Leader in digital CPD Earn 3 for Southern African Gastroenterology healthcare professionals free CEUs An approach to acute and chronic diarrhoea

Learning objectives

You will learn: • The causes of and risk factors for acute and chronic diarrhoea • How to screen and diagnose acute and chronic diarrhoea • The general principles of treating diarrhoea, with a focus on anti-diarrhoeal agents used adjunctively to oral rehydration and, if necessary, antimicrobials.

Introduction

In the healthy adult, diarrhoea is often viewed as a ‘nuisance’ disease. However, serious complications including severe dehydration and renal failure can occur and may necessitate admission to hospital. Elderly people and those in long-term care have an increased risk of death as a consequence of diarrhoea. Diarrhoea is reported to cause more deaths, an estimated 2.5 million annually, than any other condition Oral rehydration in children under five years of age living in resource-poor countries. In South Africa, therapy is central to diarrhoea accounts for 19% of deaths of children under five years of age; dehydration 1-3 the management of is the key factor in these deaths. acute diarrhoea, being Diarrhoea is classified as acute (short-term, less than 7 days), prolonged (a form of sufficient in most acute diarrhoea lasting more than 7 days), or chronic (long-term, more than 2 weeks patients to prevent in children or 4 weeks in adults). It is also classified as mild, moderate, or severe, complications due to with dehydration reflecting severity of symptoms. Oral rehydration therapy (ORT) is dehydration, but it central to the management of acute diarrhoea, being sufficient in most patients to prevent complications due to dehydration, but it has no effect on the duration of the has no effect on the disease or frequency of bowel motions.4,5 duration of the disease or frequency of bowel This review considers an approach to the management of acute and chronic diarrhoea motions in adults and children, with a special focus on anti-diarrhoeal agents that safely decrease the duration of diarrhoea adjunctive to ORT.

This report was made possible by an unrestricted educational grant from Cipla. The content of the report is independent of the sponsor.

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Causes of diarrhoea Diarrhoea almost always occurs by one or normal secretory processes; disruption of epi- more of four mechanisms: disruption of thelial cells or the epithelial tight junctions; or osmotic forces in the intestine; disruption of motility disorders (Table 1).5

Table 1. Mechanisms by which diarrhoea can occur5

Osmotic Large quantities of poorly absorbed, low molecular-weight solutes in the lumen drive the transport of excessive water into the lumen via osmotic forces

Secretory Overstimulation of the secretory capacity of the intestinal tract, usually as a result of bacterial and viral enterotoxins

Exudative Bacterial and viral pathogens destroy epithelial cells or disrupt the tight junctions of the intestinal epithelium; this allows water and electrolytes, mucus, and proteins to exude into the lumen due to the hydrostatic pressure differential, where they may accumulate and cause diarrhoea

Motility Accelerated intestinal transit time can decrease absorption, causing diarrhoea even when disorders the absorptive process itself is proceeding normally

Parasitic There are numerous potential causes of Infectious causes often lead to acute symp- pathogens are diarrhoea (Table 2). Viral pathogens are toms, but in some cases can result in chronic less common, most likely to be responsible for infectious diarrhoea in immunodeficient patients or in although there diarrhoea in infants, with rotavirus being persistent diarrhoea due to a malabsorptive is a higher the most severe enteric pathogen in children. enteropathy. It remains unclear whether gut likelihood of this Norovirus is the most common viral cause microbiota alterations are the cause or the of diarrhoea in adults. Many bacterial spe- consequence of chronic disorders with multi- being the cause cies produce toxins that can cause diarrhoea factorial pathogenesis, such as inflammatory of diarrhoea through different mechanisms. Parasitic bowel disorder (IBD). Non-infectious aetiolo- in HIV-positive pathogens are less common, although there gies of diarrhoea include medications, food individuals is a higher likelihood of this being the cause allergy or intolerance, digestive disorders, and of diarrhoea in HIV-positive individuals. anatomical disorders.4,6

Table 2. Causes of diarrhoea4,6

Viral infection Norovirus Adenovirus Rotavirus Astrovirus Cytomegalovirus Sapovirus

Bacterial infection Escherichia coli Bacillus cereus Shigella dysenteriae Aeromonas hydrophila Clostridium perfringens Campylobacter jejuni Clostridium difficile Salmonella enterica Staphylococcus aureus

Parasitic infection Cryptosporidium parvum Cyclospora cayetanensis Entamoeba histolytica Listeria monocytogenes Giardia lamblia

Medication Antibiotics Long-term use of proton pump inhibitors Magnesium-containing products

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Food allergy or Cow’s milk Soy intolerance Egg Fructose/lactose intolerance Seafood

