key: cord-0701548-ij14mbsm authors: Israel, A.; Cicurel, A. A.; Feldhamer, I.; Dror, Y.; Giveon, S. M.; Gillis, D.; Strich, D.; Lavie, G. title: The link between vitamin D deficiency and Covid-19 in a large population date: 2020-09-07 journal: nan DOI: 10.1101/2020.09.04.20188268 sha: 61b2a04ea85d234f173063f9ed9c88599310b13d doc_id: 701548 cord_uid: ij14mbsm BACKGROUND Recent studies suggest a link between vitamin D deficiency and Covid-19 infection. In our population we observe major differences in Covid-19 incidence in ethnic groups and genders in each group. METHODS We carried out a population-based study among 4.6 million members of Clalit Health Services (CHS). We collected results from vitamin D tests performed between 2010 and 2019 and used weighted linear regression to assess the relationship between prevalence of vitamin D deficiency and Covid-19 incidence in 200 localities. Additionally, we matched 52,405 infected patients with 524,050 control individuals of the same sex, age, geographical region and used conditional logistic regression to assess the relationship between baseline vitamin D levels, acquisition of vitamin D supplements in the last 4 months, and positive Covid-19. RESULTS We observe a highly significant correlation between prevalence of vitamin D deficiency and Covid-19 incidence, and between female-to-male ratio for severe vitamin D deficiency and female-to-male ratio for Covid-19 incidence in localities (P<0.001). In the matched cohort, we found a significant association between low vitamin D levels and the risk of Covid-19, with the highest risk observed for severe vitamin D deficiency. A significant protective effect was observed for members who acquired liquid vitamin D formulations (drops) in the last 4 months. CONCLUSION In this large observational population study, we show a strong association between vitamin D deficiency and Covid-19 occurrence. After adjustment for baseline characteristics and prior vitamin D levels, acquisition of liquid vitamin D formulations is associated with decreased risk for Covid-19 infection. ) . s a n d u l t r a -o r t h o d o x s u b p o p u l a t i o n s t e n d t o l i v e i n s p e c i f i c g e o g r a p h i c a r e a s . W i t h i n e a c h o f t h e s e e t h n i c g r o u p s , t h e r e a r e s i g n i f i c a n t d i f f e r e n c e s i n l i f e s t y l e , b u t p e o p l e w h o l i v e i n t h e s a m e l o c a l i t y t e n d t o f o l l o w a s i m i l a r l i f e s t y l e , o f t e n h a v e c o m m o n e t h n i c o r i g i n s , a n d m o r e i m p o r t a n t l y , i n d i v i d u a l s t e n d t o w e a r a t r a d i t i o n a l ( g e n d e r -s p e c i f i c ) a t t i r e , w i t h m o r e b o d y s u r f a c e c o v e r e d t h a n t h e g e n e r a l p o p u l a t i o n . T h e s e c o u l d a f f e c t t h e a b i l i t y o f t h e b o d y t o a b s o r b s u n l i g h t a n d p r o d u c e v i t a m i n D . P r e v i o u s r e s e a r c h h a s s h o w n t h a t v i t a m i n D d e f i c i e n c y i s m u c h m o r e p r e v a l e n t i n t h e s e t w o m i n o r i t i e s , a n d s e v e r e v i t a m i n D d e f i c i e n c y i s e n d e m i c a m o n g A r a b w o m e n 7 . I f t h e r e i s i n d e e d a n a s s o c i a t i o n b e t w e e n v i t a m i n D d e f i c i e n c y a n d h i g h e r r a t e s o f C o v i d -1 9 i n f e c t i o n , t h e n w e w o u l d e x p e c t t o o b s e r v e a s i g n i f i c a n t s t a t i s t i c a l a s s o c i a t i o n b e t w e e n t h e p r e v a l e n c e o f v i t a m i n D d e f i c i e n c y a n d C o v i d -1 9 i n c i d e n c e a c r o s s l o c a l i t i e s . M o r e o v e r , w e w o u l d e x p e c t t o s e e s i m i l a r g e n d e r -s p e c i f i c i t y f o r v i t a m i n D d e f i c i e n c y a n d C o v i d -1 9 c a s e s . C l a l i t H e a l t h S e r v i c e s ( C H S ) p r o v i d e s c o m p r e h e n s i v e h e a l t h s e r v i c e s t o o v e r 4 . 6 m i l l i o n m e m b e r s , a n d c e n t r a l l y m a n a g e s e l e c t r o n i c h e a l t h r e c o r d s ( E H R ) w i t h l o n g i t u d i n a l r e c o r d s f o r o v e r t w o d e c a d e s , i n c l u d i n g l a b o r a t o r y t e s t s , d i a g n o s e s , a n d p u r c h a s e o f m e d i c a t i o n s 8 . T h i s p r o v i d e s a u n i q u e o p p o r t u n i t y t o s t u d y t h e a s s o c i a t i o n b e t w e e n v i t a m i n D l e v e l s a n d C o v i d -1 9 i n c i d e n c e , a s w e l l a s t h e i m p a c t o f p u r c h a s e o f v i t a m i n D s u p p l e m e n t s o n t h e r i s k o f C o v i d -1 9 . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted September 7, 2020. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted September 7, 2020. . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. . h a v e l o w e r l e v e l s ( P < 0 . 