key: cord-0808072-33we8uex authors: Armann, J. P.; Doenhardt, M.; Hufnagel, M.; Diffloth, N.; Reichert, F.; Haas, W.; Schilling, J.; Haller, S.; Huebner, J.; Simon, A.; Schneider, D. T.; Brunner, J.; Trotter, A.; Roessler, M.; Schmitt, J.; Berner, R. title: Risk factors for hospitalization, disease severity and mortality in children and adolescents with COVID-19: Results from a nationwide German registry date: 2021-06-13 journal: nan DOI: 10.1101/2021.06.07.21258488 sha: 82adbe4ae15c308a2e579bb636676fcb34bba4a7 doc_id: 808072 cord_uid: 33we8uex Objective To characterize the clinical features of children and adolescents hospitalized with SARS-CoV-2 infections and to explore predictors for disease severity. Design Nationwide prospective observational cohort study. Setting Data collected from 169 out of 351 childrens hospitals in Germany between March 18, 2020 and April 30, 2021 and comparison with the Statutory Notification System. Participants 1,501 children and adolescents up to 19 years of age with laboratory confirmed SARS-CoV-2 infections who were admitted to childrens hospitals and subsequently reported to the COVID-19 registry of the German Pediatric Infectious Disease Society (DGPI). Main outcome measures Admission to intensive care, in-hospital. Results As compared to the information in the statutory notification system, up to 30% of all children and adolescents hospitalized in Germany during the study period were reported to the DGPI registry. Median age was three years (IQR, 0-12), with 36% of reported cases being infants. Although roughly half of patients in the registry were not admitted to the hospital due to their SARS-CoV-2 infection, 72% showed infection-related symptoms during hospitalization. Preexisting comorbidities were present in 28%, most commonly respiratory disorders, followed by neurological, neuromuscular, and cardiovascular diseases. Median length of hospitalization was five days (IQR 3-10). Only 20% of patients received a SARS-CoV-2-related therapy. Infants were less likely to require therapy as compared to older children. Overall, 111 children and adolescents were admitted to intensive care units (ICU). In a fully adjusted model, patient age, trisomy 21, coinfections and primary immunodeficiencies (PID) were significantly associated with intensive care treatment. In a bivariate analysis, pulmonary hypertension, cyanotic heart disease, status post (s/p) cardiac surgery, fatty liver disease, epilepsy and neuromuscular impairment were statistically significant risk factors for ICU admission. Conclusion Overall, a small proportion of children and adolescents was hospitalized in Germany during the first year of the pandemic. The majority of patients within our registry was not admitted due to COVID-19 suggesting an overestimation of the disease burden even in hospitalized children. Nevertheless, a large proportion of children and adolescents with confirmed COVID-19 reported in Germany could be captured. This allowed for detailed assessment of overall disease severity and underlying risk factors in our cohort. The main risk factors for COVID-19 disease associated intensive care treatment were older patient age, trisomy 21, PIDs and coinfection at the time of hospitalization. Trial registration Registry of hospitalized pediatric patients with SARS-CoV-2 infection (COVID-19), DRKS00021506 A r m a n n J A b s t r a c t O b j e c t i v e T o c h a r a c t e r i z e t h e c l i n i c a l f e a t u r e s o f c h i l d r e n a n d a d o l e s c e n t s h o s p i t a l i z e d w i t h S A R S -C o V -2 i d i t i e s w e r e p r e s e n t i n 2 8 % , m o s t c o m m o n l y r e s p i r a t o r y d i s o r d e r s , f o l l o w e d b y n e u r o l o g i c a l , n e u r o m u s c u l a r , a n d c a r d i o v a s c u l a r d i s e a s e s . M e d i a n l e n g t h o f h o s p i t a l i z a t i o n w a s f i v e d a y s ( I Q R 3 -1 0 ) . O n l y 2 0 % o f p a t i e n t s r e c e i v e d a S A R S -C o V -2 -r e l a t e d t h e r a p y . I n f a n t s w e r e l e s s l i k e l y t o r e q u i r e t h e r a p y a s c o m p a r e d t o o l d e r c h i l d r e n . O v e r a l l , 1 1 1 c h i l d r e n a n d a d o l e s c e n t s w e r e a d m i t t e d t o i n t e n s i v e c a r e u n i t s ( I C U ) . I n a f u l l y a d j u s t e d m o d e l , p a t i e n t a g e , t r i s o m y 2 1 , c o i n f e c t i o n s a n d p r i m a r y i m m u n o d e f i c i e n c i e s ( P I D ) w e r e s i g n