Digestive disorder Coeliac disease Inflammatory bowel disease (IBD) Crohn’s disease Ulcerative colitis Irritable bowel syndrome (IBS)

Anatomical disorder Gastroschisis Acute volvulus can cause short-bowel Necrotising enterocolitis (NEC) syndrome (SBS) Surgical resection

Risk factors for diarrhoea The cause of infectious diarrhoea depends with a high number of cases due to bacterial The cause of on geographical location, standards of food enteropathogens in the summer months and infectious hygiene, sanitation, water supply, and season. rotavirus in the winter months. Prolonged Exposure to infectious agents is the major diarrhoea, due to a longer and more serious diarrhoea risk factor for acute diarrhoea, with bacteria infection, is associated with reduced growth.4,6 depends on and viruses often transmitted by the faecal- geographical oral route. Hand washing and hygiene are People living with HIV are at increased risk location, important to prevent infection. of diarrhoea because of drug interactions standards of with antiretroviral therapy. This may be Diarrhoea is common in infants and is further aggravated by malnutrition and other food hygiene, usually acute. If chronic, it is commonly infectious diseases, which are frequent, and sanitation, caused by allergies and by infectious agents. the complications of immunocompromise, water supply, Incidence of diarrhoeal disease varies greatly gastrointestinal manifestations of primary and season with the seasons and child’s age but is mostly HIV disease, and other challenges.1,2 due to either bacterial or viral pathogens,

Screening and diagnosis Acute diarrhoea Acute diarrhoea of infectious aetiology to diarrhoeal disease (Table 3) are seldom is generally associated with other clini- used or required in patients with acute watery cal features suggesting enteric involvement diarrhoea. Routine clinical laboratory detec- including nausea, vomiting, abdominal pain tion of bacterial pathogens requires the use and cramps, bloating, flatulence, fever, pas- of differential culture media, which select for sage of bloody stools, tenesmus, and faecal the growth of certain bacteria but may fail to urgency. Specific investigation is not normally detect other bacteria, especially in the setting required in the majority of cases of acute of antibiotic use. Features that may warrant watery diarrhoea because it is usually self- microbiological stool testing are outlined in limiting and resolves without specific treat- Table 4.5,7 EARN FREE ment. Conventional diagnostic approaches CPD POINTS Table 3. Conventional diagnostic approaches to diarrhoeal disease7 Join our CPD community at www.denovomedica.com • Bacterial culture • Microscopy with and without stains or immunofluorescence and start to earn today! • Stool antigen tests for detection of protozoa and for detecting viral agents • Electron microscopy • Antigen-based tests.

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Table 4. Indications for considering microbiological stool testing

• Severe illness with: – Profuse watery diarrhoea with signs of hypovolaemia – >6 unformed stools per 24 hours – Severe abdominal pain – Need for hospitalisation • Other signs and symptoms of inflammatory diarrhoea: – Bloody diarrhoea – Many small volume stools containing blood and mucus – Fever ≥38.5°C • High-risk host features: – Age ≥70 years – Comorbidities such as cardiac disease which may be exacerbated by hypovolaemia or rapid infusion of fluid – Immunocompromising condition, including AIDS – IBD – Pregnancy • Public health concerns.

Specific In the evaluation of the patient with persis- • Travel history tent symptoms that have not responded to • Nature of the initial symptoms investigation empiric treatment, it is important to test for • Onset (sudden or gradual) is not normally parasitic organisms and to evaluate other • Duration, frequency, and characteristics required in non-infectious processes that may be the of bowel movements (particularly the pres- the majority cause of the diarrhoea. Every child with ence of blood or mucus) of cases of persistent diarrhoea should be examined for • Stool volume non-intestinal infections such as pneumo- • Tenesmus acute watery nia, sepsis, urinary tract infection, and otitis • Association with particular foods diarrhoea media, and treated for these with antimicrobi- • Use of antibiotics because it als following standard guidelines.7 • Presence or absence of other associated is usually symptoms such as nausea, vomiting, incon- self-limiting A thorough and directed history is essential tinence, fever, and weight loss. to direct further investigations as to the cause and resolves of persistent diarrhoea. Relevant questions The answers to these questions may direct fur- without specific would include: ther investigations. treatment Chronic diarrhoea Chronic diarrhoea requires a different diag- (particularly in an older person). Fatigue nostic and therapeutic work-up than acute and night sweats suggest lymphoma, whereas diarrhoea. Differential diagnosis is vast. anaemia or change in stool calibre suggests However, a careful history and thorough colorectal malignancy.8 physical examination with judicious use of selected tests often leads to a specific diag- Important causes of chronic diarrhoea that nosis and an appropriate treatment plan. can be suspected on the basis of history alone The main distinction in patients with chronic include diet, medications, and surgery or radi- diarrhoea is between functional and organic ation therapy. Specific dietary components aetiologies and it is important to consider may cause or aggravate chronic diarrhoea, comorbid symptoms and epidemiologic clues although true food allergies are rarely the when constructing a differential diagnosis. cause. The identification of a dietary cause of diarrhoea may be facilitated by a food Significant abdominal pain, fever, or gas- diary. Careful review of current medications trointestinal bleeding suggests an inflam- is essential as more than 700 drugs have been matory cause for the diarrhoea. Gas and implicated as causing diarrhoea, accounting bloating suggest carbohydrate malabsorp- for approximately 7% of drug adverse effects.8 tion. Substantial weight loss suggests mal- absorption, maldigestion, or a malignancy

