Chagas gastrointestinal disease

INTRODUCTION — Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi; the major manifestations are Chagas cardiomyopathy and gastrointestinal disease [1].

Issues related to the epidemiology and prevention of Chagas disease, acute and chronic Chagas infection, and cardiac Chagas are discussed separately. (See "Chagas disease: Epidemiology, screening, and prevention" and "Chagas disease: Acute and congenital Trypanosoma cruzi infection" and "Chagas disease: Chronic Trypanosoma cruzi infection" and "Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis" and "Chronic Chagas cardiomyopathy: Management and prognosis".)

EPIDEMIOLOGY — Among individuals with the chronic indeterminate form of Chagas disease, approximately 30 percent progress over a period of one to three decades to clinically evident cardiac involvement, digestive involvement, or both [2]. Gastrointestinal involvement is less common (10 to 21 percent). The mortality associated with Chagas gastrointestinal disease is low, but symptoms can considerably impact the quality of life. It is relatively rare in the setting of reactivation of chronic T. cruzi infection among organ transplant recipients or in patients with HIV infection, although there are reports of parasitic invasion of the peritoneum, intestine, stomach, esophagus, or larynx. (See "Chagas disease in the immunosuppressed host".)

The likelihood of digestive involvement may vary by region [3]. The digestive form is observed more frequently in the countries of the Southern Cone of South America and is rare in northern South America, Central America, and Mexico [4]. A high prevalence has been observed in the central region of Brazil. This geographic pattern is thought to be due to the distribution of different T. cruzi genotypes [5].

The burden of the gastrointestinal form can be enormous for some countries. In one study that evaluated hospitalization rates due to Chagas disease in Brazil between 2017 to 2019, there were 0.6 hospitalizations per 100,000 inhabitants, with significant regional variation. Hospitalizations increased with age and were slightly higher in males. More than 60 percent were emergencies and 50 percent were surgical procedures. In-hospital mortality was 5.8 percent and 17.2 percent went to intensive care units [6].

However, the risk for travelers to endemic countries is extremely low (≤0.8 per 1000 traveler-days) [7].

PATHOGENESIS — Both parasite and host factors are thought to influence the development of gastrointestinal manifestations and the severity of disease. Molecular techniques have demonstrated the presence of parasite DNA in digestive tissues, which correlates with inflammatory infiltrate and degree of denervation [8,9].

The parasite burden likely influences the degree of inflammation and progression of disease. In addition to parasite-dependent inflammation, there is an immune-mediated tissue injury resulting from cross-reactivity between parasite antigens and enteric neuron surface proteins [10]. Moreover, the occurrence of gastrointestinal manifestations in certain geographical areas has been attributed to variations in parasite strains [11].

The pathogenesis of disease consists of destruction of the neurons of the enteric nervous system. Both sympathetic and parasympathetic nerves are involved, and denervation occurs in both the submucosal (Meissner) and myenteric (Auerbach) plexuses. A significant reduction in the number of interstitial cells of Cajal has been demonstrated; these cells play an important role in the modulation of digestive tube motility. Histologically, neuronal reduction and focal areas of fibrosis in the smooth muscle and myenteric plexuses have been described, along with lymphocytic infiltrates at the submucosal, myenteric plexus, and smooth muscle levels. In addition, the muscularis mucosa can become hypertrophic, likely a compensatory mechanism [12]. Denervation occurs to variable degrees; it is irregular and noncontinuous. The esophagus and the distal colon are the most frequently involved segments.

The digestive form of Chagas disease is characterized by alterations in the motor, secretory, and absorptive functions of the gastrointestinal tract. Uncoordinated motor activity of the sphincters occurs as a result of denervation. In the esophagus, there is hypercontractility and increased muscular tone, and often there is failure of sphincter relaxation with swallowing. In the large intestine, there is abnormal basal colonic motility and impaired relaxation of the anal sphincter. Progressive dilation of the esophagus and colon occurs, with reduction of contractility [13,14].

