Colin D. Rudolph
GASTROESOPHAGEAL REFLUX
Gastroesophageal reflux (GER) is the spontaneous passage of gastric contents into the esophagus. It is a normal physiologic process that occurs throughout the day in healthy infants, children, and adults. In infants, refluxed material often is expelled from the mouth, a benign process known as “spitting-up,” “spilling,” or “posseting.” Gastroesophageal reflux disease (GERD) results from failure of the normal protective mechanisms that prevent damage to the aerodigestive tract following GER and is purported to manifest with a variety of symptoms and signs, shown in Figure 394-1. For almost all of these symptoms and signs, alternative etiologies must be considered prior to concluding that GERD is causative. This is particularly true in the infant and younger child because it is difficult to differentiate in young patients between GER and vomiting, and their symptoms are nonspecific.
EPIDEMIOLOGY
Half of all infants between 0 and 3 months of age and two thirds of 4- to 6-month-old infants regurgitate at least once per day. The prevalence of regurgitation decreases dramatically after 8 months of age1,2(eFig. 394.1 ). Typically, these infants are otherwise thriving and outgrow this problem by 18 to 24 months of age. Infants with GER are not at increased risk of ear, sinus, upper respiratory infections, or wheezing compared to a control population, but there may be a higher likelihood of feeding refusal than was found among the control infants.1 Gender, breast-feeding, and environmental tobacco smoke exposure are not significant factors related to infant regurgitation.2 In children between 3 to 9 years of age, symptoms of heartburn are reported in 2% to 5 %, epigastric pain in 7%, and regurgitation in 2% to 4 %.2,3,4 About 5% of adolescents report symptoms of heartburn, epigastric pain, or regurgitation.3 Follow-up studies of children and adolescents with GERD suggest that chronic symptoms may persist and require continued management through adulthood.4,5 Hiatal hernia (Fig. 394-2),6 obesity,7 and family history8,9 all may increase the risk of GERD. In a small number of infants and children, GER may cause chronic symptoms, but the true GER-related incidence for each of these is uncertain.
A higher prevalence of GERD is observed in several special populations, including children with neuromotor impairment,10 repaired esophageal atresia or other congenital esophageal conditions,6,11-13 and those with chronic respiratory disease such as cystic fibrosis.13 Although pre-term infants often receive treatment for presumed GERD,14 the true incidence of GERD is clearly overestimated.15
PATHOPHYSIOLOGY
Most episodes of physiologic GER are confined to the distal esophagus, last less than 3 minutes, and cause no symptoms. GER occurs when transient relaxations of the lower esophageal sphincter (LES), unaccompanied by swallowing, allow the escape of gastric contents into the esophagus.16 Less important causes of reflux include failure of the LES to adapt to sudden increases in intra-abdominal pressure and chronically reduced resting LES pressure. Refluxed gastric contents are cleared by a combination of factors, including bulk clearance by gravity (when in an upright position) and peristalsis as well as neutralization of residual acid by the swallowing of alkaline saliva. Complications of GER ensue following failure of a variety of protective mechanisms (eTable 394.1 ). Prolonged exposure to acid is associated with a higher risk of esophagitis, but extraesophageal complications of GER may occur despite esophageal acid exposure being in the normal range. When the esophagus is filled following gastroesophageal reflux, the upper esophageal sphincter opens and the airway closes, allowing the gastric refluxate to pass into the pharynx without being aspirated into the airway. Stimulation of esophageal or pharyngeal afferents may induce brief apnea, cough, or vomiting. Following an episode of pharyngeal reflux, the material is cleared from the pharynx by either vomiting or swallowing, and breathing resumes. Abnormalities of these airway protective mechanisms will potentially result in airway symptoms from inadvertent exposure of the larynx and airway to caustic materials.
FIGURE 394-1. Classification schema for gastroesophageal reflux disease.
DIAGNOSTIC EVALUATION
Gastroesophageal reflux (GER) is a normal physiologic event; therefore, the key to evaluation and diagnosis is to determine when GER is the cause of disease. Diagnostic approaches vary depending on the presenting symptom, and in all cases, other treatable causes of the disorder must be considered during the diagnostic evaluation.17 No test serves as the gold standard for making a diagnosis of GERD. Rather, a series of tests is often required to determine if a particular disorder is being caused by GER.
Upper Gastrointestinal Radiography (UGI) This test is often included in the evaluation of the vomiting infant. It is useful to diagnose anatomic abnormalities that present with nonbilious vomiting as with GER, such as esophageal stricture, pyloric stenosis, antral webs, or disorders of esophageal motility such as achalasia. The UGI is not useful for diagnosis of GER because reflux of ingested radiographic contrast often occurs in healthy individuals.