i f i c a n t l y a s s o c i a t e d w i t h i n t e n s i v e c a r e t r e a t m e n t . I n a b i v a r i a t e a n a l y s i s , p u l m o n a r y h y p e r t e n s i o n , c y a n o t i c h e a r t d i s e a s e , s t a t u s p o s t ( s / p ) c a r d i a c s u r g e r y , f a t t y l i v e r d i s e a s e , e p i l e p s y a n d n e u r o m u s c u l a r i m p a i r m e n t w e r e s t a t i s t i c a l l y s i g n i f i c a n t r i s k f a c t o r s f o r I C U a d m i s s i o n . C o n c l u s i o n O v e r a l l , a s m a l l p r o p o r t i o n o f c h i l d r e n a n d a d o l e s c e n t s w a s h o s p i t a l i z e d i n G e r m a n y d u r i n g t h e f i r s t y e a r o f t h e p a n d e m i c . T h e m a j o r i t y o f p a t i e n t s w i t h i n o u r r e g i s t r y w a s n o t a d m i t t e d d u e t o C O V I D -1 9 s u g g e s t i n g a n o v e r e s t i m a t i o n o f t h e d i s e a s e b u r d e n e v e n i n h o s p i t a l i z e d c h i l d r e n . N e v e r t h e l e s s , a l a r g e p r o p o r t i o n o f c h i l d r e n a n d a d o l e s c e n t s w i t h c o n f i r m e d C O V I D -1 9 r e p o r t e d i n G e r m a n y c o u l d b e c a p t u r e d . T h i s a l l o w e d f o r d e t a i l e d a s s e s s m e n t o f o v e r a l l d i s e a s e s e v e r i t y a n d u n d e r l y i n g r i s k f a c t o r s i n o u r c o h o r t . T h e m a i n r i s k f a c t o r s f o r C O V I D -1 9 d i s e a s e a s s o c i a t e d i n t e n s i v e c a r e t r e a t m e n t w e r e o l d e r p a t i e n t a g e , t r i s o m y 2 1 , P I D s a n d c o i n f e c t i o n a t t h e t i m e o f h o s p i t a l i z a t i o n . T r i a l r e g i s t r a t i o n R e g i s t r y o f h o s p i t a l i z e d p e d i a t r i c p a t i e n t s w i t h S A R S -C o V -2 i n f e c t i o n ( C O V I D -1 9 ) , D R K S 0 0 0 2 1 5 0 6 A b b r e v i a t i o n s : C I C o n f i d e n c e i n t e r v a l C O V I D -1 9 C o r o n a v i r u s d i s e a s e 2 0 1 9 R T A R a p i d a n t i g e n t e s t P I D P r i m a r y I m m u n o d e f i c i e n c y I C U I n t e n s i v e c a r e u n i t h / o H i s t o r y o f s / p S t a t u s p o s t I Q R I n t e r q u a r t i l I N T R O D U C T I O N S i n c e D e c e m b e r 2 0 1 9 , S e v e r e A c u t e R e s p i r a t o r y S y n d r o m e C o r o n a v i r u s 2 ( S A R S -C o V -2 ) [ 1 ] h a s r a p i d l y s p r e a d a n d e m e r g e d a s a g l o b a l p a n d e m i c . T h e r o l e o f c h i l d r e n a n d a d o l e s c e n t s i n t h e p a n d e m i c h a s b e e n d e b a t e d w i t h i n t h e s c i e n t i f i c c o m m u n i t y a n d b e y o n d . A l t h o u g h t h e p e d i a t r i c p o p u l a t i o n -i n c o n t r a s t t o a d u l t s [ 2 ] -u s u a l l y h a s a m i l d d i s e a s e c o u r s e a n d l o w h o s p i t a l i z a t i o n r a t e s [ 3 , 4 ] , t h e r e a r e s t i l l c h i l d r e n w h o e x p e r i e n c e s e v e r e d i s e a s e [ 5 ] a n d w h o t h e r e f o r e w o u l d b e n e f i t f r o m n o n -p h a r m a c e u t i c a l p r o t e c t i v e m e a s u r e s a n d v a c c i n a t i o n . F o r t h i s r e a s o n , i t i s c r i t i c a l t o i d e n t i f y p o p u l a t i o n s a t r i s k w i t h i n t h e p e d i a t r i c p o p u l a t i o n i n o r d e r t o i m p l e m e n t p r e v e n t i v e m e a s u r e s t a r g e t e d t o r e d u c e C O V I D -1 9 -a s s o c i a t e d m o r b i d i t y a n d m o r t a l i t y f o r v u l n e r a b l e c h i l d r e n a n d a d o l e s c e n t s , t o f o c u s i n t e r v e n t i o n s t h e r e b y p r e v e n t i n g p o t e n t i a l h a r m t o t h e p e d i a t r i . P h y s i c i a n s 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) The copyright holder for this preprint this version posted June 13, 2021. . . 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 June 13, 2021. 8 % o f a l l a n d 6 7 % o f h o s p i t a l i z e d ) c a s e s , r e p o r t i n g i n c l u d e d i n f o r m a t i o n o n p r e s e n c e o n s y m p t o m s a n d I C U s t a t u s , r e s p e c t i v e l y . I n c i d e n c e o f i n f e c t i o n s a n d s y m p t o m a t i c i n f e c t i o n s b y a g e g r o u p w a s h i g h e s t a m o n g 1 2 -t o 1 7 -y e a r -o l d c h i l d r e n . H o w e v e r , h o s p i t a l i z a t i o n s p e r 1 0 0 , 0 0 0 p o p u l a t i o n w e r e h i g h e s t a m o n g i n f a n t s ( F i g . 2 ) . . 