PART SIX Miscellaneous
41 Infections of the Luminal Digestive Tract C. Mel Wilcox and Christina Surawicz
CHAPTER OUTLINE Introduction, 454 Epidemiology, 454 Immune Competent Patients, 454 Immune Suppressed Patients, 454 Pathogenesis, 455 Clinical and Endoscopic Features, 456
Esophagus, 456 Stomach, 457 Small Intestine, 459 Colon, 461 Pathology, 461 Esophagus, 461
INTRODUCTION The diagnosis and management of luminal gastrointestinal (GI) tract infections has been an essential component of the practice of gastroenterology since the birth of the subspecialty. The emergence of endoscopy with mucosal biopsy as a safe and accurate diagnostic tool for patients with suspected infection has elevated the GI endoscopist to a key partner in the management team. The importance of the endoscopist may be best appreciated for patients who develop GI complications related to immune suppression, such as after organ transplantation, during chemotherapy, or with human immunodeficiency virus (HIV) infection. In these settings, infections are frequent, and the differential diagnosis and diagnostic approach to GI symptoms often differ from the normal host. This chapter provides an overview of GI infections from the endoscopist’s perspective based on organ systems because the clinical presentation generally points to the site of gut involvement and dictates the diagnostic strategy. Several common themes are applicable to most GI infections: 1. The clinical presentation is dictated by the infecting pathogen. 2. The specific immunodeficiency state, its pathophysiology, and severity dictate the spectrum of complicating pathogens. 3. The severity and chronicity of infection for an immunosuppressed patient are dictated by the cause, duration, and type of immunodeficiency. 4. The endoscopic features of any GI infection are variable and overlapping, making definitive diagnosis by biopsy essential when other tests such as stool culture are negative. Biopsy of normal mucosa may be necessary in some situations.
Stomach, 464 Small Bowel, 464 Colon, 464 Special Stains, 464 Differential Diagnosis, 464 Description of Techniques, 464
EPIDEMIOLOGY Immune Competent Patients The frequency of luminal GI infections, spectrum of pathogens, severity of infection, and organ involvement are dictated by the combination of exposure, predilection (host factors), and organspecific tropism of the infecting pathogen (Box 41.1). Most infections are transmitted by the fecal-oral route via contaminated food or water and are typically self-limited.1 With the increase in international travel, geography plays an increasingly important role in the prevalence of some GI infections. Traveler’s diarrhea, usually caused by enterotoxigenic Escherichia coli, is characteristically seen with travel to developing countries.2 These travelers are at increased risk of other causes of diarrhea including invasive bacteria like Campylobacter and parasites like E. histolytica. Pathogens are endemic in certain portions of the world and in specific regions within countries. For example, in the United States, histoplasmosis is endemic in the Midwest and Mississippi Valley. Mycobacterium tuberculosis (TB) is endemic in third world countries, and involvement of the GI tract is well recognized. Medications can also be an important risk factor. Antibiotics are the major risk factor for C. difficile infection (CDI). There is increasing evidence that acid suppressing medications increase the risk of most enteric infections, perhaps even CDI.3
Immune Suppressed Patients For immunosuppressed patients, the incidence and severity of infection are often linked to the cause and degree of the immunodeficiency state. In addition, they are subject to opportunistic infections, defined as infection by a microorganism that does not typically cause disease. Patients undergoing solid organ
CHAPTER 41 Infections of the Luminal Digestive Tract Abstract
Gastrointestinal infections are common and gastroenterologists typically participate in the patients’ care, especially when the disease is severe. Endoscopy is commonly performed as part of the evaluation and management of the disease. A variety of disorders may predispose the patient to infection, and in the immunosuppressed patient the cause and outcome are dictated by the severity of immunosuppression.
infection transplantation immunosuppression cytomegalovirus fungi
CHAPTER 41 Infections of the Luminal Digestive Tract BOX 41.1 Factors Involved in the
Prevalence and Type of Gastrointestinal Infections Exposures Immunodeficiency Transplant and type AIDS Cancer
Geographic location Hospital setting
transplantation are at a heightened risk of infection early after transplantation because of profound medication-induced immunodeficiency.4,5 It is also during this time that latent infections such as cytomegalovirus (CMV) and Strongyloides may become manifest. Over time, however, as drug-induced immunosuppression decreases as drugs are tapered, the incidence of infections decreases. Moreover, infections are more commonly observed after heart transplantation than liver transplantation because more potent and prolonged drug-induced immunosuppression is required to prevent cardiac rejection. For patients infected with HIV, the incidence of GI infections increases markedly as immune function deteriorates, and the infection risk can be accurately stratified by the absolute CD4 lymphocyte count and HIV-1 RNA levels as higher HIV levels and lower CD4 lymphocyte counts correlate with the risk of opportunistic infections.6–8 Rarely, opportunistic infections have been observed in the apparently normal host, but in contrast to an immunodeficient patient, these infections are typically self-limited. Generally, the more severe the immunodeficiency state required for development of an opportunistic infection, the less likely the pathogen will be observed in the normal host. For example, until the advent of transplantation, CMV was a rare pathogen, and its identification in any patient suggests some type of immune dysfunction.9,10 CMV is regarded as one of the most common opportunistic infections owing to the high prevalence of prior exposure to CMV, as reflected by seropositivity rates of more than 90% in developed countries,11,12 and to the fact that CMV disease generally occurs from recrudescence of latent infection during periods of profound immunosuppression. In summary, a careful history regarding potential exposure, cause and stage of immunodeficiency, if present, and specific epidemiologic factors germane to the clinical presentation will often help determine the potential causes of infection.
