Rotavirus: An Update on Current Diagnosis and Management
Rotavirus: An Update on Current Diagnosis and Management
Authors: Dante Pappano, MD, Senior Clinical Instructor, Pediatric Emergency Medicine, Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York; Ellen S. Bass, MD, MPH, Attending Physician, Strong Memorial Hospital; Senior Clinical Instructor, Departments of Emergency Medicine and Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York; Sharon Humiston, MD, MPH, Associate Professor, Emergency Medicine & Pediatrics, Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
Peer Reviewer: James A. Wilde, MD, FAAP, Director, Pediatric Emergency Medicine, Medical College of Georgia, Augusta; Medical Director, Georgia United Against Antibiotic Resistant Disease (GUARD)
The history of diarrheal disease in man weaves a colorful but morbid tapestry. Long before the United States existed as a nation, cholera and cholera-like disease decimated armies, deposed kings, and in India sparked a cult religious following in hopes of placating the disease's fearsome wrath.1 In the United States during the 19th century, diarrheal illness grew and expanded alongside the fledgling nation. It was carried by the gold rush to California, and otherwise disseminated across the nation's midsection by way of the expanding canal and railroad systems.1
Even in the modern era, diarrheal disease of any cause remains a serious worldwide public health concern, resulting in almost 3 million deaths annually.2 Children in the developing world are affected particularly hard, accounting for almost 2 million of these deaths, such that diarrhea is the second most common non-neonatal cause of death in children younger than 5 years, after respiratory illness.3 This article reviews the pathophysiology, clinical presentation and supportive management strategies for rotavirus.
The Editor
History
Despite its monumental importance, rotavirus was not known to be a human pathogen before 1973. On the heels of the discovery of the Norwalk virus in 1972 by other researchers,4 Bishop and colleagues5 identified idiotypical virus particles, morphologically distinct from the Norwalk virus, by electron microscopy of inflamed mucosa. Bishop later discovered that the agent was identified more easily in fecal material, and was the causative agent for as much as 81% of local cases of sporadic diarrhea.6 A year after Bishop's discovery, Flewett and colleagues suggested the name ‘rotavirus', based upon the virus' wheel-like morphology.7 (See Figure 1.)
| Figure 1. Human Rotavirus Seen Through Electron Microscopy |
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Scope of the Disease
Rotavirus is one of the most common causes of diarrheal disease. Worldwide it accounts for more than 125 million cases per year, 25% of all deaths due to diarrheal disease, and 6% of all deaths of children younger than 5 years.8 Whereas, worldwide rotavirus causes as many as 600,000 pediatric deaths annually,8 82% of these deaths occur in developing countries.9 In the United States, rotavirus-related gastrointestinal illness remains common, but the mortality rate is much lower (fewer than 40 deaths per year).10 In the United States, the burden of rotavirus gastrointestinal disease in children is better measured in terms of the 500,000 outpatient visits,11 160,000 emergency department (ED) visits, and the 50,000 hospitalizations for which it is responsible.10 In relative terms, this means that each year nearly 1 in 10 children younger than 5 years has an outpatient visit for rotavirus-related symptoms.12 Based on estimates of $2,303 per hospitalization and $57 per outpatient visit1 and other associated costs, the annual economic impact of rotavirus disease in children in the United States has been calculated to be in the $200 million range for this age group alone.12-13
Taxonomy and Classification
Since the time of Bishop's discovery there has been much advancement in the taxonomy of this wheel-shaped virus. Currently, the rotavirus genus describes a group of double-stranded RNA viruses belonging to the Reovirus family. There are seven major groups of rotavirus, groups A through G. Variations within structural viral protein six (VP6) are responsible for the group designations. Groups A, B, and C, are thought to cause human illness. Group A is the rotavirus group most associated with endemic human gastrointestinal illness,14,15 whereas groups B and C are currently thought to cause disease more regionally, or sporadically.
