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Invasive non-Typhi Salmonella (NTS) is endemic in sub-Saharan Africa where it is a leading cause of bloodstream infection. Host risk factors have been established, but little is known about environmental reservoirs and predominant modes of transmission so prevention strategies are underdeveloped. While foodborne transmission from animals to humans predominates in high-income countries, it has been postulated that anthroponotic transmission both within and outside healthcare facilities may be important in sub-Saharan Africa. Antimicrobial resistance to ampicillin, trimethoprim-sulphamethoxazole and chloramphenicol is common; wider use of alternative agents may be warranted for empiric therapy. Vaccine development targeting the leading invasive NTS serotypes Typhimurium and Enteritidis shows promise. The clinical presentation of NTS bacteremia is non-specific and in the absence of blood culture may be confused with other febrile illnesses such as malaria. Much work remains to understand and control invasive NTS in sub-Saharan Africa.
Salmonella enterica subspecies enterica includes over 2,400 serotypes found in humans and other warm-blooded animals. Non-Typhi Salmonella enterica serotypes are abbreviated using their serotype name, for example Salmonella Typhimurium .
Non-Typhi Salmonella (NTS) is among the three most common pathogens causing bacterial bloodstream infections in adults and children in sub-Saharan Africa [2, 9]. HIV-infected adults and children <3 years carry most of the burden of invasive disease and mortality in these groups is high. This contrasts to the developed world, where NTS disease is usually a self-limited colitis, and mortality is lower.
Invasive NTS disease is endemic in rural and urban sub-Saharan Africa. The burden of mortality from childhood invasive bacterial disease may be greater than that of malaria in some African communities . In rural Kenya, the estimated minimum incidence of bacteremia was 505/100,000 person-years in the <5-years age group, of which 88/100,000 person-years was NTS bacteremia. In rural Mozambique childhood bacteremia incidence was 425/100,000 person-years in children <15 years, of which NTS incidence was 120/100,000 person-years . The true incidence of bacteremia is likely to be 2-3 times this figure, as bacteremia among children dying before reaching the district hospital was unable to be ascertained in either study [5, 9]. While evaluating the impact of the conjugate pneumococcal vaccine in the Gambia an incidence of NTS bacteremia of 262/100,000 person-years among children aged ≤29 months was demonstrated . In Uganda, NTS bacteremia was reported to be rare among adults with CD4-positive T-lymphocyte counts (CD4 counts) >500 cells/mm3, but 500/100,000/year among adults with CD4 counts 200-500 cells/mm3, and 7,500/100,000/year among adults with CD4 counts <200 cells/mm3 .
Case fatality estimates for hospitalized invasive NTS disease in Africa have ranged between 4.4-27% in children [6, 11-13] and 22-47% in adults [8, 14]. Case fatality in meningitis may be higher for NTS than for any other common cause of bacterial meningitis. For example, in Malawi 64% of neonates with NTS meningitis died compared to 26% with group B Streptococcus meningitis .
While these studies provide some insight into the burden of invasive NTS disease for Africa, none are population-based and most have focused on high risk groups such as young children and HIV-infected adults. Actual incidence is likely to vary by population HIV prevalence, local conditions and age distribution. The incidence of invasive NTS disease in sub-Saharan Africa is likely to be higher than for typhoid fever, which has been estimated to occur with an incidence of 50/100,000/year in Africa . Furthermore, hospital-based studies suggest that typhoid fever may be considerably less common than invasive NTS .
Data on the frequency of complications of NTS bacteremia in Africa are limited. Meningitis, septic arthritis and osteomyelitis are described [3, 11, 17, 18], especially among children, where NTS may be more common than Staphylococcus aureus as a cause of septic arthritis . Gordon et al investigated 100 NTS-bacteremic Malawian adults for focal suppurative disease and did not identify any localized NTS infections at initial presentation .
Of 2,517 children with NTS bacteremia in Malawi over 1998-2004, 85% were <36 months old and 19-35% were estimated to be HIV-infected . During the same period 2,439 adults with NTS bacteremia were identified and approximately 95-98% were HIV-infected. A South African autopsy study of 50 patients who died with a pre-mortem clinical diagnosis of tuberculosis revealed that 94% were HIV-infected and 23% of these patients were harboring splenic NTS .
Risk factors for NTS infection in Africa have not been well characterized; consequently evidence-based prevention interventions are limited. Small African studies and evidence-based prevention studies for NTS in more developed countries may provide clues until more data from Africa are available.