PATHOGENESIS The pathogenic mechanisms of luminal GI infections include: (1) exposure to a pathogen, (2) reactivation of prior infection (recrudescence), (3) overgrowth of a commensal organism, and/or (4) local spread or dissemination. The specific organ involved with any infectious process, other than local spread, is dictated by the organ-specific tropism of the infecting pathogen. Candida and herpes simplex virus (HSV) almost exclusively infect squamous epithelium, whereas Campylobacter jejuni and Shigella species are colonic pathogens. Inherent to any discussion of pathogenesis is the issue of host-related factors. Numerous nonspecific and immune-based defense mechanisms both prevent and attenuate GI infections.13 These defenses may be altered by disease, medications, organ dysfunction or organ absence (e.g.,
splenectomy), or as a part of the aging process. Saliva provides an effective physical barrier because of its physical properties. Moreover, immunoglobulins that are present in saliva and in intestinal secretions provide an important early line of defense. Gastric acid is a barrier to enteropathogens, and hypochlorhydria has been shown to be a risk factor for the development of cholera and other GI infections.3,14 GI motility propels ingested pathogens through the gut and prevents stasis, which can lead to bacterial overgrowth. Inherent antibacterial proteins secreted by Paneth cells, termed defensins, seem to play a key role in the host response to bacterial infections of the gut.15,16 The normal gut microbiota also plays a vital role in the prevention of infection such as CDI; its role in the prevention of other infections is unknown. The mucosal immune system is composed of inflammatory cells, most notably T cells.13,17 After exposure to a foreign antigen, these cells differentiate into helper or cytotoxic cells depending on whether the cells express the CD4 or CD8 receptor. The release of cytokines by these cells plays a crucial role in limiting infection but can also result in tissue damage. The critical role of the mucosal immune system in preventing and controlling infections is best shown by the array and severity of luminal GI infections that occur in AIDS, in which there is a progressive loss of CD4 lymphocytes from both the systemic circulation and the mucosal-based immune system.18,19 Following HIV infection, there is a rapid, substantial and perhaps irreversible loss of mucosa associated lymphoid tissue based CD4 T-cells. Loss of these cells predisposes to small intestinal infections by opportunistic infections such as cryptosporidiosis and microsporidiosis. Likewise, lymphocyte dysfunction, either medication-induced or as part of an immunodeficiency state, predisposes to symptomatic primary infection or recrudescence (e.g., CMV). In immune compromised patients, most viral GI infections considered here result from recrudescence of infection rather than recent exposure (primary infection). Normally, exposure to these infections occurs during childhood, and the systemic and mucosal-based immune systems keep these infections controlled. However, with immunodeficiency, disease may become overt. Conversely, Candida is a commensal organism of the oropharynx and esophagus and, although usually present in small numbers, overt Candida infection can be observed even in the normal host under certain conditions, such as antibiotic use; use of inhaled or ingested corticosteroids; antacid therapy or hypochlorhydria states; diabetes mellitus; alcoholism; malnutrition; old age; radiation therapy to the head, neck, and chest; and esophageal motility disturbances. Alterations in cellular immunity lead to Candidal colonization and superficial infection, whereas humoral immunity (granulocytes) prevents invasive disease and dissemination. Under conditions of absolute granulocytopenia or severely impaired granulocyte function, commensal bacteria, particularly gram-positive organisms, including Streptococcus viridans, Staphylococci, and other bacilli, may invade mucosa that has been damaged from gastric acid reflux disease, from radiation therapy, or from chemotherapy, leading to an active local infection and potential dissemination.20 GI infections may result secondarily from active disease in adjacent organs. Esophageal disease may be caused by contiguously infected mediastinal lymph nodes or pulmonary parenchymal infection21 and by spread of infection via a draining fistula or obstructed lymphatics, resulting in tracheoesophageal fistula.22 Widespread lymphohematogenous dissemination of opportunistic infections causes either diffuse or focal disease anywhere in the
Section II Luminal Gastrointestinal Disorders
gut; this process is generally limited to only the most severely immunocompromised patients.23,24 Most intestinal infections result in tissue inflammation of varying degrees. Local upregulation of cytokines plays a central role in the local immune response to the pathogen but may also cause tissue injury. CMV esophagitis is associated with high mucosal concentrations of the proinflammatory cytokine tumor necrosis factor.25 Toxin production, virulence factors, and the local microbiome will also determine the clinical expression and tissue damage caused by many GI infections, especially bacterial infections.26,27 Luminal digestive tract infections occur under specific epidemiologic conditions and in the appropriate host. The tissuebased immune system is crucial for preventing opportunistic infections; when this system is absent, infection with such pathogens may be chronic and potentially life-threatening. Exposure to the pathogen is important; however, concurrent predisposing factors that were elucidated previously, such as antibiotic or chemotherapy treatment, can play a pathogenic role in both the normal and the immunosuppressed host.
CLINICAL AND ENDOSCOPIC FEATURES Numerous factors guide the approach to a patient with suspected GI infection. Given the breadth of potential etiologic pathogens, the diagnostic approach should be based on the character and chronicity of the symptoms, the organ system(s) involved, and the findings on physical examination.
