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Esophageal Infections

The esophagus is rarely infected in immunocompetent persons but is a common site of infection in patients with immune defects. Normal host defenses of the esophagus are the salivary flow, an intact mucosa, normal esophageal motility, and normal gastric acidity with the absence of excessive gastroesophageal reflux.

Humoral immunity including secretory IgA is important in protecting the mucosal integrity. However, based on the observation that patients with neutropenia and obvious defects in cell-mediated immunity have higher rates of esophageal infections, it seems likely that a major protective mechanism in the esophagus is cell-mediated immunity.

The esophagus can be involved with infections by bacteria, fungi, and viruses. Most esophageal infections are fungal (Candida albicans) or viral (herpes simplex virus or cytomegalovirus) or a combination of the two. Diagnosis of the specific etiologic agent is essential because of the availability of effective antiviral, antifungal, and antibacterial therapy.

Fungal esophagitis.

C. albicans is the most common fungus recovered from patients with fungal esophagitis. However, other species have been isolated and implicated as etiologic agents of such infections. These are Candida tropicalis, Candida parapsilosis, Candida glabrata, Histoplasma capsulatum, and Blastomyces dermatitidis.

C. albicans is found in the oropharynx of approximately 50% of the healthy population. It is also found in the skin and the bowel of immunocompetent persons. Patients with defects in cellular immunity and those treated with antibiotics may have sufficient alteration in their normal bacterial flora to have luminal candidal overgrowth. It is thought that patients with physical or chemical damage to the esophageal mucosa (e.g., acid reflux) may be at increased risk for developing candidal overgrowth and subsequent invasive disease. Indeed, the worst lesions visible in many instances of Candida esophagitis are in the distal esophagus, the area most likely to suffer from reflux damage. The mechanisms responsible for permitting mucosal adherence and subsequent invasion are unknown.

Candidiasis is by far the most common esophageal infection. In fact, it is a rather common disease with a varying spectrum of severity. It can be an asymptomatic incidental finding during endoscopy as well as an overwhelming infection causing death. In one study, 90% of the human immunodeficiency virus-infected patients with oral thrush who underwent endoscopy had mucosal lesions caused by Candida. Larger series have not confirmed this high figure; however, many of the treatments effective for oral thrush are also effective in most instances of Candida esophagitis, suggesting that diagnostic evaluation such as endoscopy might best be reserved for patients who do not respond to initial topical antifungal therapy.

In addition to acute manifestations of the disease, late sequelae can develop. Mucosal sloughing caused by an intense inflammatory response, esophageal perforation, and stricture formation have been reported.

While Candida esophagitis can occur in any patient, certain conditions seem to predispose to it.

Predisposing factors

These factors include human immunodeficiency virus infection, neutropenia, hematologic and other malignancies, organ transplantation, and immunosuppressive agents including corticosteroids, antineoplastic chemotherapy, radiation therapy, broad-spectrum antibiotics, diabetes mellitus, renal failure, alcoholism, malnutrition, old age, and chronic mucocutaneous candidiasis. In chronic mucocutaneous candidiasis, esophageal candidiasis may occur in addition to the chronic involvement of the nails, skin, and oral cavity. These patients have defective cellular immunity.

Diagnosis

Clinical presentation

Dysphagia and odynophagia. The most common symptoms of esophageal candidiasis are dysphagia and odynophagia; fever may be present. Pain may be substernal and radiate to the back. In some patients, odynophagia may be experienced only when they drink hot or cold beverages, and in others, it may be so severe that they may not be able to eat at all. The symptoms may be absent in 20% to 50% of the patients, especially those with mild infection, patients who are severely debilitated, and those with chronic mucocutaneous candidiasis.

Oral thrush may be present in children and in human immunodeficiency virus-infected individuals with esophageal candidiasis, but it is usually absent in immunocompetent adults. The plaques adhere to the underlying mucosa but can be dislodged at endoscopy revealing an inflamed, friable mucosa underneath. Candida can coexist with other pathogens in up to 30% of patients, and reliance on the endoscopic appearance alone may result in failure to identify a concomitant viral or bacterial infection. Multiple biopsies are essential to exclude coexisting disorders. During endoscopy, mucosal lesions should be brushed and submitted for cytologic evaluation and biopsied for histologic examination. Cytologic examination of brushings is more sensitive than histologic examination of the biopsy specimens since organisms may be washed off the mucosa in superficial Candida infections during the processing of the biopsy specimens.

In addition to cytologic evaluation, material obtained material obtained from esophageal brushings may be placed on a microscopic slide, and a drop of potassium hydroxide may be added to lyse the epithelial cells. Both yeast and hyphae of C. albicans can be demonstrated in this manner. Because mycelia are not found in the normal esophagus, their presence in the brushings strongly suggests the diagnosis. A Gram’s stain of esophageal brush specimens can also demonstrate the presence of yeast, hyphae, and bacteria.

