The Relationship Between Invasive Nontyphoidal Salmonella Disease, Other Bacterial Bloodstream Infections, and Malaria in Sub-Saharan Africa

Abstract

Background: Country-specific studies in Africa have indicated that Plasmodium falciparum is associated with invasive nontyphoidal Salmonella (iNTS) disease. We conducted a multicenter study in 13 sites in Burkina Faso, Ethiopia, Ghana, Guinea-Bissau, Kenya, Madagascar, Senegal, South Africa, Sudan, and Tanzania to investigate the relationship between the occurrence of iNTS disease, other systemic bacterial infections, and malaria.

Methods: Febrile patients received a blood culture and a malaria test. Isolated bacteria underwent antimicrobial susceptibility testing, and the association between iNTS disease and malaria was assessed.

Results: A positive correlation between frequency proportions of malaria and iNTS was observed (P = .01; r = 0.70). Areas with higher burden of malaria exhibited higher odds of iNTS disease compared to other bacterial infections (odds ratio [OR], 4.89; 95% CI, 1.61-14.90; P = .005) than areas with lower malaria burden. Malaria parasite positivity was associated with iNTS disease (OR, 2.44; P = .031) and gram-positive bacteremias, particularly Staphylococcus aureus, exhibited a high proportion of coinfection with Plasmodium malaria. Salmonella Typhimurium and Salmonella Enteritidis were the predominant NTS serovars (53/73; 73%). Both moderate (OR, 6.05; P = .0001) and severe (OR, 14.62; P < .0001) anemia were associated with iNTS disease.

Conclusions: A positive correlation between iNTS disease and malaria endemicity, and the association between Plasmodium parasite positivity and iNTS disease across sub-Saharan Africa, indicates the necessity to consider iNTS as a major cause of febrile illness in malaria-holoendemic areas. Prevention of iNTS disease through iNTS vaccines for areas of high malaria endemicity, targeting high-risk groups for Plasmodium parasitic infection, should be considered.

Keywords: NTS; Plasmodium; Salmonella; invasive NTS; malaria.

Figure 1.

Flowchart of Typhoid Fever Surveillance in Africa Program (TSAP) blood culture and malaria test performance. Blood culture–positive isolates: contaminants excluded (Marks F. et al, unpublished data). Gram-negative isolates: Salmonella species excluded. Malaria tests performed per site: Nioko, Burkina Faso (BF; thick/thin blood smears), Polesgo, BF (thick/thin blood smears), Butajira, Ethiopia (Rapid Diagnostic Test [RDT] and thick/thin blood smears), Asante Akim North District (AAN), Ghana (thick/thin blood smears), Bissau, Guinea-Bissau (GB; thick/thin blood smears), Kibera, Kenya (thick blood smear), Imerintsiatosika, Madagascar (MG; RDT and thick/thin blood smears), Isotry, MG (RDT and thick/thin blood smears), Pikine, Senegal (RDT if available and thick/thin blood smears), Pietermaritzburg, South Africa (SA; malaria-free zone: no malaria test performed), East Wad Medani (EWM), Sudan (thick/thin blood smears), Moshi Rural (MR), Tanzania (thick/thin blood smears), and Moshi Urban (MU), Tanzania (thick/thin blood smears). Numerators and denominators for each percentages (%) in the flowchart (in descending order from top to bottom): % of blood culture performed of recruited patients; % of malaria test performed of recruited patients; % of blood culture positive isolates of blood culture performed; % of malaria parasite–positive cases of malaria test performed; % of bacterial isolates coinfected with malaria of blood culture-confirmed positive isolates; % of nontyphoidal Salmonella (NTS), S. Typhi, Gram-positive, and non-Salmonella gram-negative isolates of blood culture-confirmed positive isolates; % of isolates with NTS-malaria coinfection, S. Typhi-malaria coinfection, gram-positive-malaria coinfection, non-Salmonella gram-negative-malaria coinfection of all bacterial isolates coinfected with malaria. Malaria species: 2801/3133 malaria positives confirmed with malaria species; 332/3133 missing data on malaria species; 2779/2801 Plasmodium falciparum; 20/2801 Plasmodium malariae; 2/2801 Plasmodium ovale. Malaria species confirmed per site listed below. Nioko, BF: 430/430 P. falciparum; Polesgo, BF: 444/444 P. falciparum. Butajira, Ethiopia: 26/110 P. falciparum and 84 missing data on malaria species. AAN, Ghana: 1111/1139 P. falciparum, 20/1139 P. malariae, 2/1139 P. ovale, and 6 missing data on malaria species. Bissau, GB: 196/206 P. falciparum and 10 missing data on malaria species. Kibera, Kenya: not available/226 (no data on malaria species). Imerintsiatosika, MG: 19/19 P. falciparum; Isotry, MG: 2/2 P. falciparum. Pikine, Senegal: 291/297 P. falciparum, and 6 missing data on malaria species. Pietermaritzburg, SA: No malaria test performed as the country is malaria-free. EWM, Sudan: 254/254 P. falciparum. MR, Tanzania: 2/2 P. falciparum; MU, Tanzania: 4/4 P. falciparum. Abbreviations: H, hospital; HC, health center; IPD, inpatient department; NA, not available; OPD, outpatient department.

