Geoffrey A. Preidis

Probiotics, Enteric and Diarrheal Diseases, and Global Health

Enteric and diarrheal diseases are a major worldwide cause of death among children under the age of 5. In this age group, diarrhea occurs 2.5 billion times per year [1] and causes 15% of childhood deaths.[2] Diarrheal diseases claim 59 million disability-adjusted life years (DALYs), nearly all from children in low- and middle-income countries.[3] Despite this enormous burden, these numbers fail to capture the full impact of enteric and diarrheal diseases. Early and frequent exposure to intestinal pathogens begins a cycle (Figure 1A) that affects digestion, nutrient absorption, growth, and immunity.[4] Repeated infections, with either overt diarrhea or subclinical enteropathy, produce acute and chronic undernutrition,[5] which leads to more frequent and severe infections.[6] Undernutrition contributes to 53% of childhood deaths [7] and is the leading risk factor for poor health outcomes in childhood;[8] survivors are at risk for developmental deficits in growth, fitness, and cognition that persist into adulthood with devastating consequences.[4] These consequences have a multiplicative effect on calculations of DALYs from diarrheal disease.[9] Open in a separate window Figure 1 The vicious cycle of diarrhea and undernutrition in susceptible children (A) The devastating synergy between enteric infections and undernutrition is influenced by the environment, the human genome, host nutrition, and the human microbiome. Various interventions (red boxes) may inhibit progression to the next step in the cycle, minimizing both acute and chronic morbidities. (B) Employing a spectrum of disease outcome measures would lend greater insight into the pathology underlying enteric and diarrheal diseases, while providing a more complete understanding of interventions targeting basic steps of enteric and diarrheal disease pathogenesis. Adapted with permission from Wiley: Nutrition Reviews,4 copyright 2008. http://www.http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1753-4887.

The Tingathe programme: A pilot intervention using community health workers to create a continuum of care in the prevention of mother to child transmission of HIV (PMTCT) cascade of services in Malawi

Loss to follow‐up is a major challenge in the prevention of mother to child transmission of HIV (PMTCT) programme in Malawi with reported loss to follow‐up of greater than 70%. Tingathe‐PMTCT is a pilot intervention that utilizes dedicated community health workers (CHWs) to create a complete continuum of care within the PMTCT cascade, improving service utilization and retention of mothers and infants. We describe the impact of the intervention on longitudinal care starting with diagnosis of the mother at antenatal care (ANC) through final diagnosis of the infant.

Task Shifting Routine Inpatient Pediatric HIV Testing Improves Program Outcomes in Urban Malawi: A Retrospective Observational Study

Background This study evaluated two models of routine HIV testing of hospitalized children in a high HIV-prevalence resource-constrained African setting. Both models incorporated “task shifting,” or the allocation of tasks to the least-costly, capable health worker. Methods and Findings Two models were piloted for three months each within the pediatric department of a referral hospital in Lilongwe, Malawi between January 1 and June 30, 2008. Model 1 utilized lay counselors for HIV testing instead of nurses and clinicians. Model 2 further shifted program flow and advocacy responsibilities from counselors to volunteer parents of HIV-infected children, called “patient escorts.” A retrospective review of data from 6318 hospitalized children offered HIV testing between January-December 2008 was conducted. The pilot quarters of Model 1 and Model 2 were compared, with Model 2 selected to continue after the pilot period. There was a 2-fold increase in patients offered HIV testing with Model 2 compared with Model 1 (43.1% vs 19.9%, p<0.001). Furthermore, patients in Model 2 were younger (17.3 vs 26.7 months, p<0.001) and tested sooner after admission (1.77 vs 2.44 days, p<0.001). There were no differences in test acceptance or enrollment rates into HIV care, and the program trends continued 6 months after the pilot period. Overall, 10244 HIV antibody tests (4779 maternal; 5465 child) and 453 DNA-PCR tests were completed, with 97.8% accepting testing. 19.6% of all mothers (n = 1112) and 8.5% of all children (n = 525) were HIV-infected. Furthermore, 6.5% of children were HIV-exposed (n = 405). Cumulatively, 72.9% (n = 678) of eligible children were evaluated in the hospital by a HIV-trained clinician, and 68.3% (n = 387) successfully enrolled into outpatient HIV care. Conclusions/Significance The strategy presented here, task shifting from lay counselors alone to lay counselors and patient escorts, greatly improved program outcomes while only marginally increasing operational costs. The wider implementation of this strategy could accelerate pediatric HIV care access in high-prevalence settings.