Strains of rotavirus can be further broken down by subgroup and serotype. The taxonomy is based upon the structural viral proteins composing the outer viral capsid. Variations in the VP6 protein determine not only group (A,B,C, others) but also subgroup (I or II).15,16 In contrast, the serotype is determined by the specificities of other structural outer capsid proteins, VP4 (a protease sensitive protein) and VP7 (a glycoprotein).15,16 The VP4 protein often is referred to as the “P” (for protease sensitive) serotype determinant. The VP7 protein often is referred to as the ‘G' (for glycoprotein) serotype determinant.15 These two determinants are important in the human immunologic response as evidenced by the production of neutralizing antibodies against these proteins.17
In theory, many different rotavirus group A strains could exist. In practice, the vast majority that cause human disease fall into one of six strains P[8]G1, P[4]G2, P[8]G3, P[8]G4, P[8]G9, and P[6]G9.16,18 Which of these strains predominate varies geographically.16,18
Group B rotavirus gastrointestinal disease in humans, also called ‘adult diarrhea rotavirus', has been most commonly reported in China, India, and Bangladesh.19 However, occasional detection of antibodies to group B rotavirus in a global sampling of human sera indicates that sporadic disease is probably more widespread geographically.20
Group C rotavirus has been reported worldwide including in the United States, but in a sporadic fashion.21 Limitations of the most commonly used assays may underestimate the disease burden related to this group.4,21
This article focuses on group A rotavirus, which is the group most likely to be seen by the practitioner in North America.
Epidemiology
Human infection with rotavirus is considered ubiquitous. Infection occurs at all age ranges, but severity of symptoms varies considerably by age.22 When infected, neonates tend to be exposed through nosocomial avenues;16 most other age groups are infected by passage from infected family members and daycare peers.22 Humans are first infected early in life, with nearly all children infected by 2 to 5 years of age.16,22 Serum evidence points to repeated infection, at least with strains novel to the individual.22
In temperate climates there is marked seasonal variation in the incidence of rotavirus infection.23,24 This variation seems to correlate best with temperature, rather than humidity, but is not present in tropical climates.23 In North Americaand the United States in particularpeak incidence of infection follows a repetitive pattern. Peak incidence in Mexico occurs in October to November. In the southwestern United States, November and December are peak months of incidence. As one moves geographically north and east, peak incidence occurs later and later in the year.
The resulting appearance is that of an annual epidemic that spreads across the United States from southwest to northeast during a three-to-four-month period.25 It is tempting to think of this as an annual spread by contagious transmission, rather than regional recrudescence due to regional climatic changes, but this is not known. In the United States, rotavirus may go entirely undetected for several months during surveillance, suggesting that annual spread is by contagious transmission from region to contiguous region.
Worldwide the likelihood of seasonal variation increases with distance from the equator. There is a marked autumn to spring predilection far north and south of the equator, and there is less variability nearer the equator.24
Transmission
Rotavirus has been shown to be transmissible by the fecal oral route.16,22 Large numbers of viral infectious particles (up to 1010 infectious particles per milliliter) are shed in the stool.4,22 However, alternative mechanisms of transmission, such as aerosol transmission may be possible. While respiratory illness with rotavirus has been described,26 another possible source of aerosolization is vomiting. Rotavirus has been isolated from emesis material in infected adults;27,28 in one outbreak nosocomial spread was postulated to have occurred at least in part through aerosols elaborated in the process of vomiting.27The probable relative contributions to human transmission are not known, but currently it is believed that the human fecal–oral route is the primary mode of transmission.16,22
Nosocomial exposure represents an important source of infection for hospitalized children.22 Rotavirus particles can survive for prolonged periods (>12 days) on materials commonly found in domestic and institutional settings. The survivability seems greatest at low humidity and on nonporous surfaces.29 In a study screening environmental surfaces for rotavirus in a pediatric inpatient ward and ward playroom in Riyadh, Saudi Arabia, 7% of all tested surfaces were contaminated. Contaminated surfaces included toys, furniture, vital signs chart, toilet handles, patient hands, and sinks.30 Rates of infection for children hospitalized with non-diarrheal illnesses range between 0.6% and 24%, depending upon the age of the child and the length of hospital stay.31,35 Of interest, various disinfectants are effective at inactivating the virus on fomite surfaces, but tap water alone is not adequately effective.33
As humans are not the only rotavirus host, the potential of zoonotic spread of rotaviral infections to humans has been understood for many years. The greatest risk of zoonotic transmission is probably to farming communities and those persons in contact with livestock, but family pets including dogs and cats represent potential, if uncommon sources of infection as well.34
Clinical Manifestations
After oral exposure, the rotavirus must travel through the stomach to the intestinal villi to infect the host. The inhospitable gastric environment represents a significant barrier to infectivity. Inactivation occurs very quickly under experimental conditions, mimicking the normal fasting stomach (pH =2.0).35 Inactivation was attenuated at pH=3.0, but was minimal at pH=4.0.35 Pepsin also is believed to be an important factor in gastric barrier function.36 The barrier effect of pH and ‘pH and concentration-dependent factors' with gastric juice is such that under experimental conditions for the study of infectivity, bicarbonate administration is necessary to prevent rotavirus inactivation.36,37 However, under these conditions in a porcine model, as little as a single plaque-forming unit of rotavirus is adequate to initiate infection.37
Rotavirus particles that are able to evade inactivation in the stomach infect the mature enterocytes in the mid and upper villi of the small intestine.38 The VP4 protein appears to be important in this process of infectivity.