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Further investigation is indicated when alarm Lower gastrointestinal endoscopy with features are present, when there is no evident mucosal biopsy is valuable in inflammatory cause, or the differential diagnosis needs and secretory diarrhoeas. Colonoscopy has a further delineation, and may include test- greater yield than sigmoidoscopy, but mul- ing of blood and stool, endoscopy, imaging tiple biopsies must be obtained. Biopsy of studies, histology, and physiological testing. normal-appearing terminal ileum is not rec- For disorders without definitive diagnostic ommended. Upper endoscopy or enteroscopy tests, therapeutic trials may be reasonable. with biopsies of the duodenum or jejunum Routine blood tests may provide clues to aeti- should be done in patients with unexplained ology and fluid and electrolyte status. Other steatorrhoea.8 blood tests should be obtained only when demanded by the clinical presentation.8

Treatment of diarrhoea The main goal of therapy is to prevent post-antibiotic-associated illness. Empiric Careful review complications secondary to dehydration antimicrobial therapy for routine acute diar- of current and its associated electrolyte disturbances rhoeal infection is not recommended, except medications and metabolic acidosis. The World Health in cases of traveller’s diarrhoea where the like- is essential as Organization recommends ORT treatment for lihood of bacterial pathogens is high enough more than 700 acute diarrhoea, with antibiotics and anti- to justify the potential side effects of antibi- parasitic drugs prescribed only in specific otics. Numerous studies have demonstrated drugs have cases. The major value of ORT is treatment that antibiotics shorten the overall duration been implicated of dehydrating forms of diarrhoea, but it of moderate-to-severe traveller’s diarrhoea as causing may not reduce number of stools or shorten to a little over 24 hours. Use of antibiotics diarrhoea, illness. Alternative or adjunctive anti-diar- for community-acquired diarrhoea should be accounting for rhoeal agents that decrease the duration of discouraged as epidemiological studies sug- diarrhoea and are safe are therefore a valu- gest that most community-acquired diarrhoea approximately able addition to ORT in the management of is viral in origin (norovirus, rotavirus, and 7% of drug diarrhoea. The three main classes of anti- adenovirus) and is not shortened by the use adverse effects diarrhoeal drug that are used to reduce stool of antibiotics.5,7 frequency and/or volume and duration of symptoms are anti-motility agents, anti-secre- Treatment of the diverse causes of chronic tories, and adsorbents.4,5,7 diarrhoea is beyond the scope of this review; however, if diarrhoea symptoms persist The use of probiotics or prebiotics for despite normal first-line investigations and treatment of acute diarrhoea in adults treatment, then referral for specialist investi- is not recommended, except in cases of gation is recommended.

Symptomatic therapy using anti-diarrhoeal agents Although anti-motility drugs may reduce the elimination of the causative organisms. For frequency of stool passage in adults, they this same reason, anti-motility agents should EARN FREE are not recommended for use in children as be avoided in patients with clinical features CPD POINTS they do not decrease the volume of stool suggestive of dysentery. Adsorbents are safe and they may prolong infection by delaying for use as an adjunct to ORT. Join our CPD community at www.denovomedica.com Diosmectite and start to earn today! Diosmectite is a natural aluminomagnesium produced during the inflammation process silicate clay with a lamellar, non-fibrous crys- and modulation of cytokine production by talline structure that confers strong adsorbent mucosal cells. Diosmectite modifies mucus properties. Its mechanisms of action are rheologic properties, inhibits mucolysis and not yet fully understood but are probably significantly increases colonic expression multiple. Diosmectite reduces inflamma- of mucin 2, the main secretory gel-forming tion; possible anti-inflammatory mechanisms mucin in the colon. Diosmectite also adsorbs include adsorption of luminal antigens bacteria, bacterial enterotoxins, viruses and

