Rebecca Dillingham

Enteric infections, diarrhea, and their impact on function and development

Enteric infections, with or without overt diarrhea, have profound effects on intestinal absorption, nutrition, and childhood development as well as on global mortality. Oral rehydration therapy has reduced the number of deaths from dehydration caused by infection with an enteric pathogen, but it has not changed the morbidity caused by such infections. This Review focuses on the interactions between enteric pathogens and human genetic determinants that alter intestinal function and inflammation and profoundly impair human health and development. We also discuss specific implications for novel approaches to interventions that are now opened by our rapidly growing molecular understanding.

Cryptosporidiosis: epidemiology and impact.

Cryptosporidium was first recognized in humans in 1976 and came to prominence in the 1980s and 1990s as a cause of severe diarrheal illness in patients with AIDS. Its hardy, chlorine-resistant oocysts, tiny size, low infectious dose, fully infectious development when shed and zoonotic potential make it a threat in drinking and recreational water, contaminated food, day care centers, hospitals, and in persons with exposure to animals or unsanitary conditions, with potentially huge, long-term impact in malnourished children, as reviewed herein.

Cholera, Diarrhea, and Oral Rehydration Therapy: Triumph and Indictment

Cholera drove the sanitary revolution in the industrialized world in the 19th century and now is driving the development of oral rehydration therapy (ORT) in the developing world. Despite the long history of cholera, only in the 1960s and 1970s was ORT fully developed. Scientists described this treatment after the discovery of the intact sodium-glucose intestinal cotransport in patients with cholera. This new understanding sparked clinical studies that revealed the ability of ORT to reduce the mortality associated with acute diarrheal disease. Despite the steady reductions in mortality due to acute dehydrating diarrheal diseases achieved by ORT, the costly morbidity due to these diseases remains, the result of a failure to globalize sanitation and to control the developmental impact of diarrheal diseases and their associated malnutrition. New advances in oral rehydration and nutrition therapy and new methods to recognize its costs are discussed in this review.

Diarrhea and Reduced Levels of Antiretroviral Drugs: Improvement with Glutamine or Alanyl-Glutamine in a Randomized Controlled Trial in Northeast Brazil

The effects of therapy with glutamine and alanyl-glutamine on diarrhea and antiretroviral drug levels in patients with acquired immune deficiency syndrome (AIDS) were examined in a randomized, double-blinded, placebo-controlled study in northeast Brazil. Patients with AIDS and with diarrhea and/or wasting were randomized into 4 groups to determine the efficacy of glutamine or high- or low-dose alanyl-glutamine given for 7 days, compared with isonitrogenous glycine given to control subjects. All patients in whom baseline antiretroviral drug levels were determined had low levels 2 h after dosing. Gastrointestinal symptom scores improved with receipt of high-dose alanyl-glutamine (P<.05) or glutamine (P<.01). Antiretroviral drug levels increased in patients given alanyl-glutamine (P=.02) or glutamine (P=.03) by 113% (P=.02) and 14% (P=.01), respectively. Antiretroviral drug resistance mutations were common in all groups. The dose-related efficacy of alanyl-glutamine and glutamine in treating diarrhea and in increasing antiretroviral drug levels shows that these supplements may help to improve therapy for patients with AIDS who have diarrhea and/or wasting in developing, tropical areas.

CYP2B6 Variants and Plasma Efavirenz Concentrations during Antiretroviral Therapy in Port-au-Prince, Haiti

BACKGROUND Polymorphisms in CYP2B6 are known to predict increased steady-state plasma concentrations of efavirenz. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations among 45 Haitians who initiated antiretroviral therapy in Port-au-Prince. METHODS An observational study characterized relationships between clinical factors, pharmacokinetics, and treatment response among antiretroviral-naive patients initiating once-daily treatment with efavirenz plus twice-daily treatment with zidovudine and lamivudine. Plasma drug concentrations were determined at weeks 2 and 4. Drug doses were directly observed by field workers or designated family members. We retrospectively characterized relationships between efavirenz concentrations and 50 single-nucleotide polymorphisms in CYP2B6 and several polymorphisms in CYP2A6, CYP3A4, CYP3A5, and ABCB1. RESULTS Plasma specimens for efavirenz analysis were obtained from study participants a mean (+/- standard deviation) of 13.9 +/- 1.6 h after they received the dose. As expected, CYP2B6 516G-->T was associated with increased plasma efavirenz concentrations (Spearman rho = 0.71; P < .001), as were 10 polymorphisms in linkage disequilibrium with 516G-->T. Distinct CYP2B6 polymorphisms were associated with decreased plasma efavirenz concentrations (greatest absolute rho = 0.48; P = .001). Associations were replicated by results from a recent pharmacokinetic study involving 34 healthy, human immunodeficiency virus-negative African Americans. CONCLUSIONS Relatively frequent CYP2B6 polymorphisms may predict decreased plasma efavirenz exposure in patients of African descent. If replicated in other cohorts, the implications of these novel associations for treatment response warrant further study.

Development of a personalized bidirectional text messaging tool for HIV adherence assessment and intervention among substance abusers

We describe the development of a two-way text messaging intervention tool for substance users who are non-adherent with HIV medications, and examine message flow data for feasibility and acceptability. The assessment and intervention tool, TxText, is fully automated, sending participants mood, substance use, and medication adherence queries by text message. Participants respond, the tool recognizes the category of response, and sends the personalized intervention message that participants designed in return. In 10months, the tool sent 16,547 messages (half initial, half follow-up) to 31 participants assigned to the TxText condition, who sent 6711 messages in response to the initial messages. Response rates to substance use (n=2370), medication (n=2918) and mood (n=4639) queries were 67, 69, and 64%, respectively. Responses indicating medication adherence, abstinence from substances, and good moods were more common than negative responses. The TxText tool can send messages daily over a 3month period, receive responses, and decode them to deliver personalized affirming or intervention messages. While we await the outcomes of a pilot randomized trial, the process analysis shows that TxText is acceptable and feasible for substance abusers with HIV, and may serve as a complement to HIV medical care.

