mild children. In addition to symptomatic oral administration for children with common type, treatment with syndrome differentiation can be considered. If combined with bacterial infection, antibacterial drugs can be added. Severely ill children are mainly symptomatic and supportive treatment. Ribavirin injection was given antiviral therapy empirically at 15 mg / kg (2 times / day). The course of treatment did not exceed 5 days.

(V) Treatment plan of integrated traditional Chinese and western medicine

The combination of traditional Chinese and western medicine for the treatment of new coronavirus pneumonia can improve the synergistic effect. For adult patients, the condition can be improved through TCM syndrome differentiation. For light patients, those with a syndrome of wind-heat type are given the traditional Chinese medicine Yinqiaosan plus and minus treatment; those with gastrointestinal symptoms and those with damp-wetting and yang-type syndrome are given the addition and subtraction of Zhipu Xialing Decoction and Sanren Decoction. For ordinary patients, those with syndromes of hot and evil stagnation of lungs can be treated with Chinese medicine Ma Xing Shi Gan Decoction; those with syndromes of dampness and stagnation of lungs can be treated with traditional Chinese medicine Da Yuan Yin, Gan Lu Fang Dan, etc., which can be controlled to some extent Progression of the disease, reducing the occurrence of common to severe; for anorexia, nausea, bloating, fatigue, anxiety and insomnia, the addition and subtraction of Chinese medicine Xiao Chai Hu Tang can significantly improve symptoms. For severe patients, if the fever persists, or even the high fever, bloating, and dry stools are closed, and those who are heat-tolerant and the lungs are closed, give the Chinese medicine Dachengqi Decoction enema to relieve fever or reduce fever, or use Chinese medicine. The treatment of Baihu Decoction, Shengjiang San and Xuanbai Chengqi Decoction were added and subtracted to cut off the condition and reduce the occurrence of heavy to critical illness. Children with light patients, when the disease belongs to the defender, can be added or subtracted from Yinqiaosan or Xiangsusan. Ordinary children, those with damp heat and closed lungs, are given Ma Xing Shi Gan Decoction and Sanren Decoction; those with moderate scorching dampness and heat such as bloating and vomiting with abdominal distension can be added or subtracted without changing Jinzhengqi San. For severe patients with epidemic and closed lung (currently rare in the country), please refer to adult Xuanbai Chengqi Decoction and Manna Disinfection Danjiao; if the poison is hot, the gas can't pass, and the medicines are not good, the Rhubarb Decoction is given to enema for emergency.

(6) Discharge standards

Patients who meet the following conditions at the same time can be considered for discharge: ①The body temperature returns to normal > 3 d; ②Respiratory symptoms are significantly improved; ③ Imaging examination of the lungs shows that the acute exudative lesions are significantly improved; At least 1 d); ⑤ After the nucleic acid test of the respiratory specimen is negative, the fecal pathogen nucleic acid test is also negative; ⑥ The total disease course exceeds 2 weeks.

(VII) Health management of discharged patients

1. For discharged patients, close follow-up is still required. Follow-up is recommended from 2 weeks and 4 weeks after discharge to the designated follow-up clinic.

2. When the patient is discharged from the hospital, the place of residence and address in the city should be specified.

3. Patients should rest at home for 2 weeks after leaving the hospital, avoid activities in public places, and must wear masks when going out.

4. According to the patient's address (including hotel or hotel), the relevant district health and health committee will organize the corresponding medical institution to do a good job of health management. Professionals will visit the patient's temperature twice a day for 2 weeks, ask their health status, and carry out related health education.

5. If fever and / or respiratory symptoms recur, the corresponding medical institution shall report to the District Health and Health Commission and the District Centers for Disease Control and Prevention in a timely manner, and assist in sending them to the designated medical institution in the area for treatment.

6. After receiving the report, the District Health and Health Committee and the District Centers for Disease Control and Prevention report to the superior department in a timely manner.