Clinical Features The most common cause of esophageal infection in both the normal host and the immunosuppressed patient is Candida, followed by the herpesviruses.28 CMV occurs more commonly in patients with AIDS, whereas HSV is more often observed in the normal host and non–HIV-infected immunosuppressed patients.29,30 Odynophagia is the characteristic symptom of esophageal infection, and infections resulting in esophageal ulceration almost uniformly cause odynophagia.28–30 Although less common, dysphagia may be observed with esophageal infections, especially Candida esophagitis, or may represent esophageal obstruction or dysmotility from the infection or its sequelae (e.g., stricture). Odynophagia is almost uniformly present and is characteristically severe with CMV esophagitis. Chest pain, weight loss, and fever may be reported. The onset of symptoms is often more subacute than the acute presentation of HSV. A prior or coexistent diagnosis of CMV infection in other organs (e.g., retinitis or colitis) is frequent. Although rare in transplant patients, retinitis may be observed in approximately 15% of AIDS patients at the time of diagnosis of GI disease.31 Bleeding is generally observed only when there is ulceration, and although generally mild, it can be severe if there is an associated coagulopathy. Pulmonary symptoms may predominate when there is fistula formation to the tracheobronchial tree or coexistent pulmonary involvement. Patients with AIDS often have multiple coexisting esophageal disorders, which further complicates management.28,32 Physical examination, particularly of the oropharynx, may be helpful in suggesting the diagnosis of esophageal infection. Approximately two-thirds of patients with AIDS and esophageal candidiasis have oral candidiasis (thrush).33 In other immunocompromised patients, oropharyngeal candidiasis is also com-
monly associated with esophageal candidiasis.28 Thrush may be absent, however, if antifungal therapy, such as nystatin, is currently administered. The presence of oropharyngeal candidiasis does not prove that Candida is the only cause of symptoms, and the absence of oropharyngeal candidiasis does not exclude Candida esophagitis. Patients with chronic mucocutaneous candidiasis may have fungal involvement of various mucous membranes, hair, nails, and skin and may have a history of adrenal or parathyroid dysfunction. Coexistent oropharyngeal ulceration is common in patients with HSV esophagitis but is infrequent in patients with CMV esophagitis or other systemic infections.31,34 After Candida species, herpesviruses are the most frequent infectious agents that cause esophagitis. After organ transplantation, HSV and CMV occur with equal frequency as causes of esophagitis,28 whereas in patients with AIDS, HSV esophagitis is uncommon and far less frequent than CMV. In a study of 100 HIV-infected patients with esophageal ulcers, HSV was found in only nine (in four patients it was a copathogen with CMV).30 HSV esophageal infection commonly manifests with the sudden onset of severe odynophagia, heartburn, or chest pain.29,30 Autopsy studies suggest that esophageal symptoms may be absent. Herpes labialis (i.e., cold sores) and oropharyngeal ulcers may coexist, antedate, or develop during the esophageal infection, whereas skin infection is rare.28 Numerous systemic manifestations, including low-grade fever or upper respiratory symptoms, may precede the onset of esophageal symptoms. In untreated immunocompetent persons, spontaneous resolution of HSV esophageal infection occurs within 2 weeks of the onset of symptoms. Rarely, bleeding is the initial presentation and may be observed in the absence of esophageal complaints. The frequency of esophageal involvement with other pathogens is rare. Bacterial esophagitis has been observed in patients with severe neutropenia, usually patients with hematologic malignancies, but occasionally it is observed after bone marrow transplantation,35 diabetic ketoacidosis,36 steroid therapy, or in AIDS.37,38 The presentation is similar to the presentation with other infectious agents.39 Fungi other than Candida species and parasitic diseases have rarely been reported to involve the esophagus.40–45 The symptoms of esophageal TB depend on the degree and type of involvement.22,46 Systemic symptoms of fever and weight loss are common. Pulmonary complaints often predominate because of a fistula to the trachea, bronchus, or pleural space. Dysphagia may be prominent with the formation of long strictures or traction diverticula resulting from the fibrotic response. Upper GI hemorrhage caused by esophageal ulcers or tuberculous arterioesophageal fistulas may rarely be the primary manifestation.47 Other mycobacterial infections such as Mycobacterium avium complex (MAC) are rare.48 Barium radiography plays a minor role in the diagnosis of esophageal infection. In any patient, the presence of severe odynophagia limits the ability to drink barium, hampering the adequacy of the examination. Although specific barium esophagram findings may be more typical for certain disorders,49 given the potential overlap, many of the findings are nonspecific, and endoscopy with biopsy is generally indicated. The wide spectrum of causes, coupled with the specific antimicrobial regimens that are required, necessitates a definitive diagnosis rather than empiric antimicrobial therapy except when Candida is highly expected. Nevertheless, a sinus tract or fistulous connection to the bronchial tree or mediastinum at the level of the hilum is highly suggestive of TB, although it may also be the result of malignancy. An esophageal neoplasm may be mimicked by an ulcerated
CHAPTER 41 Infections of the Luminal Digestive Tract
TABLE 41.1 Differential Diagnosis of Endoscopic Findings Based on Organ System
and Pathogen Finding
Clostridium difficile CMV
CMV Cryptococcus Cryptosporidium
Erosion or ulcer
CMV TB Syphilis
CMV Cryptosporidium and Cryptococcus
Bacteria CMV Histoplasma Amebae Strongyloides
CMV TB Histoplasma Blastomyces
*Edema, subepithelial hemorrhage. CMV, cytomegalovirus; HSV, herpes simplex virus; MAC, Mycobacterium avium complex; TB, Mycobacterium tuberculosis.
tuberculous granulomatous mass or CMV ulcer.50,51 Chest radiography or computed tomography (CT) scan of the chest may support the diagnosis of TB, although a tissue diagnosis will be required. Endoscopic Features The characteristics of the esophageal lesions provide very important diagnostic clues. The location, size, and appearance of all endoscopic abnormalities should be documented because these features form the basis of the differential diagnosis and are useful for comparison on follow-up endoscopic examinations. The differential diagnosis of the lesion dictates how lesions should be sampled and what recommendations for diagnostic testing should be made on the biopsy or cytologic specimens (discussed later). Serologic testing plays no significant role in the diagnosis of acute infectious esophagitis. Endoscopic examination of the esophagus is the most sensitive and specific method for diagnosing esophageal candidiasis (Table 41.1). The gross endoscopic appearance of Candida esophagitis is pathognomonic (Fig. 41.1) and may be graded according to published criteria.52 A large, well-circumscribed ulceration should not be attributed to Candida. The endoscopic characteristics of HSV esophagitis reflect the pathologic changes. HSV esophagitis appears as discrete, usually small (< 1 cm), well-circumscribed, shallow ulcers; a diffuse erosive esophagitis; or, rarely, vesicles (Fig. 41.2).28 Small, scattered lesions covered with exudate mimic esophageal candidiasis. Deep ulcers, as seen with CMV, are very rare. CMV esophagitis is characteristically associated with one or more ulcerations that can be quite striking in patients with AIDS. Nevertheless, as with other infections, variability has been reported with appearances ranging from multiple shallow ulcers, to solitary giant ulcers, to a diffuse superficial esophagitis (Fig. 41.3).53 Although serologic testing is not helpful because of the high rate of prior exposure to CMV, the absence of CMV DNA or antigenemia in the blood would suggest an alternative diagnosis. Esophageal TB can manifest with a fistula to the tracheobronchial tree that is easily visualized endoscopically and rarely as an ulcer or mass lesion resembling a neoplasm. In normal hosts from
FIG 41.1 Candida esophagitis. Multiple yellow plaques coat the esophageal lumen. In several areas, the plaque has been removed, showing a normal-appearing underlying mucosa.
endemic areas in South America, Trypanosoma cruzi may involve the myenteric plexus of the esophagus, resulting in Chagas’ disease and an appearance that is indistinguishable clinically, radio graphically, manometrically, and endoscopically from idiopathic achalasia.54 This diagnosis may be established by antibody testing. The endoscopic appearances of other rare infections have been described in case reports and resemble other infections.