Once infected, there is a two- to four-day incubation period before clinical symptoms are manifest. Severity of gastrointestinal disease may be related in part to strain and electropherotype within strains, but individual and age-related differences are likely a manifestation of differences in acquired immunity.26 Neonates are commonly asymptomatic or mildy symptomatic.39 When symptoms do occur in neonates, watery stools are predominant, but bloody mucoid stools, abdominal distension, dilated bowel loops, and even frank necrotizing enterocolitis may be seen in premature neonates.40 Adults may be asymptomatic as well. In a study of adult volunteers challenged with an oral rotavirus inoculum, 12 of 18 developed serologic evidence of infection, but only 4 (33%) of those with evidence of infection developed symptoms.41
In infants and children, acute gastroenteritis is the most common illness caused by rotavirus. Cross-sectional descriptive studies of rotavirus symptomology use diarrhea as entrance criteria, and stool testing is the most convenient method of determining infection. A recent survey of children seeking care for rotavirus diarrhea in Venezuela showed that 78% also had vomiting, 29% were dehydrated, and 30% had fever.42 An older study of U.S. children who were hospitalized with rotavirus gastroenteritis showed a higher frequency of these findings: 96% had vomiting, 83% were dehydrated, 77% had fever, perhaps consistent with the more severe nature of their hospitalized status. Vomiting typically lasted 2 to 3 days, fever lasted 3 days, and diarrhea lasted an average of 5 days, but ranged from 1 to 9 days.14 In addition to these typical gastrointestinal symptoms, the study also revealed extraintestinal symptoms: irritability in 47%, lethargy in 36%, pharyngeal erythema in 49%, rhinitis in 26%, tympanic erythema in 19%, and palpable cervical nodes in 18%.14
This original study of rotavirus symptomology has not been the only one to describe extraintestinal manifestations of rotavirus infection. Most concerning are the case reports related to the central nervous system (CNS). Case reports and series describe the recovery from cerebrospinal fluid of rotavirus antigen by enzyme immunoassay (EIA), RNA by polymerase chain reaction (PCR), or actual viral particles by electron microscopy. Clinical illness related to these cases involved aseptic meningitis, encephalitis, and seizures.43 Rotavirus has been recovered from tracheal aspirates of children with clinical pneumonia26 and from liver and kidney of children with immune deficiencies and diarrhea.44 The route of exposure in these cases of extraintestinal disease is not known. Spread to other organ systems from the proximal small bowel is suspected to be by viremia. In some of the cases of CNS disease, rotavirus RNA was recoverable from the blood by PCR. In fact, subsequent investigation has revealed rotaviral antigenemia or viremia to be a common event, occurring in 43-66% of serum samples of children with rotavirus gastroenteritis.45,46
While interesting, CNS extraintestinal rotavirus disease is exceedingly rare. Acute gastroenteritis with manifestation of vomiting, diarrhea, fever, abdominal pain, and dehydration is the most common presentation. Although usually an acute disease, the illness can have more lasting adverse effects on growth and nutrition. This was first studied systematically in the 1970s but remains a problem.47,48 Other complications of acute rotavirus gastroenteritis include hyponatremia, hypernatremia, metabolic acidosis, and diaper rash. Additionally, besides the more common acute gastroenteritis, the entity of ‘chronic rotavirus diarrhea' has been reported in children with immunodeficiency.44
Necrotizing enterocolitis occurs in the setting of rotavirus in some neonates. While the cause of necrotizing enterocolitis is multifactorial, in small series rotavirus has been found to be present in 30-40% of cases.50,51 The rotavirus-associated necrotizing enterocolitis tends to be milder and involve bowel more distally than the non-rotavirus associated necrotizing enterocolitis.50,51 Finally, following the withdrawal of the original rotavirus vaccine, the possibility of the occurrence of intussusception in the setting of naturally occurring rotavirus infection was raised. However, epidemiologic data do not support any association of intussuception with naturally occurring or wild type rotavirus infection.52,53
Pathology and Pathophysiology
