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Approach to Management of Chronic Persistent Diarrhea

Introduction

Most Cases of acute diarrhea subside by 7 days. However, some cases last up to 14 days. Persistent diarrhea or chronic diarrhea are defined when the duration of diarrhea lasts for more than two weeks.

WHO estimates that while persistent diarrhea accounts for only 10 percent of diarrheal episodes, as much as 35 percent of deaths from diarrhea in children under 5 years of age occur from it.

The major causes and the prevalence of persistent diarrhea differ between developed and developing countries. In the developing world, persistent diarrhea is usually followed by an acute episode and is associated with serial enteric infections without time to recover between episodes.1Gibbons T, Fuchs GJ. Chronic enteropathy: clinical aspects. Nestle Nutr Workshop Ser Pediatr Program 2007; 59:89.  2Bhandari N, Bhan MK, Sazawal S, et al. Association of antecedent malnutrition with persistent diarrhoea: a case-control study. BMJ 1989; 298:1284.  

In developed countries, a wide variety of disorders cause chronic diarrheas in children. The causes range from developmental and dietary factors, to diseases causing malabsorption or maldigestion, or enteric infections (especially in immunocompromised patients).3Binder HJ. Causes of chronic diarrhea. N Engl J Med 2006; 355:236.  4Bhutta ZA, Ghishan F, Lindley K, et al. Persistent and chronic diarrhea and malabsorption: Working Group report of the second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2004; 39 Suppl 2:S711.  

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Approach to Diarrhea

Chronic diarrhea may be divided into three basic categories: watery, fatty (malabsorption), and inflammatory (with blood and pus). However, not all chronic diarrhea is strictly watery, malabsorptive, or inflammatory, because some categories overlap.

Categorisation of Chronic Diarrhea:

Inflammatory

  • Milk protein intolerance
  • Food allergy
  • Inflammatory bowel disease

Malabsorption (Fatty)

  • Celiac Disease
  • Cystic Fibrosis
  • Bacterial Overgrowth

Osmotic

  • Lactase deficiency
    • Primary
    • Secondary post infectious
  • Excessive fructose intake
  • Laxative overuse

Diagnosis of chronic diarrhea in a child depends on the presentation of the patient. Diagnosis of chronic diarrhea can be difficult and requires thorough history and physical examination. In developed countries for children presenting with chronic diarrhea, most likely causes are chronic nonspecific diarrhea and celiac disease. Therefore it is always appropriate to consider these disorders early in the evaluation before extensive laboratory testing.

1. History and Physical Examination:

A detailed and careful history frequently provides hint towards the diagnosis of diarrhea:

2. Laboratory Testing:

Celiac serology: The most valuable test is for antibodies against tissue transglutaminase (anti-tTG), which is highly sensitive, specific, and more cost-effective than other antibody tests.

Stool pH, electrolytes, and reducing substances: In case of watery stools electrolyte concentrations in faeces and pH are measured in stool water after homogensiation of fresh specimen. Fecal electrolyte levels can be used to distinguish secretory from osmotic diarrhea. Although fecal pH tests and fecal electrolyte levels are helpful, they are often omitted from the initial workup.If the patient's diet includes reducing sugars, the stool can be tested for reducing substances, which if present suggest carbohydrate malabsorption. Glucose, lactose, and fructose are reducing sugars, but sucrose is not. However, malabsorbed sucrose can also be degraded by colonic bacteria to glucose and fructose, resulting in a positive test for reducing substances.

Occult blood and leukocyte markers: Both of these tests have poor sensitivity and specificity. In addition to inflammatory bowel diseases and enteric pathogens, a large number of individuals with celiac disease and rotavirus diarrhea also test positive for occult fecal blood. Fecal calprotectin levels are increased in intestinal inflammation, and may be useful for distinguishing inflammatory from noninflammatory causes of chronic diarrhea

Stool fat: The gold standard for diagnosis of steatorrhea(fat malabsorption) is quantitative estimation of stool fat, usually performed over 72 hours, while the patient eats a diet containing at least 100 g of fat per day.The 72 hr stool collection is not very feasible therefore qualitative tests are also used to detect steatorrhea.The tests included are the Sudan III stain and acid steatocrit, a rapid gravimetric method.