Clinical Features Gastric infections are typically manifested by upper abdominal pain that is generally steady and may radiate to the back. Associated symptoms may include nausea with or without vomiting; vomiting may be prominent when mucosal infection is severe. Infrequently, nausea alone in the absence of abdominal pain
Section II Luminal Gastrointestinal Disorders
may be observed. Fever and weight loss are variable. Diarrhea may be the prominent symptom if the infecting pathogen also involves the small bowel (e.g., Cryptosporidium). Bleeding, both occult and overt, is usually a marker of mucosal ulceration. However, because most gastric infections are superficial, severe bleeding is unusual unless there is an associated coagulopathy. Worldwide, Helicobacter pylori is the most common gastric infection regardless of immune status. The prevalence of an infection has generally decreased in some parts of the world, particularly in the United States, although infection can approach 80% or more in selected populations.55 The presence of H. pylori is also associated with hypochlorhydria (fasting gastric pH > 4) and the combination of H. pylori infection and HIV infection is more strongly associated with the prevalence of hypochlorhydria than either infection alone.56,57 Because of the relative infrequency of gastric infections, understanding of the presentation and endoscopic findings of most of these infections is based on case reports or small series. With the exception of H. pylori, most infections of the stomach occur in the setting of an immunodeficiency state and include CMV; parasites and mycobacteria are uncommon.58 In HIV-infected patients, there appears to be an inverse correlation between immune suppression as noted
by CD4 lymphocyte count and the prevalence of active H. pylori infection.57 The primary symptom is dictated by the underlying cause. CMV gastric infection typically produces ulceration; abdominal pain with or without bleeding is the most frequent presentation. Mucosal infections that result in gastritis without ulceration, such as cryptosporidiosis, more commonly manifest with nausea without pain or may be asymptomatic. H. pylori infection of the stomach is generally considered an asymptomatic infection in most people regardless of immune status, but can be associated with dyspepsia and duodenal or gastric ulcer. Tuberculosis may cause antral narrowing with outlet obstruction, ulcer, or intramural abscess. Physical examination is generally unrevealing. Mild abdominal pain may be elicited on palpation of the epigastrium. Radiologic studies may suggest the presence of gastric infection. Although abnormalities can often be identified, the findings are typically nonspecific, and further investigation with endoscopy is often required. Barium findings of gastric infection may include fold thickening or ulceration, whereas the most common CT finding is wall thickening, usually diffuse, and focal lesions mimicking a mass lesion (Fig. 41.4). Neoplasms result in either focal or diffuse wall thickening depending upon etiology.
FIG 41.2 Herpes simplex virus esophagitis. There are multiple small ulcers, some of which have a “volcano” appearance typical for herpes simplex virus. The intervening mucosa is normal.
FIG 41.4 Gastric mucormycosis. Computed tomography (CT) scan shows a large hypodense area in the gastric wall (arrow).
FIG 41.3 Cytomegalovirus esophagitis. A, Two ulcers in the mid-esophagus with normal surrounding mucosa. B, Large hemicircumferential ulcer in the mid-esophagus with heaped-up margins.
CHAPTER 41 Infections of the Luminal Digestive Tract Endoscopic Features Similar to all GI infections, the primary endoscopic abnormality is dictated by the infecting pathogen, and the severity of disease clinically and endoscopically depends on the presence and degree of immunodeficiency. H. pylori infection often results in no endoscopic findings or can be associated with a nodular (termed chicken skin) appearance due to the presence of lymphoid aggregates. H. pylori has also been associated with mucosaassociated lymphoid tumors which have a variable appearance, but typically ulcerated well circumscribed mass-like lesions or diffuse infiltration. CMV, the most common opportunistic gastric pathogen, generally manifests with a diffuse gastritis, characteristically with a hemorrhagic component (Fig. 41.5). Mucosal breaks are typical with focal or diffuse erosions or frank ulcerations (Fig. 41.6) that may be large, are usually well circumscribed, and may mimic a malignancy.50 Ulcerations have also been described with other bacteria, fungi, and parasites.59–62 The endoscopic features of gastric cryptosporidiosis and mycobacterial infection may appear as inflammation, polyps, or antral narrowing.63–65
FIG 41.5 Cytomegalovirus gastritis. There is diffuse subepithelial hemorrhage, some of which is confluent in the gastric antrum. Several small erosions were also present in this patient.
FIG 41.6 Pyloric channel ulcer resulting from cytomegalovirus. Hemicircumferential ulceration with a clean base in the pyloric channel. This lesion resembles a peptic ulcer.
In the normal host, gastric anisakiasis has been associated with ingestion of raw fish, and the Anisakis larvae may be visualized and removed at the time of endoscopy (Fig. 41.7).
Clinical Features The most common infections are viruses such as rotavirus and norovirus. The most common bacterial infection is enterotoxigenic E. coli (traveler’s diarrhea), but epidemics of Vibrio cholera in endemic areas can have many affected patients with significant morbidity and mortality. Parasitic infections in the small bowel are mostly protozoa, with Giardia lamblia the most common, but include Cryptosporidia, Cyclospora, and Cystoisospora. The most common symptoms are diarrhea and abdominal pain. Diarrhea due to small intestinal pathogens is watery, and may be high volume when the organism impairs absorption or causes intestinal secretion like Vibrio cholerae. Diarrhea is not bloody as the organisms that infect the small bowel are generally not invasive or minimally so, with the exception of those bacteria that infect the ileo-colonic area, such as Salmonella and Yersinia. Associated symptoms include fever and crampy abdominal pain which is often periumbilical, and malaise. Dehydration and weight loss occur when the diarrhea is severe or chronic, and fat malabsorption may occur. Symptoms of fat malabsorption include greasy stools and symptoms of fat soluble vitamin deficiencies such as osteopenia/osteoporosis (vitamin D), night blindness (vitamin A), and easy bruisability (vitamin K). With these illnesses, physical exam is usually normal unless there is volume depletion. Diagnosis is usually made by stool culture when appropriate or ova and parasite (O&P) exam. With O&P exam, three specimens over several days will give the optimal yield. There is rarely a role for radiologic imaging or even endoscopy. If CT imaging is done, it may show small bowel wall thickening with invasive pathogens but this is a nonspecific finding and can be seen with inflammatory bowel disease (IBD) and other inflammatory diseases, or even small bowel malignancy like lymphoma. The situation is different with immune suppressed individuals. With the exception of CMV, opportunistic small bowel infections are uncommon in transplant patients, but they are a hallmark
FIG 41.7 Anisakiasis. A well-circumscribed area of subepithelial hemorrhage is seen with a small worm emanating from the center of the hemorrhage. The worm was removed with biopsy forceps.