Little is known about the gross physical changes of the infected bowel in humans that may lead to the intestinal manifestations of disease described above. Ultrasound has revealed increased ileal wall thickness and less consistently mesenteric adenopathy.54,55 More is understood on the histologic level. In Bishop's initial description of human rotavirus infection, all biopsy specimens revealed histologic abnormalities,5 whereas a more recent prospective study revealed microscopic abnormalities in only 5% of biopsied specimens.56 When histologic changes do occur, they are most notable in the mucosal surface. Villi become shortened, blunted, and appear atrophic. On higher power magnification, there is denudation of the microvilli, the lamina propria becomes infiltrated with mononuclear cells, and the enterocytes become more cuboidal.5,38
There is no information on gastric tissue derangement related to rotavirus, except for a single case report of gastric rupture occurring in a 3-month-old girl with vomiting and rotavirus identified in her stool.57 Nevertheless, vomiting is a common symptom of rotavirus gastroenteritis, occurring in about 80% of those seeking care42 and about 90% or greater in those hospitalized for rotavirus gastroenteritis.14,58 Vomiting has been shown to be a dependable independent predictor of clinical dehydration in acute diarrhea of unspecified cause,59,60 but this has not been studied for rotavirus specifically. The pathophysiology of vomiting in rotavirus acute gastroenteritis has not been fully established, but abnormal gastric motor function resulting in a delay of gastric emptying has been in shown in acute versus convalescent children.61
The pathophysiologic mechanisms responsible for diarrheal fluid loss are better elucidated. Derangements of several physiologic mechanisms have been found experimentally. Sodium-glucose co-transport and sodium-amino acid co-transport are inhibited during the conditions of rotaviral infection.38 The activity of mucosal disaccharidases including sucrase, lactase, and maltase are diminished.38 Net fluid and electrolyte secretion has been observed experimentally. Additionally, there is a reduction of sodium/potassium ATPase activity, although it is not certain if this is a direct effect on the transporter or an effect related to loss of transporter-bearing enterocytes.38
The known histologic and physiologic derangements point to several possible explanations for the fluid loss. The loss of absorptive villus surface area with the relative sparing of the fluid and electrolyte-secreting secretory crypts may result in an imbalance with net fluid loss.38 A second possibility is that one of the nonstructural rotavirus proteins (NSP4) may function as a secretory viral enterotoxin. Alternatively, rotavirus infection may stimulate the enteric nervous system speeding the transit of intraluminal contents beyond the absorptive capacity. The stimulant might be the posited NSP4 enterotoxin, or as yet undetermined mechanisms.38 Finally, some investigators have proposed a post-ischemic hyperemic recovery phase of intestinal disease.62 This phase is characterized initially by hypersecretion by the rapidly dividing recovering enterocytes and secondly by a loss of hyperosmolality at the villous tips wrought by a hyperemia-disturbed countercurrent mechanism. The loss of the hyperosmolality then results in impaired water absorption from the villi.62
Diagnosis
Clinical Diagnosis. Multiple studies confirm that more than 80% of stool-positive cases of rotavirus diarrhea have vomiting and fever occurs in 30-65%. Additionally, there may be signs of dehydration and not uncommonly symptoms of respiratory infection.11,42,63,64 The stool produced often is described as watery and free of blood.64,65 However, the range of diarrhea includes cases whose clinical presentation (e.g., bloody or nonwatery) is more typical of invasive diarrheal syndromes.66
Rotavirus illness lasts 4 to 7 days in most cases, which is shorter than some other infectious causes of enteric illness.66-67
Age and seasonality can be helpful in trying to decide to include rotavirus in the differential, but definitive diagnosis cannot be made on these factors alone. Most cases are in infants and children age 6 months to 24 months, during peak months of December through March; however, infection can occur at any age, and in tropical climates there is no seasonal variation.15,66,68,69
Despite some of these defining features, the symptoms of rotavirus infection in children are not specific to this infectious agent. However, because treatment is supportive, in the right setting a presumptive diagnosis is adequate. Laboratory-aided diagnosis is often available.