Esophageal pH Monitoring and Impedance Monitoring This test utilizes a pH sensor with or without a series of sensors that measure electrical impedance. This allows evaluation of the number and duration of acid and nonacid reflux episodes into the lower and/or upper esophagus. Prolonged esophageal mucosal exposure increases the risk for esophagitis. Measurement of 24-hour esophageal acid exposure should not be used as the sole determinant of whether GER is responsible for airway symptoms such as apnea, recurrent pneumonia, wheezing, or hoarseness. Esophageal pH and impedance monitoring should be combined with a pneumogram that measures oxygen saturation and chest wall and airflow movements. If one is attempting to establish a clear cause-and-effect relationship between apnea episodes and GER, however, these time-consuming and technically challenging tests often fail to clarify if apnea is caused by GER. If esophageal pH monitoring is abnormal, there is a somewhat higher probability that GER is a contributing factor causing airway symptoms such as recurrent wheezing or pneumonia, but a normal study does not exclude GER as a potential factor, and an abnormal study does not prove a causative relationship.
FIGURE 394-2. Endoscopic photograph of hiatal hernia. (Source: Reprinted with permission from Gastrolab, Vasa, Finland: http://www.gastrolab.net.)
Upper Endoscopy with Biopsy of the Esophagus This test is useful to evaluate if there is esophagitis or other sequelae of chronic esophageal acid exposure such as stricture or Barrett esophagus. In addition, it allows diagnosis of other disorders, such as Crohn disease and eosinophilic or infectious esophagitis.
Nuclear Scintigraphy This test evaluates the distribution of isotope-labeled formula or food following normal feeding. Episodes of GER are monitored for up to an hour after feeding. Because GER may occur in normal individuals, documentation of these episodes is of little pathophysiologic use unless aspiration into the lungs is detected. If this occurs, it is a clear indication that airway protective mechanisms are deficient.
Other Diagostic Approaches Other tests may be utilized to evaluate children with airway symptoms. These include chest radiographs or computed tomography scans, laryngoscopy, and bronchoscopy with alveolar lavage for pepsin and/or lipid-laden macrophages. Often, empiric therapy may be administered on the basis of history, but a treatment response does not necessarily confirm a diagnosis of GERD, since other acid-related disorders or a placebo response may also result from treatment.
CLINICAL FEATURES AND DIAGNOSTIC EVALUATION
The approach to the evaluation and management of gastroesophageal reflux (GER) varies depending on the symptoms presenting with possible GERD. GER is a normal physiologic event, and the evaluation is therefore directed toward determining if GER is either causing or contributing to a specific symptom or sign.
Uncomplicated Reflux
A thorough history and physical examination is generally sufficient to arrive at a diagnosis of uncomplicated GER, which obviates the need for any diagnostic testing. Other potential causes of vomiting should be considered in an infant with warning signs (Table 394-1) such as forceful or bilious vomiting, abdominal tenderness or distension, gastrointestinal bleeding, diarrhea, constipation, fever, hepatosplenomegaly, a bulging fontanelle, macrocephaly or microcephaly, seizures, or an onset of vomiting after age 6 months. Infants with complications purported to be due to GER, such as weight loss, excessive irritability because of esophageal pain, feeding difficulties, apneic episodes, recurrent stridor, or pneumonia, require different management approaches.
Table 394-1. Warning Signs in the Vomiting Infant
|
Gastrointestinal bleeding: hematemesis, hematochezia |
|
Consistently forceful or bilious vomiting |
|
Consistent vomiting after 6 months of life |
|
Abdominal tenderness, distention |
|
Neurologic signs: bulging fontanel, macro/microcephaly, seizures, focal findings |
|
Protracted diarrhea |
|
Constipation |
|
Fever |
|
Lethargy |
|
Hepatosplenomegaly |
|
Faltering growth/failure to thrive |
Recurring Vomiting and Poor Weight Gain
The infant with recurrent vomiting and poor weight gain presents a more challenging problem. Other potential causes of poor weight gain need to be considered as outlined in Chapters 29 and 30. Often, inadequate calories are offered to the infant as parents attempt to reduce the frequency or volume of vomiting. In these situations, parental education is usually sufficient to resume weight gain. If appropriate calories are consumed but vomiting is severe enough to limit weight gain, thickening of the formula or increasing the caloric density of the formula is useful. No widely available prokinetic agent has been shown to be useful. Rarely, supplemental nasogastric feeding or jejunal feeding may be required to achieve weight gain. The severity of GER usually gradually decreases, and the infant can resume a more normal eating pattern by 3 to 6 months of age. Surgical therapy is almost never required to achieve good weight gain. If it is contemplated, a pediatric gastroenterologist should be consulted to consider other potential causes of vomiting.