Prospective studies of enteric NTS infection that investigate risk factors for development of bacteremia are limited. A North American study noted a bacteremia incidence of 6% among infants with NTS diarrhea, but modifiable risk factors were not identified .
Seasonal peaks of NTS disease occur with the rainy season among both adults and children [4, 8, 11, 22] suggesting that environmental risk factors are important. Fecal organisms are found at highest concentrations in drinking water sources in Africa at the onset of the wet season  and this may correspond with increased risk of waterborne NTS. Protection of source water and increased access to centrally-treated safe water, strategies such as use of narrow-mouthed, spigoted containers for water storage , and treatment of water at home by chlorination, solar disinfection, filtration, flocculation, or a combination of measures may be considered to reduce the risk for diarrhea .
Numerous outbreaks of foodborne illness due to NTS have been studied in industrialized countries and have also been described in Africa. Meat, eggs, produce, and dairy products have all been implicated as vehicles for transmission. NTS infect or colonize most mammalian species. Food animals such as chickens have been a focus of efforts to reduce transmission of NTS to humans in developed countries . NTS have also been isolated from cattle, goats, sheep and pigs in African slaughterhouses. Identification and management of hazards facilitated by microbiological sampling at critical control points from farm to fork have been utilized in developing as well as industrialized countries to improve food safety and to control NTS disease .
Animal contact, particularly handling of young chickens by children, is a well-established risk factor for acquisition of NTS disease in industrialized countries . While not often considered a common risk factor for NTS infection in developed world studies, apparent anthroponotic transmission has been suggested as being relatively more important in Africa [22, 29]. Kariuki et al demonstrated carriage of identical strains of NTS in the stool of human household contacts of children with invasive disease, and a lack of such strains from environmental and domestic animal sampling from the households, although a common source from food or water could not be ruled out . Asymptomatic NTS carriers have been demonstrated in Africa . A Kenyan study of NTS carriage at admission to hospital found that 20 (3.6%) of 556 children but none of 111 adults carried NTS . In developed countries it is known that children are likely to excrete NTS in their stool for some weeks after recovering from enteric infection.
Outbreaks of NTS have been described in hospitals in many parts of the world, occurring among patients admitted with a different diagnosis. Outbreaks of hospital-acquired NTS can be particularly severe on pediatric wards in developing countries where children may be malnourished and have other host risk factors. In African hospitals food is often provided by a patient's family. While few studies have examined risk factors for infection in hospital outbreaks, contaminated food and person-to-person transmission have been considered. High case fatality is frequently observed especially when outbreaks are caused by strains of NTS resistant to the local empiric therapy . Ten percent of 360 adult and pediatric patients with hospital-acquired diarrhea occurring in a Kenyan hospital in 1988 was due to Salmonella and 2.5% to Shigella spp. Among children recent antimicrobial use, age 6 months to 6 years, and crowded living conditions at home were associated with hospital-acquired diarrhea due to Salmonella or Shigella spp. Among adults, sharing a hospital room with somebody with diarrhea and a history of previous hospitalization were associated with hospital-acquired Salmonella or Shigella diarrhea . Prevention strategies could include patient and visitor education regarding personal hygiene and food preparation and storage, provision of safe drinking water, hand washing before and after patient contact by healthcare workers, thorough cleaning of the hospital environment, reduction in crowding, avoiding sharing beds, increasing the number of healthcare workers, adequate disinfection of reusable equipment, surveillance for NTS infections and isolation of identified cases [18, 32].
Children and infants <3 years are particularly at risk for invasive NTS disease [5, 6, 8, 9, 11-13]. Endovascular infections with NTS are described in adults >50 years of age in the industrialized world. Older age may also be a risk factor in African populations, but is dominated by HIV-associated NTS disease among younger adults.
Recent use of antimicrobial agents is an established risk factor for development of NTS colitis . Among children in a Kenyan hospital in 1988, recent antimicrobial use was associated with hospital-acquired diarrhea due to Salmonella . Prior antimicrobial use and malnutrition contribute to abnormal gastrointestinal flora with possible loss of mucosal integrity.
Malaria has long been suspected to increase the risk of invasive NTS infection and may contribute to the seasonality of NTS disease. While the mechanism underlying the association between malaria and NTS is only partially understood, malarial hemolysis may lead to impaired macrophage and neutrophil function due to the accumulation of malarial pigment by phagocytic cells, saturation of iron-binding proteins, and increased iron availability to NTS, a siderophilic organism. While some studies have shown an association between malaria and NTS bacteremia , others have demonstrated an association between recent malaria or malarial anemia and NTS compared to other causes of bacteremia [3, 11, 34]. Thus measures directed at malaria control may have the potential to lead to reduction in invasive NTS disease in tropical Africa.
