{"id":8495,"date":"2021-02-22T11:30:37","date_gmt":"2021-02-22T11:30:37","guid":{"rendered":"https:\/\/www.zoeharcombe.com\/?p=8495"},"modified":"2021-02-21T14:44:58","modified_gmt":"2021-02-21T14:44:58","slug":"nice-vitamin-d-covid-19","status":"publish","type":"post","link":"https:\/\/www.zoeharcombe.com\/2021\/02\/nice-vitamin-d-covid-19\/","title":{"rendered":"NICE, Vitamin D & Covid-19"},"content":{"rendered":"
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Executive Summary<\/strong>\n <\/p>\n * The UK National Institute for Care & Health Excellence (NICE) undertook a rapid review of vitamin D for the treatment and prevention of Covid-19. The review was published in December 2020.\n <\/p>\n * Three research questions were asked about 1) vitamin D as a treatment for Covid-19, 2) vitamin D for prevention of Covid-19 and 3) any associations observed between vitamin D and Covid-19 outcomes.\n <\/p>\n * NICE found one randomised controlled trial (RCT) to consider for question 1, no RCTs for question 2 and 12 population\/case control type studies for question 3.\n <\/p>\n * The one RCT examining vitamin D for treatment of Covid-19 found that administration of vitamin D at hospital admission significantly reduced the likelihood of being admitted to ICU and no one treated with vitamin D died. The odds ratios were striking.\n <\/p>\n * The 12 studies examining the association between vitamin D levels and incidence of Covid-19 and\/or severity of Covid-19 (including survival from) were conducted in many different countries by many different research teams. Vitamin D levels were reviewed as absolute levels and as deficient or sufficient levels. \n <\/p>\n * Two UK studies (using Biobank data) found nothing statistically significant. The other 10 studies all concluded that higher\/sufficient vitamin D levels were associated with significantly better outcomes from Covid-19. The risk ratios for lower\/insufficient vitamin D levels were striking in many cases \u2013 up to 15-fold difference in one study and often beyond the 2-fold difference used as a starting point for causality with the Bradford Hill criteria. \n <\/p>\n * Every single study, every single piece of evidence, was dismissed in the NICE document as “very low<\/em>” in quality and at “serious risk of bias<\/em>” or “very serious risk of bias<\/em>.”\n <\/p>\n * I saw a lot of evidence to support vitamin D being a valuable intervention to lessen the likelihood of bad outcomes (including death) from Covid-19. NICE essentially concluded “move along \u2013 there’s nothing to see here.” \n <\/p>\n Introduction<\/strong>\n <\/p>\n The UK National Institute for Care & Health Excellence (NICE) undertook a rapid review of vitamin D for the treatment and prevention of Covid-19. The review was published in December 2020 (Ref 1). The committee undertaking the work asked three research questions:\n <\/p>\n Research questions<\/em>\n <\/p>\n 1) What is the clinical effectiveness and safety of vitamin D supplementation for the treatment of Covid-19 in adults, young people, and children?\n <\/p>\n 2) What is the clinical effectiveness and safety of vitamin D supplementation for the prevention of SARS CoV2 infection (and subsequent Covid-19) in adults, young people, and children?\n <\/p>\n 3) Is vitamin D status independently associated with susceptibility to developing Covid-19, severity of Covid-19, and poorer outcomes from Covid-19 in adults, young people, and children?\n <\/p>\n The three key words in these research questions are 1) treatment 2) prevention and 3) association. The search for evidence was conducted on the period 2002 to October 27th, 2020. This allowed for other coronaviruses, such as SARS CoV1 (symptomatic) and MERS, to be included as indirect evidence. It transpired that only Covid-19 studies were included.\n <\/p>\n Outcomes of interest<\/em>\n <\/p>\n The main outcomes of interest for research questions 1 and 2 were mortality (all-cause and Covid-19 related) and Intensive Care Unit (ICU) admissions. There were a number of secondary outcomes of interest including hospitalization, ventilation, time to clinical cure, complications, and others. I haven’t listed all the secondary outcomes of interest because, as you will see, only one study ended up being considered as evidence for Question 1 and no studies ended up being considered as evidence for question 2. \n <\/p>\n The outcomes of interest for research question 3 were:\n <\/p>\n – Incidence of Covid-19 (laboratory\/virologically confirmed)\n <\/p>\n – Covid-19 rate (laboratory\/virologically confirmed)\n <\/p>\n<\/p>\n <\/a><\/p>\n \n – Severity of confirmed Covid-19 (for example, but not limited to, Centers for Disease Control and Prevention definition, World Health Organization definition, proxy such as hospitalisation, ventilation, ICU admission, and others)\n <\/p>\n – Poor outcomes (for example, mortality, complications, morbidities post infection, long Covid).