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Monday, 16 November 2020

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

Sunday, 27 September 2020

Selenium reduces COVID-19 risk - a back-of-the-envelope Bradford Hill analysis.







Bradford Hill introduced a checklist for assessing the strength of epidemiological evidence for causality, which is useful in the current pandemic when nutritional factors have been insufficiently tested by experiment in favour of drugs with, so far, relatively weak effects.[1]
Remember, a long time has passed and a lot of people have died while Evidence-Based Medicine was facing the wrong way.
And asking the wrong question. "What new treatment will save more lives in the ICU?" is an important question, but one with few answers and no great ones - "What can stop people who catch SARS-CoV-2 coming to the ICU?" is a better one in a pandemic, and one that might also lead to better treatment protocols.


Selenium reduces COVID-19 mortality: A Bradford Hill analysis

1) Strength of association. Very Strong.


1) On inspection of the Hubei data, it is notable that the cure rate in Enshi city, at 36.4%, was much higher than that of other Hubei cities, where the overall cure rate was 13.1% (Supplemental Table 1); indeed, the Enshi cure rate was significantly different from that in the rest of Hubei (P < 0.0001). Enshi is renowned for its high selenium intake and status [mean ± SD: hair selenium: 3.13 ± 1.91 mg/kg for females and 2.21 ± 1.14 mg/kg for males]—compare typical levels in Hubei of 0.55 mg/kg (10)—so much so that selenium toxicity was observed there in the 1960s. Selenium intake in Enshi was reported as 550 µg/d in 2013.
Similar inspection of data from provinces outside Hubei shows that Heilongjiang Province in northeast China, a notoriously low-selenium region in which Keshan is located, had a much higher death rate, at 2.4%, than that of other provinces (0.5%; P < 0.0001). The selenium intake was recorded as only 16 µg/d in a 2018 publication, while hair selenium in the Songnen Plain of Heilongjiang was measured as only 0.26 mg/kg (Supplemental Table 2).

Finally, we found a significant association between cure rate and background selenium status in cities outside Hubei (R2 = 0.72, F test P < 0.0001; Figure 1, Supplemental Table 2).[2]




Correlation between COVID-19 cure rate in 17 cities outside Hubei, China, on 18 February, 2020 and city population selenium status (hair selenium concentration) analyzed using weighted linear regression (mean ± SD = 35.5 ± 11.1, R2 = 0.72, F test P < 0.0001). Each data point represents the cure rate, calculated as the number of cured patients divided by the number of confirmed cases, expressed as a percentage. The size of the marker is proportional to the number of cases.



2) Serum samples (n = 166) from COVID-19 patients (n = 33) were collected consecutively and analyzed for total Se by X-ray fluorescence and selenoprotein P (SELENOP) by a validated ELISA. Both biomarkers showed the expected strong correlation (r = 0.7758, p < 0.001), pointing to an insufficient Se availability for optimal selenoprotein expression. In comparison with reference data from a European cross-sectional analysis (EPIC, n = 1915), the patients showed a pronounced deficit in total serum Se (mean ± SD, 50.8 ± 15.7 vs. 84.4 ± 23.4 µg/L) and SELENOP (3.0 ± 1.4 vs. 4.3 ± 1.0 mg/L) concentrations. A Se status below the 2.5th percentile of the reference population, i.e., [Se] < 45.7 µg/L and [SELENOP] < 2.56 mg/L, was present in 43.4% and 39.2% of COVID samples, respectively.
The Se status was significantly higher in samples from surviving COVID patients as compared with non-survivors (Se; 53.3 ± 16.2 vs. 40.8 ± 8.1 µg/L, SELENOP; 3.3 ± 1.3 vs. 2.1 ± 0.9 mg/L), recovering with time in survivors while remaining low or even declining in non-survivors.[3]

Vitamins B1, B6, B12, D (25-hydroxyvitamin D), folate, selenium, and zinc levels were measured in 50 hospitalized patients with COVID-19. A total of 76% of the patients were vitamin D deficient and 42% were selenium deficient. No significant increase in the incidence of deficiency was found for vitamins B1, B6, and B12. folate, and zinc in patients with COVID-19. The COVID-19 group showed significantly lower vitamin D values than the healthy control group (150 people, age/sex matching). Severe vitamin D deficiency (based on 10 ng/dL) was found in 24% of the patients in the COVID-19 group and 7.3% of the control group. Among 12 patients with respiratory distress, 11 (91.7%) were deficient in at least one nutrient. However, patients without respiratory distress showed deficiency in 30/38 people (78.9%, P-value 0.425). These results suggest that a deficiency of vitamin D or selenium may decrease the immune defenses against COVID-19 and cause progression to severe disease; however, more precise and large-scale studies are needed.[18]

100% of the patients in this study with severe outcomes, including death, were selenium deficient; 75% were vitamin D deficient; none were zinc deficient.