NOVEMBER 2020 I 5 An approach to acute and chronic diarrhoea

other potentially diarrhoeagenic substances. diosmectite reduces the duration of diar- Diosmectite can provide anti-diarrhoeal rhoea and decreases the frequency of bowel activity several days after administration (by motions after two days of treatment in chil- which time it would have been eliminated dren with mild-to-moderate acute diarrhoea. from the intestinal lumen), suggesting that Diosmectite was found to be particularly there is also likely to be a reinforcing effect of effective in rotavirus-positive children.5,9 the natural defence mechanisms contributing to the overall anti-inflammatory effect.5,9 Because of its lack of systemic absorption, diosmectite is well tolerated even by very The efficacy of diosmectite in the treatment young children and can be used as an adjunct of acute diarrhoea in children has been to ORT, as well as to antibacterial therapy investigated in several controlled clinical if needed. Due to the adsorbent properties studies. Despite varying inclusion criteria of diosmectite, it should be administered and outcome parameters, results have con- at a different time to other medications; a sistently demonstrated the efficacy of dios- delay of 60–90 minutes is recommended Diosmectite mectite, with Cochrane review showing that between administration of diosmectite and can provide it may reduce the duration of diarrhoea by other orally administered agents that rely on anti-diarrheal approximately a day, may increase clinical absorption. ORT is not adversely affected activity several resolution at day 3, and may reduce stool when administered concomitantly with 5,9 days after output. Numerous studies have shown that diosmectite. administration (by which Gelatine tannate time it would Gelatine tannate is emerging as a promising Gelatine tannate has a good safety pro- have been intestinal barrier modulator. It is a combina- file and is significantly more effective than eliminated from tion of tannic acid and gelatine that may act placebo; adults treated with gelatine tannate by creating a protective film, forming bonds had significantly less watery stools and less the intestinal with the mucin, thereby protecting the gut abdominal pain compared to patients treated lumen), from the aggressive penetration of pathogens. with placebo. In children between 3 months suggesting that Gelatine tannate is commonly used as an and 12 years of age with acute diarrhoea, a there is also intestinal faecal output regulator. It passes significant decrease in the number of stools likely to be unaltered through the stomach and once in the and an improvement in the consistency of intestine it may exert its action by restoring the stools has been observed when using gelatine a reinforcing physiological barrier function and by reducing tannate as compared to placebo.4 effect of the the pro-inflammatory effects of lipopolysac- natural defence charide in human intestinal epithelial cells.4 mechanisms contributing to Loperamide the overall anti- Loperamide is a phenylpiperidine opioid diarrhoea, acute nonspecific diarrhoea in inflammatory that slows intestinal transit time by stimu- patients two years of age and older, and for effect lating µ-opioid receptors in the myenteric reducing ileostomy output. The off-label uses plexus. It possesses antisecretory properties include the management of chemotherapy- and also blocks intestinal calcium channels. related diarrhoea. Loperamide is contraindi- Loperamide works through two mechanisms, cated in patients less than two years old and the most important being the production patients with acute ulcerative colitis, bloody of segmental contraction of the gut, which diarrhoea, and diarrhoea associated with slows the intraluminal movement of fluids bacterial infections.7 and allows greater absorption. A secondary effect is the inhibition of calmodulin leading Systematic review and meta-analysis of to reduced mucosal secretion. Loperamide is loperamide therapy for acute diarrhoea has predominantly metabolised by intestinal and shown that in children who are younger than hepatic CYP3A4 and CYP2C8 to inactive 3 years, malnourished, moderately or severely metabolites, with the potential for many drug dehydrated, systemically ill, or have bloody interactions.7,10 diarrhoea, adverse events associated with loperamide outweigh benefits, even at doses Loperamide is indicated for the treatment 0.25mg/kg per day. In children who are older of various forms of diarrhoea, including than 3 years with no/minimal dehydration, traveller’s diarrhoea, IBS-associated chronic loperamide may be a useful adjunct to ORT

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and early refeeding. In numerous studies in Although loperamide is relatively safe at children, all of those who had serious adverse therapeutic doses, increasing reports describe effects due to loperamide were younger than its misuse and abuse at very high doses either 3 years of age.3 for euphoric effects or to attenuate symptoms of opioid withdrawal; loperamide-induced A common complaint of loperamide therapy cardiac toxicity may be seen in the young in acute diarrhoea is post-treatment constipa- patient presenting in cardiac arrest or with tion. The drug has a wide margin of safety, unheralded, recurrent syncope in conjunction largely owing to its extremely low bioavail- with ECG abnormalities, including marked ability (0.3%). Common and severe adverse QT-interval prolongation, QRS-interval wid- effects of loperamide are listed in Table 4. ening, and ventricular dysrhythmias. 7,10,11