Other tests: some other tests are also done according to patients condition and clinical suspicion:

  • Inflammatory bowel disease: In case of grossly bloody stools or a family history of IBD, then complete blood count, serum albumin and ESR are recommended.
  • Protein-losing gastroenteropathy: Fecal alpha-1 antitrypsin test to measure fecal protein losses in case of reduced serum concentrations of albumin and gamma globulins, peripheral edema.
  • Cystic fibrosis: Sweat chloride testing pulmonary symptoms where there is failure to thrive, or a family history of disease is present.
  • Pancreatic insufficiency: If there is suspicion of cystic fibrosis or marked steatorrhea, the stool content of fecal elastase-1 and/or chymotrypsin is reduced in patients with pancreatic insufficiency.
  • Factitious diarrhea: A laxative screen should be performed in suspicion of laxative abuse, hypokalemia measure the stool osmolality. The measured stool osmolality is elevated in the presence of osmotically active laxatives (>290 mOsm/kg), and is reduced (

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Diagnostic Approach:

    1. Celiac disease should be excluded: Children with chronic diarrhea in developed countries should be screened for celiac disease. Screening with serum testing for antitissue transglutaminase antibodies is recommended.
    2. Functional diarrhea should be considered : Characteristics of functional diarrhea(chronic nonspecific diarrhea of childhood or toddler's diarrhea).5Kleinman RE. Chronic nonspecific diarrhea of childhood. Nestle Nutr Workshop Ser Pediatr Program 2005; 56:73.  
      • Onset of diarrhea between 6 and 36 months of age
      • Painless passage of three or more large, unformed stools daily
      • Stools usually passed only during waking hours
      • No failure to thrive (if caloric intake is adequate)

In some cases functional diarrhea is caused by excessive intake of osmotically active carbohydrates and /or restriction of fat from the diet.6Cohen SA, Hendricks KM, Mathis RK, et al. Chronic nonspecific diarrhea: dietary relationships. Pediatrics 1979; 64:402.  

If the diet history suggests this as a possibility, then an empirical trial of restricting juices and liberalizing dietary fat to 35 to 50 percent of total calories

    1. Selective testing according to stool type: Evaluation of chronic diarrhea is to determine whether the stool is watery, fatty, or inflammatory. In some cases, the stool will have a mixed appearance, requiring an evaluation for more than one category.

Watery (osmotic versus secretory):

      The water content of chronic diarrhea can be caused by secretory or osmotic processes, or a combination of the two. Distinguishing between osmotic or secretory can be done by measurement of fecal electrolytes, pH, reducing substances, and calculation of the osmotic gap.
      • Secretory: Secretory diarrhea usually is associated with large volumes of watery stools and it even persists during fasting. Therefore, it is helpful to assess the effects of fasting on stool 1 output. Pure secretory diarrheas are not very common, but may occur in cases of some congenital diarrheas, certain enteric infections, and some neuroendocrine tumors.
      • Osmotic : Osmotic diarrheas are less voluminous than secretory diarrheas and improve or resolve during fasting. The presence of reducing substances or low fecal pH (ie, pH <6) suggest carbohydrate malabsorption.
      • Inflammatory: Presence of gross blood/fecal leukocytes, or elevated fecal calprotectin indicates inflammatory diarrhea. In case of anal fissure or infants with diaper rash positive tests for occult blood may not reflect an inflammatory diarrhea.
      • Fatty:Various tests are used to detect steatorrhea. Quantitative and qualitative fecal fat tests are most accurate in patients with severe fat malabsorption caused by pancreatic insufficiency or bile acid secretory defects. Tests of fecal fat have low sensitivity and specificity for patients with other diarrheal diseases. Thus, these tests may be used as diagnostic clues to determine the order of an evaluation, but are not sufficient to definitively narrow the diagnostic possibilities.