Cellular interactions and molecular pathways involved in megacolon development/progression are not completely clear. Several biomarkers and their possible functions in the intestinal microenvironment of the chagasic megacolon have been described [15]. The presence of NOD2 innate immune receptors seems to play a protective role against the development of the digestive form of Chagas disease [16]. It has been suggested that T. cruzi infection results in alterations to the intestinal microbiome, which play a role in inflammation [17].

CLINICAL MANIFESTATIONS — Transient gastrointestinal symptoms (eg, dysphagia and retrosternal pain, abdominal pain, and diarrhea) can occur during the acute phase of infection [18,19]. However, significant gastrointestinal manifestations of Chagas disease are mainly associated with the chronic phase of infection. Manifestations range from asymptomatic motility disorders to severe dilatation of the esophagus and colon. (See "Chagas disease: Chronic Trypanosoma cruzi infection".)

Disease onset and progression — The onset of symptoms is most common between the ages of 20 and 40 years but can occur earlier. Any part of the digestive system may be affected; the esophagus and colon (particularly the rectum, sigmoid colon, and descending colon) are the most frequently involved sites. Esophageal involvement is more common than colonic involvement [13,20]. Disease progression is usually slow. In a retrospective study of 379 patients with the indeterminate chronic form followed up to 10 years, 100 (26.4 percent) and 87 (22.9 percent) progressed to digestive and cardiac forms, respectively. Female sex was the only independent predictor of progression to digestive forms (hazard ratio, 1.56). Benznidazole treatment was statistically protective for progression to cardiac, but not to digestive forms [21].

Esophageal manifestations — Esophageal manifestations of Chagas disease are similar to patients with idiopathic achalasia. Patients with minor motility abnormalities may be asymptomatic but develop progressive dysphagia and regurgitation due to neuronal loss. Dysphagia occurs initially with solids but eventually also develops with liquids. Affected patients eat more slowly and often adopt specific maneuvers such as lifting the neck or throwing the shoulders back in order to enhance esophageal emptying. Regurgitation of bland undigested food or saliva is common and, in severe cases, may result in aspiration. As the disease progresses, food may become lodged in the esophagus and cause retrosternal pain due to local irritation, ulceration, bleeding, perforation, and fistulas. In end-stage disease, malnutrition can develop [13]. Patients with megaesophagus also have an increased risk of esophageal cancer. PIK3CA gene mutations have been found to have a putative role in esophageal squamous cell carcinoma development in chagasic patients with megaesophagus [22]. (See "Achalasia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

Colonic manifestations — Colonic involvement of Chagas disease results in progressive dilation. The sigmoid colon is dilated and elongated in nearly all cases of megacolon; the rectum is involved in 80 percent of cases. Dilation of more proximal colonic segments is rare. Intestinal constipation is one of the main reasons for seeking medical evaluation. Patients usually present with slowly progressive constipation until stool evacuation becomes almost impossible. As the disease progresses, patients may report several weeks between bowel movements. This may be accompanied by bloating and, less often, colicky abdominal pain. In a minority of patients, prolonged stool retention can lead to fecalith formation. Patients usually have mild abdominal discomfort or rectal fullness and can be diagnosed by abdominal palpation and rectal examination. Fecaloma-associated stercoral ulceration can occur, and overflow diarrhea can result from fecal retention. In rare cases, pseudo-obstruction results and volvulus can lead to secondary bowel ischemia. Anorexia and malnutrition can also develop.

The prevalence of megacolon is not known because of diagnostic difficulties in remote areas. Symptoms may be absent in 25 to 30 percent of individuals with radiographic evidence of colonic dilatation. Most cases of megacolon are associated with megaesophagus [3]. An increased frequency of colorectal cancer has not been reported in patients with megacolon [23].

Other manifestations — Other parts of the digestive tract can be involved, including the stomach, small bowel, biliary tree, and salivary glands. However, symptoms secondary to involvement of these organs is rare.

●Stomach – Approximately 20 percent of patients with megaesophagus have gastric involvement. Gastric manifestations may include altered myoelectrical activity (gastric dysrhythmias), alterations in gastric emptying, distension, hypoperistalsis, hypochlorhydria, and eventually pyloric hypertrophy [24].