Table 4. Adverse effects of loperamide

Common adverse effects • Dry mouth • Flatulence • Abdominal cramps • Nausea • Ileus • Constipation • Urinary retention • Dizziness • Drowsiness

Serious adverse effects • Toxic megacolon Gelatine • Necrotising enterocolitis tannate has a • Stevens-Johnson syndrome • Toxic epidermal necrolysis good safety • Syncope profile and is • QT/QTc interval prolongation significantly • Torsades de pointes more effective • Ventricular tachycardia • Other ventricular arrhythmias than placebo • Cardiac arrest

Key learnings

• Although considered a ‘nuisance’ disease, diarrhoea can give rise to serious complications • There are numerous potential causes for diarrhoea, exposure to infectious agents is the major risk factor for acute diarrhoea • Conventional diagnostic testing is seldom used for patients with acute watery diarrhoea • A thorough and directed history is essential to direct further investigations as to the cause of persistent diarrhoea not responding to empiric treatment EARN FREE • Chronic diarrhoea requires a different diagnostic and therapeutic work-up than acute diarrhoea CPD POINTS • Of the anti-diarrhoeal agents, adsorbents and intestinal barrier modulators are safe to use adjunctive to Join our CPD community at ORT www.denovomedica.com • Anti-motility drugs may prolong infection by delaying elimination of the causative organisms and are not recommended for use in young children. and start to earn today!

NOVEMBER 2020 I 7 An approach to acute and chronic diarrhoea

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References Click on reference to access the scientific article

1. Awotiwon OF, Pillay-van Wyk V, Dhansay A, et al. Diarrhoea in 2045-2059.e6. children under five years of age in South Africa (1997-2014). 7. Riddle MS, DuPont HL, Connor BA. ACG clinical guideline: Trop Med Int Health 2016; 21(9): 1060-1070. diagnosis, treatment, and prevention of acute diarrheal 2. Motaze NV, Nwachukwu C, Humphreys E. Treatment infections in adults. Am J Gastroenterol 2016; 111(5): 602-622. EARN FREE interventions for diarrhoea in HIV-infected and HIV-exposed 8. Schiller LR, Pardi DS, Sellin JH. Chronic diarrhea: Diagnosis CPD POINTS children: a systematic review. Pan Afr Med J 2018; 29: 208. and management. Clin Gastroenterol Hepatol 2017; 15(2): 3. Li ST, Grossman DC, Cummings P. Loperamide therapy for 182-193.e3. Are you a member of acute diarrhea in children: systematic review and meta-analysis. 9. Perez-Gaxiola G, Cuello-Garcia CA, Florez ID, et al. Smectite for Southern Africa’s leading PLoS Med 2007; 4(3): e98. acute infectious diarrhoea in children. Cochrane Database Syst digital Continuing 4. Lopetuso L, Graziani C, Guarino A, et al. Gelatin tannate Rev 2018; 4(4): CD011526. Professional Development and tyndallized probiotics: a novel approach for treatment of 10. Wu PE, Juurlink DN. Loperamide toxicity. Ann Emerg Med website earning FREE diarrhea. Eur Rev Med Pharmacol Sci 2017; 21(4): 873-883. 2017; 70(2): 245-252. CPD points with access to 5. Dupont C, Vernisse B. Anti-diarrheal effects of diosmectite in 11. Teigeler T, Stahura H, Alimohammad R, et al. best practice content? the treatment of acute diarrhea in children: a review. Paediatr Electrocardiographic changes in loperamide toxicity: Case Drugs 2009; 11(2): 89-99. report and review of literature. J Cardiovasc Electrophysiol Only a few clicks and 6. Thiagarajah JR, Kamin DS, Acra S, et al. Advances in evaluation 2019; 30(11): 2618-2626. you can register to start of chronic diarrhea in infants. Gastroenterology 2018; 154(8): earning today

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This CPD accredited programme was Disclaimer Published by © 2020 deNovo Medica written for deNovo Medica by The views and opinions expressed in the article are those of the presenters and do not necessarily reflect Reg: 2012/216456/07 Glenda Hardy those of the publisher or its sponsor. In all clinical instances, medical practitioners are referred to the 70 Arlington Street, Everglen, Cape Town, 7550 BSc(Hons) Medical Cell Biology product insert documentation as approved by relevant control authorities. Tel: (021) 976 0485 I [email protected]

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