Management:

Malnutrition: Therapy should be promptly started in chronic diarrhea associated with impaired nutritional status. The malnutrition should always be considered a serious condition in infants. Sufficient calories should be provided to allow for catch-up weight gain. Continuous enteral feedings or parenteral nutrition may be necessary when oral intake is inadequate or malabsorption causes inadequate intake . Micronutrient and vitamin supplementation are part of nutritional rehabilitation, especially in malnourished children from developing countries.7Bhan MK, Bhandari N. The role of zinc and vitamin A in persistent diarrhea among infants and young children. J Pediatr Gastroenterol Nutr 1998; 26:446.   Promotion of exclusive breastfeeding in early infancy, safe complementary feeding practices, access to safe drinking water and scientific management of acute diarrhea can significantly reduce the incidence of persistent diarrhea.

Medications:

        • Probiotics: Intestinal microflora is altered in diarrheal diseases associated with chronic diarrhea. Treatment with antibiotics and probiotics play an important role in treatment. Randomized studies and meta-analyses have demonstrated efficacy of probiotic administration both in the prevention and treatment of several types of acute and protracted diarrhea.8Isolauri E. Probiotics for infectious diarrhoea. Gut 2003; 52:436.  
        • Antidiarrheal drugs: Loperamide and diphenoxylate/atropine may improve symptoms in children with severe and protracted diarrhea, but these agents have important side effects, including sedation and risk for toxic megacolon
        • Antispasmodics: Like Drotaverine hydrochloride are indicated for functional bowel disorders. Drotaverine is a selective inhibitor of phosphodiesterase isoenzyme IV, which has been found useful in smooth muscle motility disorders. Rai et al conducted a multicentric randomized double blind placebo controlled trial to study the efficacy of drotaverine in IBS (Irritable bowel syndrome). The patients who fulfilled Rome II Criteria of IBS were included in the study. A total of 180 patients with IBS were randomized to drotaverine and placebo treatment groups. Abdominal pain and stool frequency were measured every week in both the groups for all the 4 weeks of treatment duration. Drotaverine HCl was shown to provide significant improvement (P < 0.01) in global relief in abdominal pain as perceived by the patient (85.9% vs 39.5%) and the clinician (82.4% vs 36.5%) in the drotaverine group as compared with placebo. There was significant (P < 0.01) improvement in stool frequency in drotaverine HCl treatment group as compared with placebo. The drug is well tolerated without any major side effects.9Ramesh R Rai, Manisha Dwivedi, Nirmal Kumar. Efficacy and safety of drotaverine hydrochloride in irritable bowel syndrome: A randomized double-blind placebocontrolled study. Saudi J Gastroenterol. 2014 Nov-Dec; 20(6): 378-382.  

Misra and colleagues10Misra S, Pandey R. Efficacy of drotaverine in irritable bowel syndrome: a double blind, randomized, placebo-controlled trial. Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Oral presentation 29, p. 187   conducted a randomized double-blind, placebo-controlled trial for the efficacy of drotaverine in the treatment of IBS. Seventy consecutive patients between the ages of 18 and 60 diagnosed with IBS using their own criteria were studied in this prospective trial. Patients were treated with drotaverine 80 mg 3 times a day and compared with placebo during a 4-week trial and an additional 4-week follow-up period. These investigators found that drotaverine significantly reduced pain compared with placebo (P<.001). Pain severity scores also increased significantly in the drotaverine group compared with placebo (P<.001). Patients treated with drotaverine also experienced significant improvement in global relief of abdominal pain, again compared with placebo (P<.001) and significant improvement in stool frequency (P<.001). No adverse effects were observed in any of the patients either in the placebo or treatment groups.

