Recent Advances and Evidence Gaps in Persistent Diarrhea

• DOI: 10.1097/mpg.0b013e318181b334
• Publication Date: 2009-03-05T21:32:13Z
• Authors: ZA Bhutta; EA Nelson; WS Lee; PI Tarr; R Zablah; KB Phua; K Lindley; D Bass; A Phillips
• Keywords: Diarrhea; Dehydration; Research; Infant, Newborn; Infant; Infectious Disease; persistent diarrhea; Zinc; 03 medical and health sciences; 0302 clinical medicine; Child, Preschool; Recent advances; Chronic Disease; Humans; Micronutrients; evidence gaps; Cognition Disorders; Growth Disorders

Despite advances in the understanding of diarrheal disorders and management strategies, globally nearly 1.8 million children die annually as a consequence diarrhea (1). Of these, significant proportion dies following prolonged episodes diarrhea. Persistent (PD) is defined that start acutely but last for 14 days or more, usually associated with growth faltering (1,2). Unlike acute diarrhea, which dehydration chief contributor to mortality, PD has multiple diverse adverse effects on childhood outcomes, including micronutrient deficiencies, stunting (3), cognitive impairment (4). It an important morbidities mortalities from other diseases. been estimated 3 disability adjusted life-years lost (2). CURRENT CONTROVERSIES AND ISSUES Epidemiology Burden Estimates individual population-based consequences PD, this disorder poses definitional, epidemiological, diagnostic, risk analysis challenges. First, it not clear how best define PD. Although working definition nonresolved at least 2 weeks reasonable starting point, must be recognized most form continuum even lasting 7 can nutritional penalty (5). There reduction number publications related global literature diseases (Fig. 1) past decade. are little data indicate abated, likely diminished publication output also reflects reduced research interest subject. notable given between persistent may feasible focus delayed somewhat arbitrary point illness sole goal preventing advisable attempt interventions once exceeds 5 days, category "prolonged diarrhea" help us understand pathogenesis impact interventions. extensive modeling diagnostic-driven intervention recently published (6), value such effort awaits improvements technology, obligates coordination strategies.FIG. 1: Trends indexed (number articles) children, 1990–2007.Issues Pathogenesis One cannot easily determine frequency follows primary enteric illness, reason difficult design hypothetical initiation process. Also, although certainly consequences, when controlling variety potentially confounding factors, known what fraction these target caused by versus processes (which themselves marked human immunodeficiency virus [HIV] infection). A recent evaluation burden undernutrition factors (7) revealed odds 24 months increased 5% each episode (odds ratio [OR] 1.05; 95% confidence interval [CI] 1.03–1.07). In subset analysis, after height-for-age z score 6 months, 4% (OR 1.04; CI 1.0–1.08; P = 0.03). However, possible population-attributable there seems strong association several persistently detected pathogens (ie, enteroaggregative Escherichia coli, Crytosporidium parvum, Giardia lamblia) some countries (8,9), sensitive polymicrobial assessments precipitants have sparse. Therefore, assuming different agents produce we do yet know relative various infectious etiologies. addition, clinical diagnosis reflect consecutive infective episodes, in-patient studies recognized, unless microbial investigations carried out intercurrent infections will recognized. rule causes chronic appear diarrhea; example, coeliac disease now well developing developed countries), food-related enteropathies, rarer cases intractable (congenital enteropathies). our intestinal injury (1,10), still major gaps knowledge molecular mechanisms underlying etiology (include HIV populations). Small mucosa becomes named central mechanism pathophysiology (11), discriminate persisting colonization enteropathy postinfective fails heal heals slowly. former cases, becoming apparent bacterial effector molecules (eg, Salmonella, Yersinia, Shigella, enteropathogenic infections) translocated into host cell downregulate immune system play role (12). circumstances, interrelation normal flora altered, leading inflammation possibly via altered Toll-like receptor signaling (13). The stem compartment integral response damaged epithelium, influencing its wounding known, activated macrophages, signaling, microbiota (14). Their potential role, if any, remains uncertain. Most work focused categorization identifying changes absorptive, secretory, reabsorptive capacities minerals, carbohydrates, protein, fats) Additional morphological analyses small biopsies showing villous blunting cellular infiltrates. Intestinal regeneration process mitigated enable improve bowel function through appropriate considerable regenerative renewal capacities, would recovery state, kinetics tissue (15). involves epithelial migration proliferation, function, adaptation subepithelial tissues. This requires interaction types. regulation understood. believed effectors—such epidermal factor, interferon-γ, interleukin-8—play roles many aspects regeneration, mesenchymal–epithelial interactions (16,17). mannose-binding lectin (MBL) inflammation. MBL collagenous