2) Consistency - Very Strong

All epidemiological data about selenium and COVID-19 is consistent in direction and effect size. However, tests that could be done comparing COVID-19 risk in high and low selenium regions of Brazil, Scandinavia (selenium is supplemented in the food supply of Finland), and the USA would establish consistency further.

[edit 16/11/202o] - New study from South India is consistent with those from Germany, China, and South Korea:

We analysed the blood serum levels in apparently healthy (N=30) individuals and those with confirmed COVID -19 infection (N=30) in the southern part of India. Patients showed a significantly lower selenium level of 69.2 ±8.7 ng/ml than controls 79.1 ± 10.9 ng/ml, the difference was statistically significant (P=0.0003). Interestingly the controls showed a borderline level of selenium, suggesting that the level of this micronutrient is not optimum in the population studied.[19]

[edit 14/12/2020] letter from Finland in BJN compares death rate with Sweden's.

[edit 15/12/2020 deficiency of both zinc and selenium predicts COVID-19 severity in EPIC data]
"This combined deficit was observed in 0.15% of samples in the EPIC cohort of healthy subjects, in 19.7% of the samples collected from the surviving COVID-19 patients and in 50.0% of samples from the non-survivors."[22]



3) Specificity - Strong

Selenium has much weaker or less consistent associations with other diseases, except those caused by other RNA viruses, e.g. when risk of hepatocellular cancer in viral hepatitis patients is compared with risk of osteoporosis.[4, 5]


4) Temporality - Strong

Prospective ecological comparisons are temporal by design.[2] In the German study, the temporal association between low serum selenium levels and COVID-19 symptom severity was closely tracked.[3]

Nutrients 12 02098 g003 550

5) Dose-response gradient - Very Strong

A strong, consistent dose-response is seen, even at levels where the risk of selenium toxicity exists, and despite the fact that toxic levels of soil selenium are often a legacy of industrial pollution in China.[2]


6) Plausibility - Very High

Reading references 2 and 3, as well as this review of the evidence written before reference 2 was published, should be persuasive.[6] See also ref 17 for antiviral effects. This one goes up to 11.


7) Coherence - Very High

Selenium is well-studied and nothing in its story seems to contradict the idea that higher intakes will protect against COVID-19 mortality and reduce the severity of disease.
Dexamethasone, a drug which can reduce COVID-19 mortality in the ICU, enhances 1α,25-dihydroxyvitamin D3 effects by increasing vitamin D receptor transcription.[7] 
Selenium sufficiency is essential for the function of vitamin D in peripheral blood monocytes.[8] Vitamin D status also correlates with COVID-19 survival.[9]

[Edit: 20/11/20] Two conditions which are associated with selenium depletion through effects on tubular mineral resorption, sickle cell disease (aOR, 1.73; 95% CI, 1.21-2.47), and chronic kidney disease (aOR, 1.32; 95% CI, 1.29-1.36), are the comorbidities most strongly associated with COVID-19 mortality in a large US MEDICARE patient analysis.[20] Selenium status in sickle cell disease is inversely associated with markers of hemolysis, a feature of severe COVID-19 pathology.[21]


8) Experiment - Weak (Insufficient)

This is an area of neglect, but overlaps with the next section as there are several trials of selenium supplementation in other viral diseases, and animal experiments in analogous conditions, and many mechanistic experiments that are non-specific. However the interaction between SARS-CoV-2 and selenoproteins has been confirmed by experiment.[10]



9) Analogy - Strong

Selenium intake is protective, and selenium supplementation has been useful, in other viral illnesses.
However, the protective effect of high selenium intakes before infection in epidemiology appears stronger than the protective effect of selenium as a late intervention in disease.[6, 11]



10) Risk - Weak in short-term, Well-Established in long term.

