Background
Methods
Study design and participants
Recruitment and follow-up
Sample collection
Toll-like receptors stimulation assay
Cytokines, chemokines, and growth factors quantification
Malaria detection and definitions
Statistical analysis
Results
Characteristics of study participants
Characteristics | Overall cohort (N = 313) | Non-exposed (N = 22) | Exposed no PM (N = 61) | Past PM (N = 185) | Chronic PM (N = 38) | Acute PM (N = 7) | P value |
---|---|---|---|---|---|---|---|
Maternal characteristics | |||||||
Age (years, mean ± SD) | 26.1 ± 6.2 | 28.4 ± 6.4 | 27.7 ± 6.0 | 25.5 ± 6.0 | 23.8 ± 5.7 | 28.3 ± 7.2 | < 0.001 |
Gravidity (N (%)) | < 0.001 | ||||||
Primigravida | 58 (18.5) | 1 (4.5) | 2 (3.3) | 40 (21.6) | 15 (39.5) | 0 (0.0) | |
Secundigravida | 58 (18.5) | 2 (9.1) | 10 (16.4) | 38 (20.5) | 7 (18.4) | 1 (14.3) | |
Multigravida | 197 (63.0) | 19 (86.4) | 49 (80.3) | 107 (57.9) | 16 (42.1) | 6 (85.7) | |
ITN use (N (%)) | 219 (70.0) | 19 (86.4) | 47 (77.0) | 128 (69.2) | 21 (55.3) | 4 (57.1) | 0.061 |
MiP preventive strategy in COSMIC trial (N (%)) | < 0.001 | ||||||
Standard IPTp-SP | 109 (34.2) | – | 23 (37.7) | 68 (36.8) | 14 (36.8) | 4 (57.1) | |
CSST/IPTp-SP | 204 (65.2) | 22 (100.0) | 38 (62.3) | 117 (63.2) | 24 (63.2) | 3 (42.9) | |
SP doses uptake (women who received ≥ 2 doses, N (%)) | 293 (93.6) | 21 (95.5) | 55 (90.2) | 178 (96.2) | 32 (84.2) | 7 (100.0) | 0.055 |
AL treatment (women treated at least once, N (%)) | 67 (21.4) | – | 7 (11.5) | 43 (23.2) | 14 (36.8) | 3 (42.8) | 0.002 |
Gestational age at enrollment (median (IQR), weeks) | 20 (19–22) | 20 (18–26.5) | 20 (20.5–25.5) | 20 (19–21) | 20 (16–21) | 20 (20–25) | 0.445 |
Infants characteristics | |||||||
Sex (females, N (%)) | 169 (54.0) | 7 (31.8) | 36 (59.0) | 105 (56.8) | 19 (50.0) | 2 (28.6) | 0.110 |
Birth season (malaria high-transmission season, N (%)) | 243 (77.6) | 14 (63.6) | 44 (72.1) | 141 (76.2) | 37 (97.4) | 7 (100.0) | 0.002 |
Birth weight (g, mean ± SD) | 3009 ± 429.6 | 3119.1 ± 441.7 | 3041.5 ± 360.5 | 2988.2 ± 439.1 | 2967.1 ± 499.8 | 3169.3 ± 228.4 | 0.470 |
LBW (< 2500 g) (no. (%)) | 30 (9.6) | 1 (4.5) | 3 (4.9) | 20 (10.8) | 6 (15.8) | 0 (0.0) | 0.371 |
Ethnicity (N (%) | 0.017 | ||||||
Mossi | 276 (88.2) | 21 (95.4) | 55 (90.1) | 164 (88.6) | 31 (81.6) | 5 (71.4) | |
