Treatment of Acute Diarrhea in the New Millennium

We all know that diarrheal diseases continue to be a major cause of morbidity and mortality worldwide. We also know that major national and international medical and scientific bodies including the World Health Organization (WHO), the American Academy of Pediatrics, and the European Society of Pediatric Gastroenterology, Hepatology and Nutrition, have put forward very concordant sets of recommendations (1–4) meant to diffuse a scientifically sound, safe, and effective approach to the child with acute diarrhea, centered on the use of oral rehydration solutions (ORS). Yet, it seems that such sets of recommendations are very poorly implemented worldwide. Why? Why do we have this paradox? On one side, we have a treatment for acute diarrhea that is available and widely recommended and has proved to be efficacious and safe beyond any doubt, cheap, and readily available. On the other, we do not use it. To be more exact, we certainly underuse it. This is happening in the United States, Africa, Asia, and now we learn—but it was indeed predictable—also in Europe. There are evidently different reasons for this apparently inexplicable anomaly. In the United States, the major shift from recommendations issued by the American Academy of Pediatrics (3) appears to be an excessive use of intravenous rehydration in place of the safer oral rehydration therapy (ORT) (5). This occurs even though it has been well documented that in most children with acute diarrhea, rehydration can be successfully accomplished by using ORT (see the meta-analysis by Gavin et al. [6], showing that in developed countries ORT was found to provide effective treatment, without need to revert to intravenous rehydration, in a sheer 96.4% of children). In analyzing the reasons for this behavior in a survey of 104 pediatricians, Reis et al. (5) found this was mainly due to a “lack of convenience of ORT administration in the practice setting, support staff preference for intravenous versus ORT, need for additional training of support staff to implement ORT, and likelihood of reimbursement for intravenous versus ORT.” Thus, barriers such as support staff limitations and financial constraints seem to play a crucial role. This is very unfortunate from many viewpoints, including the economic one. In fact, it has been estimated that the widespread use of correct ORT in the United States would result in approximately $1 billion in savings (7), as well as in reducing unscheduled follow-up visits (8). In Africa and Asia, an in-depth insight into reasons for poor prescription rates of ORS, associated with high prescription rates for unnecessary drugs, is provided by a sociological study conducted by Desjeux et al. (9) and summarized in a letter to this journal. To investigate the reasons for this behavior, which clearly is in contrast with current WHO recommendations (10), the authors conducted an anthropologic survey in five locations in Algeria, Egypt, Thailand, and China. Among their findings was that diarrhea was often regarded by families as a banal event—either a normal occurrence or a benign disease. As a consequence, public health campaigns have dramatized the dangers of diarrhea to the point that families seeking therapy expect a prestigious drug that would be costly and immediately effective in stopping the diarrhea. Obviously, ORS does not fulfill either criterion, and this largely explains why physicians may be hesitant to prescribe it and families to rely on it alone. It also explains why private physicians, but even those in the public sector, would often prescribe many drugs, including antibiotics with antidiarrheic, antiemetic, and antipyretic agents. Last, but not least, old Europe. The article by Szajewska et al., regarding a multicenter survey conducted on behalf of the ESPGHAN Working Group on Acute Diarrhoea, showed also a rather poor adherence to ESPGHAN recommendations (2,4). The authors proposed a simulated, typical, uncomplicated case of a 6-month-old child with acute diarrhea and then asked almost 3000 pediatricians a number of questions regarding hypothetical management. The study group's findings can be summarized as follows. One doctor in six would not prescribe ORS (very similar to the United States report) but rather would prescribe more or less inappropriate fluids. Five of six would rehydrate within a longer than recommended period. Four of five would reintroduce foods much later than recommended, and when a formula is reintroduced, only one third of pediatricians would use a normal, lactose-containing formula. Also, more than one of five would use smectite (a clay very popular in France and in Eastern Europe), and one of four doctors would even recommend discontinuing breast-feeding! Another very disappointing finding is that 44% of the physicians would use antibiotics, contrary to all available evidence and all published recommendations. It would have been interesting indeed also to have an insight into the motivations for this behavior: Are the “rules” simply ignored by physicians, thus implying a problem at the educational level? Or are there social pressures, such as those evident in the United States and in the African and Asian reports? Probably, a combination of both factors plays a role. An understanding of the causes of this deviance from recommendations in Europe is necessary if we are to propose an effective change. Thus, an overall dismaying pattern emerges from all these reports, and it is no wonder that WHO's most recent estimate assesses that fewer of 50% of episodes of acute diarrhea worldwide are treated with ORS (11). One would actually be tempted to question whether adherence to recommendations is at all needed. After all, are we not dealing with a benign disease, mostly disappearing, and for which even