We can add the most relevant of extra questions to any given set of criteria - "strength of the alternative hypothesis" would be a good one for any lipid hypothesis.
Bradford Hill stated that some interventions are easier to justify than others.

On fair evidence we might take action on what appears to be an occupational hazard, e.g. we might change from a probably carcinogenic oil to a non-carcinogenic oil in a limited environment and without too much injustice if we are wrong. But we should need very strong evidence before we made people burn a fuel in their homes that they do not like or stop smoking the cigarettes and eating the fats and sugar that they do like. In asking for very strong evidence I would, however, repeat emphatically that this does not imply crossing every ‘t’, and swords with every critic, before we act.

With nutrient intakes there is often an identifiable risk, with a J-shaped curve. With selenium the risk is selenosis, which is a condition that requires chronic high exposure (I have given myself mild selenosis with around 900mcg selenium a day and it was not a terrible condition to experience and was reversible). There could be other risks. Luckily we have an experiment that tells us where the limit is.
In a low selenium country, like New Zealand or Denmark, you don't want to take more than 200mcg of extra selenium long term.[12] Pity the low dose arms here weren't retained in the intervention.


fx1

During 6871 person-years of follow-up, 158 deaths occurred. In an intention-to-treat analysis
the hazard ratio (95% confidence interval) for all-cause mortality comparing 300 µg selenium/d to placebo was 1.62 (0.66, 3.96) after 5 years of treatment and 1.59 (1.02, 2.46) over the entire follow-up period. The 100 and 200 µg/d doses showed non-significant decreases in mortality during the intervention period that disappeared after treatment cessation. Although we lacked power for endpoints other than all-cause mortality, the effects on cancer and cardiovascular mortality appeared similar.



Howsoever that may be, taking extra selenium above 200mcg per day may yet be advised if one becomes ill with COVID-19,  but an inorganic salt of selenium like sodium selenite (which is anyhow probably safer than the selenomethionine form long-term, as I'll discuss below) is preferable, according to the selenovirus expert, Ethan Will Taylor. 
(this video link does not show in the mobile version of this post but can be reached through the web view option at the bottom)



[Edit: 1/09/20] There is also very good evidence that intravenous high dose selenite is safe in the ICU setting.

Totally 19 RCTs involving 3341 critically ill patients were carried out in which 1694 participates were in the selenium supplementation group, and 1647 in the control. The aggregated results suggested that compared with the control, intravenous selenium supplement as a single therapy could decrease the total mortality (RR = 0.86, 95% CI: 0.78–0.95, P = .002, TSA-adjusted 95% CI = 0.77–0.96, RIS = 4108, n = 3297) and may shorten the length of stay in hospital (MD −2.30, 95% CI −4.03 to −0.57, P = .009), but had no significant treatment effect on 28-days mortality (RR = 0.96, 95% CI: 0.85–1.09, P = .54) and could not shorten the length of ICU stay (MD −0.15, 95% CI −1.68 to 1.38, P = .84) in critically ill patients.[13]

This, and an earlier analysis which found less benefit, did not single out viral illnesses as a subgroup - this is only evidence for safety - but the earlier analysis did find a) slightly lower mortality in trials without an initial bolus dose, b) no increased risk in patients with renal disease.[14]

I will hypothesize briefly on selenium increasing mortality at 300 mcg/day in the Danish intervention study, a dose far too low to cause selenosis.
(The conventional signs of selenosis result from selenocysteine replacing cysteine in proteins, and the relative weakness of the Se-Se bond compared with the S-S bond.)
[Edit - hypothesis improved, 23/09/20]
The question of selenium causing insulin resistance and increasing mortality in high-dose supplements, not mirrored as far as I can see in natural high-dose populations, may have a simple explanation - supplements allow us to consume micronutrients without protein.
If you have no cysteine or methionine coming in when you take Se (either because you're not eating protein, or perhaps it can happen naturally if the Se level is high in a low-protein food and diet) then the selenocysteine formed will be incorporated into all proteins, not just the ones that require it. Including the insulin receptors, which will suffer a relative loss of function.
(similarly, though for different reasons, pyridoxine toxicity can be triggered by supplementing on a low-protein diet)

If we think that insulin resistance causes CVD, then the increased risk from (mostly) natural high Se levels is not great, see fig 5 here [15], but the intervention studies have more alarming results, and I think the competition of selenium- vs sulphur-amino acids in protein fed vs unfed states can explain this. There is next to no evidence of Se toxicity from Brazil nuts, which are high in both Se and protein.



