Background
Methods
Study population
Metabolite profiling
Statistical analyses
Results
Study population
Control (n = 15) | Bell’s (n = 11) | Ent. men (n = 10) | Z. segmental (n = 14) | Z. facial (n = 16)a | Z. men_enc (n = 15)b | P valuec (all patient groups) | P valuec (VZV-positive subgroups only) | |
---|---|---|---|---|---|---|---|---|
Demographic | ||||||||
Sex [%] | ||||||||
Female | 47 | 55 | 40 | 57 | 56 | 40 | 0.89d | 0.57d |
Male | 53 | 45 | 60 | 43 | 44 | 60 | ||
Age [years] | ||||||||
Median (range) | 64 (36–91) | 45 (22–83) | 32.5 (22–76) | 60 (49–79) | 64.5 (20–89) | 55 (13–80) |
0.036
| 0.634 |
Mean (SD) | 64 (17) | 46 (20) | 41 (19) | 61 (10) | 59 (22) | 53 (21) | ||
Blood parameter | ||||||||
Leukocyte count [1000/μL] | ||||||||
Median (range) | 6.7 (1.0–11.5) | 8.3 (4.6–11.9) | 7.3 (4.0–14.0) | 5.9 (2.4–9.0) | 6.7 (4.1–13.2) | 6.9 (3.8–13.6) | 0.60 | 0.51 |
Mean (SD) | 6.8 (2.6) | 8.2 (2.3) | 7.5 (3.0) | 6.1 (2.1) | 7.2 (2.3) | 7.8 (3.3) | ||
C-reactive protein [mg/L] | ||||||||
Median (range) | 2.5 (1–29) | 3 (1–31) | 4 (1–39) | 2 (1–15) | 2.5 (1–18) | 2 (1–128) | 0.78 | 0.88 |
Mean (SD) | 5.9 (9.2) | 6.3 (9.6) | 9.3 (12.3) | 4.5 (4.4) | 4.4 (5.0) | 13.6 (32.3) | ||
CSF parameter | ||||||||
Leukocyte count [1/μL] | ||||||||
Median (range) | 1 (0–11) | 2 (0–5) | 9 (1–619) | 2 (0–18) | 17 (1–800) | 38 (2–1536) |
4.0E−06
|
7.0E−04
|
Mean (SD) | 1.9 (2.8) | 2.1 (1.5) | 129 (235) | 3.3 (4.5) | 156 (272) | 200 (400) | ||
Protein concentration [mg/L] | ||||||||
Median (range) | 385 (255–656) | 490.5 (309–829) | 518 (240–976) | 554.5 (273–880) | 503 (270–1485) | 649 (313–2048) | 0.086 | 0.29 |
Mean (SD) | 435 (134) | 497 (156) | 569 (205) | 533 (139) | 641 (342) | 823 (486) | ||
IgG index | ||||||||
Median (range) | 0.51 (0.47–0.60) | 0.47 (0.41–0.59) | 0.53 (0.47–0.63) | 0.54 (0.43–0.77) | 0.54 (0.43–0.86) | 0.55 (0.50–1.16) |
0.011
| 0.65 |
Mean (SD) | 0.53 (0.05) | 0.48 (0.05) | 0.54 (0.05) | 0.56 (0.08) | 0.57 (0.12) | 0.63 (0.18) | ||
Lactate [mmol/L] | ||||||||
Median (range) | 1.64 (1.21–2.50) | 1.57 (1.24–2.22) | 1.88 (1.55–3.55) | 1.78 (1.42–2.08) | 1.87 (1.44–4.24) | 2.73 (1.49–5.50) |
8.5E−04
|
0.006
|
Mean (SD) | 1.70 (0.30) | 1.65 (0.34) | 2.09 (0.62) | 1.76 (0.18) | 2.07 (0.67) | 2.81 (1.18) | ||
Blood-CSF-barrier disruption [%]e | ||||||||
No disruption | 60 | 55 | 20 | 54 | 50 | 21 |
f
|
f
|
Light | 40 | 45 | 70 | 39 | 31 | 36 | ||
Moderate | 0 | 0 | 10 | 7.7 | 19 | 29 | ||
Severe | 0 | 0 | 0 | 0 | 0 | 14 |
CSF metabolite detection