a new vaccine is available? Why not use any of the drugs that are on the market? Let us examine those statements. Benign? Can we define as benign a disease that kills approximately 3 million children every year (12) ? The argument that the problem is confined to developing countries is not only evidently brutal and unacceptable but also fails to consider that even in well-developed countries the morbidity load remains very high, with occasional devastating nutritional consequences if not adequately addressed (13). Disappearing? Although it is believed that the mortality rates and the severity of acute diarrheal episodes are slowly declining, incidence rates do not appear to be diminishing. In the United States, every year there are 1 to 2 episodes per child per year in children less than 5 years of age, with 220,000 hospital admissions (or approximately 10% of all admissions for children in this age range), and approximately 400 deaths per year (14). Furthermore, because it appears that the most important driving force in medical management issues in the Western world is money, let us not forget that acute diarrhea is not cheap. Acute diarrhea causes 20% of referrals to physicians for children less than 2 years of age (15) and 10% for those less than 3 (16). If we restrict the analysis only to rotavirus enteritis (the most common infectious diarrhea), there are approximately 500,000 visits and 50,000 hospital admissions, with an estimated cost of approximately $274 million in medical treatment and more than $1 billion in costs to the community (17,18). As for the new anti-rotavirus vaccine recently marketed after extensive evaluation (19), many concerns have been voiced about its possible involvement in triggering intussusception. In fact, from September 1, 1998, through July 7, 1999, 15 cases of intussusception among infants who had received the recommended vaccine were reported to the Vaccine Adverse Event Reporting System (VAERS) of the Centers for Disease Control (CDC) in Atlanta. Although the jury is still out on the issue, and a definitive association between vaccination and intussusception may be very hard to prove beyond doubt, the vaccine has been put on hold (20,21), and there is at present no indication of whether it will ever be released again. What about other agents? Let us take a closer look at currently available and possibly future agents. Using drugs to treat diarrhea is of course an ancient practice, because we have always looked for a way to shorten the disease, reduce stool output, and prevent the host of long-term consequences of diarrhea. However, despite dramatic progress in the understanding of the pathophysiology of diarrhea, the list of available agents is impressively short and disappointing. In fact, most of the “newer” agents (such as chlorpromazine, loperamide, and octreotide) have a limited effect and/or are not devoid of potentially hazardous side effects, obviating them as an option for acute diarrhea. Many pediatricians, we have seen, still generously use antibiotics. But the case for such treatment is very weak. Enteric bacterial pathogens show increased resistance to standard therapy, antibiotics are variably (usually minimally) effective, and their use may prolong the carrier status. Agents for which there is consensus on the usefulness of antimicrobial therapy in the nonimmunocompromised host beyond newborn age are only Vibrio cholerae, Shigella, Clostridium difficile, and Giardia(22). What about smectite, so popular in some of the areas surveyed in the report by Szajewska et al.? This unabsorbable clay is reported to reduce the duration of watery diarrhea (23). However, its usefulness has not been documented outside the setting of developing countries, and the scientific doubt that shortening of duration of diarrhea may simply mean quicker appearance of formed-looking, but still fluid-containing stools, seems very sound. No question thus that more studies are needed before one can accept this clay as a novel agent to be recommended. Do we then have nothing to add to ORS (not that we need anything)? There are indeed promising agents that may well have a future in the treatment of diarrhea. They include micronutrients and probiotics. In developing countries, there is evidence that supplementation with zinc is beneficial to malnourished children with acute diarrhea or even more in general to malnourished children living in areas in which there is a high risk of developing diarrhea (24). Finally, in the past few years, new interest has been generated in probiotics. Lactobacilli are among the most commonly used bacterial species for promoting health and counteracting intestinal infections. Among them, Lactobacillus rhamnosus strain GG (ATCC 53103) has been the most investigated. This strain was effective in several clinical trials, most placebo-controlled, in the prevention and/or treatment of acute diarrheal disease in children (25). We have recently shown its efficacy in a large multicenter study conducted on behalf of the ESPGHAN Working Group on Acute Diarrhea (26). Therefore, it can be concluded that we are indeed dealing with a serious, widely diffused disease causing a huge toll of morbidity, mortality, and socioeconomic costs worldwide. A disease for which an approach that has been well documented to be safe and effective exists. A disease for which sets of simple, highly consistent recommendations for treatment have been put forward (Table 1 from Szajewska et al., reports what the authors refer to as The Nine Pillars of Good Treatment of Acute Gastroenteritis) and widely diffused by prestigious, reputable national and international academic bodies. Is it not about time that we all do our part to comply and to help increase compliance?TABLE 1: The “Nine Pillars of Good Treatment of Acute Gastroenteritis”