●Small intestine – Involvement of the small bowel (Chagas enteropathy) has also been reported, with or without dilatation. Small intestinal bacterial overgrowth and chronic intestinal pseudo-obstruction can cause abdominal pain, bloating, and distension [25]. (See "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis", section on 'Clinical features' and "Chronic intestinal pseudo-obstruction: Etiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

●Biliary tract – Cholecystomegaly and choledochodilation are rare. An increased prevalence of cholelithiasis has been reported among patients with Chagas disease [13].

●Salivary glands – Hypertrophy of the salivary glands develops in up to 25 percent of individuals with megaesophagus; the esophageal salivary reflex produces hypersalivation [26].

DIAGNOSIS — Chagas gastrointestinal disease should be suspected in individuals with gastrointestinal symptoms who have lived in endemic countries of Latin America and those born to women from endemic countries. Symptoms consistent with gastrointestinal Chagas disease include dysphagia, odynophagia, regurgitation, progressive constipation, or its complications (eg, sigmoid volvulus and bowel ischemia). There is no diagnostic test to establish gastrointestinal involvement of Chagas disease. A presumptive diagnosis of Chagas disease can be made in patients with motor abnormalities that are consistent with Chagas disease and positive laboratory diagnosis of chronic Chagas disease. Issues related to laboratory diagnosis of chronic Chagas disease is discussed in detail separately. (See "Chagas disease: Chronic Trypanosoma cruzi infection", section on 'Diagnosis'.)

EVALUATION FOR GASTROINTESTINAL INVOLVEMENT — Patients with a diagnosis of chronic T. cruzi infection by serologic testing should be assessed for the presence of gastrointestinal symptoms [27]. (See "Chagas disease: Chronic Trypanosoma cruzi infection".)

Our approach — Evaluation for gastrointestinal involvement may be considered in patients from countries where the gastrointestinal form of Chagas diseases is frequent (mainly the Southern Cone of South America) in the presence or absence of symptoms; megacolon and megaesophagus can be present in up to 20 percent of asymptomatic patients [28,29].

Whether to perform barium esophagram and colon enema on every patient or to limit those studies only to patients with symptoms consistent with gastrointestinal Chagas disease depends on the prevalence of digestive involvement in the country of origin. Brazilian guidelines recommend a barium enema for all patients with chronic Chagas disease [30]. Patients who are asymptomatic should be reassessed annually for gastrointestinal symptoms; each year approximately 2 percent of patients develop clinical manifestations of the disease and there are no known markers of disease progression. Symptoms consistent with gastrointestinal Chagas disease include dysphagia, odynophagia, regurgitation, weight loss, aspiration, cough, progressive constipation, or its complications (eg, fecaloma, sigmoid volvulus, and bowel ischemia) [31]. Patients at risk for Chagas disease with proven achalasia should be tested for T. cruzi infection [32]. (See "Chagas disease: Chronic Trypanosoma cruzi infection", section on 'Diagnosis'.)

In patients with upper gastrointestinal symptoms, we perform esophageal manometry and a barium esophagram. In addition, we perform an upper endoscopy to exclude a malignancy at the esophagogastric junction that can mimic Chagas disease. (See 'Patients with suspected esophageal involvement' below.)

Evaluation for colonic involvement due to Chagas disease consists of contrast-enhanced imaging (eg, computed tomography scan, barium enema). In addition, we perform a colonoscopy to exclude a mechanical obstruction and complications associated with megacolon. Anorectal manometry can be considered but is not diagnostic and cannot distinguish Chagas from other causes of pelvic floor dyssynergia in constipation.

Patients with suspected esophageal involvement

Barium esophagram — Finding on barium esophagram in patients with Chagas are similar to patients with idiopathic achalasia and include (see "Achalasia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Barium esophagram'):

●Dilation of the esophagus (image 1)

●Narrow esophagogastric junction with "bird-beak" appearance caused by the persistently contracted lower esophageal sphincter (LES)

●Aperistalsis

●Delayed emptying of barium (There is a linear correlation between the transit time and the grade of the megaesophagus, from 300 seconds in stage I to >33,000 seconds in stage IV [29].)