Figure 1.

Flowchart of Typhoid Fever Surveillance in Africa Program (TSAP) blood culture and malaria test performance. Blood culture–positive isolates: contaminants excluded (Marks F. et al, unpublished data). Gram-negative isolates: Salmonella species excluded. Malaria tests performed per site: Nioko, Burkina Faso (BF; thick/thin blood smears), Polesgo, BF (thick/thin blood smears), Butajira, Ethiopia (Rapid Diagnostic Test [RDT] and thick/thin blood smears), Asante Akim North District (AAN), Ghana (thick/thin blood smears), Bissau, Guinea-Bissau (GB; thick/thin blood smears), Kibera, Kenya (thick blood smear), Imerintsiatosika, Madagascar (MG; RDT and thick/thin blood smears), Isotry, MG (RDT and thick/thin blood smears), Pikine, Senegal (RDT if available and thick/thin blood smears), Pietermaritzburg, South Africa (SA; malaria-free zone: no malaria test performed), East Wad Medani (EWM), Sudan (thick/thin blood smears), Moshi Rural (MR), Tanzania (thick/thin blood smears), and Moshi Urban (MU), Tanzania (thick/thin blood smears). Numerators and denominators for each percentages (%) in the flowchart (in descending order from top to bottom): % of blood culture performed of recruited patients; % of malaria test performed of recruited patients; % of blood culture positive isolates of blood culture performed; % of malaria parasite–positive cases of malaria test performed; % of bacterial isolates coinfected with malaria of blood culture-confirmed positive isolates; % of nontyphoidal Salmonella (NTS), S. Typhi, Gram-positive, and non-Salmonella gram-negative isolates of blood culture-confirmed positive isolates; % of isolates with NTS-malaria coinfection, S. Typhi-malaria coinfection, gram-positive-malaria coinfection, non-Salmonella gram-negative-malaria coinfection of all bacterial isolates coinfected with malaria. Malaria species: 2801/3133 malaria positives confirmed with malaria species; 332/3133 missing data on malaria species; 2779/2801 Plasmodium falciparum; 20/2801 Plasmodium malariae; 2/2801 Plasmodium ovale. Malaria species confirmed per site listed below. Nioko, BF: 430/430 P. falciparum; Polesgo, BF: 444/444 P. falciparum. Butajira, Ethiopia: 26/110 P. falciparum and 84 missing data on malaria species. AAN, Ghana: 1111/1139 P. falciparum, 20/1139 P. malariae, 2/1139 P. ovale, and 6 missing data on malaria species. Bissau, GB: 196/206 P. falciparum and 10 missing data on malaria species. Kibera, Kenya: not available/226 (no data on malaria species). Imerintsiatosika, MG: 19/19 P. falciparum; Isotry, MG: 2/2 P. falciparum. Pikine, Senegal: 291/297 P. falciparum, and 6 missing data on malaria species. Pietermaritzburg, SA: No malaria test performed as the country is malaria-free. EWM, Sudan: 254/254 P. falciparum. MR, Tanzania: 2/2 P. falciparum; MU, Tanzania: 4/4 P. falciparum. Abbreviations: H, hospital; HC, health center; IPD, inpatient department; NA, not available; OPD, outpatient department.

Figure 2.

Correlation between frequency proportions of malaria and invasive nontyphoidal Salmonella (iNTS) compared to malaria with other invasive bacteria across 13 sites. Spearman correlation coefficient (r) is analyzed based on the proportion of frequencies of malaria, iNTS, Salmonella Typhi, gram-positive and non-Salmonella gram-negative bacterial isolates per site, controlled by each site study period. (Proportions of frequencies are calculated as iNTS, S. Typhi, gram-positive bacteria, non-Salmonella gram-negative bacteria positivity out of blood culture performed; malaria positivity out of malaria test performed.) Scattered dots represent each study sites. Frequencies of bacteremias and Plasmodium parasite positivity per site are noted in Figure 1. Thirteen sites exhibited in the scattered dots are grouped per surveillance period below or above the median duration of surveillance period (20 months). Sites colored in red dots are those with surveillance period of >20 months: Ethiopia, Ghana, Kenya, South Africa, and Tanzania (urban and rural). Sites colored in blue dots are those with a surveillance period of ≤20 months: Burkina Faso (Nioko and Polesgo), Guinea-Bissau, Madagascar (Imerintsiatosika and Isotry), Senegal, and Sudan. Some sites with same or similar values may appear overlapped, but all 13 sites are dotted in the plot. 3 S. Paratyphi A isolates from Senegal are grouped under NTS in this analysis.