Esophagitis
Esophagitis may be caused by GER, presenting with symptoms including hematemesis, anemia, and atypical seizurelike movements with torsion of the neck known as Sandifer syndrome. Symptoms of excessive irritability and feeding refusal are purported to be due to GERD, but no studies demonstrate improvement of these symptoms following GERD treatment in infants.18 However, adults with esophageal pain and dysphagia improve following pharmacologic treatment.19 The approach to the infant with feeding refusal is discussed in Chapter 31 and to the infant with excessive crying in Chapter 83. The differential diagnostic approach to gastrointestinal bleeding is reviewed in Chapter 387. In the older child, esophagitis may present with complaints of substernal or chest pain. In the older child with heartburn, an empiric trial of antisecretory therapy is generally the most reasonable initial approach to therapy. If symptoms resolve, therapy can be continued for 3 to 4 months, and further evaluation is required only if symptoms recur at the cessation of therapy. Definitive diagnosis of esophagitis requires that visible breaks in the esophageal mucosa are observed with endoscopy (Fig. 394-3). Esophageal biopsy is necessary to differentiate between other potential causes of esophagitis, such as infectious etiologies or eosinophilic esophagitis. Treatment of GER-induced esophagitis should focus on reducing the acid exposure of the esophagus with adequate doses of antisecretory agents; generally, a proton pump inhibitors is used and provides effective treatment.20-24 Severe, prolonged erosive esophagitis can result in the development of either peptic strictures or a Barrett esophagus (eFig. 394.2 ). Peptic strictures can be dilated, and recurrence can be prevented with either long-term, aggressive medical therapy with a proton pump inhibitor or antireflux surgery. Barrett esophagus presents with intestinal metaplasia in the distal esophagus.25 It is thought to represent a premalignant lesion, with evolution to esophageal adenocarcinoma over many years. There is no definitive treatment, but vigorous medical therapy or antireflux surgery is usually recommended. Because of the long-term risk of adenocarcinoma, children with this diagnosis should undergo surveillance esophagoscopy and biopsy every 3 to 5 years.26
Nonerosive Reflux Disease
Nonerosive reflux disease exhibits typical symptoms of GERD but normal esophagoscopy in children and adolescents.27 These patients rarely progress to actual erosive esophageal disease, but symptoms may be troubling. Diagnosis of this disorder in infants and younger children is challenging because symptom reporting is inaccurate and lacks specificity. Symptoms of irritability have previously been used as an indication of GERD, but placebo-controlled trials demonstrate a lack treatment efficacy.18 Therefore, definitive diagnosis requires documentation of symptom correlation with GER episodes by pH probe and/or esophageal impedance.
Acute Life-Threatening Events
Acute life-threatening events have been associated with GER in infants but may be caused by other disorder, as described in Chapter 119. Episodes associated with GER typically are obstructive in nature and occur while the patient is awake, supine, and within 1 hour of a feeding.28 Central apnea has not been clearly associated with GER, and apneic episodes in premature infants15 have not been shown to be improve with GER therapy. Diagnosis is generally best made from the typical history. Episodes occur infrequently, so even carefully performed combined 24-hour esophageal pH and monitoring combined with measurements of air flow and chest wall impedance may be unable to document episodes. Therapeutic options include thickened feedings and acid-suppressant therapy. Position therapy with prone positioning after meals can be considered, but generally the fear of an increased potential of sudden infant death syndrome in an infant with previous acute life-threatening events limits the advisability of this approach. Antireflux surgery is effective, but because the episodes are self-resolving and decrease in frequency after age 6 months in most infants, surgery is very rarely indicated.
FIGURE 394-3. Endoscopic photographs of reflux esophagitis. Note the breaks in the mucosa. (Source: Reprinted with permission from Gastrolab, Vasa, Finland: http://www.gastrolab.net.)
Asthma
Asthma is associated with GER, being observed in up to 50% of children with asthma. However, well-controlled trials that evaluated the efficacy of proton pump inhibitor therapy in adult asthma patients demonstrate no benefit of therapy except in those patients with nighttime asthma symptoms.29,30 Well-controlled pediatric trials are inconclusive.31,32 GER may be considered as a contributing factor in patients with nocturnal asthma and possibly those patients requiring either continuous oral corticosteroids, high-dose inhaled corticosteroids, more than two courses of treatment with systemic corticosteroids per year, or those with persistent asthma unable to wean medical management. It is likely that those children with steroid-resistant asthma along with a positive pH study or symptoms such as heartburn or regurgitation are most likely to benefit from therapy, but no test has proven to reliably predict those patients who will respond to either medical or surgical therapy. The best approach to diagnosis and therapy remains uncertain.
Recurrent Pneumonia
Recurrent pneumonia may result from GER-associated aspiration, but this appears to be a relatively uncommon cause of recurrent pneumonia,33 likely being most frequent in children with neurologic disease or laryngeal anatomic disorders. Proving that GER is causing aspiration pneumonia in an individual patient is often difficult. Normal esophageal pH monitoring does not exclude GER as a cause of recurrent aspiration. Broncho-alveolar lavage with increased pepsin or large numbers of lipid-laden macrophages suggests that aspiration occurs. Treatment of GER is often indicated once other causes of recurrent pneumonia are ruled out, but the efficacy of medical therapy is unclear. In children with neurologic disease, proton pump inhibitor therapy appears to decrease the frequency of pneumonia,34 but in otherwise normal children,35 this therapy may increase pneumonia risk. In some children with more severe pulmonary disease, antireflux surgery may be considered.
