Predicting the severity of dengue fever in children on admission based on clinical features and laboratory indicators: application of classification tree analysis.

BACKGROUND: Dengue fever is a re-emerging viral disease commonly occurring in tropical and subtropical areas. The clinical features and abnormal laboratory test results of dengue infection are similar to those of other febrile illnesses; hence, its accurate and timely diagnosis for providing appropriate treatment is difficult. Delayed diagnosis may be associated with inappropriate treatment and higher risk of death. Early and correct diagnosis can help improve case management and optimise the use of resources such as hospital staff, beds, and intensive care equipment. The goal of this study was to develop a predictive model to characterise dengue severity based on early clinical and laboratory indicators using data mining and statistical tools. METHODS: We retrieved data from a study of febrile illness in children at Angkor Hospital for Children, Cambodia. Of 1225 febrile episodes recorded, 198 patients were confirmed to have dengue. A classification and regression tree (CART) was used to construct a predictive decision tree for severe dengue, while logistic regression analysis was used to independently quantify the significance of each parameter in the decision tree. RESULTS: A decision tree algorithm using haematocrit, Glasgow Coma Score, urine protein, creatinine, and platelet count predicted severe dengue with a sensitivity, specificity, and accuracy of 60.5%, 65% and 64.1%, respectively. CONCLUSIONS: The decision tree we describe, using five simple clinical and laboratory indicators, can be used to predict severe cases of dengue among paediatric patients on admission. This algorithm is potentially useful for guiding a patient-monitoring plan and outpatient management of fever in resource-poor settings.

Typhoid fever among hospitalized febrile children in Siem Reap, Cambodia.

Typhoid fever was confirmed by positive blood culture in 5 (3.7%) of 134 febrile children hospitalized in Cambodia. Typhoid was suspected in an additional 25 (18.7 %) blood culture-negative children based on: a positive immunoglobulin M lateral flow assay (IgMFA) (16); a positive polymerase chain reaction (PCR) for Salmonella typhi (2); or clinical assessment (7). The specificity of the IgMFA and PCR assays requires further study.

A retrospective study of factors which determine a negative blood culture in Cambodian children diagnosed with enteric fever.

BACKGROUND: Blood cultures are used to confirm a diagnosis of enteric fever but reported sensitivities can be as low as 40%. AIMS: To determine the factors associated with a negative blood culture in Cambodian children with suspected enteric fever. METHODS: In a retrospective study of hospitalised Cambodian children given a discharge diagnosis of enteric fever, the following factors associated with a negative blood culture were analysed: age, blood culture volume, prior antibiotic therapy, duration of illness and disease severity. RESULTS: In 227 hospitalised Cambodian children with a discharge diagnosis of enteric fever, it was confirmed in 70% by a positive blood culture. There was no association between a negative blood culture and younger age, lower blood volumes for culture, prior antibiotic therapy, a late presentation or milder disease. CONCLUSIONS: Although blood culture sensitivity was higher than expected, alternative simple, rapid and sensitive tests are needed for diagnosing enteric fever.

Evaluation of the diagnostic accuracy of a typhoid IgM flow assay for the diagnosis of typhoid fever in Cambodian children using a Bayesian latent class model assuming an imperfect gold standard.

Rapid diagnostic tests are needed for typhoid fever (TF) diagnosis in febrile children in endemic areas. Five hundred children admitted to the hospital in Cambodia between 2009 and 2010 with documented fever (≥ 38°C) were investigated using blood cultures (BCs), Salmonella Typhi/Paratyphi A real-time polymerase chain reactions (PCRs), and a Typhoid immunoglobulin M flow assay (IgMFA). Test performance was determined by conventional methods and Bayesian latent class modeling. There were 32 cases of TF (10 BC- and PCR-positive cases, 14 BC-positive and PCR-negative cases, and 8 BC-negative and PCR-positive cases). IgMFA sensitivity was 59.4% (95% confidence interval = 41-76), and specificity was 97.8% (95% confidence interval = 96-99). The model estimate sensitivity for BC was 81.0% (95% credible interval = 54-99). The model estimate sensitivity for PCR was 37.8% (95% credible interval = 26-55), with a specificity of 98.2% (95% credible interval = 97-99). The model estimate sensitivity for IgMFA (≥ 2+) was 77.9% (95% credible interval = 58-90), with a specificity of 97.5% (95% credible interval = 95-100). The model estimates of IgMFA sensitivity and specificity were comparable with BCs and better than estimates using conventional analysis.

A prospective study of the causes of febrile illness requiring hospitalization in children in Cambodia.