Gourounsi | 34 (10.8) | 1 (4.6) | 4 (6.6) | 21 (11.4) | 7 (18.4) | 2 (28.6) | |
Fulani | 3 (1.0) | 0 (0.0) | 2 (3.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | |
Follow-up time (total time at risk, person-months) | 2782.6 | 175.1 | 544.7 | 1664.1 | 330.4 | 68.3 | |
Clinical malaria episode (N (%)) | 189 (60.4) | 11 (50.0) | 37 (60.7) | 113 (61.1) | 24 (63.2) | 4 (57.1) | 0.872 |
Time to first clinical malaria episode (median, months) | 10.3 | 10.2 | 10.6 | 10.2 | 10.5 | 11.4 | 0.990 |
TLR-mediated cytokine responses
PME and cytokine responses at birth
Cytokines* | Exposed/no PM vs non-exposed | Past PM vs non-exposed | Chronic PM vs non-exposed | Acute PM vs non-exposed | |||||
---|---|---|---|---|---|---|---|---|---|
Coeff (SE) |
P
| Coeff (SE) |
P
| Coeff (SE) |
P
| Coeff (SE) |
P
| ||
TLR7/8 responses using log10 of ratio cytokines concentrations | |||||||||
Pro | IFN-α | 0.15 (0.08) | 0.079 | 0.19 (0.08) |
0.018
| 0.09 (0.09) | 0.359 | 0.08 (0.15) | 0.591 |
IL-1RA | 0.15 (0.12) | 0.223 | 0.22 (0.11) |
0.049
| 0.15 (0.14) | 0.263 | 0.22 (0.22) | 0.308 | |
IL-1β | 0.13 (0.20) | 0.522 | 0.36 (0.18) |
0.049
| 0.32 (0.22) | 0.140 | 0.11 (0.35) | 0.765 | |
TNF | 0.28 (0.24) | 0.238 | 0.55 (0.22) |
0.013
| 0.31 (0.26) | 0.229 | 0.36 (0.42) | 0.387 | |
Th1 | IL-12 | 0.18 (0.16) | 0.259 | 0.34 (0.14) |
0.015
| 0.30 (0.17) | 0.074 | 0.30 (0.27) | 0.276 |
IL-2 | 0.12 (0.07) | 0.092 | 0.15 (0.06) |
0.019
| 0.14 (0.08) | 0.081 | 0.09 (0.12) | 0.448 | |
IL-2R | 0.16 (0.10) | 0.103 | 0.23 (0.09) |
0.012
| 0.19 (0.11) | 0.081 | 0.15 (0.18) | 0.398 | |
IFN-γ | 0.18 (0.12) | 0.137 | 0.29 (0.11) |
0.008
| 0.25 (0.13) | 0.056 | − 0.03 (0.21) | 0.898 | |
Th2 | IL-13 | 0.14 (0.13) | 0.272 | 0.25 (0.12) |
0.031
| 0.25 (0.14) | 0.079 | 0.26 (0.22) | 0.237 |
Chemokines | MIP-1α | 0.47 (0.27) | 0.085 | 0.72 (0.25) |
0.004
| 0.59 (0.30) |
0.049
| 0.57 (0.48) | 0.237 |
MIP-1β | 0.36 (0.25) | 0.143 | 0.56 (0.22) |
0.013
| 0.52 (0.26) |
0.049
| 0.54 (0.43) | 0.214 | |
RANTES | 0.17 (0.10) | 0.097 | 0.23 (0.09) |
0.015
| 0.21 (0.11) | 0.062 | 0.07 (0.18) | 0.697 | |
Growth factors | EGF | 0.10 (0.06) | 0.087 | 0.12 (0.05) |
0.017
| 0.09 (0.06) | 0.125 | 0.09 (0.10) | 0.360 |
FGF | 0.16 (0.09) | 0.069 | 0.22 (0.08) |
0.005
| 0.23 (0.09) |
0.017
| 0.32 (0.15) |
0.037
| |
G-CSF | 0.18 (0.13) | 0.170 | 0.35 (0.12) |