Supraesophageal Reflux Disease
Other purported supraesophageal complications of GER include hoarseness, chronic cough, recurrent croup, sinusitis, and otitis media. Of these, only chronic cough has been shown to improve with prolonged medical therapy.36-38Dental erosions are observed more frequently in patients with GER, but treatment responses are not well studied.
TREATMENT
Treatment options are listed in Table 394-2. In uncomplicated gastroesophageal reflux (GER) characterized by a lack of warning signals or potential complications in an infant with GER, reassurance of the parents, including education regarding the range of normal frequency for vomiting and the potential complications of GER, is usually sufficient for management.17 Some infants with cow milk allergy have symptoms indistinguishable from those of GER. Therefore, a 2-week trial of a hypoallergenic or elemental formula may be considered in some symptomatic infants. Thickening of formula with rice cereal (1–2 tbsp/oz formula) or use of an antiregurgitant formula may also be considered as an option for therapy if the vomiting is causing substantial parental angst. Feeding with a thickened formula usually requires “cross-cutting” of the nipple and may lead to increased cough or feeding problems in some infants. Prone position therapy was previously recommended as a potential therapeutic approach for all infants with GER, but in otherwise well infants, prone position sleeping should not be recommended because it increases the risk of sudden infant death syndrome. Pharmacologic therapy is not indicated for the management of infants with uncomplicated GER. Vomiting usually decreases in frequency over the first year of life and resolves by 12 months of age. If symptoms worsen or do not improve by 18 to 24 months of age, the diagnosis should be reevaluated.
Table 394-2. Treatment of Gastroesophageal Reflux Disease
|
Nonpharmacologic |
|
Position changes (prone sleeping not recommended) |
|
Formula thickening |
|
Antiregurgitant formula thickens in stomach |
|
High calorie formula |
|
Time-limited trial of hypoallergenic formula |
|
Nasogastric/jejunal feeds if undernourished or for airway complications |
|
Weight loss if overweight |
|
Pharmacologic |
|
Antacids (for intermittent symptoms; not for use in infants) |
|
Surface agents (eg, sucralfate, sodium alginate) |
|
Motility agents (no available agents clearly effective) |
|
Acid suppressive agents (eg, H2 receptor antagonists, proton pump inhibitors) |
|
Surgical |
|
Surgical fundoplication (usually laparoscopic) |
|
Feeding by gastrostomy or jejunostomy |
|
Esophagogastric dissociation (only in very selected cases) |
Pharmacologic Therapy
In children and adolescents with esophagitis, pharmacologic therapy with a proton pump inhibitor (PPI) is highly effective.39-42 If ineffective, etiologies other than GERD or inadequate dosing should be considered before considering surgical therapy. In infants under 1 year of age, pharmacokinetics are less predictable and safety is less well validated,43,44 although they appear to be as safe as histamine-2-receptor blockers. Erosive esophagitis was thought to require lifelong therapy, but recent data suggests that up to half of otherwise normal children with erosive esophagitis can be safely withdrawn from medical therapy.45 However, in children with anatomic disorders or neurodevelopmental delay, withdrawal from PPI treatment is less likely to succeed. PPI’s should not be abruptly discontinued if administered for more than several weeks, since rebound gastric hyperacidity will lead to symptoms even in normal individuals.46 Weaning slowly over several weeks to months is recommended. Antacids, histamine-2-receptor blockers, and PPI’s may be used for symptomatic relief in older children and adolescents with nonerosive reflux disease. The efficacy of medical therapy for supraesophageal complications of GER is controversial in children and adults, as discussed previously. PPI therapy has been shown to improve a variety of symptoms and decrease pneumonia in patients with neurodevelopmental delay.47,48
Surgical Therapy
Surgical therapy uses one of several antireflux procedures depending on the preference of the surgeon and type of patient.49,50-52 The most frequently performed procedure is the Nissen fundoplication (Figs. 394-4 and eFig. 394.3 ). The operative mortality associated with Nissen fundoplication, the most commonly performed antireflux surgical procedure, is about 1%. Major complications include breakdown of the wrap, which occurs in 4% to 12%, intrathoracic herniation of the wrap, slipping of the wrap over the body of the stomach, and bowel obstruction. Other complications include gas bloat with postprandial discomfort, dysphagia, gagging, or retching. Dumping syndrome and feeding refusal may also follow antireflux surgery. In general, the risks of all complications appear to be lower in normal patients than in those patient groups most likely to require fundoplication, including patients with severe neurologic disease, esophageal atresia, and chronic lung disease caused by bronchopulmonary dysplasia, cystic fibrosis, or asthma. It appears that the presence of forceful vomiting with associated autonomic signs of pallor and tachycardia, rather than regurgitation, predicts persistent postoperative retching dysfunction following fundoplication.53 Laparoscopic fundoplication reduces the morbidity and shortens the hospital stay of pediatric patients undergoing antireflux surgery and is therefore preferable when available.
