Table 1

Studies assessing correlation between CRP levels and bacterial infection and diagnostic performance of CRP in LMICs

Study	Country	Age group	Inpatients/Outpatients	Disease characteristics	Number of patients	Gold standard for bacterial infection	CRP test	Diagnostic performance				Correlation with bacterial infection
Study	Country	Age group	Inpatients/Outpatients	Disease characteristics	Number of patients	Gold standard for bacterial infection	CRP test	AUROC (95% CI)	Cut-off*	Sensitivity†	Specificity†	Correlation with bacterial infection
Studies in Africa
Carrol et al5	Malawi	2 months to 16 years	Inpatients	Pneumonia or meningitis	377	Culture, microscopy, antigen or PCR from blood, cerebrospinal fluid and/or lung aspirate	Beckman Coulter image immunochemistry system	0.81 (0.73 to 0.89) for serious bacterial	N/A	N/A	N/A	Median CRP values were significantly higher in HIV-negative and HIV-positive patients with serious bacterial infections compared with those without (253 vs 127 mg/L, p=0.0005 and 291 vs 135 mg/L, p=0.0005, respectively).
Díez-Padrisa et al6	Mozambique	<5 years	Inpatients	Clinical severe pneumonia (no malaria)	586	Blood culture	Immunoturbidimetric assay, ADVIA Chemisty CRP 2 (Siemens)	0.79	20.9	95	45	CRP levels were higher in those with positive bacterial culture vs those with negative bacterial culture (177.65 mg⁄L vs 26.5 mg⁄L, p<0.001). Median CRP levels (>18.5 to ≤97.9) were predictive of bacterial culture positivity (OR 15.31, 95% CI 1.91 to 122.45, p=0.01).
Díez-Padrisa et al6	Mozambique	<5 years	Inpatients	Clinical severe pneumonia (no malaria)	586	Blood culture	Immunoturbidimetric assay, ADVIA Chemisty CRP 2 (Siemens)	0.79	38	85	57
Hildenwall et al14	Tanzania	3 months to 5 years	Outpatients	Fever (malaria negative)	428	Positive urine or blood culture or symptoms suggestive pneumonia as defined in the IMCI	Afinion AS100 Analyzer (Axis-Shield)	0.62	19	44.6 (33.2 to 56.6)	78.5 (73.0 to 83.1)	Of those with CRP <20 mg/L (n=256, 59.8%), 84% had no signs of bacterial infection. Of those with CRP >80 mg/L (n=33, 7.7%), 36.7% were positive for bacterial infection.
Huang et al8	Gambia and Kenya	2 months to 5 years	Inpatients	Pneumonia	Pneumonia: n=204 Matched controls: n=186	Blood culture or radiograph	ELISA (R&D Systems)	0.72 (0.59 to 0.86)	150, ≥200	70.5	56.1	Median CRP plasma concentration was significantly higher in those with probable bacterial infection (positive blood culture or radiograph) vs those with probable viral infection (negative radiograph and low WBC) (283 vs 175 µg/mL, p<0.001).
Mahende et al10	Tanzania	2 months to 5 years	Outpatients	Fever	691	Blood culture	Cobas c111 (Roche Diagnostics)	0.83	37.3	74.2	77.8
Page et al12	Niger	6 months to 5 years	Inpatients	Severe acute malnutrition	256	Blood, urine, stool culture and radiograph	NycoCard Reader (Abott)	0.66 (0.59 to 0.79) all patients, 0.72 (0.63 to 0.80) malaria-negative patients	47.5	46.5	80.4	Median CRP levels were significantly higher in those with pneumonia (radiograph positive) vs those with no proved bacterial infection (40.8 vs 12 mg/L, p=0.0014).
Page et al12	Niger	6 months to 5 years	Inpatients	Severe acute malnutrition	256	Blood, urine, stool culture and radiograph	NycoCard Reader (Abott)		13	81.1	58.7
Studies in South-East Asia
Mueller et al11	Cambodia	7–49 years	Outpatients	Acute fever	Febrile patients: 1193, Matched controls: 282	Microbiological results including culture, PCR, ELISA, RDTs	Latex bead immune-turbidimetric method adapted on Integra 400 (Roche Diagnostics)	NA	21.3	52.5	84.3
Wangrangsimakul et al13	Thailand	≥15 years	Inpatients and outpatients	Acute fever	231	Microbiological results including culture, PCR, ELISA, RDTs	NycoCard Reader (Abott, USA)	0.91 (0.85 to 0.96)	36	88.9 (79.3 to 95.1)	86.4 (65.1 to 97.1)
Lubell et al9	Cambodia, Laos, Thailand	5–49 years	Inpatients and outpatients	Acute fever	1372	Microbiological results including culture, antigen detection, PCR and ELISA for JEV IgM ELISA	NycoCard Reader (Abott, USA)	0.89 (0.8 to 0.97)	10	95 (92 to 97)	49 (46 to 53)	CRP levels were significantly lower in patients with a viral infection than other infections (p<0.0001 in all comparisons across countries).
Lubell et al9	Cambodia, Laos, Thailand	5–49 years	Inpatients and outpatients	Acute fever	1372		NycoCard Reader (Abott, USA)	0.89 (0.8 to 0.97)	20	86 (82 to 88)	67 (63 to 71)
Studies in multiple settings
Higdon et al7	Bangladesh, Gambia, Kenya, Mali, South Africa, Thailand and Zambia	<5 years	Inpatients	Pneumonia	Pneumonia: n=3597, controls: n=822	Blood culture or positive lung aspirate or pleural fluid culture or PCR‡	CRP Gen3 or CRP VARIO (Roche Diagnostics)	0.87	37.1	77 (69 to 84)	82 (78 to 85)	77% of HIV-negative cases with confirmed bacterial pneumonia vs 17% (n=556) cases with RSV pneumonia had CRP ≥40 mg/L (p<0.001).

*mg/L.
†%; 95% CI.
‡Compared with ‘RSV pneumonia’—nasopharyngeal/oropharyngeal or induced sputum PCR-positive without confirmed/suspected bacterial pneumonia.
AUROC, area under the receiver operator characteristic curve; CRP, C reactive protein; IMCI, integrated management of childhood illness; LMICs, low-income and middle-income countries; N/A, not available; RDT, rapid diagnostic test; RSV, respiratory syncytial virus; WBC, white blood cell count.