Lactoferrin and Lysozyme Supplementation for Long-term Diarrhea Sequelae

Current diarrhea management strategies in low- and middle-income countries (oral rehydration solution, ReSoMal and zinc) focus primarily on the management of dehydration and micronutrient replacement and appear to have negligible impact in preventing future diarrheal episodes or improving nutritional outcomes. Lactoferrin and lysozyme are milk-derived nutritional supplements that may reduce the risk of diarrheal episodes and accelerate nutritional recovery by treating or preventing underlying enteric infections and/or improving enteric function. Children with moderate or severe wasting are at particularly high-risk of death, diarrhea recurrence, and nutritional deterioration following a diarrheal episode. This factorial, double-blind, placebo-controlled, randomized trial aims to determine the efficacy of lactoferrin and lysozyme supplementation in decreasing diarrhea incidence and improving nutritional recovery in children convalescing from diarrhea and wasting. We will explore whether these interventions improve outcomes by reducing enteric pathogens, improving enteric function and/or increasing hemoglobin concentrations in these children. This study aims to enroll 600 Kenyan children aged 6-24 months from facilities in Western Kenya. Enrolled children will be randomized to 16-weeks of lactoferrin, lysozyme, a combination of the two, or placebo and be followed up for 24 weeks total, with bi-weekly home visits by community health workers and clinic visits at 4, 10, 16, and 24 weeks. Results of this study will inform management strategies for children with moderate/severe wasting at high risk for mortality, morbidity, and nutritional deterioration following diarrhea.

Aim 1: To determine whether a 16-week course of lactoferrin, lysozyme or a combination of both shortens time to WHO-defined recovery from wasting (MUAC ≥12.5cm) and reduces the incidence of moderate-to-severe diarrhea during the subsequent 6-months following presentation to a health facility with diarrhea among children with moderate/severe childhood wasting (MUAC <12.5 cm at the time of screening).

Hypothesis: Children randomized to lactoferrin, lysozyme, or the combination of both will experience a lower incidence of moderate-to-severe diarrhea and an earlier recovery from wasting (increased MUAC) over the subsequent 6-months than placebo-treated children. Combination therapy will provide synergistic benefit in reducing diarrhea and improving nutritional recovery.

Aim 2: To explore whether a 16-week course of lactoferrin, lysozyme or combination therapy improves secondary clinical, nutritional, enteric pathogen, and enteric function outcomes.

Hypothesis: Children randomized to lactoferrin, lysozyme, or the combination will experience fewer hospitalizations and deaths, improved linear growth, a reduced prevalence of specific enteric bacteria associated with linear growth failure (Campylobacter, LT-ETEC, EAEC, typical EPEC and/or Shigella), improved markers of enteric dysfunction (myeloperoxidase, alpha antitrypsin, neopterin, and the lactulose:rhamnose ratio) and improved hemoglobin, as compared to placebo-treated children.

Aim 3: To evaluate acceptability, adherence and cost-effectiveness of lactoferrin and/or lysozyme in Kenya.

Hypothesis: Both therapies will be highly acceptable to caregivers and health workers. Adherence to the therapies will be high among participants (≥ 95%). Lactoferrin and lysozyme, alone and in combination, will be more cost-effective interventions for reducing moderate-to-severe diarrhea in the short-term as compared to the standard-of-care.

Inclusion criteria

• Age 6-24 months
• Managed as an outpatient or inpatient for diarrhea at one of the recruiting sites
• MUAC <12.5 cm at the time of screening
• Plan to stay within the study area for the next 6 months or greater

Exclusion criteria

• Age younger than 6 months or older than 24 months
• Caregiver does not provide consent to study participation
• History of 2 or more blood transfusions in the past 12 months
• Exclusively breastfeeding at the time of enrollment
• History of congenital defect or syndrome that prevents age-appropriate feeding (e.g. cleft palate)
• History of allergy to dairy products
• Child is not ready to return home (is not yet discharged), or discharged against medical advice
• Unwilling to participate in the dual sugar permeability sub-study if selected
• Enrollment in another study