FIGURE 394-4. The Nissen fundoplication operation. A: The lower esophagus is mobilized, allowing the fundus of the stomach to be pulled up and around the lower esophagus. B and C: The fundal wrap has sutures placed to form a collar around the lower esophagus. The tightness and length of the collar vary among surgeons.
Gastrostomy with gastrojejunal tube feedings is an alternative to gastrostomy with fundoplication. Another recently described option for children who are at severe risk of aspiration and do not feed by mouth is esophageal-gastric separation with the creation of a Roux-en-Y to the intestine for esophageal drainage. No pediatric studies compare the long-term outcome, costs, or risks of long-term medical therapy versus surgical therapy in those children who respond to medical therapy, but adult studies suggest that in many instances, prolonged medical therapy is more cost effective and has lower overall morbidity.
INFLAMMATORY DISORDERS OF THE ESOPHAGUS OTHER THAN GERD
A variety of infections, caustic agents, and other systemic inflammatory disorders are associated with esophageal inflammatory disease. Systemic disorders, including Behçet disease, Crohn disease, graft-versus-host disease, sarcoidosis, and chronic granulomatous disease, are discussed elsewhere. Esophageal involvement may occur with most skin diseases that affect the oral cavity (eg, epidermolysis bullosa, Stevens-Johnson syndrome). Infections causing esophagitis in the immunosuppressed patient are discussed in the next section, but severe mucosal inflammation commonly results from chemotherapy and radiation therapy. Graft-versus-host disease following bone marrow transplant may also cause acute or chronic esophagitis. All of these can cause substantial chronic inflammation with resultant esophageal stricture.
INFECTIONS OF THE ESOPHAGUS
Infections of the esophagus are rare except the immunocompromised host.54 The typical presenting symptoms of esophageal infection are dysphagia and odynophagia. Other presentations of esophageal infection include hematemesis and chest pain. The most common infectious agents causing esophagitis include candida, herpes simplex and cytomegalovirus. Other potential agents include tuberculosis; varicella-zoster virus; human papillomavirus; human immunodeficiency virus (HIV); Epstein-Barr virus; and Staphylococcus, Streptococcus, Nocardia, Trypanosoma, Leishmania, Cryptosporidium, and Blastomyces species. Risk factors for esophageal infections include hematologic malignancy,55 radiation or chemotherapy, and immunodeficiency, especially due to HIV or chronic mucocutaneous candidiasis. Patients with severe malnutrition, diabetes mellitus, esophageal stasis from disorders such as achalasia or scleroderma, and those receiving inhaled56 or systemic corticosteroids or acid-suppressive medications are at increased risk for candida esophagitis. Definitive diagnosis of the cause of infectious esophagitis usually requires endoscopic examination with viral culture, immuno-fluorescent staining, and cytology to identify the causative organism. Occasionally, more than 1 agent may cause infection, as occurs in herpes simplex or cytomegalovirus in which candidal infection may overlay the viral-induced ulcer.57Treatment and complications of infection with each pathogen are discussed in Section 17. The management of the most common infections affecting the esophagus is discussed below.
CANDIDA ESOPHAGITIS
Candida esophagitis is usually caused by Candida albicans but other Candida species may also cause esophagitis. Because oropharyngeal candidiasis is present in only about half of those with esophageal candidal infection, the absence of oral lesions dose not exclude disease. In the immunocompromised patient with HIV or malignancy, candidal esophagitis is the most frequent cause of the new onset of dysphagia, and empiric therapy with fluconazole is therefore recommended prior to any diagnostic evaluation if the patient has no systemic symptoms.54,58 If no improvement occurs after 2 to 3 days of therapy, then endoscopy is indicated to rule out other causes of symptoms. Rarely, candidal esophagitis may cause feeding refusal in otherwise healthy infants.59 Candida esophagitis is characterized on radiographic contrast studies by findings of discrete plaques distributed along the esophageal wall. The endoscopic appearance of candidal esophagitis ranges from a few scattered white plaques overlying a normal mucosa to a thick, cottage cheese–appearing pseudomembrane overlying an ulcerated mucosa (eFig. 394.4 ). Histology demonstrates evidence of acute and chronic inflammation with ulceration. Both budding yeast and hyphae forms are usually present. Cultures of the tissue do not differentiate between commensal or infectious status for Candida and therefore are helpful only in determining drug sensitivity. If there are no systemic symptoms, candida esophagitis is usually responsive to treatment with fluconazole. Invasive candidal esophagitis with systemic symptoms such as fever is usually responsive to treatment with fluconazole for 2 weeks but in more severe cases either amphotericin or caspofungin are effective.60
HERPES ESOPHAGITIS
Herpes simplex virus type 1 is the second-most common cause of infectious esophagitis in the immunocompromised host. It may also cause the acute onset of severe dysphagia and odynophagia in immunocompetent children and adolescents.61,62 Herpes simplex virus type 1 causes vesicles and discrete, sharply demarcated ulcers with a surrounding raised edge or halo that are visualized both radiographically and by endoscopy. In more severe cases, a diffuse hemorrhagic esophagitis denudes the mucosa entirely. Biopsies taken from the ulcer margin may demonstrate ballooning degeneration, ground glass–appearing intranuclear (Cowdry type A) bodies, and multinuclear giant cells. Brushing and biopsy specimens should be routinely placed in special viral media for culture of herpes simplex virus to establish a diagnosis. More specific techniques for the identification of herpes simplex virus, including monoclonal antibody identification of infected cells and in situ hybridization for herpes simplex virus DNA, improve the diagnostic yield.