0.004
| 0.29 (0.14) |
0.047
| 0.38 (0.23) | 0.099 | |
GM-CSF | 0.34 (0.16) |
0.033
| 0.53 (0.14) |
< 0.001
| 0.36 (0.17) |
0.032
| 0.64 (0.27) |
0.020
| |
HGF | 0.08 (0.06) | 0.151 | 0.11 (0.05) |
0.029
| 0.06 (0.06) | 0.299 | 0.04 (0.10) | 0.676 | |
TLR9 responses using log10 of ratio cytokines concentrations | |||||||||
Th2 | IL-5 | − 0.08 (0.07) | 0.283 | − 0.11 (0.07) | 0.008 | − 0.20 (0.08) |
0.009
| − 0.14 (0.13) | 0.267 |
Growth factors | FGF | 0.08 (0.07) | 0.231 | 0.14 (0.06) |
0.028
| 0.15 (0.07) | 0.050 | 0.14 (0.12) | 0.234 |
G-CSF | 0.11 (0.08) | 0.187 | 0.17 (0.07) |
0.016
| 0.15 (0.09) | 0.082 | 0.09 (0.09) | 0.505 | |
TLR3 responses using log10 of ratio cytokines concentrations | |||||||||
Th2 | IL-5 | − 0.06 (0.06) | 0.392 | − 0. 12(0.06) |
0.046
| − 0.15 (0.07) |
0.033
| − 0.02 (0.11) | 0.841 |
Chemokines | IP-10 | 0.13 (0.11) | 0.222 | 0.22 (0.10) |
0.026
| 0.32 (0.12) |
0.008
| 0.10 (0.19) | 0.584 |
Unstimulated samples using log10 of crude cytokines concentrations | |||||||||
Pro | IFN-α | − 0.11 (0.07) | 0.154 | − 0.14 (0.07) |
0.038
| − 0.15 (0.08) | 0.069 | − 0.01 (0.13) | 0.948 |
IL-1RA | − 0.24 (0.12) | 0.055 | − 0.23 (0.11) |
0.040
| − 0.23 (0.14) | 0.086 | − 0.37 (0.21) | 0.084 | |
IL-1β | − 0.35 (0.24) | 0.152 | − 0.58 (0.22) |
0.008
| − 0.50 (0.26) | 0.057 | − 0.62 (0.42) | 0.142 | |
TNF | − 0.40 (0.26) | 0.117 | − 0. 61(0.23) |
0.009
| − 0.49 (0.28) | 0.079 | − 0.47 (0.45) | 0.296 | |
Anti | IL-10 | − 0.22 (0.32) | 0.485 | − 0.60 (0.29) |
0.041
| − 0.45 (0.35) | 0.204 | − 0.92 (0.56) | 0.105 |
IL-7 | − 0.34 (0.10) |
< 0.001
| − 0.40 (0.09) |
< 0.001
| − 0.35 (0.11) |
< 0.001
| − 0.40 (0.17) |
0.021
| |
Th1 | IL-15 | − 0.39 (0.16) |
0.015
| − 0.52 (0.14) |
< 0.001
| − 0.52 (0.17) |
0.003
| − 0.36 (0.28) | 0.190 |
IL-2 | − 0.15 (0.08) | 0.064 | − 0.16 (0.07) |
0.032
| − 0.18 (0.09) | 0.053 | − 0.12 (0.14) | 0.382 | |
IFN-γ | − 0.14 (0.08) | 0.094 | − 0.17 (0.07) |
0.023
| − 0.21 (0.09) |
0.024
| − 0.10 (0.14) | 0.494 | |
Th2 | IL-13 | − 0.25 (0.12) |
0.038
| − 0.22 (0.11) |
0.042
| − 0.32 (0.13) |
0.014
| − 0.12 (0.21) | 0.056 |
IL-4 | − 0.27 (0.14) | 0.057 | − 0.40 (0.13) |
0.002
| − 0.26 (0.15) | 0.096 | − 0.07 (0.25) | 0.769 | |
Th17 | IL-17 | − 0.13 (0.07) |
0.046
| − 0.15 (0.06) |
0.016
| − 0.17 (0.07) |
0.017
| − 0.18 (0.12) | 0.128 |