Section II Luminal Gastrointestinal Disorders
FIG 41.8 Duodenal Mycobacterium avium complex (MAC). A, Multiple well-circumscribed papular lesions typical for intestinal MAC. B, Acid-fast staining of mucosal biopsy specimens shows numerous mycobacteria filling the lamina propria.
of AIDS, where Cryptosporidium and Microsporidia are frequent pathogens, causing watery diarrhea, which is often severe. Less common is MAC, a pathogen principally restricted to patients with AIDS that is usually widely disseminated at the time of diagnosis66 (Fig. 41.8). A localized proximal small bowel infection can occur with CMV, and distal ileitis has been reported with CMV, bacteria, mycobacteria, fungi, and parasites.24,67–73 Severe watery diarrhea causing dehydration is characteristic of intestinal cryptosporidiosis, whereas less severe diarrhea is observed with most other pathogens. Although crampy abdominal pain may be observed with any diarrheal disorder, more constant abdominal pain would be most typical for CMV enteritis and MAC.66 Because CMV generally causes focal mucosal ulceration sparing the intervening mucosa, abdominal pain and overt bleeding can be observed in the absence of diarrhea. An acute abdomen can result from intestinal perforation due to CMV.74 Endoscopic Features Most patients with small bowel infections will not need endoscopy, with the exception of those who are immune suppressed or those in whom a diagnosis of IBD is entertained. The endoscopic findings of small bowel infections vary from normal to widespread hemorrhage and ulceration. Focal erosions and ulcerations are typical for a viral infection with CMV, whereas minimal mucosal changes, if any, are common with parasitic diseases. Small bowel atrophy is associated with some of these infections and endoscopically mimics celiac sprue.75 MAC infection has a characteristic appearance of small to confluent nodular lesions, often with a yellow color resembling Whipple’s disease (see Fig. 41.8). Disseminated fungal infections can also manifest with small
FIG 41.9 Cytomegalovirus ileitis. There is well-circumscribed hemicircumferential ulceration at the ileocolonic anastomosis after heart transplant and right hemicolectomy.
nodular lesions.76 Rarely, obstructive symptoms may predominate if there is an obstructive process. Stricture and ulceration of the ileum is typical for TB and rare for CMV (Fig. 41.9); these are best characterized by radiographic rather than endoscopic examination.77 Ileitis can also be observed with some bacterial infections, including Yersinia species and Salmonella species. The endoscopic and radiographic features of any severe ileitis may mimic Crohn’s disease and underscores the importance of ileal
CHAPTER 41 Infections of the Luminal Digestive Tract examination with mucosal biopsy if colonoscopy is performed. Capsule endoscopy may also help characterize small bowel infections, although mucosal biopsy would require double-balloon enteroscopy.
Clinical Features The most common symptoms are diarrhea and abdominal pain. In contrast to the large volume, watery diarrhea seen with small bowel pathogens, diarrhea due to colon pathogens tends to be smaller volume, can be bloody if the pathogen is invasive, and may be associated with tenesmus when there is rectal involvement, as is common with Shigella infection. Abdominal pain is most often left-sided unless there is right colon inflammation, as is seen with Shiga toxin E. coli (STEC). Other symptoms can include fever, malaise, and signs of volume depletion.77 The physical examination is generally dictated by the infecting pathogen. With acute bacterial colitis, the patient may appear toxic and have significant abdominal tenderness suggesting an acute abdomen, and the pain may predominate over the diarrhea. The most common pathogens are, in order, Campylobacter, Salmonella, Shigella and STEC, both 0157:H7 strains and non-0157 strains. Rates of C. difficile infection have increased dramatically since the year 2000, and it should be considered in all acute diarrheal illnesses, not just as a consequence of antibiotics. CDI may complicate the illness in patients with IBD, especially in those with colonic involvement and with immune suppression. As the symptoms of IBD and CDI are the same, management can be challenging when CDI is adequately treated but the symptoms persist. Another challenge in management of IBD is the patient with ulcerative colitis (UC) who is severely ill and is refractory to immunomodulator therapy; in this situation, coinfection with CMV should be considered and endoscopy and biopsy can play an important role.78 Less common bacterial pathogens are Yersinia (which has a predilection for the ileocolonic area and can thus mimic appendicitis and Crohn’s disease), Plesiomonas, Aeromonas and noncholera Vibrios. Tuberculosis also has a predilection for the ileo colonic area.79 The most common parasite to infect the colon is E. histolytica. Evaluation. Recent American College of Gastroenterology guidelines (2016) on acute infectious diarrhea recommend microbiologic assessment of stool (i.e., stool culture for enteric pathogens) for immune competent individuals with dysentery (that is not travel related) and persistent diarrhea (14–30 days).80 For travel-related diarrhea, empiric therapy was recommended, with the therapy depending on the severity of the illness. For diagnosis of CDI, most laboratories are moving to polymerase chain reaction (PCR) for detecting the toxin B gene in stools. Some still use enzyme-linked immunosorbent assay tests for toxin A and B.81 Because PCR is very sensitive and 5% to 15% of individuals are carriers for C. difficile, only diarrheal stools should be tested. For diagnosis of TB, PCR of biopsy specimens is recommended as well as culture. For Strongyloides, serology and stool test combined give the best yield. In immune suppressed patients, the spectrum of pathogens includes the aforementioned, as well as opportunistic ones. Depending on the clinical setting, CMV may be the most frequent opportunistic pathogen. Colonic CMV infection characteristically manifests as a chronic watery diarrhea; pain is often a prominent feature, and occult and overt bleeding may occur given the mucosal ulceration that is typical of colonic disease.82