Biopsy specimens should be stained with hematoxylin-eosin to assess the severity of the inflammation. Silver and periodic acid-Schiff stains of biopsy specimens may confirm the presence of fungal elements.

In patients with acquired immunodeficiency syndrome, concomitant infection with viruses (e.g., cytomegalovirus, herpes simplex virus) may be present. Cytoplasmic and nuclear inclusion bodies and other findings suggestive of viral infection also should be looked for in both biopsy and brush specimens.

Diagnostic studies

Endoscopy. Fiberoptic endoscopy is the most useful method in the diagnosis of Candida esophagitis. Direct observation of the esophageal mucosa may allow the differentiation of Candida esophagitis from other infections (e.g., herpes) and from varices, carcinoma, or peptic disease, which may have a similar radiologic picture. The endoscopic appearance of esophageal candidiasis is graded on a scale from I to intravenous. The lesions range from small, raised white plaques to ulceration and confluent plaque formation appearing as friable pseudomembranes.

Radiologic studies. If a barium swallow is performed, the esophagram is normal in most patients. When radiologic abnormalities are found, the infection is usually severe. A double-contrast esophagram may increase the yield of positive findings. The esophagus usually has a «shaggy» appearance due to superficial ulcerations, but deep ulcerations may also be present. Abnormal motility with diminished peristalsis and occasional spasm may be seen. Esophageal stricture is commonly present in chronic mucocutaneous candidiasis. This may be a focal narrowing in the upper esophagus or may involve the entire length.

Treatment

Before the initiation of any specific therapy for esophageal candidiasis, the underlying predisposing factor should be identified.

Patients with acquired immunodeficiency syndrome and mild-to-moderate symptoms who have oral thrush may be treated initially with one of the topical agents such as nystatin (Mycostatin) suspension, clotrimazole troches or one of the «azoles» may be an alternative form of therapy before undergoing a diagnostic procedure.

Patients with leukopenia or with severe symptoms or systemic signs should undergo endoscopy to obtain biopsy and brushing specimens for fungi, viruses, and bacteria.

Orally administered systemic antifungal agents include the «azoles» and polyene antibiotics. The most commonly used «azoles» include ketoconazole (Nizoral), fluconazole (Diflucan), and itraconazole (Sporanox). All are effective in treating esophageal candidiasis.

Ketoconazole may be used at high doses. However, its gastrointestinal side effects; decreased absorption in achlorhydric patients or patients on acid antisecretory drugs such as histamine-2 (H2) blockers, proton-pump inhibitors, and prostaglandin analogs; hepatotoxicity may limit its usefulness.

Fluconazole is extremely efficacious in treating oral candidiasis and Candida and other fungal esophagitis with or without tissue invasion. Fluconazole may be administered via oral or parenteral routes. Its oral absorption is efficient and does not require the presence of gastric acid. It is minimally metabolized and excreted by the urine. Drug interactions have been demonstrated between fluconazole (and the other «azoles») and other medications, including phenytoin, oral anticoagulants, sulfonylureas, cyclosporin A, rifampin, and barbiturates. Fluconazole augments the effects of warfarin, necessitating careful observation of patients receiving both of these agents. Fluconazole may increase serum levels of cyclosporin A. Serum cyclosporin A and creatinine levels must be monitored carefully in patients receiving both of these drugs. Fluconazole and the other azoles also appear to increase the serum levels of phenytoin and oral hypoglycemic agents. Fluconazole appears to have minimal antisteroidogenic effects in humans at currently recommended doses. This results from fluconazole highly specific affinity for fungal cytochrome P-450 enzymes, with virtually no affinity for the mammalian system. This is an important advantage of fluconazole over ketoconazole in patients with acquired immunodeficiency syndrome, who often have adrenal insufficiency secondary to adrenal cytomegalovirus infection.

TABLE. AVAILABLE AGENTS FOR THE TREATMENT OF FUNGAL ESOPHAGITIS
Agent Treatment Schedule
Topical
Nystatin 1-3 million units (10-30 mL) 4-5 times daily, swish and swallow
Clotrimazole 1 troche (10 mg) 5 times daily
Systemic
Amphotericin B 0.3-0.6 mg/kg/d intravenously
Ketoconazole 200-400 mg once daily, orally
Fluconazole 50-200 mg once daily, orally
100-200 mg twice daily intravenously
Itraconazole 200 mg once daily

Itraconazole has a longer half life than ketoconazole but its absorption is also reduced by hypochlorhydria. These two azoles are metabolized by the liver and excreted in the bile. Dose adjustments are not required in the patient with renal failure. Total treatment dosage is about 100 to 200 mg.

