Eric D. Mintz

Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study

BACKGROUND Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries. We designed the Global Enteric Multicenter Study (GEMS) to identify the aetiology and population-based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia. METHODS The GEMS is a 3-year, prospective, age-stratified, matched case-control study of moderate-to-severe diarrhoea in children aged 0-59 months residing in censused populations at four sites in Africa and three in Asia. We recruited children with moderate-to-severe diarrhoea seeking care at health centres along with one to three randomly selected matched community control children without diarrhoea. From patients with moderate-to-severe diarrhoea and controls, we obtained clinical and epidemiological data, anthropometric measurements, and a faecal sample to identify enteropathogens at enrolment; one follow-up home visit was made about 60 days later to ascertain vital status, clinical outcome, and interval growth. FINDINGS We enrolled 9439 children with moderate-to-severe diarrhoea and 13,129 control children without diarrhoea. By analysing adjusted population attributable fractions, most attributable cases of moderate-to-severe diarrhoea were due to four pathogens: rotavirus, Cryptosporidium, enterotoxigenic Escherichia coli producing heat-stable toxin (ST-ETEC; with or without co-expression of heat-labile enterotoxin), and Shigella. Other pathogens were important in selected sites (eg, Aeromonas, Vibrio cholerae O1, Campylobacter jejuni). Odds of dying during follow-up were 8·5-fold higher in patients with moderate-to-severe diarrhoea than in controls (odd ratio 8·5, 95% CI 5·8-12·5, p<0·0001); most deaths (167 [87·9%]) occurred during the first 2 years of life. Pathogens associated with increased risk of case death were ST-ETEC (hazard ratio [HR] 1·9; 0·99-3·5) and typical enteropathogenic E coli (HR 2·6; 1·6-4·1) in infants aged 0-11 months, and Cryptosporidium (HR 2·3; 1·3-4·3) in toddlers aged 12-23 months. INTERPRETATION Interventions targeting five pathogens (rotavirus, Shigella, ST-ETEC, Cryptosporidium, typical enteropathogenic E coli) can substantially reduce the burden of moderate-to-severe diarrhoea. New methods and accelerated implementation of existing interventions (rotavirus vaccine and zinc) are needed to prevent disease and improve outcomes. FUNDING The Bill & Melinda Gates Foundation.

Global Trends in Typhoid and Paratyphoid Fever

Typhoid and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in south-central and Southeast Asia, where enteric fever is associated with poor sanitation and unsafe food and water. High-quality incidence data from Asia are underpinning efforts to expand access to typhoid vaccines. Efforts are underway to develop vaccines that are immunogenic in infants after a single dose and that can be produced locally in countries of endemicity. The growing importance of Salmonella enterica serotype Paratyphi A in Asia is concerning. Antimicrobial resistance has sequentially emerged to traditional first-line drugs, fluoroquinolones, and third-generation cephalosporins, posing patient treatment challenges. Azithromycin has proven to be an effective alternative for treatment of uncomplicated typhoid fever. The availability of full genome sequences for S. enterica serotype Typhi and S. enterica serotype Paratyphi A confirms their place as monomorphic, human-adapted pathogens vulnerable to control measures if international efforts can be redoubled.

Not Just a Drop in the Bucket: Expanding Access to Point-of-Use Water Treatment Systems

Since 1990, the number of people without access to safe water sources has remained constant at approximately 1.1 billion, of whom approximately 2.2 million die of waterborne disease each year. In developing countries, population growth and migrations strain existing water and sanitary infrastructure and complicate planning and construction of new infrastructure. Providing safe water for all is a long-term goal; however, relying only on time- and resource-intensive centralized solutions such as piped, treated water will leave hundreds of millions of people without safe water far into the future. Self-sustaining, decentralized approaches to making drinking water safe, including point-of-use chemical and solar disinfection, safe water storage, and behavioral change, have been widely field-tested. These options target the most affected, enhance health, contribute to development and productivity, and merit far greater priority for rapid implementation.

