Supplementation With Lactoferrin and Lysozyme Ameliorates Environmental Enteric Dysfunction: A Double-Blind, Randomized, Placebo-Controlled Trial.

INTRODUCTION: Environmental enteric dysfunction (EED) predisposes children throughout the developing world to high rates of systemic exposure to enteric pathogens and stunting. Effective interventions that treat or prevent EED may help children achieve their full physical and cognitive potential. The objective of this study is to test whether 2 components of breast milk would improve a biomarker of EED and linear growth during the second year of life. METHODS: A prospective, randomized, double-blind, placebo-controlled clinical trial among children aged 12-23 months was conducted in rural Malawi. The experimental group received a daily supplement of 1.5 g of lactoferrin and 0.2 g of lysozyme for 16 weeks. The primary outcome was an improvement in EED, as measured by the change in the percentage of ingested lactulose excreted into the urine (Δ%L). RESULTS: Among 214 children who completed the study, there was a significant difference in Δ%L between the control and experimental groups over 8 weeks (an increase of 0.23% vs 0.14%, respectively; P = 0.04). However, this relative improvement was not as strongly sustained over the full 16 weeks of the study (an increase of 0.16% vs 0.11%, respectively; P = 0.17). No difference in linear growth over this short period was observed. The experimental intervention group had significantly lower rates of hospitalization and the development of acute malnutrition during the course of the study (2.5% vs 10.3%, relative risk 0.25; P < 0.02). DISCUSSION: Supplementation with lactoferrin and lysozyme in a population of agrarian children during the second year of life has a beneficial effect on gut health. This intervention also protected against hospitalization and the development of acute malnutrition, a finding with a significant clinical and public health importance. This finding should be pursued in larger studies with longer follow-up and optimized dosing.

Lactoferrin and lysozyme to reduce environmental enteric dysfunction and stunting in Malawian children: study protocol for a randomized controlled trial.

BACKGROUND: Chronic childhood malnutrition, as manifested by stunted linear growth, remains a persistent barrier to optimal child growth and societal development. Environmental enteric dysfunction (EED) is a significant underlying factor in the causal pathway to stunting, delayed cognitive development, and ultimately morbidity and mortality. Effective therapies against EED and stunting are lacking and further clinical trials are warranted to effectively identify and operationalize interventions. METHODS/DESIGN: A prospective randomized placebo-controlled parallel-group randomized controlled trial will be conducted to determine if a daily supplement of lactoferrin and lysozyme, two important proteins found in breast milk, can decrease the burden of EED and stunting in rural Malawian children aged 12-23 months old. The intervention and control groups will have a sample size of 86 subjects each. All field and laboratory researchers will be blinded to the assigned intervention group, as will the subjects and their caregivers. The percentage of ingested lactulose excreted in the urine (Δ%L) after 4 h will be used as the biomarker for EED and linear growth as the measure of chronic malnutrition (stunting). The primary outcomes of interest will be change in Δ%L from baseline to 8 weeks and to 16 weeks. Intention-to-treat analyses will be used. DISCUSSION: A rigorous clinical trial design will be used to assess the biologically plausible use of lactoferrin and lysozyme as dietary supplements for children at high risk for EED. If proven effective, these safe proteins may serve to markedly reduce the burden of childhood malnutrition and improve survival. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02925026 . Registered on 4 October 2016.

Chronic infections of the small intestine.

PURPOSE OF REVIEW: Chronic infections of the small intestine cause significant morbidity and mortality globally. This review focuses on the recent advances in the field of our understanding of selected intestinal infections. RECENT FINDINGS: Primary and secondary immunodeficiency increase the susceptibility to many chronic intestinal infections. Endoscopy and intestinal biopsies are central to establishing a diagnosis of these conditions. Tuberculosis (TB) remains a major global health challenge. Emerging therapeutic agents to counteract multidrug-resistant strains have shown clinical efficacy, but concerns regarding mortality remain. PCR-based diagnostic TB tests have the potential to reduce diagnostic delays, but remain to be validated for intestinal infections. Adjunctive diagnostic imaging modalities can differentiate infections from Crohn's disease with increasing accuracy. Whipple's disease remains rare, but there have been substantial advances in our understanding of the causative organism Tropheryma whipplei. Extended treatment with broad-spectrum antibiotics is effective in most cases. The narrow therapeutic window and limited armamentarium for treating invasive filamentous fungal infections contribute to their significant morbidity and high rates of mortality. SUMMARY: The speed and accuracy of diagnosing chronic intestinal infections have improved with recent imaging and laboratory methodologies. Significant research opportunities remain for clinicians and scientists to improve the diagnostic accuracy and clinical outcomes of chronic intestinal infections.