found serum primarily binds mannose N-acetyl glucosamine residues (18). Upon binding, mediates elimination wide bacteria, yeasts, viruses, protozoa activation complement direct phagocyte receptors (19). deficiency proposed one common forms (20) implicated HIV-infected individuals (21,22). Research area mainly concentrated defense against Cryptosporidium parvum infection shown homozygous structural gene mutations were cryptosporidiosis 8.2; 1.5–42; 0.02) (21). subsequent case-control study Haitian cryptosporidiosis, levels markedly lower (P 0.002) than controls (22). perceived inconsistent. Children predisposition E coli O157:H7 infections. precise predispose fully understood (23). subtle genetic merit further representative settings. Recent Developments Diarrhea Prevention Implications evidence efficacy zinc treating (24), recommendation made promulgate (25). attempts planned use prevent treat rates duration affect incidence prevalence. modality deliver populations determined. extent prevention vaccination reduce malnutrition unknown. Rotavirus cause severe dehydrating young accounting 610,000 deaths, 2.4 hospital admissions, outpatient visits (26). 10.6 deaths ages younger years during period 2000–2003, account 1.76 (17%) (http://www.who.int/whr/2005/annex/annexes3-4_en.pdf). anticipated vaccines rotavirus immunization programs provides opportunity plays development malnutrition. probable, demonstrated, diminish economic considerations vaccines, resolved resource-poor where greatest. At time, emphasis being placed scaling up vaccine strategies novel fiscal support mechanisms, advanced marketing commitments financing initiatives. additional question concern suboptimal regions south Asia, mucosal less effective. Given need assess nutrition ongoing systematic surveillance introduction assessment surveillance, existing enumeration systems, could critical decision making new preventive strategies. Such cost-benefit should limited include estimates preventing, treating, enhancing probiotics functional foods. These modalities used (27,28). relatively few determining their Embellishments genetically engineered function. Recently, butyrate recommended treatment shigellosis upregulation cathelicidin, antimicrobial peptide innate system. pathway action unknown, isoleucine vitamin D induce peptides, raising possibility stimulating defences (29). RESEARCH AGENDA IN PERSISTENT DIARRHEA field, section below considers salient areas designed provide timely useful information. Priorities listed above, epidemiology lacunae. include: Clear delineation link syndrome-based categories prognostic specificity progression Delineation progresses consequential long-term deficits neurodevelopment robust (secular, nutritional, interventional) communities receded Above, highlighted perception filled We propose emphasized study, follows: Assessment immunopathology relationship noninfected Interaction microbiota, responses, expression, absorption Improved so develop therapeutic approaches promote healing both Identification perpetuators trends Management Health Systems consideration current recommendations recognition identify operational research: Should all treated aggressively PD? If not, triage those warrant treatment? What enteral regimens parenteral approaches, optimal sustenance remarkable success green banana rice lentil diets (1,30), luminal nutrients needs elucidation. Micronutrient Interventions To extend benefits micronutrients questions addressed well-designed cohort studies: intake (zinc alone combination others) (31,32), algorithm portrayed Fig. worldwide circumstances? accounts variable micronutrients, within populations? optimum mode supplementation vs fortification) timing administration micronutrients? FIG. 2: Suggested diarrhea.CONSENSUS APPROACH TO THE PREVENTION TREATMENT OF general consensus countries. Early unhygienic milk breast recurrent poorly managed predisposing prevented. generally prevalent poor poverty alleviation social sector ensure complementary feeding fundamentally important. Thus, promotion exclusive breast-feeding avoidance formula feeding, adequate weaning hygienic nutritious foods postinfectious coupled environmental control measures provision safe water. absence latter, hand washing point-of-use water purification needed no specialized low lactose because, despite alterations digestive absorptive metabolic balance indicates satisfactory carbohydrate, fat take place diets. tested formulas traditional (30,33); key challenge scale health systems. dietary therapy using inexpensive, home-available, culturally acceptable ingredients manage ambulatory settings countries, augmented referral hospital-based complicated special required (1,33). CONCLUSIONS continues pose enormous challenges globally. view overall mortality represents larger portion diseases, child due annually. learn more about disorder, particularly define, diagnose, triage, implement evaluated evidence-justified precipitating concurrent infections, therapy, supplements, therapy. epidemiology, response, performed parallel. ultimate implementation infrastructure maintenance. agenda summarized above improving future control. Addressing issues require collaboration care professionals, scientists, public economists, policymakers.