Host Response to Probiotics Determined by Nutritional Status of Rotavirus-infected Neonatal Mice

Objectives: Beneficial microbes and probiotics are promising agents for the prevention and treatment of enteric and diarrheal diseases in children; however, little is known about their in vivo mechanisms of action. We used a neonatal mouse model of rotavirus diarrhea to gain insight into how probiotics ameliorate acute gastroenteritis. Methods: Rotavirus-infected mice were treated with 1 of 2 strains of human-derived Lactobacillus reuteri. We assessed intestinal microbiome composition with 16S metagenomic sequencing, enterocyte migration and proliferation with 5-bromo-2′-deoxyuridine, and antibody and cytokine concentrations with multiplex analyses of intestinal explant cultures. Results: Probiotics reduced diarrhea duration, improved intestinal histopathology, and enhanced intestinal microbiome richness and phylogenetic diversity. The magnitude of reduction of diarrhea by probiotics was strain specific and influenced by nutritional status. L reuteri DSM 17938 reduced diarrhea duration by 0, 1, and 2 days in underweight, normal weight, and overweight pups, respectively. The magnitude of reduction of diarrhea duration correlated with increased enterocyte proliferation and migration. Strain ATCC PTA 6475 reduced diarrhea duration by 1 day in all of the mice without increasing enterocyte proliferation. Both probiotic strains decreased concentrations of proinflammatory cytokines, including macrophage inflammatory protein-1&agr; and interleukin-1&bgr;, in all of the animals, and increased rotavirus-specific antibodies in all but the underweight animals. Body weight also influenced the host response to rotavirus, in terms of diarrhea duration, enterocyte turnover, and antibody production. Conclusions: These data suggest that probiotic enhancement of enterocyte proliferation, villus repopulation, and virus-specific antibodies may contribute to diarrhea resolution, and that nutritional status influences the host response to both beneficial microbes and pathogens.

Implementing the Jadelle implant for women living with HIV in a resource-limited setting: concerns for drug interactions leading to unintended pregnancies.

An analysis of 570 HIV-infected women in Swaziland using the Jadelle implant showed that age, condom use, the provider who placed the implant, and CD4+ cell count had no effect on unintentional pregnancy rates. Antiretroviral regimen at the time of pregnancy, however, correlated with pregnancy outcomes (P <0.001). None of the women on nevirapine or lopinavir/ritonavir-based regimens (n = 208 and 13, respectively) became pregnant, whereas 15 women on efavirenz (n = 121; 12.4%) became pregnant.

If you text them, they will come: using the HIV infant tracking system to improve early infant diagnosis quality and retention in Kenya.

Objective:The objective of this study is to evaluate the impact of the HIV Infant Tracking System (HITSystem) for quality improvement of early infant diagnosis (EID) of HIV services. Design and Setting:This observational pilot study compared 12 months of historical preintervention EID outcomes at one urban and one peri-urban government hospital in Kenya to 12 months of intervention data to assess retention and time throughout the EID cascade of care. Participants:Mother–infant pairs enrolled in EID at participating hospitals before (n = 320) and during (n = 523) the HITSystem pilot were eligible to participate. Intervention:The HITSystem utilizes Internet-based coordination of the multistep PCR cycle, automated alerts to trigger prompt action from providers and laboratory technicians, and text messaging to notify mothers when results are ready or additional action is needed. Main outcome measures:The main outcome measures were retention throughout EID services, meeting time-sensitive targets and improving results turn-around time, and increasing early antiretroviral therapy (ART) initiation among HIV-infected infants. Results:The HITSystem was associated with an increase in the proportion of HIV-exposed infants retained in EID care at 9 months postnatal (45.1–93.0% urban; 43.2–94.1% peri-urban), a decrease in turn-around times between sample collection, PCR results and notification of mothers in both settings, and a significant increase in the proportion of HIV-infected infants started on antiretroviral therapy at each hospital(14 vs. 100% urban; 64 vs. 100% peri-urban). Conclusion:The HITSystem maximizes the use of easily accessible technology to improve the quality and efficiency of EID services in resource-limited settings.

Composition and function of the undernourished neonatal mouse intestinal microbiome

Undernutrition remains one of the key global health challenges facing children today. Distinct microbial profiles have been associated with obesity and undernutrition, although mechanisms behind these associations are unknown. We sought to understand how protein-energy undernutrition alters the microbiome and to propose mechanisms by which these alterations influence the malnourished phenotype. Outbred CD1 neonatal mice were undernourished by timed separation from lactating dams, while control animals nursed ad libitum. 16S rRNA gene sequencing and compositional analysis identified microbes from luminal contents of ileum, cecum and colon, while whole metagenome shotgun sequencing identified microbial gene content. Our results suggest that the most important determinant of microbiome composition is body compartment; communities derived from ileum are distinct from those from cecum and colon as observed by phylogenetic clustering analysis. However, within each compartment, microbiota from undernourished and control mice cluster separately. At the phylum level, undernourished mice harbor more Verrucomicrobia and less Bacteroidetes in the distal intestine; these changes are driven by an increase in Akkermansia muciniphila and decreases in Bacteroides and Alistipes. Undernourished mice have an overall loss of microbial community richness and diversity and are deficient in multiple microbial genetic pathways including N-glycan, inositol phosphate and one-carbon metabolism. Losses in these microbial genes may confer less efficient extraction of energy from nondigestible dietary components including glycans and phytates, whereas epigenetic alterations provide a means of persistently altering metabolism even after adequate nutrition is restored. Thus, the microbiome of an undernourished host may perpetuate states of poor nutrition via multiple mechanisms.