A Massive Epidemic of Multidrug-Resistant Typhoid Fever in Tajikistan Associated with Consumption of Municipal Water

From 1 January through 30 June 1997, 8901 cases of typhoid fever and 95 associated deaths were reported in Dushanbe, Tajikistan. Of 29 Salmonella serotype Typhi isolates tested, 27 (93%) were resistant to ampicillin, chloramphenicol, nalidixic acid, streptomycin, sulfisoxazole, tetracycline, and trimethoprim-sulfamethoxazole. In a case-control study of 45 patients and 123 controls, Salmonella Typhi infection was associated with drinking unboiled water (matched odds ratio, 7; 95% confidence interval, 3-24; P<.001). Of tap water samples, 97% showed fecal coliform contamination (mean level, 175 cfu/100 mL). Samples taken from water treatment plants revealed that fecal coliform contamination occurred both before and after treatment. Lack of chlorination, equipment failure, and back-siphonage in the water distribution system led to contamination of drinking water. After chlorination and coagulation were begun at the treatment plants and a water conservation campaign was initiated to improve water pressure, the incidence of typhoid fever declined dramatically.

The Global Enteric Multicenter Study (GEMS) of Diarrheal Disease in Infants and Young Children in Developing Countries: Epidemiologic and Clinical Methods of the Case/Control Study

Background. Diarrhea is a leading cause of illness and death among children aged <5 years in developing countries. This paper describes the clinical and epidemiological methods used to conduct the Global Enteric Multicenter Study (GEMS), a 3-year, prospective, age-stratified, case/control study to estimate the population-based burden, microbiologic etiology, and adverse clinical consequences of acute moderate-to-severe diarrhea (MSD) among a censused population of children aged 0–59 months seeking care at health centers in sub-Saharan Africa and South Asia. Methods. GEMS was conducted at 7 field sites, each serving a population whose demography and healthcare utilization practices for childhood diarrhea were documented. We aimed to enroll 220 MSD cases per year from selected health centers serving each site in each of 3 age strata (0–11, 12–23, and 24–59 months), along with 1–3 matched community controls. Cases and controls supplied clinical, epidemiologic, and anthropometric data at enrollment and again approximately 60 days later, and provided enrollment stool specimens for identification and characterization of potential diarrheal pathogens. Verbal autopsy was performed if a child died. Analytic strategies will calculate the fraction of MSD attributable to each pathogen and the incidence, financial costs, nutritional consequences, and case fatality overall and by pathogen. Conclusions. When completed, GEMS will provide estimates of the incidence, etiology, and outcomes of MSD among infants and young children in sub-Saharan Africa and South Asia. This information can guide development and implementation of public health interventions to diminish morbidity and mortality from diarrheal diseases.

Epidemic cholera in Ecuador: multidrug–resistance and transmission by water and seafood

To determine risk factors for cholera in an epidemic-disease area in South America, a case-control investigation was performed in Guayaquil, Ecuador, in July 1991. Residents > 5 years old who were hospitalized for treatment of acute, watery diarrhoea and two matched controls for each were interviewed regarding sources of water and food, and eating, drinking, and hygienic habits. Interviewers inspected homes of case-patients and controls to document water treatment, food-handling, and hygienic practices. Faecal specimens and shellfish were cultured for Vibrio cholerae O 1. Isolates were tested for susceptibility to a variety of antimicrobial agents. Drinking unboiled water (odds ratio [OR] = 4.0, confidence interval [CI] = 1.8-7.5), drinking a beverage from a street vendor (OR = 2.8, CI = 1.3-5.9), eating raw seafood (OR = 3.4, CI = 1.4-11.5), and eating cooked crab (OR = 5.1, CI = 1.4-19.2) were associated with illness. Always boiling drinking water at home (OR = 0.5, CI = 0.2-0.9) was protective against illness. The presence of soap in either the kitchen (OR = 0.3, CI = 0.2-0.8) or bathroom (OR = 0.4, CI = 0.2-0.9) at home was also protective. V. cholerae O 1 was recovered from a pooled sample of a bivalve mollusc and from 68% of stool samples from case-patients. Thirty-six percent of the isolates from stool specimens were resistant to multiple antimicrobial agents. Specific prevention measures may prevent transmission through these vehicles in the future. The appearance of antimicrobial resistance suggests the need for changes in current methods of prevention and treatment.