It makes sense to me that selenomethionine, very useful as it will increase selenoprotein levels quickly if you don't have much time, should be replaced with sodium selenite for long-term coverage.

Brazil nuts are a variable quantity, a sample of nuts sold in NZ in 2008 had an average of 19 mcg per nut and increased selenoprotein levels more than selenomethionine.[16]

Plasma selenium increased by 64.2%, 61.0%, and 7.6%; plasma GPx by 8.3%, 3.4%, and -1.2%; and whole blood GPx by 13.2%, 5.3%, and 1.9% in the Brazil nut, selenomethionine, and placebo groups, respectively. Change over time at 12 wk in plasma selenium (P < 0.0001 for both groups) and plasma GPx activity in the Brazil nut (P < 0.001) and selenomethionine (P = 0.014) groups differed significantly from the placebo group but not from each other. The change in whole blood GPx activity was greater in the Brazil nut group than in the placebo (P = 0.002) and selenomethionine (P = 0.032) groups.

[Edit 02/09/20] - thanks to Mike Angell for this link; while all selenium sources are probably protective against death and ongoing harm from COVID-19, only selenite is likely to have an additional antiviral effect, and has low toxicity.[17]

A rational protocol for using selenium in prevention and treatment of COVID-19, fully consistent with the evidence discussed here, is described at the end of this paper:
https://www.frontiersin.org/articles/10.3389/fnut.2020.00164/full



All scientific work is incomplete - whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have, or to postpone the action that it appears to demand at a given time.

Austin Bradford Hill, 1965.






References:

[1] Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58(5):295-300.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1898525/pdf/procrsmed00196-0010.pdf

[2] Jinsong Zhang, Ethan Will Taylor, Kate Bennett, Ramy Saad, Margaret P Rayman, Association between regional selenium status and reported outcome of COVID-19 cases in China, The American Journal of Clinical Nutrition, Volume 111, Issue 6, June 2020, Pages 1297–1299, https://doi.org/10.1093/ajcn/nqaa095

[3] Moghaddam, A.; Heller, R.A.; Sun, Q.; Seelig, J.; Cherkezov, A.; Seibert, L.; Hackler, J.; Seemann, P.; Diegmann, J.; Pilz, M.; Bachmann, M.; Minich, W.B.; Schomburg, L. Selenium Deficiency Is Associated with Mortality Risk from COVID-19. Nutrients 2020, 12, 2098.

[4] Yu MW, Horng IS, Hsu KH, Chiang YC, Liaw YF, Chen CJ. Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection. Am J Epidemiol. 1999;150(4):367-374. doi:10.1093/oxfordjournals.aje.a010016

[5] Wang, Y., Xie, D., Li, J. et al. Association between dietary selenium intake and the prevalence of osteoporosis: a cross-sectional study. BMC Musculoskelet Disord 20, 585 (2019). https://doi.org/10.1186/s12891-019-2958-5

[6] Bermano, G., Méplan, C., Mercer, D., & Hesketh, J. (2020). Selenium and viral infection: Are there lessons for COVID-19? British Journal of Nutrition, 1-37. doi:10.1017/S0007114520003128
https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/selenium-and-viral-infection-are-there-lessons-for-covid19/BE3AC78D5C92725BE83C4E474ECBB548

[7] Hidalgo AA, Deeb KK, Pike JW, Johnson CS, Trump DL. Dexamethasone enhances 1alpha,25-dihydroxyvitamin D3 effects by increasing vitamin D receptor transcription. J Biol Chem. 2011;286(42):36228-36237. doi:10.1074/jbc.M111.244061

[8] Schütze N, Fritsche J, Ebert-Dümig R, et al. The selenoprotein thioredoxin reductase is expressed in peripheral blood monocytes and THP1 human myeloid leukemia cells--regulation by 1,25-dihydroxyvitamin D3 and selenite. Biofactors. 1999;10(4):329-338. doi:10.1002/biof.5520100403