When indicated, cross-sectional imaging may show colon wall thickening which is nonspecific. Cross-sectional imaging is reasonable to consider when there is severe abdominal pain and there are signs of toxicity. Colon wall thickening is nonspecific, and can be seen with invasive infections as well as ischemic colitis, and may be predominantly right-sided with STEC infection.83 Additional findings on CT may include small bowel thickening or lymphadenopathy.84,85 Depending on the infectious cause, radiographic abnormalities may be either focal or diffuse. Barium enema examination, if indicated, should not be performed in patients with suspected colonic infection until all stool studies are collected. Endoscopic Features Colonoscopy can be very helpful in diagnosis of colitis, where the endoscopic findings can range from normal to severe pancolonic edema and ulceration. The colitis may be patchy, segmental, or diffuse. Campylobacter, Shigella, Salmonella, and E. coli 0157H7 infections may appear similar endoscopically with mucosal edema, subepithelial hemorrhage, erosions, and ulcers of varying size86 (Figs. 41.10 and 41.11). Distal disease is typical for Campylobacter and Shigella infections, whereas infections with Salmonella and Yersinia preferentially involve the right colon and ileum.86,87 Salmonella typhi infection results in lymphoid hyperplasia leading to ulceration at the site of Peyer’s patches; this may explain its location in the bowel.88 In mild cases of C. difficile the colon may be normal, or there may be colitis in more severe cases. In the most severe form, pseudomembranous colitis, there are the classic appearing yellowish plaque-like membranes that are typically confluent (Fig. 41.12). However, pseudomembranes may be absent in patients with IBD and CDI, which may make the diagnosis more challenging. Subepithelial hemorrhage is characteristic of CMV infection, as is ulceration of variable distribution89 (Fig. 41.13). An appearance of IBD, either UC or Crohn’s disease, has been described with bacterial and CMV infections. Colorectal biopsy will usually make the distinction between infection and IBD89 but cannot usually distinguish acute infection superimposed on chronic IBD. HSV can rarely involve the colon, but generally only the distal rectum and anus are involved, given the tropism of HSV for squamous mucosa. Amebic colitis may resemble a fulminant colitis or more commonly cause multiple ulcers that can be mistaken for Crohn’s disease (Fig. 41.14).90 The colonoscopic findings of cryptosporidiosis may be minimal edema or normal-appearing colon. TB may manifest with a mass lesion or serpiginous ulceration and nodularity.91 Fungi have rarely been reported to involve the colon, with histoplasmosis noted to cause ulceration or mass lesions resembling carcinoma.24,92 Helminthic and other pathogens of the colon have also been described (Fig. 41.15).93,94
PATHOLOGY The pathologic features of GI infections depend on the infecting pathogen, and tissue tropism dictates the organ(s) of involvement.
Esophagus The gross pathologic appearance of esophageal candidiasis ranges from a few white or yellow plaques on the mucosal surface to a dense, thick plaque coating the mucosa and encroaching on the esophageal lumen. Although potentially misinterpreted as “ulcer,”
Section II Luminal Gastrointestinal Disorders
FIG 41.10 Campylobacter colitis. A, Focal area of subepithelial hemorrhage and erosion in the cecum. B, Hematoxylin and eosin staining of cecal biopsy specimens shows preserved architecture, mucosal edema, subepithelial hemorrhage, and acute inflammatory cells. These findings are typical for acute, self-limited colitis resulting from a bacterial infection.
FIG 41.11 Yersinia colitis. Marked edema, hemorrhage and ulceration in the colon.
FIG 41.12 Clostridium difficile colitis. Typical yellow plaques are in the distal colon.
this plaque material is composed of desquamated squamous epithelial cells, admixed with fungal organisms, inflammatory cells, and bacteria.51 True ulceration (granulation tissue) is rarely caused by Candida alone and has been documented most commonly in patients with profound granulocytopenia or when Candida is a coinfection with another cause of ulceration.32 More deep-seated submucosal infections can occur with some fungi, and disseminated fungal infections can lead to ulceration. Viral infection characteristically results in mucosal erosion and ulceration regardless of the site of infection. HSV infection is generally limited to squamous mucosa, where the earliest manifestation is a vesicle. As these vesicles enlarge and ulcerate, they coalesce to form larger, superficial lesions, which are typically focal, leaving the intervening mucosa normal. Microscopic examination of the squamous epithelial cells at the ulcer edge reveals multinucleation, ground-glass nuclei, and eosinophilic Cowdry’s type A inclusion bodies that may take up half of the nuclear volume. With progression, these inclusion bodies may be surrounded by halos and may become more basophilic, filling, enlarging, and deforming the nucleus. The histologic hallmark of CMV esophagitis is mucosal ulceration. Although variable, deep ulcers are very characteristic for disease in patients with AIDS, whereas in other immunocompromised patients, lesions tend to remain more superficial. Despite the depth of the lesions, perforation is rare. In contrast to HSV, the viral cytopathic effect of CMV is located in endothelial and mesenchymal cells in the granulation tissue of the ulcer base rather than in squamous cells. Inclusions are large (cytomegalic) and often have an eosinophilic appearance that may be located either in the nucleus or in the cytoplasm.95 The inclusions can assume an atypical appearance, especially in patients with AIDS96; immunohistochemical stains play a valuable role in selected patients to confirm the presence of CMV, and they often highlight more infected cells than are appreciated by routine hematoxylin and eosin staining.97 CMV may coexist with HSV or Candida or other pathogens in patients with AIDS. The gross pathologic appearance of bacterial esophagitis depends on the etiologic pathogen and ranges from diffuse, shallow ulcerations
CHAPTER 41 Infections of the Luminal Digestive Tract
FIG 41.13 Cytomegalovirus (CMV) colitis. A, Diffuse subepithelial hemorrhage typical for CMV infection. B, Immunohistochemical stain for CMV antigens highlights the numerous infected cells. C, Large, well-circumscribed ulcerations potentially suggesting Crohn’s disease.