\n <\/p>\n Inclusion & exclusion criteria<\/em>\n <\/p>\n The inclusion criteria for research questions 1 and 2 were: systematic review of randomised controlled trials (RCTs); RCTs; and controlled clinical trials. The exclusion criteria for research questions 1 and 2 were: case-control studies; cross section studies; case series and case reports; and qualitative studies (Ref 2).\n <\/p>\n The inclusion criteria for research question 3 were: systematic review of non-randomised studies; prospective and retrospective cohort studies; case-control studies; cross-sectional studies; and case series. The exclusion criteria for research question 3 were case reports.\n <\/p>\n Studies found meeting criteria<\/em>\n <\/p>\n For research question 1, one study was included (Entrenas Castillio et al<\/em> 2020 RCT Spain) (Ref 3).\n <\/p>\n For research question 2, no studies were included.\n <\/p>\n For research question 3, 12 studies were included (see below).\n<\/p>\n I checked the studies found with a vitamin D expert, who knows the literature far better than I do, and he thought that the committee had found the studies that met their criteria. I am proceeding on the basis that the studies available for each of these research questions are as presented in the report.\n <\/p>\n The results<\/strong>\n <\/p>\n Research question 1<\/em>\n <\/p>\n The one study included to answer this research question was conducted in a hospital in Spain. This study involved 76 patients who were hospitalised with lab-confirmed Covid-19. They were randomised in a 2:1 ratio to the treatment arm or the control arm; so 50 people ended up in the treatment arm and 26 in the control arm. The treatment was administration of oral calcifediol (vitamin D3) (0.532 mg) on the day of admission. Patients in the calcifediol treatment group continued with oral calcifediol (0.266 mg) on days 3 and 7, and then weekly until discharge or ICU admission. People in the control arm were not given any vitamin D. Other treatment between the patients remained the same. \n <\/p>\n Of the 50 patients treated with calcifediol, 1 required admission to ICU (2%) while, of 26 untreated patients, 13 required admission (50%). That was a statistically significant and clinically significant difference. Of the patients treated with calcifediol, none died, and all were discharged without complications. The 13 patients not treated with calcifediol, who were not admitted to the ICU, were discharged. Of the 13 patients admitted to the ICU, 2 died and the remaining 11 were discharged.\n <\/p>\n The odds ratio (OR) for ending up in ICU was 0.02 (95 %CI 0.002\u22120.17) for the treatment group vs the no-treatment group. That was almost a 0% chance of the vitamin D group ending up in ICU. When the results were adjusted for differences between the two groups for hypertension and type 2 diabetes, the odds ratio was still 0.03 (95 %CI: 0.003-0.25). \n <\/p>\n The NICE document dismissed this evidence as “very low<\/em>” in quality and at “very serious risk of bias<\/em>” for ICU admission and as “very low<\/em>” in quality and at “very serious risk of bias<\/em>” for mortality.\n <\/p>\n Research question 2<\/em>\n <\/p>\n NICE found nothing to examine for the research question about prevention.\n <\/p>\n Research question 3<\/em>\n <\/p>\n NICE found 12 studies to help with the research question \u2013 is there any evidence for vitamin D being associated with developing Covid-19 or the severity of Covid-19 if diagnosed? The 12 studies were all from 2020. Two studies each came from France, the UK, the US, and from Spain and one each came from China, Germany, Israel, and Turkey. The studies were mainly of population studies and case-control studies. \n <\/p>\n We’ll whizz through them \u2013 extracting the salient point from the original papers. (I’m going to keep numbers and confidence intervals to a minimum for ease of reading. All of these can be found in the paper abstracts, which the references can point you to. Many of the findings are so significant in the normal sense of the word, that confirmation of the statistical significance will just clutter the narrative).\n <\/p>\n