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 June 13, 2021. ; https://doi.org/10.1101/2021.06.07.21258488 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. The copyright holder for this preprint this version posted June 13, 2021. T a b l e 1 . G e n e r a l c h a r a c t e r i s t i c s o f h o s p i t a l i z e d c h i l d r e n a n d a d o l e s c e n t s w i t h a l a b o r a t o r y -c o 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. The copyright holder for this preprint this version posted June 13, 2021. T r e a t m e n t M e d i a n l e n g t h o f h o s p i t a l i z a t i o n w a s f i v e d a y s ( I Q R 3 -1 0 ) . O n l y 2 0 % ( n = 2 9 4 ) o f p a t i e n t s r e c e i v e d a S A R S -C o V -2 -r e l a t e d ( d e f i n e d b y t h e p h y s i c i a n w h o r e p o r t e d t h e c a s e ) t h e r a p y d u r i n g t h e i r h o s p i t a l i z 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 June 13, 2021. ; s t P o i s s o n r e g r e s s i o n w a s u s e d t o m o d e l r e l a t i o n s h i p s b e t w e e n r i s k f a c t o r s a n d I C U a d m i s s i o n a s a m a r k e r f o r d i s e a s e s e v e r i t y ( T a b l e 3 / F i g u r e 3 ) . S i n c e n o I C U p a t i e n t w a s r e p o r t e d t o h a v e p s y c h i a t r i c d i s o r d e r s o r t o h a v e r e c e i v e d t r a n s p l a n t a t i o n , t h e s e p o t e n t i a l r i s k f a c t o r s w e r e e x c l u d e d f r o m t h e r e g r e s s i o n a n a l y s e s . I n a b i v a r i a t e m o d e l , t h e f o l l o w i n g w e r e s i g n i f i c a n t l y a s s o c i a t e d w i t h a s e v e r e c o u r s e o f d i s e a s e r e q u i r i n g I C U a d m i s s i o n : a g e > 1 y e a r , p r e -e x i s t i n g a u t o i m m u n o l o g i c 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 June 13, 2021. . 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 June 13, 2021. . 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 June 13, 2021. D I S C U S S I O N W i t h n e a r l y 5 0 % o f h o s p i t a l s p a r t i c i p a t i n g , a s w e l l a s i n c l u d i n g d a t a o f a l a r g e p r o p o r t i o n o f c h i l d r e n , h o s p i t a l i z e d w i t h S A R S -C o V -2 -i n f e c t i o n , t h e D G P I r e g i s t r y h a s p r o v i d e d t h e m e a n s t o r e l i a b l y a n a l y z e t h e c l i n i c a l s p e c t r u m o f h o s p i t a l i z e d c h i l d r e n a n d a d o l e s c e n t s w i t h S A R S -C o V -2 i n f e c t i o n s i o u g h i n f a n t s w e r e h o s p i t a l i z e d a t a h i g h e r r a t e t h a n o l d e r c h i l d r e n r e l a t i v e t o t h e i r s h a r e i n t h e g e n e r a l p o p u l a t i o n [ 1 2 , 1 7 ] , o n l y 1 4 % o f i n f a n t s r e q u i r e d a S A R S -C o V -2 -r e l a t e d t h e r a p y . I n t e r e s t i n g l y , t h i s i s a s i g n i f i c a n t l y l o w e r p r o p o r t i o n t h a n f o r o l d e r a g e g r o u p s . I n a d d i t i o n , p r e m a t u r e l y b o r n i n f a n t s w e r e l e s s l i k e l y t o r e q u i r e t h e r a p y a s c o m p a r e d t o o l d e r c h i l d r e n . H o w e v e r , t h i s d o e s n o t i n d i c a t e t h a t i n f a n t s a r e m o r e l i k e l y t o e x p e r i e n c e a s e v e r e d i s e a s e c o u r s e . I n f 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 June 13, 2021. ; t h a n c h i l d r e n ' s h o s p i t a l s . G i v e n t h e o v e r a l l l o w n u m b e r o f h o s p i t a l i z e d c h i l d r e n a n d a d o l e s c e n t s -a s w e l l a s c r i t i c a l l y i l l c h i l d r e n -r e l i a b l e p r e d i c t i o n o f o u t c o m e r e m a i n s d i f f i c u l t . A n a l y z i n g d e f i n e d d i s e a s e s , p a t i e n t s w i t h p u l m o n a r y h y p e r t e n s i o n , c y a n o t i c h e a r t d i s e a s e , s / p c a r d i a c s u r g e r y , f a t t y l i v e r d i s e a s e , n e u r o m u s c u l a r i m p a i r m e n t a n d e p i l e p s y s e e m t o h a v e a h i g h e 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 13, 2021. ; 1 5 n o t c o r r e s p o n d t o s e v e r e d i s e a s e i n o u r c o h o r t g i v e n t h a t 8 0 % p a t i e n t s d i d n o t r e q u i r e S A R S -C o V -2 r e l a t e d t h e r a p . 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 June 13, 2021. ; g n e d a n d s t a r t e d t h e r e g i s t r y ; J . 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