D FIG 41.14 Amebic colitis. A, Patchy erosions and ulcer are suggestive of inflammatory bowel disease. B, Well circumscribed ulcer. C, Acute colitis with overlying inflammatory exudate which D, on close-up shows the typical amoebic structures. (A, Courtesy John L. Meisel, MD.)
to ulcers associated with erythema, plaques, pseudomembranes, nodules, or hemorrhage. Microscopic examination reveals pseudomembranes and bacterial invasion that may be superficial and limited to squamous epithelium or may be invasive and transmural with infiltration of blood vessels (i.e., phlegmonous esophagitis). Esophageal
actinomycosis is characterized by ulceration and sinuses leading from abscess cavities with sulfur granules and filamentous grampositive branching bacteria seen on tissue biopsy specimens.40 In the one reported case, B. henselae esophagitis resulted in multiple nodules resulting from a lobulated proliferation of capillary vessels lined by plump endothelial cells.38
Section II Luminal Gastrointestinal Disorders as culture or PCR testing. Biopsy cannot distinguish a bacterial infection superimposed on chronic IBD.
FIG 41.15 Schistosomiasis of the colon. Solitary nodule in the descending colon.
Although generally an excellent stain, hematoxylin and eosin staining may not identify all pathogens. Various pathogen-specific stains are available to aid in the identification of nearly all common GI infections (with the exception of non-herpesviruses). These stains highlight infecting pathogens and make identification easier. Immunohistochemical stains for viral antigens are very helpful when examining for herpesviruses.100 Because a battery of stains is not routinely performed on all biopsy specimens, communication with the pathologist is essential to ensure appropriate pathologic evaluation.101 Intestinal TB and MAC may be hard to distinguish because both may have granulomas present in ulcer tissue, with mycobacteria identifiable by mycobacterial staining. MAC, in contrast to TB, may not result in well-formed granulomas. Staining for MAC with PAS stain characteristically yields an abundance of organisms (see Fig. 41.8B), whereas tuberculous bacilli may be few in number, even in patients with AIDS.
DIFFERENTIAL DIAGNOSIS Stomach Bacterial infection of the stomach is generally limited to H. pylori infection, which has the characteristic chronic active gastritis often with lymphoid aggregates.98 These bacteria may be highlighted accurately by additional staining methods, including immunohistochemical stains. Phlegmonous gastritis, whose pathogenesis is not well understood, may involve gram-positive and gram-negative bacilli.99
Small Bowel Small bowel biopsy is helpful to detect parasites like Giardia, Cryptosporidia, Cystoisospora, and Strongyloides. When the lamina propria is filled with macrophages, a periodic acid–Schiff (PAS) stain will be positive in MAC infection, differentiating it from Whipple’s disease. Rare findings include lymphoma or other obscure infections. Biopsy of normal appearing mucosa is indicated when looking for infections or a cause of chronic diarrhea.
Colon The main role of colorectal biopsy for the diagnosis of colitis is to distinguish infection from IBD. In the former, normal colonic architecture is usual, inflammation is predominantly acute, and there are no basal lymphoid aggregates. In UC, the inflammation is diffuse and limited to the mucosa. The hallmark is distorted crypt architecture, with acute and chronic inflammation and basal inflammation with plasma cells and lymphoid aggregates. In Crohn’s disease, inflammation is typically patchy, but can be transmural. Granulomas can be found in up to 20% of biopsies, and can be found in biopsies of normal mucosa. However, granulomas are not specific for Crohn’s disease, and can be seen with tuberculosis (they are typically more numerous though may not be caseating), Yersinia, schistosomiasis (surrounding the organism) and rarely in syphilis. Colorectal biopsy may also show ulcers with ameba on the surface (see Fig. 41.14). Colorectal biopsy is also helpful to diagnose a CMV superinfection complicating IBD, especially UC, if typical inclusions are seen, but should be supplemented with another technique such
Diagnostic considerations are determined by the clinical presentation, risk group, severity of immunodeficiency, and specific endoscopic findings. Although overlap is broad, some endoscopic abnormalities are typical for a specific pathogen and may be organ-specific (see Table 41.1). In the esophagus, CMV esophagitis and the idiopathic esophageal ulcer of AIDS are difficult to differentiate.31,102 These two processes generally result in one or more large ulcers. Pill-induced esophagitis must be excluded by history because the pathologic findings of esophageal biopsy specimens are similar. Likewise, distal esophageal ulcer may suggest gastroesophageal reflux disease, and the histopathologic features cannot distinguish this from idiopathic esophageal ulcer. The clinical history is different, however, and the endoscopic appearance helps suggest gastroesophageal reflux. Small esophageal ulcers can be observed in the acute phase of HIV infection, which can mimic viral or pill-induced esophagitis.103 Esophageal strictures can result from opportunistic infections.104 The history coupled with mucosal biopsy helps differentiate infection from gastroesophageal reflux disease. The appearance of the small bowel is similar in many infections and can be normal. The cause of bacterial colitis, with the exception of C. difficile, can rarely be differentiated by presentation or endoscopic appearance alone, although some infections may favor a proximal or distal location. In this setting, stool culture and blood culture may be diagnostic. In an immunosuppressed patient with chronic diarrhea, one or more colonic ulcers associated with subepithelial hemorrhage are highly suggestive for CMV, but this appearance can result from other disorders as well.89,105
Description of Techniques No specific techniques are generally required for the endoscopic evaluation of GI infection. Based on the suspected cause clinically, endoscopically, and pathologically, additional stains may be required, necessitating close collaboration with the pathologist to diagnose these infections accurately. Because most infections can be diagnosed on tissue biopsy alone, multiple biopsy specimens of endoscopic abnormalities should be obtained to increase
Fibrinoinflammatory exudate on top of ulcer with neutrophils, no inclusions. HSV in epithelium at edge of ulcer
CMV in granulation tissue at base of ulcer
FIG 41.16 A, Location of viral cytopathic effect in mucosal ulceration. Herpes simplex virus (HSV) can be found at the ulcer edge, whereas cytomegalovirus (CMV) is located in granulation tissue deep in the ulcer bed. B, Large cells with intranuclear inclusions typical for CMV. C, Multinucleated cells in squamous tissue typical for HSV. (From Lazenby AJ: Gastroenterologist/pathologist partnership. Tech Gastrointest Endosc 4:95–100, 2002.)
Scope turned in
Scope withdrawn with biopsy
FIG 41.17 A–H, Biopsy technique for esophageal ulceration. The scope is turned into the lesion to sample the ulcer. Larger mucosal samples can be acquired in this fashion. (Redrawn from Wilcox CM: Approach to esophageal disease in AIDS: a primer for the endoscopist. Tech Gastrointest Endosc 4:59–65, 2002.)
