key: cord-1010119-qnz9v9ta authors: Dierckx, T.; Van Elslande, J.; Salmela, H.; Decru, B.; Wauters, E.; Gunst, J.; Van Herck, Y.; CONTAGIOUS consortium,; Wauters, J.; Stessel, B.; Vermeersch, P. title: The metabolic fingerprint of COVID-19 severity date: 2020-11-12 journal: nan DOI: 10.1101/2020.11.09.20228221 sha: 317bf79f8c55c703c8520328b8abb0dfeea1e66b doc_id: 1010119 cord_uid: qnz9v9ta Corona virus disease 2019 (COVID-19) has been associated with a wide range of divergent pathologies, and risk of severe disease is reported to be increased by a similarly broad range of co-morbidities. The present study investigated blood metabolites in order to elucidate how infection with severe acute respiratory syndrome coronavirus 2 can lead to such a variety of pathologies and what common ground they share. COVID-19 patient blood samples were taken at hospital admission in two Belgian patient cohorts, and a third cohort that included longitudinal samples was used for additional validation (total n=581). A total of 251 blood metabolite measures and ratios were assessed using nuclear magnetic resonance spectroscopy and tested for association to disease severity. In line with the varied effects of severe COVID-19, the range of severity-associated biomarkers was equally broad and included increased inflammatory markers (glycoprotein acetylation), amino acid concentrations (increased leucine and phenylalanine), increased lipoprotein particle concentrations (except those of very low density lipoprotein, VLDL), decreased cholesterol levels (except in large HDL and VLDL), increased triglyceride levels (only in IDL and LDL), fatty acid levels (decreased poly-unsaturated fatty acid, increased mono-unsaturated fatty acid) and decreased choline concentration, with association sizes comparable to those of routine clinical chemistry metrics of acute inflammation. Our results point to systemic metabolic biomarkers for COVID-19 severity that make strong targets for further fundamental research into its pathology (e.g. phenylalanine and omega-6 fatty acids). 1 * , J a n v a n E l s l a n d 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. (which was not certified by peer review) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice . A b s t r a c t C o r o n a v i r u s d i s e a s e 2 0 1 9 ( C O V I D -1 9 ) h a s b e e n a s s o c i a t e d w i t h a w i d e r a n g e o f d i v e r g e n . 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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 I n t r o d u c t i o n S e v e r e c o r o n a v i r u s d i s e a s e 2 0 1 9 ( C O V I D -1 9 ) , t h e d i s e a s e c a u s e d b y s e v e r e a c u t e r e s p i r a t o r o w e v e r , t r a d i t i o n a l H D L , L D L a n d c h o l e s t e r o l q u a n t i f i c a t i o n m e t h o d s u s e d i n c l i n i c a l s e t t i n g s l a c k t h e r e s o l u t i o n t 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. (which was not certified by peer review) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint a n a l y t i c a l l y c a p t u r e t h e l i p o p r o t e i n p r o f i l e 1 7 . N u c l e a r m a g n e t i c r e s o n a n c e ( N M R ) s p e c t r o s c o p y c a n b e u s e d t o a d d r e s s t h i s l i m i t a t i o n 1 8 , a n d e n a b l e s a m o r e s y s t e m i c i n v e s t i g a t i o n b y s i m u l t a n e o u s l y q u a n t i f y i n g a l a r g e n u m b e r o f m e t r i c s r e l e v a n t t o t h e C O V I D -1 9 s e t t i n g i n c l u d i n g e n e r g y -r e l a t e d m e t a b o l i t e s , a m i n o a c i d a n d f a t t y a c i d c o n c e n t r a t i o n s a n d g l y c o p r o t e i n a c e t y l a t i o n ( G l y c A ) i s t i n c t a d v a n t a g e s o v e r t r a d i t i o n a l i n f l a m m a t o r y b i o m a r k e r s s u c h a s C -r e a c t i v e p r o t e i n ( C R P ) i n i t s a s s o c i a t i o n t o i n f l a m m a t o r y c o n d i t i o n s 1 8 , 3 1 , 3 2 . D u e t o i t s m o r e p e r s i s t e n t a n d c o m p o s i t e n a t u r e , b e i n g a r e a d -o u t f o r m a n y d i f f e r e n t i n f l a m m a t o r y p r o c e s s e s , G l y c A c a n b e i n t e r p r e t e d a s a s u m m a r y m e a s u r e o f a s u b j e c t ' s ' b a s e l i n e ' c h r o n i c i n f l a m m a t o r y b u r d e n 3 3 . I n l i g h t o f t h e c o m m o n t h e m e o f l o w -g r a d e i n f l a m m a t i o n i n p o p u l a t i o n s w i t h h i g h e r r i s k f o r s e v e r e C O V I D -1 9 1 3 a n d r c t i o n c a n l e a d t o s u c h a v a r i e t y o f p a t h o l o g i e s a n d w h a t c o m m o n g r o u n d t h e s e p a t h o l o g i e s s h a r e , w e u s e d N M R e x p e r i m e n t s t o q u a n t i f y c h r o n i c i n f l a m m a t o r y b u r d e n , l i p o p r o t e i n p a r t i c l e c o n c e n t r a t i o n s ( a s w e l l a s t h e i r c h o l e s t e r o l a n d . 