Laboratory Diagnosis. Because it is not possible to diagnose rotavirus infection based upon clinical presentation, specific diagnostic tests were developed. Laboratory diagnosis requires using methods to detect rotavirus in stool and rectal swab specimens. Electron microscopy was the first detection method followed by enzyme-linked immunosorbent assay (ELISA) and later latex agglutination (LA) tests.68 Other testing methods include radioimmunoassay, counterimmunoelectro-osmophoresis, tissue culture, polyacrylamide gel electrophoresis (PAGE), and polymerase chain reaction (PCR). Serum can be tested using acute and convalescent-phase antibody titers and demonstrating a fourfold or greater increase in antibody to rotavirus antigen. In addition, serologic evidence of rotavirus can be accomplished by ELISA immunofluroescence, neutralization, and complement fixation.70
Of all of these tests, only ELISA and LA have found their way to common clinical use. During their advent, published studies revealed sensitivity ranges from 70% to 90% and specificity ranges from 80% to 100%.63,71,72 Modern ELISA-based chromatographic immunoassays are now the most commonly used; Specific commercial test kits often advertise sensitivities and specificities in the high 90-100% range, cost US$12-15 per kit, and can yield results in 10 to 15 minutes.73-75 Some latex agglutination tests still are used and have similar performance characteristics, but are more labor intensive.76
Treatment
Currently, there are no specific antiviral chemotherapeutic agents recommended or routinely employed against rotavirus. For typical rotaviral acute gastroenteritis, therapeutic intervention most often is limited to supportive care. Specifically, ensuring hydration is the most important consideration in children with this illness. However in specific cases, certain additional modalities, discussed below, can be considered. Treatment for specific complications of rotavirus acute gastrointestinal disease other than dehydration, (e.g., hyponatremia, hypernatremia, metabolic acidosis, diaper rash) and others will not be addressed beyond this introductory paragraph. While derangements of sodium accompany less than 5% of cases of rotavirus acute gastroenteritis, caution in management of these children is necessary because central pontine myelinolysis has been reported in the setting of caring for a child with severe hyponatremia.77 Metabolic acidosis may occur in the setting of rotavirus acute gastroenteritis.78,79 The anion gap may be useful in helping to determine if the acidosis is due to perfusion–related metabolic disturbances or diarrheal bicarbonate loss.80,81 Diaper rashes are a common accompaniment to diarrhea and are best managed early with barrier creams and pastes.82 Extraintestinal infection, including central nervous system involvement, is rare enough that recommended treatment options do not exist at this time.
Hydration and Nutrition
Maintenance of hydration and correction of dehydration are the most important goals of treating rotavirus acute gastroenteritis. The appropriate setting and mode of hydration delivery depends upon the age of the child, the symptoms, and the symptom severity. Severely dehydrated patients will require intravenous rehydration and possibly intensive supportive care. Moderately and mildly dehydrated children should receive oral rehydration solution (ORS), while children who are not dehydrated may continue their age-appropriate diet once vomiting has ceased,83 while increasing their fluid intake with usual dietary fluids with ORS or with recommended home fluids.84,85 (See Figure 2.)
| Figure 2. Approach to Hydration and Nutrition |
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Intravenous Fluid Rehydration. Intravenous rehydration is indicated in severely dehydrated children, less severely dehydrated children who continue to vomit after the initiation of oral rehydration solution, and children with abdominal distension, obstruction, or ileus.83 Some would add to this list of indications the following: excessive stool losses (>15mL/kg/hour)86 and social considerations, specifically the ability and willingness of parents to perform the labor intensive task of administration of ORS.83 Access may be difficult in the most severely dehydrated children who are also those who need it the most. In the presence of shock, venous access must be obtained in the most expedient means possible; standard peripheral intravenous access, intraosseus, or central venous access.87 In less severely dehydrated children without bowel obstruction but in whom intravenous fluid is nevertheless indicated, nasogastric ORS may be used while access is being obtained.83,88
Intravenous therapy is often the goal of many families seeking care at an ED for acute rotaviral gastroenteritis. However, many children seeking care in an ED do not require intravenous management, but can be treated with oral rehydration. Some EDs report performing intravenous rehydration in less than 10% of patients presenting with acute gastroenteritis.89
Recipes for rapid intravenous rehydration vary. Crystalloids are recommended, and generally isotonic fluids (normal saline or lactated Ringers) are used, at least initially,90,91 but not uniformly.61 For severely dehydrated children, an initial bolus of 20 mL/kg and a volume in the range of 60 to 100 mL/kg over several hours is often indicated.91 However, clinical judgment and frequent reassessment are critical. For less severely dehydrated children, initial rapid intravenous rehydration may be achieved with as little as 30mL/kg, then supplemented with oral rehydration. Many children in this category will cease vomiting once rehydrated.78,86,92
Whether continued intravenous or oral rehydration should continue in the inpatient setting after initial rapid ED rehydration is decided on a case-by-case basis. Most patients who were less severely dehydrated will be able to tolerate oral fluids and be discharged.78,83,92 Patients who are severely dehydrated on intake generally require admission and may require additional evaluation for illnesses mimicking severe dehydration (e.g., congestive heart failure, myocarditis, hemolytic uremic syndrome, intussusception, midgut volvulus, elevated intracranial pressure, sepsis, encephalitis, meningitis).