Tropical sprue in 2014: the new face of an old disease.

Tropical sprue (TS), once known to be a common cause of malabsorption syndrome (MAS) in India and other tropical countries, is believed to be uncommon currently in spite of contrary evidence. Several recent studies from India showed TS to be the commonest cause of sporadic MAS in Indian adults. TS is diagnosed in patients presenting with suggestive clinical presentation, which cannot be explained by another cause of MAS and investigations revealing malabsorption of two unrelated substances, abnormal small-intestinal mucosal histology, which responds to treatment with antibiotics such as tetracycline and folic acid. There is substantial overlap between TS and postinfectious irritable bowel syndrome. There have been several advances in epidemiology, pathogenesis, and diagnosis of TS, hitherto an enigmatic condition.

[Tropical sprue as a differential diagnosis to coeliac disease in a patient on immunosuppressive medication]. / Tropisk sprue som differentialdiagnose til cøliaki hos patient i immunsupprimerende behandling.

A Danish woman who was on immunosuppressive medication due to a previous liver transplantation travelled to Indonesia for three weeks. After returning she developed nonfebrile severe, watery diarrhoea, dehydration and malnutrition. A thorough examination revealed small intestine changes, which were compatible with coeliac disease. However, the HLA-type and the serology did not support this diagnosis. Treatment for tropical sprue was initiated, resulting in complete remission. Tropical sprue is suggested to be an infectious disease. It is usually seen in people with prolonged stay in tropical areas, but this patient's medication may have predisposed her.

Pathogenesis of tropical sprue: a pilot study of antroduodenal manometry, duodenocaecal transit time & fat-induced ileal brake.

BACKGROUND & OBJECTIVES: Small intestinal bacterial overgrowth (SIBO) due to ileal brake-induced hypomotility may cause tropical sprue (TS). We evaluated effect of infusion of fat or placebo in duodenum randomly in patients with TS and healthy controls on antroduodenal manometry (ADM) and mediators of ileal brake, and duodenocaecal transit time (DCTT). METHODS: ADM and DCTT (lactulose hydrogen breath test, HBT) were evaluated with placebo and fat in eight controls and 13 patients with TS (diagnostic criteria: tests showing malabsorption of two unrelated substances, abnormal duodenal histology, absence of other causes, response to antibiotics and folate). RESULTS: Patients with TS (6 had SIBO by glucose HBT) were similar in age and gender with controls. After fat infusion, proximal gut motility index (MI) was reduced compared to fasting state in TS, and DCTT was longer in TS than controls (200 min, 120-380 vs. 130, 70-160, P=0.001), though comparable after placebo (70 min, 30-140 vs. 60, 40-90). TS patients had higher PYY and neurotensin than controls after fat infusion. DCTT after fat infusion correlated with plasma level of PYY in TS but not in controls. Post-fat PYY and neurotensin levels were higher in TS with lower BMI (<16 kg/m [2] ) than those with higher BMI. Parameters of ileal brake (post-fat DCTT, PYY and neurotensin) were higher in patients with than without SIBO. INTERPRETATION & CONCLUSIONS: Fat infusion reduced proximal gut MI, increased DCTT, PYY, and neurotensin among patients with TS. Malabsorbed fat might cause exaggerated ileal brake reducing gut motility, promoting SIBO and bacterial colonization and malabsorption in TS.

[Tropical sprue in an expatriate]. / Sprue tropicale chez un expatrié.

INTRODUCTION: Tropical sprue is a postinfective malabsorption syndrome that occurs in some tropical endemic areas. CASE REPORT: A 65-year-old Caucasian patient, with no significant past medical history, living in Cambodia for 10 years, presented with a 23 kg weight loss and chronic diarrhea. Clinical examination was unremarkable. Laboratory tests showed a moderate nutritional deficiency syndrome. The upper gastrointestinal endoscopy showed duodenal villous atrophy and histological analysis confirmed subtotal villous atrophy with important intraepithelial lymphocytosis. The diagnosis of tropical sprue was considered on the epidemiological, clinical and biological context, and the absence of other cause of villous atrophy. A three-month duration treatment with antibiotics, folic acid and vitamin B12 was initiated. The clinical course was favorable with disappearance of diarrhea in 15 days. One year later, the patient had resumed his usual weight, and laboratory tests and duodenal biopsies were normal. CONCLUSION: The diagnosis of tropical sprue should be systematically discussed in any malabsorption syndrome with villous atrophy in a patient living or having lived in the tropics.

