Fig. 4: Evaluation of the immune dysregulation framework in public and SUBSPACE data.

a, Myeloid (left) and lymphoid (right) scores (calculated as z-scores relative to healthy participants) calculated for all public samples (n = 2,096). The box plots represent the median and interquartile range (IQR) whereas whiskers represent the range of data excluding outliers (1.5× the IQR). The association of increasing scores (y axis) with increasing severity (x axis) was calculated using the JT t-test. Myeloid and lymphoid dysregulation scores were associated with severity (P < 2.2 × 10⁻¹⁶ for both scores). b, Theoretical framework for defining immune dysregulation with myeloid dysregulation on one axis and lymphoid dysregulation on the other. This provides a means of subgrouping patients into four subgroups depending on the level of dysregulation present: (1) balanced: both dysregulation scores low; (2) lymphoid dysregulation: only lymphoid dysregulation score elevated; (3) myeloid dysregulation: only myeloid dysregulation score elevated; and (4) system-wide dysregulation: both myeloid and lymphoid dysregulation scores elevated. c, The immune dysregulation framework applied to public co-normalized data (n = 2,096). Cut-offs are defined by a z-score of 1.65 relative to healthy participants. The black dots represent patients with severe infections (defined by ICU admission), whereas the tan dots represent nonsevere infections. d, Barplot representing the proportion of severe infections (y axis) by immune dysregulation framework subgroup (x axis). The OR was calculated using two-sided Fisher’s exact test unadjusted for multiple comparisons, comparing patients with dysregulation on any axis relative to the balanced subgroup. Dysregulation on either the myeloid or the lymphoid axis (inclusive of lymphoid dysregulation (n = 449), myeloid dysregulation (n = 197) and system-wide dysregulation (n = 259) subgroups) was associated with severe infections with an OR of 5.2 (95% CI 3.9–7.0, P < 2.2 × 10⁻¹⁶) compared with patients in the balanced subgroup (n = 1,191). e, Myeloid (left) and lymphoid (right) scores (calculated as z-scores relative to healthy participants) were calculated for baseline SUBSPACE samples with phenotype data available (n = 2,212). The box plots represent the median and IQR whereas the whiskers represent the range of data excluding outliers (1.5× the IQR). The association of increasing scores (y axis) with severity (x axis) was calculated using the JT t-test. Myeloid dysregulation and lymphoid dysregulation scores were associated with severity (P < 2.2 × 10⁻¹⁶ for both scores). f, Forest plots showing log(OR) and 95% CIs of 30-d mortality across each site, calculated using logistic regression and showing strong association with mortality: myeloid dysregulation score (left) and lymphoid dysregulation score (right). Patient numbers by site were: ACUTELINES (n = 275), Amsterdam (n = 717), Cincinnati Children’s Hospital Medical Center (n = 184), Charles University (n = 12), SAVE-MORE (n = 452), Stanford University (n = 236), University of Florida (n = 172) and VICTAS (n = 137). g, The immune dysregulation framework applied to SUBSPACE co-normalized data (n = 2,212). Cut-offs were defined by a z-score of 1.65 relative to healthy patients. The black dots represent critically ill patients, whereas the tan dots represent noncritically ill patients. h, Barplot representing the proportion of severe infections (y axis) by immune dysregulation framework subgroup (x axis). The OR was calculated using two-sided Fisher’s exact test unadjusted for multiple comparisons, comparing patients with dysregulation on any axis relative to the balanced subgroup. Dysregulation on either the myeloid or the lymphoid axis (inclusive of lymphoid dysregulation (n = 615), myeloid dysregulation (n = 133) and system-wide dysregulation (n = 1,050) subgroups) was associated with severe infections with an OR of 7.1 (95% CI 5.6–8.9, P < 2.2 × 10⁻¹⁶) compared with patients in the balanced subgroup (n = 564).