Four stages of Chagas disease are recognized based on the findings on barium esophagram noting the degree of megaesophagus and severity of motor abnormalities [33]. The degree of megaesophagus is associated with the severity of dysphagia but does not reflect the duration of the disease.

●Stage I (delayed emptying) – Normal diameter of esophagus (<10 cm); minimal contrast retention; presence of a residual air column above the contrast

●Stage II (moderate esophageal enlargement with motor incoordination) – Moderate dilatation, with some contrast retention; increase in uncoordinated motor activity; relative hypertonicity of the inferior third of the esophagus

●Stage III (hypotonic and large achalasic esophagus) – Large increase in diameter and substantial contrast retention; hypotonic esophagus with weak or absent motor activity

●Stage IV (atonic esophagus) – Large increase in volume, atonic, elongated esophagus lying on the right diaphragmatic dome

Esophageal manometry — Esophageal manometry can provide quantitative information regarding esophageal function; changes in esophageal motility may be present even in asymptomatic patients [2,34,35]. In addition, it can diagnose other motility disorders that can cause dysphagia. It is difficult to distinguish between idiopathic achalasia and achalasia secondary to Chagas by esophageal manometry; however, the LES pressure is usually low in patients with Chagas disease and high in patients with idiopathic achalasia [35].

Diagnostic manometric findings of achalasia include a nonrelaxing or partially relaxing LES and aperistalsis upon deglutition. (See "Achalasia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Esophageal manometry'.)

Esophageal manometry can demonstrate mild esophageal motor abnormalities that are not detected by barium swallow [36]. In patients without esophageal dilation, nonspecific esophageal motor abnormalities include multipeaked peristaltic contractions, aperistalsis limited to the lower esophagus plus a relaxing LES, and total aperistalsis with a relaxing LES. The basal LES pressure in Chagas is usually normal or slightly lower than normal. However, in patients with achalasia and massive dilated megaesophagus there is not a well-defined manometric pattern (while the upper esophageal sphincter is hypotonic and has impaired relaxation in the majority of patients, the lower sphincter does not have a characteristic manometric pattern) [37].

Upper gastrointestinal endoscopy — Finding on upper endoscopy in patients with Chagas are similar to patients with idiopathic achalasia and include a dilated esophagus that contains residual material, sometimes in large quantities. The appearance of the LES may range from normal to a thickened muscular ring with a rosette configuration on retroflexed view. This technique has a very high sensitivity but a low specificity to diagnose megaesophagus.

The following classification has been proposed for staging megaesophagus [38]:

●Stage I – Greater salivary retention, presence of reduced peristaltic waves, and no dilatation

●Stage II – Mild dilation with greater retention of liquids and possibly food residue

●Stage III – Upstream dilatation with difficulty of passage of the endoscope through the cardia

●Stage IV – Clear esophageal tortuosity mainly in the distal third of the esophagus

Histologic sections may demonstrate a nonspecific chronic inflammatory infiltrate, but parasites are rarely seen [39]. (See "Achalasia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Upper endoscopy'.)

Patients with suspected colonic involvement

Contrast radiography — Conventional abdominal radiography may demonstrate increased luminal air; fecaloma can also be visualized, if present. Findings suggestive of Chagas disease on contrast-enhanced abdominal imaging (eg, computed tomography scan, magnetic resonance imaging, or barium enema) include decreased bowel haustra and a dilated, atonic colon [40]. Dilatation usually occurs in the distal colon, including sigmoid and rectum; rarely, dilatation occurs in other segments or in the entire colon. Megacolon is defined as a sigmoid colon or descending colon diameter >6.5 cm, ascending colon >8 cm in diameter, or cecum >12 cm in diameter. Dilatation is frequently associated with an increase in colon length. Dolichocolon is defined as a length from the anus to the transition to the descending colon >70 cm.