BACKGROUND: Febrile illnesses are pre-eminent contributors to morbidity and mortality among children in South-East Asia but the causes are poorly understood. We determined the causes of fever in children hospitalised in Siem Reap province, Cambodia. METHODS AND FINDINGS: A one-year prospective study of febrile children admitted to Angkor Hospital for Children, Siem Reap. Demographic, clinical, laboratory and outcome data were comprehensively analysed. Between October 12(th) 2009 and October 12(th) 2010 there were 1225 episodes of febrile illness in 1180 children. Median (IQR) age was 2.0 (0.8-6.4) years, with 850 (69%) episodes in children <5 years. Common microbiological diagnoses were dengue virus (16.2%), scrub typhus (7.8%), and Japanese encephalitis virus (5.8%). 76 (6.3%) episodes had culture-proven bloodstream infection, including Salmonella enterica serovar Typhi (22 isolates, 1.8%), Streptococcus pneumoniae (13, 1.1%), Escherichia coli (8, 0.7%), Haemophilus influenzae (7, 0.6%), Staphylococcus aureus (6, 0.5%) and Burkholderia pseudomallei (6, 0.5%). There were 69 deaths (5.6%), including those due to clinically diagnosed pneumonia (19), dengue virus (5), and melioidosis (4). 10 of 69 (14.5%) deaths were associated with culture-proven bloodstream infection in logistic regression analyses (odds ratio for mortality 3.4, 95% CI 1.6-6.9). Antimicrobial resistance was prevalent, particularly in S. enterica Typhi, (where 90% of isolates were resistant to ciprofloxacin, and 86% were multi-drug resistant). Comorbid undernutrition was present in 44% of episodes and a major risk factor for acute mortality (OR 2.1, 95% CI 1.1-4.2), as were HIV infection and cardiac disease. CONCLUSION: We identified a microbiological cause of fever in almost 50% of episodes in this large study of community-acquired febrile illness in hospitalized children in Cambodia. The range of pathogens, antimicrobial susceptibility, and co-morbidities associated with mortality described will be of use in the development of rational guidelines for infectious disease treatment and control in Cambodia and South-East Asia.

Enteric fever in Cambodian children is dominated by multidrug-resistant H58 Salmonella enterica serovar Typhi with intermediate susceptibility to ciprofloxacin.

Infections with Salmonella enterica serovar Typhi isolates that are multidrug resistant (MDR: resistant to chloramphenicol, ampicillin, trimethoprim-sulphamethoxazole) with intermediate ciprofloxacin susceptibility are widespread in Asia but there is little information from Cambodia. We studied invasive salmonellosis in children at a paediatric hospital in Siem Reap, Cambodia. Between 2007 and 2011 Salmonella was isolated from a blood culture in 162 children. There were 151 children with enteric fever, including 148 serovar Typhi and three serovar Paratyphi A infections, and 11 children with a non-typhoidal Salmonella infection. Of the 148 serovar Typhi isolates 126 (85%) were MDR and 133 (90%) had intermediate ciprofloxacin susceptibility. Inpatient antimicrobial treatment was ceftriaxone alone or initial ceftriaxone followed by a step-down to oral ciprofloxacin or azithromycin. Complications developed in 37/128 (29%) children admitted with enteric fever and two (1.6%) died. There was one confirmed relapse. In a sample of 102 serovar Typhi strains genotyped by investigation of a subset of single nucleotide polymorphisms, 98 (96%) were the H58 haplotype, the majority of which had the common serine to phenylalanine substitution at codon 83 in the DNA gyrase. We conclude that antimicrobial-resistant enteric fever is common in Cambodian children and therapeutic options are limited.

Emergence of community-associated methicillin-resistant Staphylococcus aureus carriage in children in Cambodia.

We previously described the first reported isolation of methicillin-resistant Staphylococcus aureus (MRSA) (a case series of pediatric community-associated MRSA infections) in Cambodia. We define the rate of pediatric MRSA carriage in the same population and characterize the associated bacterial genotypes by using pulsed-field gel electrophoresis and multilocus sequence typing. A prospective cohort study of MRSA carriage conducted over one month at the Angkor Hospital for Children, Siem Reap, Cambodia, identified MRSA carriage in 87 (3.5%) of 2,485 children who came to the outpatient department, and 6 (4.1%) of 145 inpatients, including at least two with cases of nosocomial acquisition. Genotyping of all 93 MRSA isolates resolved 5 genotypes. Most (91%) isolates were assigned to sequence type 834. Only 28 (32%) of 87 MRSA carriers identified in the outpatient department had no history of recent healthcare contact. The study findings have important implications for healthcare in a setting where diagnostic microbiology and access to antimicrobial drugs with efficacy against MRSA are limited.

Emergence of community-associated methicillin-resistant Staphylococcus aureus associated with pediatric infection in Cambodia.

BACKGROUND: The incidence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infection is rising in the developed world but appears to be rare in developing countries. One explanation for this difference is that resource poor countries lack the diagnostic microbiology facilities necessary to detect the presence of CA-MRSA carriage and infection. METHODOLOGY AND PRINCIPAL FINDINGS: We developed diagnostic microbiology capabilities at the Angkor Hospital for Children, Siem Reap, western Cambodia in January 2006 and in the same month identified a child with severe community-acquired impetigo caused by CA-MRSA. A study was undertaken to identify and describe additional cases presenting between January 2006 and December 2007. Bacterial isolates underwent molecular characterization using multilocus sequence typing, staphylococcal cassette chromosome mec (SCCmec) typing, and PCR for the presence of the genes encoding Panton-Valentine Leukocidin (PVL). Seventeen children were identified with CA-MRSA infection, of which 11 had skin and soft tissue infection and 6 had invasive disease. The majority of cases were unrelated in time or place. Molecular characterization identified two independent MRSA clones; fifteen isolates were sequence type (ST) 834, SCCmec type IV, PVL gene-negative, and two isolates were ST 121, SCCmec type V, PVL gene-positive. CONCLUSIONS: This represents the first ever report of MRSA in Cambodia, spread of which would pose a significant threat to public health. The finding that cases were mostly unrelated in time or place suggests that these were sporadic infections in persons who were CA-MRSA carriers or contacts of carriers, rather than arising in the context of an outbreak.