key: cord-0757724-imoafu1g authors: Guerin, P. J.; McLean, A. R. D.; Rashan, S.; Lawal, A. A.; Watson, J. A.; Nathalie Strub-Wourgaft, N.; White, N. J. title: Definitions matter: heterogeneity of COVID-19 disease severity criteria and incomplete reporting compromise meta-analysis date: 2021-06-04 journal: nan DOI: 10.1101/2021.06.04.21257852 sha: 3677a5edab0e56ac63c5c3316a587642468d83c4 doc_id: 757724 cord_uid: imoafu1g Therapeutic efficacy in COVID-19 is dependent upon disease stage and severity (treatment effect heterogeneity). Unfortunately, definitions of severity vary widely. This compromises the meta-analysis of randomised controlled trials (RCTs) and the therapeutic guidelines derived from them. The World Health Organisation "living" guidelines for the treatment of COVID-19 are based on a network meta-analysis (NMA) of published RCTs. We reviewed the 81 studies included in the WHO COVID-19 living NMA and compared their severity classifications with the severity classifications employed by the international COVID-NMA initiative. The two were concordant in only 35% (24/68) of trials. Of the RCTs evaluated 69% (55/77) were considered by the WHO group to include patients with a range of severities (12 mild-moderate; 3 mild-severe; 18 mild-critical; 5 moderate-severe; 8 moderate-critical; 10 severe-critical), but the distribution of disease severities within these groups usually could not be determined, and data on the duration of illness and/or oxygen saturation values were often missing. Where severity classifications were clear there was substantial overlap in mortality across trials in different severity strata. This imprecision in severity assessment compromises the validity of some therapeutic recommendations; notably extrapolation of "lack of therapeutic benefit" shown in hospitalised severely ill patients on respiratory support to ambulant mildly ill patients is not warranted. Both harmonised unambiguous definitions of severity and individual patient data meta-analyses are needed to guide and improve therapeutic recommendations in COVID-19. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.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 June 4, 2021. ( S u p p l e m e n t a r y T a b l e 2 ) . T All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 June 4, 2021. ; https://doi.org/10.1101/2021.06.04.21257852 doi: medRxiv preprint r a c t e d t h e m e a n a g e , m o r t a l i t y a n d p o s s i b l e s e v e r i t y r a n g e o f p a t i e n t s l i s t e d o n l All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 June 4, 2021. ; https://doi.org/10.1101/2021.06.04.21257852 doi: medRxiv preprint o f s e v e r i t y s h o u l d b e b a s e d o n a v a i l a b l e d a t a a n d o u t c o m e s , a n d i n c l u d e d i s e a s e s p e c i f i c f a c t o r s l i n k e d t o p a t i e n t p r o g n o s i s ( i n d e p e n d e n t o f u n d e r l y i n g p a t i e n t f a c t o r s ) . T h e l a r g e v a r i a t i o n i n m o r t a l i t y o b s e r v e d b e t w e e n t r i a l s s u p p o s e d l y i n c l u d i n g p a t i e n t s w i t h s i m i l a All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 June 4, 2021. ; D a t a s h a r i n g s t a t e m e n t : A l l t h e d a t a u s e d i n t h i s s t u d y a r e p u b l i c l y a v a i l a b l e a n d p r o p e r l y c i t e d . H o w e v e r , m o r e g u i d e d i n s t r u c t i o n t o g e t a c c e s s t o t h e d a t a f o r t r a n s p a r e n c y a n d r e p r o d u c i b i l i t y w i l l b e p r o v i d e d o n r e q u e s All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. r a l l o a d d y n a m i c s , d u r a t i o n o f v i r a l s h e d d i n g , a n d i n f e c t i o u s n e s s : a s y s t e m a t i c r e v i e w a n d m e t a -a n a l y s i s . T h e L a n c e t M i c r o b e 2 0 2 1 ; 2 ( 1 ) : e 1 3 -e 2 . All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. F i g u r e 1 . S e v e r i t y d e f i n i t i o n s f r o m W H O , U S N I H g u i d e l i n e s a n d o r g a n i s a t i o n s c o n d u c t i n g r e v i e w o f e v i d e n c e i . e . t h e W H O -C O V I D -1 9 L i v i n g N e t w o r k M e t a -A n a l y s i s a n d t h e C O V I D -N M A i m i t a t i v e . F i g u r e 2 . P o s s i b l e r a n g e o f p a t i e n t s e v e r i t y i n s t u d i e s a s c l a s s i f i e d b y W H O -C O V I D -1 9 L i v i n g N e t w o r k M e t a -A n a l y s i s g r o u p ( b l a c k c i r c l e s ) a n d C O V I D -N M A i n i t i a t i v e ( r e d s q u a r e s ) . M a t c h e d s e v e r i t y d e f i n i t o n b e t w e e n t h e t w o g r o u p s ( g r e e n t r i a n g l All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Mehboob 2020