Herpes simplex esophagitis symptoms usually resolve within 1 to 2 weeks in the immuno-competent patient. Treatment with topical analgesia is effective, but if initiated early in the course, acyclovir, valacyclovir, or famciclovir shorten the disease course. In immunocompromised patients, the infection usually will not resolve without therapy or the return of normal immune activity. Acyclovir is effective in treating most patients, with symptoms usually resolving within the first week of therapy. Acyclovir prophylaxis following bone marrow and solid-organ transplantation has diminished the frequency of herpes simplex virus esophagitis in the immediate posttransplant period for seropositive patients. Herpes simplex virus strains that are resistant to acyclovir have been treated with foscarnet, but foscarnet-resistant strains also have emerged. Vidarabine is an alternative treatment in these patients. Acid suppressors may be used as adjunctive therapy for symptoms of gastroesophageal reflux, but long-term therapy should be avoided because it predisposes to esophageal fungal infection.
CMV ESOPHAGITIS
Cytomegalovirus esophagitis may cause ulceration of the esophagus in the immunocom-promised host.63,64 The ulcers are much larger in size than those typical of herpes simplex virus. Serology and culture of blood, urine, or stool may suggest the diagnosis of cytomegalovirus, but endoscopy with biopsy is required for diagnosis. Histologic examination of cells infected with cytomegalovirus (CMV) reveals distinctive abnormalities that include cellular enlargement and inclusion bodies in both the nucleus and the cytoplasm. Monoclonal antibodies to CMV and CMV DNA hybridization improve diagnostic yields of biopsy. CMV esophagitis is treated with ganciclovir or foscarnet. However, therapeutic response is often slow, and the disease recurs unless the underlying immune deficiency is corrected.
HIV ESOPHAGITIS
HIV esophagitis is observed in infected patients with CD4 counts of less than 100, or those with primary infection may develop large esophageal ulcers in the absence of a clear infectious agent.65 The inflammatory infiltrate contains both CD4+ and CD8+ T cells and cytotoxic molecule perforin. HIV antigen p24 is also present in the inflammatory infiltrate, strongly suggesting that infiltration of the esophageal mucosa with activated T cells causes ulceration.66Oral corticosteroid treatment usually heals the lesions when antiretroviral therapy is not effective.
PILL-INDUCED ESOPHAGITIS
Medication in pill form may occasionally lodge in the esophagus, dissolve, and cause significant inflammation (Fig. 394-5).67 Typically, patients complain of the acute onset of severe dysphagia and chest pain. Occasionally, patients have relatively little pain and can present with stricture. Most children have no underlying esophageal disease, but those with esophageal narrowing because of esophageal strictures, achalasia, or motility disorders are at increased risk. The more common pills associated with pill-induced esophagitis are tetracycline, doxycycline,68 aspirin, nonsteroidal anti-inflammatory agents, slow-release potassium preparations, and guar gum–containing diet pills. The primary cause of injury is associated with adherence of the pill to the esophageal mucosa, with dissolution of the pill resulting in local irritation. Contributing factors include taking pills with little or no fluid, taking pills late at night when there is decreased salivation, and lying down shortly after taking a pill. Typically, symptoms start shortly after ingestion and include retrosternal pain and dysphagia. A characteristic history and knowledge of the pill types that commonly are associated with pill esophagitis is usually sufficient for diagnosis. When the diagnosis is in doubt, endoscopy is the most sensitive diagnostic test and may demonstrate findings ranging from erythema to esophageal ulceration. Symptoms generally resolve within 1 to 3 weeks of discontinuing pill administration or with improved approaches to taking pills when continued ingestion of medication is necessary. Acid blockers or local anesthetics may be helpful in patients with severe symptoms.