Pneumonia and Malnutrition are Highly Predictive of Mortality among African Children Hospitalized with Human Immunodeficiency Virus Infection or Exposure in the Era of Antiretroviral Therapy

OBJECTIVE To identify clinical characteristics predicting death among inpatients who are infected with or exposed to human immunodeficiency virus (HIV) during a period of pediatric antiretroviral therapy scale-up in sub-Saharan Africa. STUDY DESIGN Retrospective review of medical records from every child with HIV infection (n = 834) or exposure (n = 351) identified by routine inpatient testing in Kamuzu Central Hospital, Lilongwe, Malawi, September 2007 through December 2008. RESULTS The inpatient mortality rate was high among children with HIV infection (16.6%) and exposure (13.4%). Clinically diagnosed Pneumocystis pneumonia or very severe pneumonia independently predicted death in inpatients with HIV infection (OR 14; 95% CI 8.2 to 23) or exposure (OR 21; CI 8.4 to 50). Severe acute malnutrition independently predicted death in children who are HIV infected (OR 2.2; CI 1.7 to 3.9) or exposed (OR 5.1; CI 2.3 to 11). Other independent predictors of death were septicemia, Kaposi sarcoma, meningitis, and esophageal candidiasis for children infected with HIV, and meningitis and severe anemia for inpatients exposed to HIV. CONCLUSIONS Severe respiratory tract infections and malnutrition are both highly prevalent and strongly associated with death among hospitalized children who are HIV infected or exposed. Novel programmatic and therapeutic strategies are urgently needed to reduce the high mortality rate among inpatients with HIV infection and HIV exposure in African pediatric hospitals.

The Newest “Omics”—Metagenomics and Metabolomics—Enter the Battle against the Neglected Tropical Diseases

The international Human Microbiome Project trumpeted the coming of age of the field of metagenomics, the study of entire communities of microbes and their contributions to health and disease. In parallel, the field of metabolomics emerged as the systematic, nonbiased analysis of all low-molecular-weight small molecules, or metabolites, produced by a system in response to an environmental stimulus. These fields have enabled discoveries pertinent to a number of human conditions — namely, acute gastroenteritis, antibiotic-associated diarrhea, inflammatory bowel disease, irritable bowel syndrome, liver disease, undernutrition and obesity — and have begun to shed new light on multiple aspects of the neglected tropical diseases.

Low Rates of Mother-to-Child HIV Transmission in a Routine Programmatic Setting in Lilongwe, Malawi

Background The Tingathe program utilizes community health workers to improve prevention of mother-to-child transmission (PMTCT) service delivery. We evaluated the impact of antiretroviral (ARV) regimen and maternal CD4+ count on HIV transmission within the Tingathe program in Lilongwe, Malawi. Methods We reviewed clinical records of 1088 mother-infant pairs enrolled from March 2009 to March 2011 who completed follow-up to first DNA PCR. Eligibility for antiretroviral treatment (ART) was determined by CD4+ cell count (CD4+) for women not yet on ART. ART-eligible women initiated stavudine-lamivudine-nevirapine. Early ART was defined as ART for ≥14 weeks prior to delivery. For women ineligible for ART, optimal ARV prophylaxis was maternal AZT ≥6 weeks+sdNVP, and infant sdNVP+AZT for 1 week. HIV transmission rates were determined for ARV regimens, and factors associated with vertical transmission were identified using bivariate logistic regression. Results Transmission rate at first PCR was 4.1%. Pairs receiving suboptimal ARV prophylaxis were more likely to transmit HIV (10.3%, 95% CI, 5.5–18.1%). ART was associated with reduced transmission (1.4%, 95% CI, 0.6–3.0%), with early ART associated with decreased transmission (no transmission), compared to all other treatment groups (p = 0.001). No association was detected between transmission and CD4+ categories (p = 0.337), trimester of pregnancy at enrollment (p = 0.100), or maternal age (p = 0.164). Conclusion Low rates of MTCT of HIV are possible in resource-constrained settings under routine programmatic conditions. No transmissions were observed among women on ART for more than 14 weeks prior to delivery.