Most have found that routine laboratory values do not contribute to care.88,92 Several authors have investigated serum bicarbonate as a predictor of severe dehydration and need for admission, but only one has shown the value of this approach.78 Additionally, ancillary testing is essential if there is suspicion of other illnesses besides rotaviral acute gastroenteritis, or if there is concern of other complications of gastroenteritis besides dehydration (e.g., hypoglycemia).
Oral Rehydration Solution. ORS was introduced in 1979 and has become the mainstay of treatment of children with mild to moderate dehydration.85 It has been hugely successful, credited with saving 3 million children's lives annually.85
Recommended ORSs contain water, sodium, glucose or rice syrup solids, potassium, chloride, and either bicarbonate or citrate. (See Table 1.) However, there is some variability in the relative concentrations of these constituents. The original World Health Organization (WHO) ORS contained 90 mEq/L sodium, 111 mmol/L of glucose, and was hyperosmolar at 310 mOsm/L.93 In 2001 the osmolality was reduced to 245 mOsm/L, the sodium was reduced to 75 mEq/L, and glucose was reduced to 75 mmol/L. This change was based on the meta-analysis of available data, which revealed several benefits with the reduced-osmolarity formulation over the standard WHO ORS in children with non-cholera diarrhea: decreased stool output, decreased vomiting, and decreased need for intravenous therapy.93 It should be noted, however, that there was an increase in the risk of hyponatremia with the reduced-osmolarity ORS. In the United States, non-WHO commercial products are used for ORS most frequently. Most of these contain less salt (between 45 to 75 mEq/L sodium) and a little more glucose (140 mmol/L). (See Table 1.)
| Table 1. Constituents of Common Oral Rehydration Solutions |
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ORS should be given frequently in small amounts with a target of 50-100mL/kg during a four-hour period, depending upon the degree of dehydration (mild or moderate).83 For the average 12-kg 2-year-old child, providing one teaspoon every two minutes if mildly dehydrated, or one teaspoon every one minute if severely dehydrated, satisfies these recommendations. Additionally stool and diarrheal losses must be assessed and replaced under this plan. Following the four-hour rehydration period, normal age-appropriate feeding restarts with increased fluid intake.83
Recommended Home Fluids. Recommended home fluids were developed to identify widely available fluids or easily home-prepared fluids that might help prevent dehydration in non-dehydrated children. Acceptable solutions vary by nation.85 In the United States, fluids that might be considered for this category include breast milk, formula, water, homemade salt and sugar solutions, soups, diluted fruit juices, and sports drinks, but much controversy exists over which fluids are acceptable and recommendations tend to be clinician dependent.84
Feeding
In contrast to the marked decrease in mortality advanced by the initiation of oral rehydration therapy, nutritional morbidity remains problematic.49 Because ORS is calorie poor,86 early feeding is recommended as soon as rehydration has taken place.83-85 Early feeding has been shown to promote recovery, and shorten the duration of diarrhea.84 Current recommendations accent the avoidance of foods high in fat and simple sugar, and promote complex carbohydrates, lean meats, yogurt, fruits, and vegetables.83 Although uncommon, acquired lactose intolerance may require limitation of lactose-containing solutions.84
The classic BRAT (bananas, rice, applesauce, and toast) diet has fallen out of vogue, being described as low energy, low protein, and low fat.83 However, recent advances in gastroenterologic science may spark renewed interest in this old favorite. Translating theory to practice, green bananas and pectin were shown to reduce diarrheal fluid loss in children with persistent diarrhea in a Bangladesh study.94 The benefit of rice is not only theoretic: rice-based ORSs have been shown to be superior to standard glucose-based ORSs when considering only volume of stool output.95