Abnormal small intestinal permeability in patients with idiopathic malabsorption in tropics (tropical sprue) does not change even after successful treatment.

BACKGROUND: Though tropical sprue (TS) is common in tropics, studies on small intestinal permeability (SIP) in TS are scant. METHOD: SIP was evaluated using (1)H nuclear magnetic resonance (NMR) spectroscopy of urinary lactulose and mannitol in 24 patients with TS (22 before and 15 after treatment with tetracycline and folate) and in 31 healthy subjects (HS). Effect of treatment of TS on SIP and its relationship with outcome were studied. RESULT: Subjects were comparable in terms of age and gender. Before treatment, urinary lactulose (0.24 mmol, 0-1.09 mmol versus 0.09 mmol, 0-0.68 mmol, P=0.02) and lactulose-to-mannitol (L/M) ratio (0.11, 0-0.41 versus 0.042, 0-0.26, P=0.001) were higher in TS than in HS, though mannitol was comparable (2.7 mmol, 0.61-10.5 mmol versus 3.8 mmol, 1.3-16.4 mmol, P=0.08). Patients improved after treatment [stool frequency (9, 4-20/day versus 1, 1-2/day, P<0.0001), weight (44.4, 32-69 kg, versus 56, 39-84 kg, P<0.0001), fecal fat (10.1, 6-26 g/24 h versus 4.4, 3.0-6.7 g/24 h, P<0.0001), D-xylose (0.57, 0.28-1.2 g/5 g/5 h versus 1.1, 0.2-2.1 g/5 g/5 h, P<0.0001), and small intestinal bacterial overgrowth (SIBO) resolved in 10/24 (41.7%) versus 1/15 (6.6%), P=0.02]. Though urinary lactulose (0.17, 0-4.3 mmol versus 0.09, 0-0.68 mmol, P=0.11) and mannitol (2.17, 0.8-36.7 mmol versus 3.84, 1.3-16.4 mmol, P=0.06) were comparable, L/M ratio was higher in TS than in HS (0.09, 0-0.22 versus 0.042, 0-0.26, P=0.002). L/M ratio was more often abnormal (cutoff 0.078) in TS than in HS [14/22 (63.6%) versus 3/31 (9.7%); P=0.0001], which persisted even after treatment [9/15 (60%) as compared with HS; P=0.0006]. Persistently abnormal SIP was associated with less weight gain and frequent stools following treatment. CONCLUSION: SIP is often abnormal in TS and remains unchanged even after successful treatment that was associated with less weight gain and more frequent stool.

[Tropical sprue]. / Sprue tropicale.

Tropical sprue associates prolonged diarrhea, a malabsorption syndrome, and nutritional deficiency in patients who live in or have visited tropical areas. Pathogenesis is still unknown but an infectious cause is suspected. Macrocytic anemia and hypoalbuminemia are present, together with progressive villus atrophy of the small intestine. Treatment with tetracycline, folic acid and proper nutritional support generally results in full recovery.

Tropical sprue in two foreign residents, with evidence of Tropheryma whippelii in one case.

Tropical sprue is a rare disease in travelers. Its etiology remains unclear. We report two cases of tropical sprue occurring in long-term residents in Nepal and Cameroon. In one case, Tropheryma whippelii, the agent of Whipple's disease, was identified. Many infectious agents have been suggested to be the etiological agent of tropical sprue, but no association with Whipple's disease has yet been reported.

Tropical sprue.

Tropical sprue (TS) is a clinical entity of unknown etiology characterized by an acquired chronic diarrheal illness and malabsorption that affects indigenous inhabitants and expatriates, either long-term residents or short-term visitors, in the tropical countries. The exact pathogenetic sequence of TS remains incompletely characterized. Bacterial overgrowth, disturbed gut motility, and hormonal and histopathologic abnormalities contribute to the development of TS in a susceptible host. Treatment with tetracycline and folate is effective in some patients, although relapses after treatment are common. Research in the areas of microbial factors, pathogenesis, immunogenetics, and hormonal and immune regulation, using modern diagnostic techniques, may be able to settle some of the unanswered issues and open new venues for diagnosis, prevention, and treatment of tropical sprue.

Tropical sprue: revisited.

