Improved hemophagocytic lymphohistiocytosis index predicts prognosis of adult Epstein-Barr virus-associated HLH patients

Figures & data

Table 1. The Hscore [10].

Parameter	No. of points (criteria for scoring)
Known underlying immunosuppression^a	0 (no) or 18 (yes)
Temperature (°C)	0 (<38.4), 33 (38.4–39.4), or 49 (>39.4)
Organomegaly	0 (no), 23 (hepatomegaly or splenomegaly), or 38 (hepatomegaly and splenomegaly)
No. of cytopenias^b	0 (1 lineage), 24 (2 lineages), or 34 (3 lineages)
Ferritin (ng/mL)	0 (<2000), 35 (2000–6000), or 50 (>6000)
Triglyceride (mmoles/liter)	0 (<1.5), 44 (1.5–4), or 64 (>4)
Fibrinogen (gm/liter)	0 (>2.5) or 30 (≤2.5)
Serum glutamic oxaloacetic transaminase (IU/liter)	0 (<30) or 19 (≥30)
Hemophagocytosis features on bone marrow aspirate	0 (no) or 35 (yes)

^aHuman immunodeficiency virus positive or receiving long-term immunosuppressive therapy (i.e. glucocorticoids, cyclosporine, azathioprine). ^bDefined as a hemoglobin level of ≤9.2 gm/dl and/or a leukocyte count of ≤5000/mm³ and/or a platelet count of ≤110,000/mm³.

Table 2. Clinical characteristics of adult patients with EBV-HLH.

	Overall (N = 246)	Survival group (N = 93)	Death group (N = 153)	P
Sex (M/F)	152/94	53/40	99/54	0.227
Age (years)	32 (18,73)	28 (18,70)	33 (18,73)	0.035
Allogeneic transplant (Y/N)	59/187	25/68	34/119	0.407
Fever (Y/N)	245/1	92/1	153/0	0.378
Temperature (°C)	39.5 ± 0.8	39.4 ± 0.8	39.5 ± 0.8	0.406
BM hemophagocytosis (Y/N)	179/67	68/25	111/42	0.923
Hepatomegaly (Y/N)	95/151	33/60	62/91	0.431
Splenomegaly (Y/N)	219/27	80/13	139/14	0.240
WBC (×10^9/L)	2.06 (0.05, 19.44)	2.53 (0.14, 14.21)	1.93 (0.05, 19.44)	0.018
ANC (×10^9/L)	1.21 (0.00, 13.36)	1.36 (0.01, 10.50)	1.08 (0, 13.36)	0.018
Hb (g/L)	93 ± 22	94 ± 23	92 ± 22	0.519
PLT (×10^9/L)	62 (2, 743)	89 (2, 380)	57 (2, 743)	0.001
CRP (mg/L)	10 (0, 167)	6.78 (0, 160)	16.5 (0.16, 167)	<0.001
ALT (U/L)	76 (6, 765)	81 (6, 672)	76 (6, 765)	0.985
AST (U/L)	85 (3, 1767)	70 (3, 1103)	85 (3, 1767)	0.652
LDH (U/L)	471 (36, 12733)	436 (36, 3112)	537 (73, 12,733)	0.036
GGT (U/L)	142 (12, 1487)	164 (12, 1280)	130 (14, 1487)	0.920
ALP (U/L)	206 (12, 2266)	252 (28, 2036)	186 (12, 2266)	0.578
TBIL (μmol/L)	21.87 (6.01, 657.41)	20.03 (6.35, 657.41)	22.62 (6.01, 560.65)	0.072
DBIL (μmol/L)	9.43 (1.20, 432.72)	8.33 (1.57, 418.94)	11.86 (1.2, 432.72)	0.182
IBIL (μmol/L)	12.35 (2.88, 238.47)	11 (3.16, 238.47)	12.64 (2.88, 127.93)	0.056
ALB (g/L)	30.0 ± 6.3	31.4 ± 6.8	29.2 ± 5.8	0.008
GLB (g/L)	27.4 ± 7.8	28.9 ± 8.1	26.4 ± 7.5	0.016
Cr (μmol/L)	56.35 (24.5, 544.3)	52.2 (30.2, 118.7)	57.8 (24.5, 544.3)	0.003
eGFR (mL/min/1.73m^2)	127.54 ± 52.18	140.20 ± 45.35	119.85 ± 54.64	0.002
BUN (mmol/L)	5.41 (1.19, 111.60)	4.56 (1.55, 19.72)	5.8 (1.19, 111.6)	0.001
TG (mmol/L)	2.37 (0.43, 14.67）	2.29 (0.6, 8.06)	2.41 (0.43, 14.67)	0.144
K (mmol/L)	3.86 ± 0.50	3.77 ± 0.43	3.92 ± 0.53	0.029
Ca (mmol/L)	2.01 ± 0.20	2.04 ± 0.20	1.99 ± 0.20	0.066
Na (mmol/L)	135.2 ± 5.3	136.2 ± 5.1	134.5 ± 5.3	0.015
CO2 (mmol/L)	23.8 ± 3.6	24.6 ± 3.2	23.3 ± 3.7	0.007
FIB (g/L)	1.54（0.20, 59.20）	1.61 (0.44, 7.69)	1.45 (0.2, 59.2)	0.751
Coagulation abnormalities (Y/N)	133/113	44/49	89/64	0.098
β2M (mg/L)	4.44 (0.02, 22.40)	3.62 (0.02, 11.6)	4.79 (1.07, 22.4)	0.002
PCT (ng/mL)	0.46 (0, 120.99)	0.37 (0.02, 8.77)	0.52 (0, 120.99)	0.010
ESR (mm/1h)	14 (1, 140)	16 (1, 140)	14 (1, 104)	0.573
Ferritin (μg/L)	2195.3 (17.9, 171,633.0)	2000 (36.3, 171,633)	2427 (17.9, 142,311.5)	0.199
NK cell activity (%)	15.07 (6.38, 52.83)	15.1 (6.65, 44.68)	14.79 (6.38, 52.83)	0.943
Decreased CD107a (Y/N)	93/77	34/34	59/43	0.316
sCD25 (pg/mL)	22276 (469, 122,130)	14277 (469, 122,130)	30200 (882, 65,430)	<0.001
Plasma EBV-DNA copies	2600 (0, 3.5E + 07)	1600 (0, 1.0E + 07)	4800 (0, 3.5E + 07)	0.247
EBV-DNA copies in PBMC	12,000 (0, 7.76E + 09)	3400 (0, 1.0E + 07)	18,000 (0, 7.76E + 09)	0.069