Malnutrition was associated with NTS bacteremia among children in Kilifi, Kenya [5, 11]. Malnutrition, measles and diarrheal disease were common reasons for admission among children who subsequently developed hospital-acquired NTS disease in Rwanda . While children <3 years of age are at greater risk for NTS disease, those <4 months old appear to be relatively protected, perhaps both by maternal antibody  and exclusive breast-feeding which provides colostrum and limits exposure to unsafe water and food.
NTS bacteremia is more common among HIV-infected individuals [2, 29] and the association with HIV infection is strongest among adults. Recurrent NTS bacteremia is a World Health Organization (WHO) Stage 4 defining condition. Prophylactic trimethoprim-sulfamethoxazole (SXT) is recommended to prevent the occurrence of opportunistic infections among HIV-infected patients . This strategy appears to remain effective, even in areas with high levels of resistance to SXT among pathogens such as NTS . Combination antiretroviral therapy has been associated with dramatic reductions in the incidence of NTS colitis and NTS bacteremia among HIV-infected persons in the developed world . HIV infection is also a risk factor for bacteremia among children, including NTS bacteremia. HIV was associated with any bacteremia among children in Kilifi, Kenya, OR 3.22 (95% CI 2.34–4.44) and with NTS bacteremia, OR 3.21 (95% CI 1.95-5.28) .
Use of medications that reduce gastric acidity is associated with increased risk of gastrointestinal infection . Infants have relative gastric achlorhydria compared with adults which may contribute to their risk of NTS disease.
Persons homozygous for sickle cell disease are at particular risk for bacterial sepsis, including NTS bacteremia. Among 78 consecutive cases of acute osteomyelitis complicating sickle cell disease in Nigeria, with a mean age of 12 years (range 9 months-50 years), 32 were able to have cultures of blood or pus performed and half the cases were due to Salmonella .
Fever or sweats were noted among 95% of 100 Malawian adults and splenomegaly among 38% at initial presentation with NTS bacteremia, features also seen in malaria. The median (range) hemoglobin in this 99% HIV-infected group was 6.8g/dL (2.5-11.7g/dL) . Fever and splenomegaly predicted NTS bacteremia among hospitalized adults in Malawi . In Tanzania, patients admitted to hospital for antimalarial treatment were more likely to die if their malaria slide was negative than if it was positive , suggesting that a lack of capacity to diagnose and treat non-malaria infections such as bacterial sepsis may contribute to outcome. Among 166 children with NTS bacteremia in Kenya, splenomegaly was present in 44% of cases, fever in 94% . In the same rural district, 26% of all inpatient childhood deaths were associated with bacteremia whereas 22% of such deaths were associated with malaria. Of children dying with malaria, 21% were also bacteremic .
NTS bacteremia frequently occurs without gastrointestinal symptoms in adults  and children . Peters et al have noted that while adult patients with pneumococcal or mycobacterial sepsis could often be diagnosed clinically prior to blood culture results becoming available, patients with NTS sepsis were much more difficult to diagnose on clinical grounds due to nonspecific symptoms and signs . The syndrome of childhood pneumonia overlaps with both malaria and NTS sepsis [3, 11, 18]. Because clinical diagnosis of NTS bacteremia is difficult, blood culture facilities are needed to diagnose it and to conduct accurate surveillance to guide public health policy. Unfortunately adequate clinical laboratory infrastructure is frequently lacking in resource-poor countries in Africa .
Outcomes were studied among 100 Malawian adults with NTS bacteremia, 99% of whom were HIV-infected; 47% died within one month, 77% died within a year of index presentation, and 43% of initial survivors developed at least one recurrence of NTS bacteremia. Molecular testing revealed that recurrence was due to recrudescence rather than reinfection in most instances . Recrudescence probably occurs due to persistence of NTS intracellularly in the reticuloendothelial system.
