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Table 3 Causal Mediation Analysis of [NET+Ns] as mediator of multi-organ failure in severe COVID-19

From: Circulating neutrophil extracellular trap (NET)-forming ‘rogue’ neutrophil subset, immunotype [DEspR + CD11b +], mediate multi-organ failure in COVID-19—an observational study

Exposure (causal variable): t1-SOFA, or t1-SF

Mediator: [NET+Ns], or [ANC]

Outcome: t2-SOFA, or ICUFD, or t2-SF-ratio

Natural direct effecta

Natural indirect effectb

Total Effectc

Percent mediatedd

Percent eliminatede

Indirect effect of eliminating [NET+Ns]f-h

Causal pathway hypotheses

Effect

(95% CI)

Effect

(95% CI)

Effect

(95% CI)

Effect

(95% CI)

Effect

(95% CI)

Effect

(95% CI)

 A] Direct effect: t1-SOFA→ t2-SOFA

Indirect effect: t1-SOFA→[NET+Ns]→t2-SOFA

3.3

(2.0, 4.7)

2.6

(-1.4, 5.9)

5.9

(1.7, 9.9)

44.1

(16.5, 110.6)

46.9

(15.8, 124.6)

0.98 f

(0.29, 2.06)

 B] Direct effect: t1-SOFA → ICUFD

Indirect effect: t1-SOFA →[NET+Ns]→ICUFD

-12.3

(-17.9, -6.2)

-11.0

(-18.5, 4.3)

-23.3

(-33.0, -6.3)

47.1

(22.0, 72.3)

51.1

(22.8, 80.4)

3.0 g

(0.85, 7.09)

 C] Direct effect: t1-SF → t2-SF

Indirect effect: t1-SF →[NET+Ns]→t2-SF

124

(-263, 364)

46

(-224, 481)

170

(103, 235)

27.2

(-107, 372)

15.6

(-9.7, 64.2)

16.8 h

(-4.6, 42.8)

 D] Direct effect: t1-SF → ICUFD

Indirect effect: t1-SF →[NET+Ns]→ICUFD

1.7

(-18.1, 43.9)

13.8

(-36.0, 34.3)

15.4

(5.1, 20.7)

89.3

(-131, 225.5)

22.6

(-15.5, 43.4)

 

 E] Direct effect: t1-SOFA → t2-SOFA

Indirect effect: t1-SOFA →[ANC]→t2-SOFA

2.5

(1.0, 4.3)

1.1

(-0.7, 2.2)

3.6

(1.9, 4.8)

31.1

(-18.0, 63.0)

36.5

(-28.2, 70.8)

 

 F] Direct effect: t1-SOFA → ICUFD

Indirect effect: t1-SOFA →[ANC]→ICUFD

-13.6

(-22.0, -6.8)

-1.1

(-8.7, 6.2)

-14.6

(-21.0, -9.5)

7.4

(-45.5, 77.8)

0.1

(-54.7, 67.0)

 
  1. Legend: Causal effect estimates are for t1-SOFA from Q1-Q3 (1 to 6.25), and for t1-SF ratio from Q1-Q3 (135.8 to 346.2) in this prospective pilot cohort. [ANC], absolute neutrophil counts from CBC-differential; ICUFD, ICU-free days at day 28 with death as [-1]; NET, neutrophil extracellular traps; [NET+Ns], immunotyped (DEspR+CD11b+)NET-forming neutrophil counts (103[K]/μL); SF, SF ratio SpO2/FiO2; SOFA, sequential organ failure assessment score (points) without neurological component; t1, time of consented blood sample draw for analysis of NET+N levels; t2, time before ICU/hospital-discharge or ICU-death < 28 days; 95% CI (n, m), were calculated using bootstrapping with 10,000 replicates
  2. aNatural direct effect: the direct effect of exposure on outcome if the mediator [NET+Ns] is set at the value it would naturally take when SOFA-1 score is at its reference value
  3. bNatural indirect effect: the effect of exposure on outcome mediated by DEspR+[NET+Ns], accounting for exposure and mediator interaction
  4. cTotal Effect: the total effect of exposure on outcome through direct and indirect pathways
  5. dThe percent of the effect of the exposure on the outcome mediated by DEspR+[NET+N] counts
  6. eThe percent of the effect of exposure on the outcome that would be eliminated by reducing the DEspR+[NET+N] count to 0 (total effect - controlled direct effect under a hypothetical situation where DEspR+[NET+N] is 0) / total effect)
  7. fIn patients with t1-SOFA ≥ 2, the indirect effect of eliminating [NET+Ns] decreased t2-SOFA by 0.98 points (95% CI: 0.27,2.13), ~15% absolute risk reduction (arr) (37). In patients with t1-SOFA ≥ 4, the indirect effect of eliminating [NET+Ns] is 1.41 95% CI (0.47,3.05), ~22% arr
  8. gIn patients with t1-SOFA ≥ 2, outcome model fit in those with t1-SOFA ≥ 2; 50% rrr, relative risk reduction compared to corticosteroid therapy (38-39)
  9. hIn patients with t1-SF ratio <300, outcome model fit in those with t1-SF ratio <300, not including interaction (p>0.77)
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Translational Medicine Communications

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