Intravenous amphotericin B should be considered in symptomatic patients who fail to respond to the above regimen and in those in whom systemic involvement is suspected. In the absence of systemic Candida infection, a low-dose regimen of 10 to 20 mg per day for 10 days may be given. The dosage may be increased if the patient does not respond favorably. If systemic infection is present, the dosage should be increased gradually to 0.5 mg/kg per day. Most patients are treated for 6 weeks. The major serious side effect of amphotericin is renal toxicity, which is usually reversible.

A major problem in the treatment of esophageal candidiasis is relapse after therapy is discontinued, especially in patients with acquired immunodeficiency syndrome, in whom immunosuppression is unrelenting. If the underlying predisposing factors persist, the chances for permanent cure are low and maintenance therapy may be necessary (e.g., fluconazole 100 mg/day). However, in patients with reversible predisposing conditions (e.g., radiotherapy, steroid use), a single course of therapy for 10 to 21 days should be successful.

Nutritional support of the patient is very important. If the patient can swallow, the diet should be supplemented with liquid enteral formulas to ensure that adequate calories are received. If the patient is unable to swallow, parenteral nutrition should be given until the patient can receive enteral feedings.

Viral esophagitis is also a common esophageal disorder, especially in immunocompromised patients, which may clinically mimic Candida esophagitis. The herpes viruses are the most common etiologic agents of viral esophagitis, with herpes simplex virus and cytomegalovirus predominating. In patients with acquired immunodeficiency syndrome, Epstein-Barr virus, varicella zoster virus, and human immunodeficiency virus-1 also have been implicated in esophageal ulcerations.

Herpes simplex virus esophagitis. Herpetic esophagitis may be seen in healthy, normal individuals, especially after strenuous physical exertion and stress. The infection in such individuals is self-limited and resolves in approximately 7 to 10 days. Recovery generally indicates intact humoral and cellular immunity. Persistence or recurrence of the disease may be a sign of acquired immuno-deficiency, requiring further workup of the patient.

Predisposing factors

Immunocompromise

(1)Malignancy, mainly of the hematopoietic and lymphoreticular systems.

(2)Transplantation

(3)Immunosuppressive drugs, steroids

(4)Antineoplastic chemotherapy

(5)acquired immunodeficiency syndrome

Severe debilitation

(1)Elderly

(2)Burns

Antecedent trauma

(1)Nasogastric tubes

(2)Tracheal intubation

(3)Gastroesophageal reflux disease and peptic esophagitis

Diagnosis

Clinical presentation. Herpetic infection of the esophagus usually presents as a triad of fever, odynophagia, and substernal pain that increases with feeding. The pain may radiate to the back. Patients may complain of pain on palpation of the xiphoid process. Gingival stomatitis may be present. Disseminated herpes simplex virus infection is seen in 30% of the patients. Multiple organ involvement with the virus (e.g., gastric and respiratory infection) is usually life-threatening. Simultaneous infection with other organisms (bacteria, fungi, and other viruses) is common. Severely debilitated patients may not complain of pain; therefore, a high index of suspicion should be present if these patients have dysphagia and decreased oral intake.

Diagnostic studies

(1)Endoscopy. Endoscopic examination of the esophagus is the preferred diagnostic approach in these patients. Biopsies and brushings of the affected mucosa should be obtained. Biopsies should be obtained from the edge of the ulcers.

(a)The endoscopic appearance varies according to the stage of the viral infection.

(i)Early – vesicles of various sizes.

(ii)Mid – small, punched-out superficial ulcers covered with yellow, fibrinous exudates.

(iii)Late – coalescing ulcers forming a diffuse, erosive esophagitis with large areas of shallow ulceration.

(b)The lesions often become overgrown with Candida and bacteria. The virus may be cultured from ulcer margins and vesicles. A smear of the ulcer base should be processed for Candida. Histologically, the epithelial cells at the border of the ulcers contain inclusion bodies. The chromatin of the infected nuclei is displaced toward the periphery of the nucleus, giving a «rim» appearance. Multinucleated giant cells are often present.

(2)Barium swallow. Double-contrast radiography may show ulcers or plaques. The picture may be indistinguishable from that of Candida esophagitis.

Diagnosis of herpes esophagitis is often difficult because the characteristic nuclear inclusions or multinucleate giant cells of herpes simplex virus infection may be absent in endoscopic biopsy specimens. Immunoperoxidase and in situ hybridization techniques may be used to detect the herpes simplex virus when nuclear inclusions are not readily apparent in infected epithelium. In situ hybridization and immunoperoxidase techniques should be used also to detect other viruses such as cytomegalovirus, Epstein-Barr, and human immunodeficiency virus-1. The diagnosis of herpes simplex virus esophagitis may still be missed when no infected epithelium is present in the biopsy specimen. The presence of aggregates of large mononuclear cells (macrophages) with convoluted nuclei adjacent to infected epithelium in the exudates of herpetic esophagitis seems to be a characteristic inflammatory response in ulcerative herpetic esophagitis. The presence of these mononuclear cells in a biopsy specimen that initially does not show herpetic inclusions warrants additional studies to rule out herpes virus infection.