Typhoid fever in the United States, 1999-2006.

CONTEXT Typhoid fever in the United States has increasingly been due to infection with antimicrobial-resistant Salmonella ser Typhi. National surveillance for typhoid fever can inform prevention and treatment recommendations. OBJECTIVE To assess trends in infections with antimicrobial-resistant S. Typhi. DESIGN Cross-sectional, laboratory-based surveillance study. SETTING AND PARTICIPANTS We reviewed data from 1999-2006 for 1902 persons with typhoid fever who had epidemiologic information submitted to the Centers for Disease Control and Prevention (CDC) and 2016 S. Typhi isolates sent by participating public health laboratories to the National Antimicrobial Resistance Monitoring System Laboratory at the CDC for antimicrobial susceptibility testing. MAIN OUTCOME MEASURES Proportion of S. Typhi isolates demonstrating resistance to 14 antimicrobial agents and patient risk factors for antimicrobial-resistant infections. RESULTS Patient median age was 22 years (range, <1-90 years); 1295 (73%) were hospitalized and 3 (0.2%) died. Foreign travel within 30 days of illness was reported by 1439 (79%). Only 58 travelers (5%) had received typhoid vaccine. Two hundred seventy-two (13%) of 2016 isolates tested were resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole (multidrug-resistant S. Typhi [MDRST]); 758 (38%) were resistant to nalidixic acid (nalidixic acid-resistant S. Typhi [NARST]) and 734 NARST isolates (97%) had decreased susceptibility to ciprofloxacin. The proportion of NARST increased from 19% in 1999 to 54% in 2006. Five ciprofloxacin-resistant isolates were identified. Patients with resistant infections were more likely to report travel to the Indian subcontinent: 85% of patients infected with MDRST and 94% with NARST traveled to the Indian subcontinent, while 44% of those with susceptible infections did (MDRST odds ratio, 7.5; 95% confidence interval, 4.1-13.8; NARST odds ratio, 20.4; 95% confidence interval, 12.4-33.9). CONCLUSION Infection with antimicrobial-resistant S. Typhi strains among US patients with typhoid fever is associated with travel to the Indian subcontinent, and an increasing proportion of these infections are due to S. Typhi strains with decreased susceptibility to fluoroquinolones.

Cholera Surveillance during the Haiti Epidemic — The First 2 Years

BACKGROUND In October 2010, nearly 10 months after a devastating earthquake, Haiti was stricken by epidemic cholera. Within days after detection, the Ministry of Public Health and Population established a National Cholera Surveillance System (NCSS). METHODS The NCSS used a modified World Health Organization case definition for cholera that included acute watery diarrhea, with or without vomiting, in persons of all ages residing in an area in which at least one case of Vibrio cholerae O1 infection had been confirmed by culture. RESULTS Within 29 days after the first report, cases of V. cholerae O1 (serotype Ogawa, biotype El Tor) were confirmed in all 10 administrative departments (similar to states or provinces) in Haiti. Through October 20, 2012, the public health ministry reported 604,634 cases of infection, 329,697 hospitalizations, and 7436 deaths from cholera and isolated V. cholerae O1 from 1675 of 2703 stool specimens tested (62.0%). The cumulative attack rate was 5.1% at the end of the first year and 6.1% at the end of the second year. The cumulative case fatality rate consistently trended downward, reaching 1.2% at the close of year 2, with departmental cumulative rates ranging from 0.6% to 4.6% (median, 1.4%). Within 3 months after the start of the epidemic, the rolling 14-day case fatality rate was 1.0% and remained at or below this level with few, brief exceptions. Overall, the cholera epidemic in Haiti accounted for 57% of all cholera cases and 53% of all cholera deaths reported to the World Health Organization in 2010 and 58% of all cholera cases and 37% of all cholera deaths in 2011. CONCLUSIONS A review of NCSS data shows that during the first 2 years of the cholera epidemic in Haiti, the cumulative attack rate was 6.1%, with cases reported in all 10 departments. Within 3 months after the first case was reported, there was a downward trend in mortality, with a 14-day case fatality rate of 1.0% or less in most areas.