Three radiographic stages have been proposed [33]:

●Stage 0 – No alterations in barium enema

●Stage I – Dolichocolon

●Stage II – Dolichomegacolon

Colonoscopy — Finding on colonoscopy in patients with Chagas are nonspecific. Histology may demonstrate a nonspecific chronic inflammatory infiltrate, but parasites are rarely seen.

Anorectal manometry — The main findings are anorectal motor dysfunction and abnormal anorectal inhibitory reflex (a normal anorectal inhibitory reflex is defined as sphincter pressure drop superior to 20 mmHg below the resting pressure). However, these motor abnormalities are nonspecific and are seen in patients with chronic constipation [28].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of esophageal motility abnormality associated with Chagas disease includes primary idiopathic achalasia and malignancy (pseudoachalasia). Esophageal involvement in Chagas disease can be differentiated from primary idiopathic achalasia by serology and from pseudoachalasia due to an esophagogastric malignancy with upper endoscopy. (See "Achalasia: Pathogenesis, clinical manifestations, and diagnosis".)

Megacolon can result from neurologic (eg, Parkinson disease, diabetic neuropathy), metabolic disorders, and systemic diseases (eg, systemic sclerosis). Other causes of colonic dilation include Ogilvie syndrome, mechanical obstruction, and toxic megacolon. Patients with mechanical obstruction and Ogilvie syndrome frequently complain of crampy abdominal pain. A "cut-off sign" (lack of gas in the distal colon or rectum) or small bowel air-fluid levels may be seen on abdominal radiographs. In patients with a mechanical obstruction, an obstructing lesion can be visualized with contrast enema. (See "Acute colonic pseudo-obstruction (Ogilvie's syndrome)".)

Patients with toxic megacolon have evidence of significant systemic toxicity with fever, tachycardia, altered sensorium, and abdominal pain. Patients with toxic megacolon often have a history of severe bloody diarrhea or other signs or symptoms of chronic inflammatory bowel disease. On abdominal upright and plain films, there is evidence of colonic distension, but the normal colonic haustral pattern is either absent or severely disturbed with "thumb-printing" due to the presence of submucosal edema or thickening of the colonic wall. (See "Toxic megacolon".)

MANAGEMENT — Antitrypanosomal therapy has not been proven to affect progression of gastrointestinal disease [21,41-43]. Management focuses on symptom amelioration (dysphagia in the case of megaesophagus and constipation in the case of megacolon) [30,44].

●Megaesophagus – The management of megaesophagus is similar to patients with idiopathic achalasia and is aimed at decreasing the resting pressure in the lower esophageal sphincter (LES) to a level at which the sphincter no longer impedes the passage of ingested material. Treatment approaches include dietary measures, pharmacologic treatment, and endoscopic/surgical interventions. Dietary measures for all patients with achalasia include eating slowly in an upright position, chewing food well, avoiding hard and dry foods, drinking water during or after meals (as that may aid with food ingestion), and avoiding lying down shortly after eating.

Patients with stage I and II may have a good response with dietary changes and pharmacologic treatment. Pharmacologic therapy with isosorbide and nifedipine are effective in reducing esophageal symptoms by lowering esophageal sphincter pressure; isosorbide appears to be more effective, however, nifedipine appears to be better tolerated [45].

Patients with stage III and IV, and some with stage I and II, nonresponsive to dietary changes and/or pharmacologic treatment, usually require additional intervention.

For patients with advanced-stage megaesophagus (stage IV) who have average surgical risk, preferred options for treatment include laparoscopic Heller myotomy with a partial fundoplication, and peroral endoscopic myotomy (POEM) [36]. In Chagas patients with achalasia, POEM may be more effective than surgical myotomy [46]. However, the choice of initial procedure depends on local expertise. If laparoscopic myotomy or POEM fails to improve symptoms, a more complex surgical procedure is required (eg, esophagectomy) [13,47]. Pneumatic dilation is an option for patients with stage I to III disease but should be avoided in stage IV due to the risk of perforation. (See 'Esophageal manifestations' above and "Overview of the treatment of achalasia" and "Surgical myotomy for achalasia", section on 'Sigmoid megaesophagus'.)