Breast Milk. Many pediatric patients presenting with rotavirus acute gastroenteritis will have breast milk as a solitary or main food source. While considered the optimal source of food for the healthy young infant, there are additional potential benefits conferred to the infant with diarrheal disease. Besides passive immunization in the form of anti-rotaviral IgA,49,96 other breast milk constituents (e.g., lactoferrin and lactadherin) seem to have antirotaviral effects.97,98 However, it is less clear if breastfeeding can be considered an effective treatment per se for rotavirus infection. Some studies have failed to demonstrate an effect, others have shown mild benefit, and still others have demonstrated both marked amelioration of symptoms and also preventative effects.99 Certainly, most recommend a continuation of breast feeding during acute gastroenteritis,96,100 but the addition of conventional ORS is recommended in those who are mildly or moderately dehydrated.83
Treatment of Vomiting
The use of antiemetic agents for the treatment of gastroenteritis associated with vomiting remains somewhat controversial. In the past, the untoward side effects consisting especially of sedation, akathesia, and dystonia that sometimes accompanied the use of older antiemetics was thought to be disruptive to oral rehydration therapy.86,101 However, the advent of the better-tolerated 5-HT3 receptor antagonist class of antiemetic agents has opened the door to reconsideration of the use of antiemetic agents for vomiting in childhood gastroenteritis. In recent years, three randomized controlled clinical trials have demonstrated benefit of ondansetron, not only in terms of reduction of vomiting,102-104 but decreased need for intravenous rehydration and decreased rate of hospital admission.102-104 Diarrhea was increased, however, and there were higher ED revisit rates in children given ondansetron in one study.103,104 Based upon this information and the discomfort associated with nausea and vomiting, some physicians have moved toward more frequent use of 5-HT3 receptor antagonist antiemetics.101 However, the American Academy of Pediatrics (AAP) has not endorsed the use of antiemetic agents.83
Treatment of Diarrhea
Conventional Antidiarrheal Agents. There are a number of conventional physiologically active over-the-counter compounds that alter the frequency, volume, or texture of diarrhea. Chief among these are antimotility agents, antisecretory agents, and adsorbents. In general, these pharmacologic agents have not been recommended for use against diarrhea.83 Opiate and anticholinergic agents are especially to be avoided because of demonstrated toxicity and side effects in children.83 While certain adsorptive agentsattapulgite in particular appear safe and reduce diarrhea, there are limited data on the reduction of fluid loss.83,105 Concern exists that focus on cosmetic improvement of diarrhea texture may distract parents attention from a child's hydration status.
Probiotics. Probiotics are one treatment option whose safety and efficacy may lead to more commonplace use in the future.106 Probiotics, available as tablets, granules, acidophilus milk, and naturally within live culture yogurts, are whole live bacterial species that are either normally found colonizing the human bowel or are very similar to these species. Probiotics were specifically considered but not supportedin the AAP's practice parameter on the management of acute gastroenteritis in children.83 The AAP parameter specifically stated that efficacy rather than safety was the concern resulting in the consensus.83 However, considerable research has been performed since the 1996 statement supporting the effectiveness of probiotics.106
The mechanisms by which various species of Lactobacillus and Bifidobacterium genera contribute to intestinal health still are being elucidated, but may be multifactorial. Some have suggested that these organisms, which are just some of the normal colonizing bacteria in humans, form a monolayer and thus function literally as a microbial barrier against more pathologic enteric species.107 While not every study has demonstrated benefit, in a recent meta-analysis of therapeutic trials in humans, the pooled effect of probiotic use resulted in 0.7 fewer days of diarrhea and 1.6 fewer stools by day 2 of illness.107
Zinc. Zinc-based enzymes play a critical role in cell function and growth.90 Tissues with high turnover may demand more zinc to fulfill demands of re-growth. Many studies of acute childhood diarrhea, but not rotavirus specifically, have shown a decrease in duration of diarrhea when zinc was supplemented at 1 to 4 times the recommended daily allowance.108 This reduction for most studies was in the range of 0.4 to 1.4 days.108 The WHO now recommends 14 days of zinc supplementation for all children with acute diarrhea: 10 mg daily for infants younger than 6 months, and 20 mg daily for all infants and children older.90 It should be noted that vomiting may be a side effect of zinc administration.108 Further, the studies showing efficacy were performed in developing nations where zinc deficiency is common.108 The AAP's 1996 practice parameters do not address zinc supplementation during diarrheal disease.83