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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 t r i g l y c e r i d e c o n t e n t ) , a m i n o a c i d a n d f a t t y a c i d c o n c e n t r a t i o n s , a n d e n e r g y r e l a t e d m e t a b o l i t e s i n t h r e e s a m p l e s e t s f r o m c o n f i r m e d S A R S -C o V -2 i n f e c t e d p a t i e n t s i n t w o B e l g i a n h o s p i t a l s , c o l l e c t e d a t t i m e o f h o s p i t a l a d m i s s i o n f o r C O V I D -1 9 . W e i d e n t i f i e d b i o m a r k e r s a s s o c i a t e d w i t h C O V I D -1 9 s e v e r i t y ( m i l T A G I O U S c o h o r t s t u d y i s a p r o s p e c t i v e o b s e r v a t i o n a l t r i a l f o r w h i c h i n f o r m e d c o n s e n t w a s o b t a i n e d f o r a l l p a r t i c i p a n t s ( c l i n i c a l t r i a l s . g o v i d e n t i f i e r N C T 0 4 3 2 7 5 7 0 ) . M a r c h -J u n e 2 0 2 0 ) f o r w h o m a l e f t -o v e r s a m p l e f r o m r o u t i n e b i o c h e m i s t r y a t t h e t i m e o f h o s p i t a l p r e s e n t a t i o n w a s a v a i l a b l e w e r e i n c l u d e d . A l l i n c l u d e d p a t i e n t s t e s t e d . 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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 p o s i t i v e f o r S A R S -C o V -2 u s i n g r e a l -t i m e p o l y m e r a s e c h a i n r e a c t i o n , p e r f o r m e d i n a c c o r d a n c e w i t h W H O g u i d e l i n e s 3 5 . P o s i t i v e P C R r e s u l t s w e r e o b t a i n e d a t t i m e o f a d m i s s i o n s a m p l i n g ( m e d i a n 0 d a y s , r a n g e -6 t o 2 d a y s f o r t h e U Z L c o h o r t , r a n g e -8 t o 0 d a y s f o r t h e J E S S A c o h o r t , r e s p e c t i v e l y ) . 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. (which was not certified by peer review) preprint The copyright holder for this this version posted November 12, 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) preprint The copyright holder for this this version posted November 12, 2020. ; a d m i s s i o n w e r e a l s o d i f f e r e n t b e t w e e n t h e t w o c o h o r t s : a v e r a g e w h i t e b l o o d c e l l c o u n t , n e u t r o p h i l c o u n t a n d e o s i n o p h i l c o u n t , a s w e l l a s C R P l e v e l s , f e r r i t i n l e v e l s a n d a c t i v a t e d p a r t i a l t h r o m b o p l a s t i n t i m e w e r e s i g n i f i c a n t l y h i g h e r i n t h e J e s s a c o h o r t , w h e r e a s s l . T h e s e m e t r i c s a r e i m p o r t a n 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. (which was not certified by peer review) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint c o m p o n e n t s o f J u l k u n e n e t a l ' s ' I n f e c t i o u s D i s e a s e S c o r e ' ( I D S ) , w h i c h c a n p a r t l y e x p l a i n t h e I D S ' s s t r o n g a s s o c i a t i o n t o C O V I D -1 9 s e v e r i t y ( o d d s r a t i o s o f 4 a n d 4 . 5 f o r t h e U Z L a n d J e s s a c o h o r t , r e s p e c t i v e l y ) . . 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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint . . 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) preprint The copyright holder for this this version posted November 12, 2020. s e v e r i t y i s i n l i n e w i t h r e p o r t s o f l o w o c c u r r e n c e o f s e v e r e C O V I D -1 9 o u t c o m e s a m o n g p h e n y l k e t o n u r i a p a t i e n t s , w h i c h w a s p r e v i o u s l y a s c r i b e d t o t h i s p o p u l a t i o n ' s l o w e r r a t e s o f v i t a m i n D d e f i c i e n c y a s a r e s u l t o f t h e p r o t e i n s u b s t i t u t e s i n t h e i r d i 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 this version posted November 12, 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 this version posted November 12, 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 this version posted November 12, 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 this version posted November 