Presentation of life-threatening invasive nontyphoidal Salmonella disease in Malawian children: A prospective observational study

Abstract

Nontyphoidal Salmonellae commonly cause invasive disease in African children that is often fatal. The clinical diagnosis of these infections is hampered by the absence of a clear clinical syndrome. Drug resistance means that empirical antibiotic therapy is often ineffective and currently no vaccine is available. The study objective was to identify risk factors for mortality among children presenting to hospital with invasive Salmonella disease in Africa. We conducted a prospective study enrolling consecutive children with microbiologically-confirmed invasive Salmonella disease admitted to Queen Elizabeth Central Hospital, Blantyre, in 2006. Data on clinical presentation, co-morbidities and outcome were used to identify children at risk of inpatient mortality through logistic-regression modeling. Over one calendar year, 263 consecutive children presented with invasive Salmonella disease. Median age was 16 months (range 0-15 years) and 52/256 children (20%; 95%CI 15-25%) died. Nontyphoidal serovars caused 248/263 (94%) of cases. 211/259 (81%) of isolates were multi-drug resistant. 251/263 children presented with bacteremia, 6 with meningitis and 6 with both. Respiratory symptoms were present in 184/240 (77%; 95%CI 71-82%), 123/240 (51%; 95%CI 45-58%) had gastrointestinal symptoms and 101/240 (42%; 95%CI 36-49%) had an overlapping clinical syndrome. Presentation at <7 months (OR 10.0; 95%CI 2.8-35.1), dyspnea (OR 4.2; 95%CI 1.5-12.0) and HIV infection (OR 3.3; 95%CI 1.1-10.2) were independent risk factors for inpatient mortality. Invasive Salmonella disease in Malawi is characterized by high mortality and prevalence of multi-drug resistant isolates, along with non-specific presentation. Young infants, children with dyspnea and HIV-infected children bear a disproportionate burden of the Salmonella-associated mortality in Malawi. Strategies to improve prevention, diagnosis and management of invasive Salmonella disease should be targeted at these children.

Fig 1. Malawian children admitted to hospital with invasive Salmonella disease, recruitment and outcomes.

(A) Blood and CSF cultures taken from children admitted to Queen Elizabeth Central Hospital, Blantyre, Malawi in 2006; those yielding Salmonella isolates; and outcomes of children with invasive Salmonella disease. (B) Recruitment pathway for children following detection of Gram-negative bacteria in blood and/or CSF culture. (C) Kaplan-Meier estimate of survival (in days) of children following admission with invasive Salmonella disease.

Fig 2. Variability in outcome, co-morbidity and clinical presentation of invasive Salmonella disease in Malawian children with age and season of presentation.

Graphs indicate variation in mortality (A and B), co-morbidity (C and D) and clinical presentation (E and F) with age and month of the year. Each plot is overlaid on a histogram of the frequency of iNTS disease presentation with age (A, C and E) or bar-charts indicating monthly frequency of iNTS disease and monthly rainfall (B, D and F).

Fig 3. Survival of children with invasive Salmonella disease.

Kaplan-Meier estimates of survival (in days) following admission with invasive Salmonella disease in children aged 0–6 months and >6 months (A), children with and without HIV co-infection (B), and children with and without a history of dyspnea at presentation (C).

Fig 4. Clinical presentation and comorbidities of invasive Salmonella disease and mortality in Malawian children.

(A) Area-proportionate Venn diagram indicating the different presenting clinical syndromes of pediatric invasive Salmonella disease. Gastroenteritis is defined as children with a history of diarrhea or vomiting, and a respiratory presentation as the presence of cough, shortness of breath or respiratory distress. (B) Area-proportionate Venn diagram indicating comorbidities (HIV, malaria and severe malnutrition) of children presenting with invasive Salmonella disease. Figures are absolute numbers (percentages in brackets) of children in each group, with mortality in each group given below and are shown for individual variables and for children in whom these overlapped. Discrepancies between totals in the figures and the text are due to children with missing data for one of the categories depicted.