PMID- 36823262
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230328
IS  - 2197-425X (Print)
IS  - 2197-425X (Electronic)
IS  - 2197-425X (Linking)
VI  - 11
IP  - 1
DP  - 2023 Feb 24
TI  - Elevated free interleukin-18 associated with severity and mortality in 
      prospective cohort study of 206 hospitalised COVID-19 patients.
PG  - 9
LID - 10.1186/s40635-022-00488-x [doi]
LID - 9
AB  - BACKGROUND: Divergence between deterioration to life-threatening COVID-19 or 
      clinical improvement occurs for most within the first 14 days of symptoms. 
      Life-threatening COVID-19 shares clinical similarities with Macrophage Activation 
      Syndrome, which can be driven by elevated Free Interleukin-18 (IL-18) due to 
      failure of negative-feedback release of IL-18 binding protein (IL-18bp). We, 
      therefore, designed a prospective, longitudinal cohort study to examine IL-18 
      negative-feedback control in relation to COVID-19 severity and mortality from 
      symptom day 15 onwards. METHODS: 662 blood samples, matched to time from symptom 
      onset, from 206 COVID-19 patients were analysed by enzyme-linked immunosorbent 
      assay for IL-18 and IL-18bp, enabling calculation of free IL-18 (fIL-18) using 
      the updated dissociation constant (K(d)) of 0.05 nmol. Adjusted multivariate 
      regression analysis was used to assess the relationship between highest fIL-18 
      and outcome measures of COVID-19 severity and mortality. Re-calculated fIL-18 
      values from a previously studied healthy cohort are also presented. RESULTS: 
      Range of fIL-18 in COVID-19 cohort was 10.05-1157.7 pg/ml. Up to symptom day 14, 
      mean fIL-18 levels increased in all patients. Levels in survivors declined 
      thereafter, but remained elevated in non-survivors. Adjusted regression analysis 
      from symptom day 15 onwards showed a 100 mmHg decrease in PaO(2)/FiO(2) (primary 
      outcome) for each 37.7 pg/ml increase in highest fIL-18 (p < 0.03). Per 50 pg/ml 
      increase in highest fIL-18, adjusted logistic regression gave an odds-ratio (OR) 
      for crude 60-day mortality of 1.41 (1.1-2.0) (p < 0.03), and an OR for death with 
      hypoxaemic respiratory failure of 1.90 [1.3-3.1] (p < 0.01). Highest fIL-18 was 
      associated also with organ failure in patients with hypoxaemic respiratory 
      failure, with an increase of 63.67 pg/ml for every additional organ supported 
      (p < 0.01). CONCLUSIONS: Elevated free IL-18 levels from symptom day 15 onwards 
      are associated with COVID-19 severity and mortality. ISRCTN: #13450549; 
      registration date: 30/12/2020.
CI  - (c) 2023. The Author(s).
FAU - Nasser, Syed M T
AU  - Nasser SMT
AUID- ORCID: 0000-0002-4700-862X
AD  - Intensive Care Department, Surrey and Sussex NHS Foundation Trust, Redhill, UK. 
      syed.nasser1@nhs.net.
AD  - Intensive Care Department, Royal Surrey County Hospital, Egerton Road, Guildford, 
      GU2 7XX, UK. syed.nasser1@nhs.net.
FAU - Rana, Anas A
AU  - Rana AA
AD  - Centre for Computational Biology, Birmingham University, Birmingham, UK.
FAU - Doffinger, Rainer
AU  - Doffinger R
AD  - Department of Clinical Biochemistry and Immunology, Cambridge University 
      Hospitals NHS Trust, Cambridge, UK.
FAU - Kafizas, Andreas
AU  - Kafizas A
AD  - The Grantham Institute for Climate Change and the Environment, Imperial College 
      London, South Kensington, London, UK.
AD  - Department of Chemistry, Molecular Science Research Hub, Imperial College London, 
      White City, London, UK.
FAU - Khan, Tauseef A
AU  - Khan TA
AD  - Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, 
      Toronto, Canada.
FAU - Nasser, Shuaib
AU  - Nasser S
AD  - Department of Allergy, Cambridge University Hospitals NHS Trust, Cambridge, UK.
LA  - eng
PT  - Journal Article
DEP - 20230224
PL  - Germany
TA  - Intensive Care Med Exp
JT  - Intensive care medicine experimental
JID - 101645149
PMC - PMC9949911
OTO - NOTNLM
OT  - Autoimmunity
OT  - Coronavirus
OT  - Cytokines
OT  - Inflammasomes
OT  - Pneumonia
OT  - Viral
COIS- SMTN is a person of significant control in BIOSIRIUS Ltd, which owns patent 
      applications on interleukin-related therapies. SN and RD are board advisors of 
      BIOSIRIUS Ltd. AR, TK and AK have no conflict of interest disclosures to declare.
EDAT- 2023/02/24 06:00
MHDA- 2023/02/24 06:01
PMCR- 2023/02/24
CRDT- 2023/02/23 23:59
PHST- 2022/07/07 00:00 [received]
PHST- 2022/12/19 00:00 [accepted]
PHST- 2023/02/23 23:59 [entrez]
PHST- 2023/02/24 06:00 [pubmed]
PHST- 2023/02/24 06:01 [medline]
PHST- 2023/02/24 00:00 [pmc-release]
AID - 10.1186/s40635-022-00488-x [pii]
AID - 488 [pii]
AID - 10.1186/s40635-022-00488-x [doi]
PST - epublish
SO  - Intensive Care Med Exp. 2023 Feb 24;11(1):9. doi: 10.1186/s40635-022-00488-x.