Complementary and Alternative Medicine and Food Additives. A number of substances considered as foods, food additives, or herbal medicines have been studied for their anti-rotaviral effects. Brazilian investigators studied the effects of 12 traditional Brazilian herbal medicines against human rotavirus. Three of these (Artocarpus integrifolia, Myristica fragrans, and Spongias lutea) displayed in vitro antirotaviral activity.109 Japanese investigators revealed anti-rotaviral effects of both green tea and black tea extracts.110 These substances have not been investigated in vivo. Barring future evidence to the contrary, caffeinated tea is not recommended because of its diuretic effects.90
There have been three randomized controlled clinical trials of homeopathic therapy for acute childhood diarrhea, but not for rotavirus specifically. In a meta-analysis of these three studies the pooled effect was a reduction of 0.8 days of diarrhea.111 While the trials appear well designed, the application of homeopathy to diarrheal disease has been met with some resistance. Homeopathy was not addressed in the 1996 AAP practice parameters.83 Because the choice of homeopathic medication is individualized based upon particular features of the diarrheal illness, it is not known if homeopathic medications are effective when prescribed by practitioners who are not trained in homeopathic methods.
Future Therapeutic Modalities
Interesting research continues to explore future therapeutic modalities. The most promising among these is racecadotril, an enkephalinase inhibitor, with antisecretory effects. This drug is well tolerated and has been shown to decrease stool volume, reduce required oral rehydration intake, and decrease ED revisits.112-114 Other potential future therapies exist. Human interferon alpha, for example, was discovered to be elevated in the serum of children with rotavirus acute gastroenteritis.115 When human interferon alpha is given orally to rotavirus infected neonatal pigs, the mortality rate decreases substantially.116 Another potential future modality capitalizes on the replication cycle of the organism. A cysteine protease inhibitor and a serine protease inhibitor have been shown to reduce diarrhea in rotavirus infected mice.117 More recently, a soybean trypsin inhibitor showed protection against rotavirus-induced derangement of intestinal enzyme and digestive functions.118,119 Various tissue growth factors have been studied as well; the rationale for these factors is to speed recovery of the damaged intestinal mucosa.120 (These drugs have not been approved by the FDA.)
Prevention
Active Immunization. Natural infection with rotavirus is known to confer clinical immunity against the infecting subgroup.121,122 Additionally, serum antibody titers against rotavirus are known to be protective against clinical illness.123 Building upon this knowledge, the first live oral rotavirus vaccine was licensed by the U.S. Food and Drug Administration (FDA) in 1998. However, during the first year of usage there were 15 cases of intussusception reported to the Vaccine Adverse Events Reporting System (VAERS), and the vaccine was withdrawn.124 Because of the burden to society in terms of morbidity, mortality, and other societal costs, investigation into new rotavirus vaccines continues. A new rotavirus vaccine is in use in Central and South America; two new vaccines are in advanced stages of testing for U.S. licensure, and RotaTeq received FDA approval in February of 2006.124,125
Summary
Rotavirus is a wheel-shaped RNA virus that routinely infects the proximal small bowel, resulting in acute gastroenteritis. The virus is spread by the oral-fecal route and results in vomiting, diarrhea, fever, and abdominal pain. In the United States, the most common serious complication is dehydration. Various therapies against vomiting and diarrhea are emerging, but the focus should not be removed from assessment and treatment of dehydration. In these cases, the use of oral rehydration therapy and intravenous rehydration in severe and refractory cases may be lifesaving.
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The history of diarrheal disease in man weaves a colorful but morbid tapestry. Long before the United States existed as a nation, cholera and cholera-like disease decimated armies, deposed kings, and in India sparked a cult religious following in hopes of placating the disease's fearsome wrath. In the United States during the 19th century, diarrheal illness grew and expanded alongside the fledgling nation.Subscribe Now for Access
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