12, 2020. ; https://doi.org/10.1101 https://doi.org/10. /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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint 3 7 . V a n E l s l a n d e , J . e t a l . A n t i b o d y r e s p o n s e a g a i n s t S A R S -C o V -2 s p i k e p r o t e i n a n d n u c l e o p r o t e i n e v a l u a t e d b y f o u r a u t o m a t e d i m m u n o a s s a y s a n d t h r e e E L I S 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. (which was not certified by peer review) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint 4 7 . C o n n e l l y , M . A . e t a l . G l y c A , a m a r k e r o f a c u t e p h a s e g l y c o p r o t e i n s , a n d t h e r i s k o f i n c i d e n t t y p e 2 d i a b e t e s m e l l i t u s : I m m u n e , H a e m a t o l o g i c a l , a n d . 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) preprint The copyright holder for this this version posted November 12, 2020. D i e t a r y o m e g a -6 , b u t n o t o m e g a -3 , p o l y u n s a t u r a t e d o r s a t u r a t 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. (which was not certified by peer review) preprint The copyright holder for this this version posted November 12, 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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 a m i n o t r a n s f e r a s e , A P T T : a c t i v a t e d p a r t i a l t h r o m b o p l a s t i n t i m e , A S T : a s p a r t a t e t r a n s a m i n a s e , B M I : b o d y m a s s i n d e x , C R P : c -r e a c t i v e p r o t e i n , C V D : c a r d i o v a s c u l a r d i s e a s e , e G F R : e s t i m a t e d g l o m e r u l a r f i l t r a t i o n r 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. (which was not certified by peer review) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101 https://doi.org/10. /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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101 https://doi.org/10. /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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101 https://doi.org/10. /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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101 https://doi.org/10. /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) preprint The copyright holder for this this version posted November 12, 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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint . 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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint . 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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint F i g u r e 7 : S e l e c t e d b i o m a r k e r s i n s e v e r e a n d c r i t i c a l c a s e s o f t h e C O N T A G I O U S c o h o r t . S e v e r i t y 3 a n d 4 , s e v e r e a n d c r i t i c a l , r e s p e c t i v e l y . W h e r e d e p i c t e d , t h e y -a x i s o n t h e r i g h t s i d e o f t h e g r a p h n o r m a l i z e s t h e d a t a u s i n g t h e m e a n a n d s t a n d a r d d e v i a t i o n s o b s e r v e d i n F i n n i s h d e m o g r a p h 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. (which was not certified by peer review) preprint The copyright holder for this this version posted November 12, 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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint ( D i s + 3 0 , p u r p l e ) . I n d i c a t e d a r e p -v a l u e s o f M a n n -W h i t n e y U t e s t s c o m p a r i n g t h e i n d i c a t e d t i m e p o i n t s . W h e r e d e p i c t e d , t h e y -a x i s o n t h e r i g h t s i d e o f t h e g r a p h n o r m a l i z e s t h e d a t a u s i n g t h e m e a n a n d s t a n d a r d d e v i a t i o n s o b s e r v e d i n F i n n i s h d e m o g r a p h i c c o h o r 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. (which was not certified by peer review) preprint The copyright holder for this this version posted November 12, 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) preprint The copyright holder for this this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint Total cholesterol in lipoprotein particles 0.1 0.2 0.5 1.0 2.0 5.0 10.0 . 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 this version posted November 12, 2020. ; https://doi.org/10.1101/2020.11.09.20228221 doi: medRxiv preprint non−LDL Cholesterol in non−HDL