FIGURE 394-5. Endoscopic photograph of pill esophagitis from ingestion of alendronate. (Reprinted with permission from Gastrolab, Vasa, Finland: http://www.gastrolab.net.)
CORROSIVE ESOPHAGITIS
Ingestion of strong caustic agents (Table 394-3) can injure the esophagus and stomach, as well as damage the airway.69 The American Association of Poison Control Centers reports close to 20,000 caustic ingestions per year in children under 6 years of age. In young children or those with developmental delay, ingestion is usually accidental, whereas in adolescents, intestinal ingestion may occur as a suicide attempt. Acids have a disagreeable taste, usually cause immediate pain, and are rapidly expelled unless intentionally ingested. In contrast, alkali agents are tasteless and odorless, so they are swallowed without difficulty. Acids cause coagulation necrosis of the mucosa, with an eschar forming that limits the depth of injury. The injury more often involves the body and antrum of the stomach, sparing the fundus. In about 20% of acid ingestion, there is esophageal injury. Alkalis produce liquefactive necrosis with intense inflammation of the surrounding tissue and thrombosis of adjacent vessels, which may result in further necrosis. Granular alkalis such as those in drain cleaners usually cause focal injury that is limited to the oropharynx or proximal esophagus but may result in more diffuse esophageal and gastric injury. Liquid alkali ingestion is more likely to cause severe injury to the entire esophagus and stomach. The stomach is not significantly protected by its own acid production because the neutralizing capacity of gastric acid is insignificant compared with the alkalinity of even small volumes of strong alkalis.
Table 394-3. Common Caustic Agents Ingested by Children
|
Alkalis |
|
Sodium hydroxide |
|
Potassium hydroxide (batteries) |
|
Calcium hydroxide (cement) |
|
Dishwasher detergents |
|
Drain pipe cleaners |
|
Dairy pump cleaners |
|
Oven cleaners |
|
Powdered laundry detergents |
|
Photographic developer |
|
Acids |
|
Automobile batteries |
|
Toilet bowel cleaners |
|
Disinfectants |
|
Drain cleaners |
|
Rust removers |
|
Metal cleaners |
|
Concrete cleaners |
|
Glass etching |
|
Jewelry cleaners |
|
Fertilizer |
|
Other industrial cleaners |
|
Caustic Agents That Generally Do Not Damage the Esophagus |
|
Sodium hypochlorite (household bleach) |
|
Hair relaxants |
CLINICAL FEATURES AND MANAGEMENT
Symptoms following caustic ingestion include oral pain, ulcerations, drooling, dysphagia, vomiting, and abdominal pain. Concurrent airway damage may also cause symptoms of stridor, retractions, and nasal flaring or hoarseness. The symptoms may develop rapidly or be delayed for several hours. However, clinical manifestations are poor predictors of esophageal injury. The presence or absence of oral cavity burns is not useful to predict whether there is esophageal damage, since over half of children with esophageal burns following caustic ingestions have no oral lesions.69,70-71
The management approach for caustic ingestion varies depending on symptoms and patient age. Emetics and buffers should not be given because of the risk of vomiting with subsequent aspiration and because of the excessive heat production that can result from neutralization. Issues of airway and circulatory stabilization must be addressed with severe ingestion. If there are airway symptoms such as stridor, emergent evaluation and stabilization of the airway is mandatory. In young children with a questionable history of ingestion, no symptoms, and no physical findings, observation for several hours usually indicates that there is not substantial esophageal damage.72 In these children, additional evaluation is unnecessary if they have the ability to tolerate clear liquids. Parents should receive instructions to obtain follow-up evaluation if there is any suggestion of airway compromise or dysphagia. Ingestion of bleach or hair relaxants is rarely associated with significant adverse effects, so these patients may also be observed with no further intervention.73,74 Patients with symptoms require admission, intravenous hydration, and observation for airway symptoms. Nasogastric tubes should not be passed in the acute setting because they may perforate a damaged esophagus or stomach. If the child has upper airway symptoms, corticosteroids may be helpful, and intubation or tracheostomy may be necessary.
Endoscopic evaluation is recommended between 12 and 36 hours after ingestion to allow evaluation of the degree of esophageal injury. Earlier endoscopy may not adequately define the full extent of injury, since injury may evolve over the first 12 hours; esophagoscopy after 48 hours is associated with increased risk of perforation. Endoscopic findings are graded by convention as no injury, grade I (superficial erythema or mucosal hyperemia), grade IIa and IIb (shallow linear and circular ulcers limited to the mucosa), or grade III (ulceration deep into the muscle or transmural perforation).75 Most perforations occur within 48 hours following ingestion and are associated with symptoms of mediastinitis or peritonitis. Emergent surgical treatment for perforation or transmural necrosis is mandatory. Patients with grade II or III injury should not be fed orally.76 If the injury is severe, prolonged periods of enteral or parenteral nutrition may be required. A naso-gastric or nasojejunal tube may be placed safely in some patients at the time of endoscopy. Alternatively, surgical gastrostomy or jejunostomy may be performed. Treatment with broad-spectrum antibiotics is routinely recommended to prevent bacterial invasion of the esophageal mucosa. Prospective studies in children77 and a large meta-analysis show no benefit for corticosteroid treatment.78 Some physicians have advocated early esophageal dilation to prevent stricture formation, but early dilation appears to carry an increased risk for perforation. Those patients with circumferential lesions at presentation are at risk for esophageal stricture. Typically, these develop at 2 to 8 weeks following the initial ingestion.