Section II Luminal Gastrointestinal Disorders
diagnostic yield. Even when the mucosa appears normal, multiple biopsy specimens should be taken when infection is suspected. During endoscopy, mucosal lesions can be brushed and submitted for cytologic evaluation, or biopsy specimens can be obtained for histologic diagnosis. Esophageal brushings with cytologic evaluation may be diagnostically helpful in certain diseases, such as those resulting from Candida and HSV, but are not helpful for diagnosis of CMV disease. Viral culture of biopsy specimens may increase the diagnostic yield, although false-positive and false-negative results occur, and viral cultures are less sensitive than multiple biopsy specimens. Use of shell vial techniques improves the turnaround time for CMV culture to 48 hours. Bacterial culture of colonic biopsy specimens has been found in some series to enhance the diagnostic yield but is not typically done. Cytologic brushings and endoscopic mucosal biopsy specimens should be taken from the ulcer edge when HSV disease is suspected because the viral cytopathic effect is best identified in epithelial cells rather than in granulation tissue in the ulcer bed.106 In contrast, a biopsy specimen of the ulcer base must be obtained when viral infection is suspected with CMV (Fig. 41.16). Multiple biopsy specimens (up to 10) may be required to establish the diagnosis in patients with AIDS and should be taken from the base of the ulcer.107 Overall, mucosal biopsy for histologic diagnosis is the preferred method to distinguish the cause of ulcer.108 Culture of an aliquot of stool obtained at colonoscopy and bacterial culture of mucosal biopsy specimens may increase the diagnostic yield.109 As mentioned previously, many histologic stains are available to identify pathogens. Immunohistochemical staining on biopsy samples using specific monoclonal antibodies to viruses such as HSV and CMV helps confirm the diagnosis when the viral cytopathic effect is difficult to appreciate. We generally rely on histology for the diagnosis of viral GI infections and use brushings and viral culture selectively. A technique first described for gastric biopsies, whereby the forceps are tilted into the lesion and the tissue is avulsed, is especially useful for taking samples from esophageal lesions (Fig. 41.17). Lastly, as noted previously, communication with the pathologist is essential so that appropriate attention can be drawn to specific pathogens and so that special stains can be performed.
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8. Xiao J, Gao G, Li Y, et al: Spectrums of opportunistic infections and malignancies in HIV-infected patients in tertiary care hospital, China, PLoS ONE 8:e75915, 2013. 10. Lancini D, Faddy HM, Flower R, et al: Cytomegalovirus disease in immunocompetent adults, Med J Aust 201:578–580, 2014. 28. Baehr PH, McDonald GB: Esophageal infections: risk factors, presentation, diagnosis, and treatment, Gastroenterology 106:509–532, 1994. 29. Wang HW, Kuo CJ, Lin WR, et al: Clinical characteristics and manifestation of herpes esophagitis, Medicine (Baltimore) 95:e3187, 2016. 30. Wilcox CM, Schwartz DA, Clark WS: Esophageal ulceration in human immunodeficiency virus infection: causes, diagnosis, and management, Ann Intern Med 123:143–149, 1995. 32. Wilcox CM: Evaluation of a technique to evaluate the underlying mucosa in patients with AIDS and severe Candida esophagitis, Gastrointest Endosc 42:360–363, 1995. 49. Levine MS, Rubesin SE, Laufer I: Barium esophagography: a study for all seasons, Clin Gastroenterol Hepatol 6:11–25, 2008. 52. Wilcox CM, Schwartz DA: Endoscopic-pathologic correlates of Candida esophagitis in acquired immunodeficiency syndrome, Dig Dis Sci 41:1337–1345, 1996. 53. Wilcox CM, Straub RA, Schwartz DA: Prospective endoscopic characterization of cytomegalovirus esophagitis in patients with AIDS, Gastrointest Endosc 40:481–484, 1994. 55. Eusebi LH, Zagari RM, Bazzoli F: Epidemiology of Helicobacter pylori infection, Helicobacter 19:1–4, 2014. 56. Nevin DT, Morgan CJ, Graham DY, et al: Helicobacter pylori gastritis in HIV-infected patients: a review, Helicobacter 19:323–329, 2014. 77. Dickinson B, Surawicz CM: Infectious diarrhea: an overview, Curr Gastroenterol Rep 16:399, 2014. 78. Lee HS, Park SH, Kim SH, et al: Risk factors and clinical outcomes associated with cytomegalovirus colitis in patients with acute severe ulcerative colitis, Inflamm Bowel Dis 22:912–918, 2016. 80. Riddle MS, DuPont HL, Connor BA: ACG clinical guideline: diagnosis, treatment, and prevention of acute diarrheal infections in adults, Am J Gastroenterol 111:602–622, 2016. 82. Blanshard C, Francis N, Gazzard BG: Investigation of chronic diarrhoea in acquired immunodeficiency syndrome: a prospective study of 155 patients, Gut 39:824–832, 1996. 89. Wilcox CM, Chalasani N, Lazenby A, et al: Cytomegalovirus colitis in acquired immunodeficiency syndrome: a clinical and endoscopic study, Gastrointest Endosc 48:39–43, 1998. 100. Abreu MT, Harpaz N: Diagnosis of colitis: making the initial diagnosis, Clin Gastroenterol Hepatol 5:295–301, 2007. 102. Wilcox CM, Schwartz DA: Endoscopic characterization of idiopathic esophageal ulceration associated with human immunodeficiency virus infection, J Clin Gastroenterol 16:251–256, 1993. 107. Wilcox CM, Straub RF, Schwartz DA: A prospective evaluation of biopsy number for the diagnosis of viral esophagitis in patients with HIV infection and esophageal ulcer, Gastrointest Endosc 44:587–593, 1996. 108. Wilcox CM, Rodgers W, Lazenby A: Prospective comparison of brush cytology, viral culture, and histology for the diagnosis of ulcerative esophagitis in AIDS, Clin Gastroenterol Hepatol 2:564–567, 2004.
A complete reference list can be found online at ExpertConsult .com
CHAPTER 41 Infections of the Luminal Digestive Tract
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CHAPTER 41 Infections of the Luminal Digestive Tract
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