Ceramic water filters impregnated with silver nanoparticles as a point-of-use water-treatment intervention for HIV-positive individuals in Limpopo Province, South Africa: a pilot study of technological performance and human health benefits.

Waterborne pathogens present a significant threat to people living with the human immunodeficiency virus (PLWH). This study presents a randomized, controlled trial that evaluates whether a household-level ceramic water filter (CWF) intervention can improve drinking water quality and decrease days of diarrhea in PLWH in rural South Africa. Seventy-four participants were randomized in an intervention group with CWFs and a control group without filters. Participants in the CWF arm received CWFs impregnated with silver nanoparticles and associated safe-storage containers. Water and stool samples were collected at baseline and 12 months. Diarrhea incidence was self-reported weekly for 12 months. The average diarrhea rate in the control group was 0.064 days/week compared to 0.015 days/week in the intervention group (p < 0.001, Mann-Whitney). Median reduction of total coliform bacteria was 100% at enrollment and final collection. CWFs are an acceptable technology that can significantly improve the quality of household water and decrease days of diarrhea for PLWH in rural South Africa.

Planning for climate change: The need for mechanistic systems-based approaches to study climate change impacts on diarrheal diseases

Increased precipitation and temperature variability as well as extreme events related to climate change are predicted to affect the availability and quality of water globally. Already heavily burdened with diarrheal diseases due to poor access to water, sanitation and hygiene facilities, communities throughout the developing world lack the adaptive capacity to sufficiently respond to the additional adversity caused by climate change. Studies suggest that diarrhea rates are positively correlated with increased temperature, and show a complex relationship with precipitation. Although climate change will likely increase rates of diarrheal diseases on average, there is a poor mechanistic understanding of the underlying disease transmission processes and substantial uncertainty surrounding current estimates. This makes it difficult to recommend appropriate adaptation strategies. We review the relevant climate-related mechanisms behind transmission of diarrheal disease pathogens and argue that systems-based mechanistic approaches incorporating human, engineered and environmental components are urgently needed. We then review successful systems-based approaches used in other environmental health fields and detail one modeling framework to predict climate change impacts on diarrheal diseases and design adaptation strategies.

Pilot RCT of bidirectional text messaging for ART adherence among nonurban substance users with HIV.

OBJECTIVE This pilot study tested the preliminary efficacy of a theory-based bidirectional text messaging intervention (TEXT) on antiretroviral (ART) adherence, missed care visits, and substance use among people with HIV. METHOD Participants with recent substance use and ART nonadherence from 2 nonurban HIV clinics were randomized to TEXT or to usual care (UC). The TEXT intervention included daily queries of ART adherence, mood, and substance use. The system sent contingent intervention messages created by participants for reports of adherence/nonadherence, good mood/poor mood, and no substance use/use. Assessments were at preintervention, postintervention, and 3-month postintervention follow-up. Objective primary outcomes were adherence, measured by past 3-month pharmacy refill rate, and proportion of missed visits (PMV), measured by medical records. The rate of substance-using days from the timeline follow-back was a secondary outcome. RESULTS Sixty-three patients participated, with 33 randomized to TEXT and 30 to UC. At preintervention, adherence was 64.0%, PMV was 26.9%, and proportion of days using substances was 53.0%. At postintervention, adherence in the TEXT condition improved from 66% to 85%, compared with 62% to 71% in UC participants (p = .04). PMV improved from 23% to 9% for TEXT participants and 31% to 28% in UC participants (p = .12). There were no significant differences between conditions in substance-using days at postintervention. At 3-month follow-up, differences were not significant. CONCLUSIONS Personalized bidirectional text messaging improved adherence and shows promise to improve visit attendance, but did not reduce substance using days. This intervention merits further testing and may be cost-efficient given its automation.

Modeling the sustainability of a ceramic water filter intervention

Ceramic water filters (CWFs) are a point-of-use water treatment technology that has shown promise in preventing early childhood diarrhea (ECD) in resource-limited settings. Despite this promise, some researchers have questioned their ability to reduce ECD incidences over the long term since most effectiveness trials conducted to date are less than one year in duration limiting their ability to assess long-term sustainability factors. Most trials also suffer from lack of blinding making them potentially biased. This study uses an agent-based model (ABM) to explore factors related to the long-term sustainability of CWFs in preventing ECD and was based on a three year longitudinal field study. Factors such as filter user compliance, microbial removal effectiveness, filter cleaning and compliance declines were explored. Modeled results indicate that broadly defined human behaviors like compliance and declining microbial effectiveness due to improper maintenance are primary drivers of the outcome metrics of household drinking water quality and ECD rates. The model predicts that a ceramic filter intervention can reduce ECD incidence amongst under two year old children by 41.3%. However, after three years, the average filter is almost entirely ineffective at reducing ECD incidence due to declining filter microbial removal effectiveness resulting from improper maintenance. The model predicts very low ECD rates are possible if compliance rates are 80-90%, filter log reduction efficiency is 3 or greater and there are minimal long-term compliance declines. Cleaning filters at least once every 4 months makes it more likely to achieve very low ECD rates as does the availability of replacement filters for purchase. These results help to understand the heterogeneity seen in previous intervention-control trials and reemphasize the need for researchers to accurately measure confounding variables and ensure that field trials are at least 2-3 years in duration. In summary, the CWF can be a highly effective tool in the fight against ECD, but every effort should be made by implementing agencies to ensure consistent use and maintenance.