Shah et al11Dheeraj Shah*, Manish Narang, Hina Akhtar. Efficacy and Safety of Drotaverine Hydrochloride in Children with Recurrent Abdominal Pain: A Randomized Placebo Controlled Trial. Abstracts presented 51st National Conference of Indian Academy of Pediatrics January 8-12, 2014. Accessed on 19.08.15   conducted a study to assess the efficacy and safety of drotaverine in comparison to placebo in children with recurrent abdominal pain. One hundred thirty two children aged between 4 years and 12 years (stratified equally in age group of 4-6 years and 6-12 years), with recurrent abdominal pain (defined as at least three episodes of pain interfering with normal activities within a three month period) of non-organic etiology, randomized to receive drotaverine (N=67) or placebo (N=65). For children aged between 4 to 6 years, 10 mL of the drug or placebo suspension (providing 20 mg of drotaverine hydrochloride in those receiving drug) thrice a day for four weeks. For children aged more than six years, one tablet containing 40 mg drotaverine hydrochloride or placebo thrice a day for four weeks. During four weeks of follow up, children receiving drotaverine had fewer episodes of pain abdomen [mean (SD) number of episodes 9.3 (11.2) vs. 21.2 (31.9); P=0.011; mean difference -11.9; 95% CI -2.9, -21.0] and lesser chance of missing school [mean (SD) number of days 0.25 (0.85) vs. 0.74 (1.62); P=0.05; mean difference -0.5 days; 95% CI -0.98, 0.00] in comparison to placebo. The number of pain free days during follow up were similar in both groups [mean (SD) 8.0 d vs 8.7 d; P=0.24]. No serious adverse events were recorded in any of the group. It was concluded that drotaverine hydrochloride is effective and safe in maintaining spasmolysis/ analgesia in children with recurrent abdominal pain of unspecified etiology.

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Conclusion:

        • A wide variety of problems can cause chronic diarrhea in infants and children, including functional and infectious causes as well as heritable disorders of immune regulation, macronutrient digestion, mucosal barrier function, and transport.
        • To establish a diagnosis within this diverse set of disorders, an algorithmic approach is helpful. The first step is a detailed history, which may provide clues to the diagnosis or diagnostic category.
        • Management should include micronutrient supplement-ation, step-wise diet based regimens and good supportive care is required.
        • Treatment with probiotics is recommended.
        • Drotaverine is indicated in functional bowel disorders as it helps in relief of global symptoms.

References:

      1. Gibbons T, Fuchs GJ. Chronic enteropathy: clinical aspects. Nestle Nutr Workshop Ser Pediatr Program 2007; 59:89.
      2. Bhandari N, Bhan MK, Sazawal S, et al. Association of antecedent malnutrition with persistent diarrhoea: a case-control study. BMJ 1989; 298:1284.
      3. Binder HJ. Causes of chronic diarrhea. N Engl J Med 2006; 355:236.
      4. Bhutta ZA, Ghishan F, Lindley K, et al. Persistent and chronic diarrhea and malabsorption: Working Group report of the second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr 2004; 39 Suppl 2:S711.
      5. Kleinman RE. Chronic nonspecific diarrhea of childhood. Nestle Nutr Workshop Ser Pediatr Program 2005; 56:73.
      6. Cohen SA, Hendricks KM, Mathis RK, et al. Chronic nonspecific diarrhea: dietary relationships. Pediatrics 1979; 64:402.
      7. Bhan MK, Bhandari N. The role of zinc and vitamin A in persistent diarrhea among infants and young children. J Pediatr Gastroenterol Nutr 1998; 26:446.
      8. Isolauri E. Probiotics for infectious diarrhoea. Gut 2003; 52:436.
      9. Ramesh R Rai, Manisha Dwivedi, Nirmal Kumar. Efficacy and safety of drotaverine hydrochloride in irritable bowel syndrome: A randomized double-blind placebocontrolled study. Saudi J Gastroenterol. 2014 Nov-Dec; 20(6): 378-382.
      10. Misra S, Pandey R. Efficacy of drotaverine in irritable bowel syndrome: a double blind, randomized, placebo-controlled trial. Program and abstracts of the 65th Annual Scientific Meeting of the American College of Gastroenterology; October 16-18, 2000, New York, NY. Oral presentation 29, p. 187
      11. Dheeraj Shah*, Manish Narang, Hina Akhtar. Efficacy and Safety of Drotaverine Hydrochloride in Children with Recurrent Abdominal Pain: A Randomized Placebo Controlled Trial. Abstracts presented 51st National Conference of Indian Academy of Pediatrics January 8-12, 2014. Accessed on 19.08.15
      12. Report on the survey of all pediatric uses of medicinal products in Europe EMA/794083/2009
Dr. B.C. Chhaparwal

MD (Paed), DCH, FICP(USA), FACN(USA),
FIAP, MAMS, FIAMS.

Emeritus Professor- Pediatrics, MGM Medical College, Indore
Formerly:
Vice Chancellor, Devi Ahilya Vishwavidyalaya, Indore
Professor of Pediatrics , MGM Medical College, Indore

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