Since basal lower esophageal sphincter pressure is already lessened in most Chagasic patients with megaesophagus, the endoscopic injection of botulinum toxin is expected to have a minimal effect on them. There is no study on the long-term effects of this approach in a large number of Chagas disease patients [48].

●Megacolon – Constipation due to megacolon can be improved with physical activity, a high-fiber diet, abundant fluid intake, pharmacologic therapy (eg, osmotic laxatives), and intermittent enemas or suppositories with glycerol [49]. Fecal impaction requires manual disimpaction. Indications for surgical intervention include severe persistent constipation refractory to medical therapy or complications secondary to fecalomas (eg, sigmoid volvulus, stercoral ulcer). Options for surgical intervention include rectosigmoidectomy with retrocecal interpositioning or rectosigmoidectomy with end-to-side low colorectal anastomosis [50].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chagas disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Chagas disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi. Transient gastrointestinal symptoms can occur during the acute phase of infection. However, significant gastrointestinal manifestations of Chagas disease are mainly associated with the chronic phase of infection. The likelihood of digestive involvement may vary by geographic region. (See 'Introduction' above and 'Epidemiology' above.)

●Pathogenesis – The pathogenesis of disease consists of destruction of the neurons of the enteric nervous system. Uncoordinated motor activity of the sphincters occurs as a result of denervation. In the esophagus, there is hypercontractility and increased muscular tone, and often there is failure of sphincter relaxation with swallowing. In the large intestine, there is abnormal basal colonic motility and impaired relaxation of the anal sphincter. (See 'Pathogenesis' above.)

●Clinical manifestations – The onset of symptoms is most common between the ages of 20 and 40 years but can occur earlier. Any part of the digestive system may be affected; the esophagus and colon (particularly the rectum, sigmoid colon, and descending colon) are the most frequently involved sites. Clinical manifestations of gastrointestinal Chagas disease include dysphagia, odynophagia, regurgitation, progressive constipation, and its complications (eg, sigmoid volvulus and bowel ischemia). (See 'Clinical manifestations' above.)

●Evaluation for gastrointestinal involvement – Patients with a diagnosis of chronic T. cruzi infection by serologic testing should be assessed for the presence of gastrointestinal symptoms. Evaluation for gastrointestinal involvement is indicated in patients with symptoms consistent with gastrointestinal Chagas disease. Whether to perform barium esophagram and colon enema on every patient or to limit those studies only to patients with symptoms consistent with gastrointestinal Chagas disease depends on the prevalence of digestive involvement in the country of origin. There is no diagnostic test to establish gastrointestinal involvement of Chagas disease. The tests performed for evaluation of gastrointestinal involvement of Chagas disease can diagnose motor abnormalities that are consistent with but not specific to Chagas disease. (See 'Evaluation for gastrointestinal involvement' above.)

●Our approach to diagnosis – In patients with symptoms suggestive of upper gastrointestinal Chagas (eg, dysphagia, odynophagia, regurgitation), we perform esophageal manometry and a barium esophagram. In addition, we perform an upper endoscopy to exclude a malignancy at the esophagogastric junction that can mimic Chagas disease. In patients with lower gastrointestinal symptoms, evaluation for colonic involvement due to Chagas disease consists of contrast-enhanced imaging (eg, computed tomography scan or barium enema) and anorectal manometry. In addition, we perform a colonoscopy to exclude a mechanical obstruction and complications associated with megacolon. (See 'Our approach' above and "Chagas disease: Chronic Trypanosoma cruzi infection", section on 'Diagnosis'.)

●Management - There are insufficient data to support that treatment with antitrypanosomal drugs affects progression of digestive Chagas disease. We suggest not administering antitrypanosomal therapy for patients with Chagas gastrointestinal disease (Grade 2C); management focuses on symptom amelioration. (See 'Management' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Caryn Bern, MD, MPH, who contributed to an earlier version of this topic review.