Chronic strictures may require serial dilations initially to establish patency, and in some patients, dilation will be needed chronically to maintain the adequate lumen diameter.79 More severe strictures may require esophagectomy with esophageal replacement by gastric or colon interposition.80 Alternatively, severe strictures may be managed by stenting,81 although this approach is controversial. Long-term outcomes depend on the degree of stricture formation and response to dilation. In all cases, there appears to be an increased risk for esophageal carcinoma as adults; however, regular endoscopic screening of patients with a history of corrosive esophagitis is not currently recommended.82
EOSINOPHILIC ESOPHAGITIS
Eosinophilic esophagitis is characterized by an intense eosinophilic infiltrate of the esophageal wall. It is a transmural process that differs from GERD and has been increasingly recognized in children and adults since 1995 when it was described in children.83 It is unclear whether the increasing frequency of diagnosis represents an actual increased incidence or improved recognition of a disease entity that was previously incorrectly diagnosed as GERD.84,85
PATHOPHYSIOLOGY AND GENETICS
Eosinophilic esophagitis (EE) affects boys more often than girls by a ratio of 3–4:1. Patients commonly have a personal and family history of atopy. Both food allergies and aeroallergens may be triggers of EE. Eotaxin-3 and interleukins 5 and 13 appear to be involved in the pathogenesis of the disease such that related pathways may provide future therapeutic targets.86,87
CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
The clinical presentation of eosinophilic esophagitis (EE) is similar to but distinct from that of GERD (Table 394-4) with symptoms of abdominal pain, nausea, vomiting, and growth failure. Common symptoms include feeding refusal in infants, gagging, and solid food aversion in preschool children and dysphagia in adolescents.88,89 In up to 6% of children presenting with EE, dysphagia and food impaction are caused by esophageal stricture resulting from intramural fibrosis.90 The initial diagnosis requires esophageal biopsy, since there are no characteristic serologic or radiologic markers. The esophagoscopy reveals a combination of characteristic visual features: edema and linear furrowing throughout the entire esophagus, a ringed (trachealization) appearance, and white adherent plaques that represent superficial eosinophilic abscesses.91,92 The density and location of esophageal eosinophilia differ that of peptic esophagitis, with density being generally higher in EE (≥ 15 eosinophils/hpf) with involvement of the entire proximal to distal esophagus, whereas in peptic esophagitis, eosinophilic density is lower (< 7/hpf) and limited to the distal esophagus just above the gastroesophageal junction.92,93Other histopathologic changes of acid-related reflux (ie, basal cell layer hyperplasia and increased papillary height) are found in both conditions.93,94 Esophageal pH monitoring may be normal in EE, but an abnormal study does not exclude it because poor acid clearance may be secondary to esophageal dysmotility from inflammation.95
TREATMENT
Allergy testing may identify likely allergic causes of eosinophilic esophagitis, in which case, treatment begins with a trial of an elimination diet. Patch testing may be more sensitive than scratch or serologic allergy testing for identification of involved allergens, but it is not universally available. An alternative strategy of eliminating common food allergens has also proven successful.96 In infants, a trial of an elemental or hypoallergenic formula is often useful, but the use of these formulas in older children and adolescents is difficult because of problems with adherence. Antisecretory therapy with proton pump inhibitors may lead to symptomatic improvement in some patients, but the esophagitis does not improve, so risk of disease progression and stricture continues. Treatment with either systemic or topical corticosteroids is usually effective,97,98-99 and topical therapy, using agents such as inhaled fluticasone propionate or swallowed beclomethasone, is preferable to systemic therapy. Issues such as ability to adhere to therapy, perceived effects on quality of life, and cost of elemental diets need to be considered while making treatment choices for an individual patient.100 Unfortunately, confirmation of an adequate treatment response requires repeated esophageal biopsies. Refinement of the diagnostic criteria may allow for more focused treatment. There is currently is no consensus approach to treatment or ongoing management. It is unclear if a goal of complete mucosal healing is appropriate, but currently, most experts hope to achieve both symptom resolution and mucosal healing. It does not appear that children outgrow eosinophilic esophagitis, so recurrence is common within months of treatment cessation.
Table 394-4. Comparison of Features of Gastroesophageal Reflux with Eosinophilic Esophagitis