Metabolite-based relationships among disease entities
Global differences in metabolite profiles in VZV reactivation
Forward selection and internal validation of biomarkers
Comparison of diagnostic performance of CSF metabolites and standard CSF parameters
Z. men_enc vs. | Z. facial vs. | Z. segmental vs. | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Control | Z. segmental | Z. facial | Ent. men | Bell’s | Z. segmental | Bell’s | Control | Bell’s | Control | |
(A) Standard CSF parameter | ||||||||||
Leukocyte count | 0.97*** | 0.94*** | 0.63 | 0.68 | 0.96*** | 0.70 |
0.72
| 0.80* | 0.54 | 0.68 |
Protein concentration | 0.81* | 0.67 | 0.62 | 0.62 |
0.73
| 0.52 | 0.59 | 0.69 | 0.61 | 0.68 |
IgG index | 0.74* | 0.62 | 0.60 | 0.66 | 0.90** | 0.51 | 0.77* | 0.58 | 0.83** | 0.63 |
Lactate | 0.86** | 0.82** | 0.71 | 0.70 | 0.88** | 0.67 | 0.75* | 0.74* | 0.65 | 0.65 |
(B) Metabolites | ||||||||||
Best internally validated markera | SM C16:1 | SM C16:1 | PC ae C34.0 | lysoPC a C26:1 | Glycine | PC aa C32:0 | SM(OH) C14:1 | Tryptophan | Arginine | Serine |
AUC | 0.92*** | 0.90*** | 0.83** | 0.87** | 0.96*** | 0.76* | 0.86** | 0.84** | 0.90*** | 0.77* |
(C) Best classifierb | ||||||||||
No. of markers | 2 | 3 | 1 | 2 | 2 | 2 | 3 | 4 | 1 | 3 |
Markers (frequency) | Glycine (1.0) PC aa C30:0 (0.9) | Leukocytes (1.0) SM C16:1 (1.0) total DMA (0.60) | PC ae C34:0 (1.0) | lysoPC a C26:1 (1.0) PC aa C32:0 (1.0) | Leukocytes (1.0) Glycine (1.0) | Leukocytes (0.73) PC aa C32:1 (1.0) | SM(OH) C14:1 (1.0) Glycine (0.96) Tryptophan (1.0) | Tryptophan (1.0) SM(OH) C14:1 (0.71) Leukocytes (1.0) Serine (0.84) | Arginine (1.0) | Serine (1.0) PC ae C36:3 (0.88) Methionine (0.67) |
AUC | 1.00 | 0.95 | 0.83 | 0.90 | 1.00 | 0.77 | 0.92 | 0.86 | 0.90 | 0.86 |
95% CI | 0.87–1.0 | 0.76–1.0 | N/A | 0.57–1.0 | 0.89–1.0 | 0.51–0.91 | 0.61–0.98 | 0.55–0.98 | N/A | 0.53–0.96 |
Correlation between metabolite concentrations and leukocyte count
Diagnostic comparison of leukocyte count and the four Z. meningoencephalitis-associated metabolites
Sensitivity | Specificity | PPV | NPV | AUC (95% CI) | P valuea | |
---|---|---|---|---|---|---|
Leukocyte count | 0.80 | 0.70 | 0.57 | 0.88 | 0.77 (0.64–0.91) | 0.003 |
SM C16:1 | 0.73 | 0.77 | 0.61 | 0.85 | 0.81 (9.68–0.94) | 0.001 |
Glycine | 0.80 | 0.70 | 0.57 | 0.88 | 0.78 (0.64–0.93) | 0.002 |
lysoPC a C26:1 | 0.93 | 0.62 | 0.56 | 0.95 | 0.79 (0.66–0.93) | 0.002 |
PC ae C34:0 | 0.53 | 1.00 | 1.00 | 0.80 | 0.84 (0.71–0.97) | < 0.0001 |