Coagulation abnormalities: prolonged PT and/or APTT. Decreased CD107a: ≤10% difference before and after NK cell stimulation and/or <2.8 difference before and after CTL cell stimulation. BM: bone marrow; WBC: white blood cells; ANC: absolute neutrophil count; Hb: hemoglobin; PLT: platelets; CRP: C-reactive protein; ALT: alanine transaminase; AST: aspartate transaminase; LDH: lactate dehydrogenase; GGT: gamma-glutamyl transferase; ALP: alkaline phosphatase; TBIL: total bilirubin; DBIL: direct bilirubin; IBIL: indirect bilirubin; ALB: albumin; GLB: globulin; Cr: Creatinine; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate; TG: triglyceride; K: Potassium; Ca: Calcium; Na: Sodium; CO₂: Carbon dioxide binding force; FIB: fifibrinogen; β₂M: β-2-microglobin; PCT: procalcitonin; ESR: Erythrocyte sedimentation rate; NK: natural killer; sCD25: soluble CD25; PBMC: peripheral blood mononuclear cells.

Figure 1. Overall survival curve of EBV-HLH.

Figure 2. Survival curves of EBV-HLH patients with and without transplantation.

Figure 3. Composite ROC curve of multiple indicators.

Table 3. ROC curves of each clinical index.