OBJECTIVE: To review the experience of patients presenting with clinical manifestations of tropical sprue and assess their diagnosis and management, response to treatment and follow up. METHODS: This single center retrospective descriptive study was done at Shifa International Hospital, Islamabad from January 1994 to January 2003. All patients who presented with diarrhea, anorexia, weight loss and anemia and who proved to have partial villous atrophy on intestinal biopsy and had responded to treatment with antibiotic and folic acid,were included in this review. RESULTS: A total of 42 patients were encountered during these years. There were 31 (74.0%) males and 11 (26%) females. The age ranged from 17-66 years. All patients presented with diarrhea, weight loss, anorexia and had megaloblastic anemia. In all patients, a distal duodenal biopsy showed partial villous atrophy. All were treated with tetracycline 1 g per day and folic acid 5 mg per day and responded to treatment within 4 weeks. Total treatment lasted 3 months and resulted in complete resolution of symptoms and gain of weight. The follow up lasted for a mean of 5 years and no relapses were noted. CONCLUSION: Tropical sprue presents with diarrhea, anorexia, weight loss, and megaloblastic anemia. The partial villous atrophy has been a constant finding. The response to treatment to tetracycline and folic acid has been uniformly successful.

Tropical sprue is associated with contamination of small bowel with aerobic bacteria and reversible prolongation of orocecal transit time.

BACKGROUND: In tropical sprue (TS), response to antibiotics may suggest a role for bacterial contamination of the small bowel, which is known in diseases with prolonged orocecal transit time (OCTT). METHODS: We studied 13 patients with TS (diagnosed by standard criteria) for frequency, nature and degree of bacterial contamination of the small bowel by quantitative culture of jejunal aspirate, glucose hydrogen breath test (GHBT), and OCTT by lactulose hydrogen breath test before and after treatment. Twelve patients with constipation-predominant irritable bowel syndrome (IBS) and 12 healthy subjects served as controls. RESULTS: Ten of 13 patients with TS had bacterial contamination compared with 3/12 with IBS (all aerobic, P < 0.05). Median colony count in TS (36 000 CFU/mL, 400 to > 100 000) was higher than IBS (700 CFU/mL, 100-1000, P < 0.05). Gram-negative aerobic bacilli were commonly isolated in TS but not in IBS. Median OCTT was longer in TS (180 m, 40 - 240) than IBS (110 m, 70 - 150, P = 0.008) and healthy subjects (65 m, 40 - 110, P = 0.0007, Wilcoxon rank sum test). Orocecal transit time in TS correlated with fecal fat (Spearman's rank correlation coefficient 0.69, P < 0.05). Orocecal transit time and fecal fat, repeated in 8/13 patients, decreased with treatment for TS (195 m, 130-240 vs 125 m, 90-200, P = 0.02; 8 g/24 h, 6.8-19.6 vs 7 g/24 h, 4.2-9, P = 0.04, respectively). CONCLUSION: Aerobic bacterial contamination of the small bowel is common in patients with TS. Prolonged OCTT in TS correlated with fecal fat and normalized in a subset of patients after treatment.

Tropical malabsorption.

Tropical malabsorption remains an important clinical problem for both the indigenous population of tropical countries and for short-term visitors and longer-term residents from the industrialized world. In young children, persistent diarrhea and malabsorption can result in severe retardation of growth and development. The most common cause is an intestinal infection notably the small intestinal protozoa including Giardia intestinalis, Cryptosporidium parvum, Isospora belli, Cyclospora cayetanensis, and the microsporidia. Tropical sprue still remains an important diagnostic option but is less common than it was 20 to 30 years ago. It is important to attempt to make a specific microbiological diagnosis as this will influence the choice of antibiotic. However, if laboratory facilities are not available, it is possible to offer empirical therapy although this may involve a trial of more than one antibiotic.

[Chronic diarrhea after a journey to Sri Lanka]. / Chronische Diarrhö nach Aufenthalt in Sri-Lanka.

A 51-year-old woman was referred for evaluation of chronic diarrhea. She had spent a 14 day vacation in Sri Lanka three years ago. The clinical examination of the patient was unremarkable. Values for protein, iron, zinc, copper and folic acid were decreased and the Shilling- and D-xylose tests revealed pathological results. Gliadin and Endomysium antibodies were not detectable. Histologic examination of the duodenum displayed chronic duodenitis with increased epithelial regeneration and villous atrophy. In the MRI a segment of the mid small bowel with increased thickness of the intestinal wall was described. Abdominal CT-scans demonstrated multiple, enlarged mesenteric lymph nodes. Laparoscopy with biopsies of the ileum and mesenteric lymph nodes excluded a malignant lymphoma, mycobacteriosis or Whipple's disease. Oral therapy with tetracyclines (250 mg q. i. d.) and substitution of folic acid and iron led to rapid improvement of the clinical symptoms which persisted after cessation of the antibiotic therapy. In view of the clinical course tropical sprue has to be assumed despite the short duration of the journey to a tropical region.