Empiric treatment of childhood sepsis according to WHO guidelines  with penicillin and chloramphenicol or ampicillin and gentamicin may not provide adequate cover for NTS disease that is resistant to ampicillin, trimethoprim-sulfamethoxazole, and chloramphenicol. Gentamicin has limited activity against intracellular pathogens, so although isolates may appear susceptible in vitro, gentamicin cannot be relied upon in vivo. WHO guidelines advise that where there is known substantial antimicrobial resistance to traditional first-line antimicrobials, use of a third-generation cephalosporin may be appropriate . The CSF penetration of ceftriaxone makes it a good choice for meningitis. A recent report on pediatric NTS meningitis from Malawi over 1997-2006 demonstrated a static case fatality rate of approximately 50% but a fall in permanent sequelae over time, possibly associated with a change in duration of therapy from two to four weeks . CDC recommends ciprofloxacin for the treatment of NTS bacteremia in HIV-infected adults, for 4-6 weeks if the CD4 count is <200cells/mm3, followed by long-term secondary prophylaxis . Data to guide duration of therapy or secondary prophylaxis for neonates, meningitis patients and HIV-infected persons in Africa is lacking. S. Typhi with decreased ciprofloxacin susceptibility, often associated with nalidixic acid resistance, may not respond adequately to ciprofloxacin therapy. It is not known whether this is also true for NTS . When patients with NTS bacteremia do not respond to appropriate antimicrobial therapy a search for focal disease and for schistosomiasis co-infection is warranted.
S. Typhimurium and S. Enteritidis are the most common serotypes of NTS causing human disease in sub-Saharan Africa [8, 11, 13, 29, 35, 48]. The acquisition of a plasmid conveying a multidrug resistant (MDR) phenotype may be associated with successful spread and has been observed with S. Typhimurium in Malawi . S. Isangi was a rare serotype in South Africa until 2002 when it expanded to account for 20% of NTS isolates from national surveillance and was found to produce an extended-spectrum β-lactamase (ESBL) .
Antimicrobial resistance of NTS to trimethoprim-sulfamethoxazole, ampicillin and chloramphenicol has become common in sub-Saharan Africa limiting the value of these agents for management of invasive NTS [4, 6, 8, 18].
Virulence of NTS is dependent on ability to grow within macrophages of the reticuloendothelial system . Extracellular replication and bacteremic dissemination also occurs. Resistance to complement killing, by way of long chain lipopolysaccharide, is an important virulence trait. Both complement and specific antibody together are required to kill Salmonella in vitro. While healthy African adult serum was able to kill NTS, serum from children <16 months old often did not contain sufficient specific antibody titers to kill effectively . This probably explains the predisposition of young children to invasive NTS disease and may go some way towards understanding a mechanism by which the immune dysregulation of HIV infection contributes to NTS disease risk. Such immunologic clues suggest that vaccine development directed towards the common invasive serotypes could be a useful approach to control invasive NTS disease.
As Streptococcus pneumoniae and Haemophilus influenzae invasive disease are controlled by vaccine strategies, invasive Salmonella may consolidate its position as a leading cause of community-acquired bloodstream infection in sub-Saharan Africa.
Despite the substantial burden of illness and death caused by invasive NTS disease, much remains to be done to understand and control invasive NTS in sub-Saharan Africa. A clearer understanding of incidence, complications, and case fatality rates at the population level would be valuable to understand how to prioritize health resources. Scale-up of access to blood culture or to improved alternative diagnostic methods is needed to support such studies, to improve patient care, and to inform policy. Research to determine the major environmental sources, modes of transmission, and to characterize risk factors for mucosal colonization or infection and for invasive disease is urgently needed. It would be useful to understand more about the syndrome of invasive NTS in sub-Saharan Africa, including what proportion of persons with NTS diarrhea or NTS carriage also develop invasive disease, pathogenesis, the prevalence of carriage and chronic shedding, and the risk of NTS bacteremia attributable to co-morbid conditions such as malnutrition, malaria, and HIV infection. Algorithms for the management of febrile illness need to be continually reevaluated to address the relative importance of malaria versus invasive bacterial infections such as NTS. Clinical effectiveness studies and surveillance for antimicrobial resistance and serotype distribution are needed to inform clinical management strategies, to detect changes in patterns of disease and to assist in vaccine development.
Authors received support from US National Institutes of Health awards AIDS International Training and Research Program, Fogarty International Center, D43 PA-03-018 (HOR, JAC), International Studies of AIDS-associated Co-infections AI062563 (HOR, JAC), the Duke University Center for AIDS Research AI64518 (HOR, JAC), the Duke Clinical Trials Unit and Clinical Research Sites AI069484-01 (JAC), and from the Hubert-Yeargan Center for Global Health and a Duke Clinical Research Institute Synderman Award, Duke University Medical Center (SCM).
Potential conflicts of interest. All authors: no conflicts.