	Boundary value	Sensitivity	Speciality	AUC	95%CI	P
Age (years)	27.3	0.739	0.473	0.580	0.505–0.655	0.035
WBC (×10^9/L)	3.21	0.441	0.765	0.590	0.514–0.666	0.018
ANC (×10^9/L)	2.555	0.352	0.848	0.591	0.515–0.668	0.018
PLT (×10^9/L)	80.5	0.548	0.725	0.629	0.555–0.704	0.001
CRP (mg/L)	15.05	0.529	0.725	0.647	0.571–0.723	<0.001
LDH (U/L)	575.5	0.48	0.685	0.580	0.508–0.653	0.036
ALB (g/L)	34.1	0.344	0.837	0.597	0.524–0.671	0.010
GLB (g/L)	30.5	0.398	0.745	0.583	0.509–0.656	0.030
Cr (μmol/L)	63.95	0.451	0.731	0.612	0.541–0.683	0.003
BUN (mmol/L)	4.695	0.698	0.538	0.624	0.553–0.695	0.001
eGFR (mL/min/1.73m^2)	133.8471	0.660	0.570	0.620	0.549–0.690	0.002
K (mmol/L)	3.675	0.706	0.473	0.588	0.516–0.661	0.020
Na (mmol/L)	133.5	0.742	0.444	0.597	0.524–0.669	0.011
CO2 (mmol/L)	24.75	0.559	0.712	0.626	0.553–0.698	0.001
β2M (mg/L)	3.65	0.717	0.518	0.624	0.548–0.701	0.002
PCT (ng/mL)	1.84	0.275	0.942	0.602	0.529–0.676	0.010
sCD25 (pg/mL)	27779	0.531	0.808	0.674	0.598–0.750	<0.001
	18175	0.688	0.615

AUC: Area under the curve; CI: confidence interval.

Table 4. Single factor Cox proportional risk regression analysis of indicators associated with prognosis.

	C-index (95%CI)	HR (95%CI)	P
PLT (×10^9/L)	0.626 (0.577–0.675)	0.995 (0.992–0.997)	<0.001
CRP (mg/L)	0.637 (0.586–0.688)	1.007 (1.004–1.010)	<0.001
Cr (μmol/L)	0.577 (0.526–0.628)	1.010 (1.006–1.013)	<0.001
BUN (mmol/L)	0.606 (0.557–0.655)	1.012 (1.001–1.023)	0.033
eGFR (mL/min/1.73m^2)	0.568 (0.515–0.621)	0.995 (0.992–0.999)	0.007
CO2 (mmol/L)	0.631 (0.580–0.682)	0.901 (0.861–0.943)	<0.001
β2M (mg/L)	0.608 (0.557–0.659)	1.075 (1.032–1.118)	<0.001
PCT (ng/mL)	0.611 (0.562–0.660)	1.029 (1.018–1.040)	<0.001
sCD25 > 18,000/≤18,000 (pg/mL)	0.607 (0.564–0.650)	2.484 (1.700–3.629)	<0.001

HR: Hazard ratio; CI: confidence interval; C-index: concordance index.

Table 5. binary logistic regression analysis to establish joint indicators to predict prognosis.

	β	OR	95%CI for exp (B)	P
eGFR (mL/min/1.73m^2)	−0.009	0.991	0.985–0.998	0.010
PCT > 1.8/≤1.8 (ng/mL)	1.204	6.779	1.946–23.616	0.003
sCD25 > 18,000/≤18,000 (pg/mL)	1.914	3.335	1.728–6.435	<0.001
Constant	0.672	1.957		0.163

logit(p) = 1.914*sCD25 + 1.204*PCT-0.009*eGFR (sCD25 and PCT are dichotomous variables and are taken as 1 for values greater than the bound and 0 for the opposite). OR: Odds ratio; CI: confidence interval.

Table 6. Multi-factor Cox proportional risk regression analysis of indicators associated with prognosis.

	HR	95%CI	P
eGFR < 90/≥90 (mL/min/1.73m^2)	1.74	1.172–2.584	0.006
PCT > 1.8/≤1.8 (ng/mL)	1.707	1.118–2.606	0.013
sCD25 > 18,000/≤18,000 (pg/mL)	2.362	1.556–3.587	<0.001

Figure 4. Survival of patients with discordant versus concordant indices.

Figure 5. Survival of patients after index stratification.

Figure 6. IH index vs. HScore.

Figure 7. IH index vs. Index.

Figure 8. IH index vs. allo-HSCT.

Sitter T. Kreatinin und glomeruläre filtrationsrate (GFR): serie laborparameter, folge 6 [serum creatinine and estimated glomerular filtration rate]. MMW Fortschr Med. 2021;163(10):50–51.

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Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.