A Waterborne Outbreak of Gastroenteritis with Multiple Etiologies among Resort Island Visitors and Residents: Ohio, 2004

BACKGROUND The implementation of treated municipal water systems in the 20th century led to a dramatic decrease in waterborne disease in the United States. However, communities with deficient water systems still experience waterborne outbreaks. In August 2004, we investigated an outbreak of gastroenteritis on South Bass Island, Ohio, an island of 900 residents that is visited by >500,000 persons each year. METHODS To identify the source of illness, we conducted a case-control study and an environmental investigation. A case was defined as diarrhea in a person who traveled to the island during the period from May 1 through 30 September 2004 and became ill within 2 weeks after the visit. Healthy travel companions served as matched control subjects. We also performed an environmental assessment and extensive testing of island water sources. RESULTS Among the 1450 persons reporting illness, Campylobacter jejuni, norovirus, Giardia intestinalis, and Salmonella enterica serotype Typhimurium were identified in 16, 9, 3, and 1 persons, respectively. We interviewed 100 case patients and 117 matched control subjects. Case patients were more likely to drink water on the island than control subjects (68% vs. 35%; matched odds ratio, 4.3; 95% confidence interval, 2.2-9.3). Sampling of ground water wells indicated contamination with multiple fecal microbes, including Escherichia coli, C. jejuni, Salmonella species, and Giardia species. Irregularities in sewage disposal practices that could have contaminated the underground aquifer were noted. CONCLUSIONS The combined epidemiological and environmental investigation indicated that sewage-contaminated ground water was the likely source of this large outbreak. Long-term changes to the islands water supply and sewage management infrastructure are needed.

Evaluation of Rapid Diagnostic Tests for Typhoid Fever

ABSTRACT Laboratory diagnosis of typhoid fever requires isolation and identification of Salmonella enterica serotype Typhi. In many areas where this disease is endemic, laboratory capability is limited. Recent advances in molecular immunology have led to the identification of sensitive and specific markers for typhoid fever and technology to manufacture practical and inexpensive kits for their rapid detection. We evaluated three commercial kits for serologic diagnosis of typhoid fever. Patients presenting with ≥ 4 days of fever were enrolled at two hospitals in Southern Vietnam. Cases were patients with serotype Typhi isolated from blood samples, and controls were patients with other laboratory-confirmed illnesses. Serotype Typhi isolates were confirmed and tested for antimicrobial susceptibility at the Pasteur Institute in Ho Chi Minh City. The Widal test was run at the hospitals and the Pasteur Institute. Sera were shipped frozen to the Centers for Disease Control and Prevention and tested by using Multi-Test Dip-S-Ticks, TyphiDot, and TUBEX to detect immunoglobulin G (IgG), IgG and IgM, and IgM, respectively. Package insert protocol instructions were followed. We enrolled 59 patients and 21 controls. The sensitivity and specificity findings were as follows: 89 and 53% for Multi-Test Dip-S-Ticks, 79 and 89% for TyphiDot, 78 and 89% for TUBEX, and 64 and 76% for Widal testing in hospitals and 61% and 100% for Widal testing at the Pasteur Institute. For all assays, the sensitivity was highest in the second week of illness. The Widal test was insensitive and displayed interoperator variability. Two rapid kits, TyphiDot and TUBEX, demonstrated promising results.