Chemokines | MIP-1α | − 0.29 (0.28) | 0.297 | − 0.56 (0.25) |
0.029
| − 0.50 (0.31) | 0.102 | − 0.37 (0.49) | 0.453 |
RANTES | − 0.23 (0.12) | 0.050 | − 0.25 (0.11) |
0.023
| − 0.28 (0.13) |
0.029
| − 0.19 (0.21) | 0.371 | |
Growth factors | EGF | − 0.11 (0.07) | 0.106 | − 0.12 (0.06) |
0.047
| − 0.15 (0.07) |
0.049
| − 0.09 (0.12) | 0.446 |
FGF | − 0.12 (0.08) | 0.151 | − 0.15 (0.08) |
0.049
| − 0. 17(0.09) | 0.070 | − 0.17 (0.15) | 0.244 | |
G-CSF | − 0.21 (0.17) | 0.229 | − 0.37 (0.15) |
0.019
| − 0.37 (0.15) |
0.045
| − 0.33 (0.30) | 0.276 | |
GM-CSF | − 0.36 (0.19) | 0.058 | − 0.59 (0.17) |
< 0.001
| − 0.60 (0.21) |
0.004
| − 0.59 (0.33) | 0.079 | |
HGF | − 0.19 (0.07) |
0.008
| − 0.20 (0.06) |
0.002
| − 0.19 (0.08) |
0.015
| − 0.15 (0.12) | 0.221 | |
VEGF | − 0.45 (0.22) |
0.041
| − 0.59 (0.20) |
0.003
| − 0.43 (0.24) | 0.070 | − 0.35 (0.38) | 0.356 |
TLR-mediated cytokine responses and risk of clinical malaria during the first year of life
Cytokines** | Unstimulated | TLR3 responses | TLR7/8 responses | TLR9 responses | ||||
---|---|---|---|---|---|---|---|---|
Crude | Crude | Ratios | Crude | Ratios | Crude | Ratios | ||
AHR (95% CI) | AHR (95% CI) | AHR (95% CI) | AHR (95% CI) | AHR (95% CI) | AHR (95% CI) | AHR (95% CI) | ||
Pro | IFN-α | 0.24 (0.05–1.10) | ||||||
IL-1RA* | 0.61 (0.36–1.03) | 0.70 (0.50–0.98) | ||||||
IL-1β | 1.16 (0.98–1.37) | 1.15 (0.97–1.36) | 1.18 (1.01–1.39) | |||||
TNF | ||||||||
Anti | IL-10 | 1.12 (0.99–1.25) | ||||||
IL-7 | 1.80 (1.26–2.58) | 1.54 (1.11–2.15) | ||||||
Th1 | IL-15 | 1.22 (0.96–1.54) | ||||||
IL-12* | 1.28 (0.97–1.69) | 1.26 (0.95–1.68) | 0.27 (0.07–1.15) | 0.76 (0.59–0.98) | 0.46 (0.20–1.04) | |||
IL-2 | ||||||||
IL-2R | ||||||||
IFN-γ | ||||||||
Th2 | IL-13 | |||||||
IL-5 | ||||||||
IL-4 | ||||||||
Th17 | IL-17 | |||||||
IL-6 | ||||||||
Chemokines | IL-8 | |||||||
IP-10* | 0.64 (0.38–1.08) | 0.66 (0.46–0.93) | 0.75 (0.59–0.96) | |||||
MCP-1 | ||||||||
MIG | 0.77 (0.56–1.05) | |||||||
MIP-1α | 1.13 (0.97–1.31) | |||||||
MIP-1β | ||||||||
RANTES | ||||||||
EOTAXIN | 1.83 (1.11–3.01) | 1.60 (0.99–2.58) | 0.19 (0.03–1.14) | 1.72 (1.01–2.94) | 0.46 (0.24–0.86) | |||
Growth factors | EGF | 0.29 (0.08–1.07) | ||||||
FGF | 1.63 (0.91–2.93) | |||||||
G-CSF | 1.24 (0.97–1.57) | |||||||
GM-CSF* | 1.28 (1.01–1.15) | |||||||
HGF | ||||||||
VEGF |