[9] Martín Giménez, V.M., Inserra, F., Ferder, L. et al. Vitamin D deficiency in African Americans is associated with a high risk of severe disease and mortality by SARS-CoV-2. J Hum Hypertens (2020). https://doi.org/10.1038/s41371-020-00398-z

[10] Wang, Y et al. SARS-CoV-2 suppresses mRNA expression of selenoproteins associated with ferroptosis, ER stress and DNA synthesis. Preprint, 2020/07/31. 10.1101/2020.07.31.230243
https://www.researchgate.net/publication/343365020_SARS-CoV-2_suppresses_mRNA_expression_of_selenoproteins_associated_with_ferroptosis_ER_stress_and_DNA_synthesis

[11] Steinbrenner H, Al-Quraishy S, Dkhil MA, Wunderlich F, Sies H. Dietary selenium in adjuvant therapy of viral and bacterial infections. Adv Nutr. 2015;6(1):73-82. Published 2015 Jan 15. doi:10.3945/an.114.007575

[12] Rayman MP, Winther KH, Pastor-Barriuso R, et al. Effect of long-term selenium supplementation on mortality: Results from a multiple-dose, randomised controlled trial. Free Radic Biol Med. 2018;127:46-54. doi:10.1016/j.freeradbiomed.2018.02.015

[13] Zhao Y, Yang M, Mao Z, et al. The clinical outcomes of selenium supplementation on critically ill patients: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2019;98(20):e15473. doi:10.1097/MD.0000000000015473

[14] Manzanares W, Lemieux M, Elke G, Langlois PL, Bloos F, Heyland DK. High-dose intravenous selenium does not improve clinical outcomes in the critically ill: a systematic review and meta-analysis. Crit Care. 2016;20(1):356. Published 2016 Oct 28. doi:10.1186/s13054-016-1529-5

[15] Angelica Kuria, Hongdou Tian, Mei Li, Yinhe Wang, Jan Olav Aaseth, Jiajie Zang & Yang Cao (2020) Selenium status in the body and cardiovascular disease: a systematic review and meta-analysis, Critical Reviews in Food Science and Nutrition, DOI: 10.1080/10408398.2020.1803200  https://www.tandfonline.com/doi/full/10.1080/10408398.2020.1803200

[16] Thomson CD, Chisholm A, McLachlan SK, Campbell JM. Brazil nuts: an effective way to improve selenium status. Am J Clin Nutr. 2008;87(2):379-384. doi:10.1093/ajcn/87.2.379
https://academic.oup.com/ajcn/article/87/2/379/4633360

[17] Kieliszek M, Lipinski B. Selenium supplementation in the prevention of coronavirus infections (COVID-19) [published online ahead of print, 2020 May 24]. Med Hypotheses. 2020;143:109878. doi:10.1016/j.mehy.2020.109878
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246001/

[18] Im, JH et al. Nutritional status of patients with coronavirus disease 2019 (COVID-19) Int J Infectious Diseases, August 11, 2020
https://www.ijidonline.com/article/S1201-9712(20)30647-0/fulltext

[19] Majeed, M et al. An Exploratory Study of Selenium Status in Normal Subjects and COVID-19 Patients in South Indian population: Case for Adequate Selenium Status: Selenium Status in COVID-19 Patients. Nutrition. Available online 11 November 2020, 111053
https://www.sciencedirect.com/science/article/pii/S0899900720303361

[20] 
Chen Dun, Christi M. Walsh, Sunjae Bae, Amesh Adalja, Eric Toner, Timothy A. Lash, Farah Hashim, Joseph Paturzo, Dorry L. Segev, Martin A. Makary. A Machine Learning Study of 534,023 Medicare Beneficiaries with COVID-19: Implications for Personalized Risk Prediction.
medRxiv 2020.10.27.20220970; doi: https://doi.org/10.1101/2020.10.27.20220970

[21] Delesderrier E, Cople-Rodrigues CS, Omena J, et al. Selenium Status and Hemolysis in Sickle Cell Disease Patients. Nutrients. 2019;11(9):2211. Published 2019 Sep 13. doi:10.3390/nu11092211


Thursday, 2 July 2020

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.





Wednesday, 27 May 2020

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

Thursday, 2 April 2020

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


Wednesday, 25 March 2020

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/19837254
Effects 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.