0 0 1 ) , a n d w e o b s e r v e a r e m a r k a b l e l e f t t a i l o f A r a b f e m a l e s w i t h e x t r e m e l y l o w l e v e l s o f v i t a m i n D , r a r e l y s e e n i n t h e o t h e r t w o p o p u l a t i o n s . F i g u r e 2 d i s p l a y s t h e s t a t i s t i c a l d i s t r i b u t i o n o f b a s e l i n e v i t a m i n D l e v e l s a m o n g p a t i e n t s w h o w e r e f u r t h e r t e s t e d p o s i t i . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. i s a s s o c i a t e d w i t h s i g n i f i c a n t l y i n c r e a s e d r i s k . M o d e l ( 2 ) i s a m u l t i v a r i a b l e m o d e l i n c o r p o r a t i n g t h e e t h n i c g r o u p : l i v i n g i n a n e t h n i c g r o u p w h e r e t h e r e i s h i g h p r e v a l e n c e o f S A R S -C o V -2 i n f e c t i o n i n c u r s b y i t s e l f a s i g n i f i c a n t r i s k ( O R 3 . 4 4 2 f o r i n d i v i d u a l s l i v i n g i n U l t r a -o r t h o d o x c o m m u n i t i . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. . https://doi.org/10.1101/2020.09.04.20188268 doi: medRxiv preprint n o r t h e r l y l a t i t u d e i s a s s o c i a t e d w i t h h i g h e r m o r t a l i t y r a t e a n d h o s p i t a l i z a t i o n r a t e f o r C o v i d -1 9 w o r l d w i d e 2 . S e v e r a l p o t e n t i a l m e c h a n i s m s h a v e b e e n p r o p o s e d t o e x p l a i n t h e o b s e r v e d a s s o c i a t i o n b e t w e e n v i t a m i n D l e v e l s a n d t h e r i s k o f C o v i d -1 9 i n f e c t i o . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. a m a r k e r o f l o w v i t a m i n D l e v e l s , w i t h o u t t h e b e n e f i t o f v i t a m i n D d r o p s i n c r e a s i n g o r o p h a r y n g e a l c o n c e n t r a t i o n . P a t i e n t s w h o p u r c h a s e d v i t a m i n D t a b l e t s a r e a l s o n o t l i k e l y t o h a v e a c q u i r e d v i t a m i n D d r o p s i n a n o n C H S m a n a g e d p h a r m a c y , a s o p p o s e d t o o t h e r p e o p l e f o r w h i c h w e h a v e n o t r a c e o . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. . https://doi.org/10.1101/2020.09.04.20188268 doi: medRxiv preprint e x p l a i n w h y s o m a n y c o r o n a v i r u s e s a r e p r e s e n t i n b a t s 2 0 . N a t u r a l l y , a l m o s t a l l o t h e r m a m m a l s l i v e i n t h e f r e e a i r a n d g e t a b u n d a n t s u n l i g h t , a n d e v e n h u m a n s , t h r o u g h o u t h i s t o r y , h a d t o s p e n d a l a r g e p a r t o f t h e d a y o u t d o o r s i n o r d e r t o h u n t , p r o d u c e a n d g a t h e r f o o d . O n l y t h e t e c h n o l o g i c a l a d v a n c e . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. R e s u l t s f r o m t h i s s t u d y s u g g e s t t h a t p o p u l a t i o n s s h o u l d b e u r g e d t o g e t m o r e s u n l i g h t e x p o s u r e i n o r d e r t o d e c r e a s e C o v i d -1 9 r i s k . O r a l v i t a m i n D u p t a k e s h o u l d b e e n c o u r a g e d , p r e f e r a b l y i n t h e f o r . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. . . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. F i g u r e 1 : D i s t r i b u t i o n o f b l o o d v i t a m i n D l e v e l s m e a s u r e d b e t w e e n y e a r s 2 0 1 0 -2 0 2 0 i n t h e t h r e e s u b p o p u l a t i o n s i n m a l e s ( u p p e r p a n e l ) , a . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. F i g u r e 2 : D i s t r i b u t i o n o f v i t a m i n D m e a s u r e d i n t h e b l o o d b e t w e e n y e a r s 2 0 1 0 -2 0 2 0 a m o n g i n d i v i d u a l s l a t e r i n f e c t e d w i t h S A R S -C o V -2 p a t i e n t s a n d t h e r e s t o f t h e p o p u l a t i o . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. F i g u r e 3 : R e l a t i o n s h i p b e t w e e n s e v e r e v i t a m i n D d e f i c i e n c y p r e v a l e n c e a n d C o v i d -1 9 i n c i d e n c e b y e t h n i c g r o u p a n d l o c a l i t . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. F i g u r e 4 : R e l a t i o n s h i p b e t w e e n f e m a l e -t o -m a l e r a t i o o f s e v e r e v i t a m i n D d e f i c i e n c y , a n d f e m a l e t o -m a l e S A R S -C o V -2 i n c i d e n c e b y e t h n i c g r o u p a n d l o c a l i t . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted September 7, 2020. . T a b l e 1 : D e m o g r a p h i c s o f p o s i t i v e S A R S -C o V -2 p o s i t i v e t e s t s a m o n g C H S e t h n i c g r o u p 1 , 5 1 8 , 4 6 5 1 , 6 0 2 , 8 0 7 3 , 1 2 1 , 2 7 2 6 2 7 , 6 5 2 6 2 1 , 7 4 4 1 , 2 4 9 , 3 9 6 1 3 0 , 6 7 9 1 2 9 , 9 1 0 2 6 0 , 5 8 9 S A R S -C o V -2 p o s i t i v e 1 3 , 3 2 5 1 4 , 0 8 1 2 7 , 4 0 6 7 , 0 3 1 1 0 , 2 0 4 1 7 , 2 3 5 4 , 4 0 3 3 , 4 9 . 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