Both brushings and biopsy specimens may be cultured for herpes simplex virus to increase the diagnostic yield.

Treatment

Supportive measures. Patients may benefit from viscous lidocaine swallows for local anesthesia, especially before eating. Patients who have severe, unremitting odynophagia may require intravenous hyperalimentation.

Acyclovir (Zovirax) has been shown to be effective in the prompt resolution of symptoms. The dosage used is usually 6.2 mg/kg intravenously every 8 hours, for a 10- to 14-day course. Acyclovir 200 mg, five times a day by mouth, may be used in mild-to-moderate disease.

Valacyclovir and famciclovir seem to have similar efficacy as acyclovir, but may be administered three times a day.

Cytomegalovirus esophagitis. Cytomegalovirus is one of the most common opportunistic infectious agents causing disease in patients with acquired immunodeficiency syndrome. In the gastrointestinal tract, it most often infects the colon and esophagus.

Clinical presentation. Cytomegalovirus esophagitis may mimic herpes simplex virus, Candida, and peptic esophagitis. Patients may seek treatment for odynophagia, dysphagia, fever, nausea, vomiting, or decreased oral intake. Hemoptysis, hematemesis, melena, or esophageal perforation and sepsis may occur.

Diagnostic studies

Endoscopy. The endoscopic appearance of cytomegalovirus esophagitis may resemble that of herpes simplex virus or Candida esophagitis. Discrete, deep ulcers may be present. Biopsies should be taken from the center of the lesions.

Pathology. Histologic diagnosis of cytomegalovirus infection is made with hematoxylin-eosin stain by identifying typically enlarged cells with characteristic intranuclear and intracytoplasmic inclusion bodies. More sensitive techniques such as in situ deoxyribonucleic acid hybridization and immune histochemical staining using cytomegalovirus-specific antibodies have increased the diagnostic yield. Infected cells are often identified in the granulation tissue and in stromal papillae of the mucosa and the endothelium but never in the squamous epithelium. Thus, deep biopsies are necessary for diagnosis.

Viral cultures of the brushings and biopsies should be done to increase the diagnostic accuracy and yield. Because multiple infections may coexist in these patients, other agents such as bacteria, fungi, and other viruses should be excluded.

Treatment. Ganciclovir sodium (5 mg/kg body weight twice daily for 14-21 days) has been used successfully in severely ill patients with improvement in the symptoms of esophagitis. However, patients may require long-term maintenance therapy and are subject to the myelosuppressive toxicity of the drug. Foscarnet (foscavir) is used in refractory diseases or when side effects of gancyclovir sodium are limiting. It is effective in clinically resistant cases of cytomegalovirus. Its major side effect is reversible renal insufficiency. Cidofovir, due to its long half-life, may be administered once weekly. It also causes reversible renal insufficiency. Relapse rate is 50% in patients with acquired immunodeficiency syndrome.

Idiopathic Esophageal Ulcer related to primary human immunodeficiency virus infection. Large, deep ulcers resembling cytomegalovirus or herpes simplex virus ulcers may occur in patients with acquired immunodeficiency syndrome and, when other etiologies are excluded are attributed to human immunodeficiency virus. Endoscopic cure may be obtained with treatments with oral prednisone or thalidomide.

Bacterial esophagitis may be a distinct clinical and pathologic entity in immunocompromised patients. In a neutropenic patient with either fever or a bacteremia of unknown source, esophagitis must be considered as a possible cause. In some patients with bacteremia, the same organism may be seen on endoscopic biopsy specimens from the esophagus. Most of the organisms isolated from tissue specimens and blood in these patients are gram-positive cocci or rods and enteric gram-negative bacilli. Antibiotics should be directed at the specific pathogen isolated.

Esophageal tuberculosis. Involvement of the esophagus with tuberculosis is rare. The condition may result from reactivated lung disease or direct extension of the infection from adjacent mediastinal or hilar lymph nodes, vertebral bodies, aortic aneurysms, pharynx, or larynx. Disease can also occur when a patient with active pulmonary tuberculosis swallows large numbers of organisms that colonize preexisting mucosal disease. However, most patients with tuberculous esophagitis have no evidence of active pulmonary involvement on chest x-ray.

Clinical presentation. Epigastric pain and dysphagia are the most common presenting symptoms. The symptoms in some patients are vague and nonspecific.

Diagnosis

Radiologic findings are usually diverse and may include extrinsic compression by lymph nodes, ulceration, and stricture resembling esophageal malignancy.

Endoscopy

The endoscopic lesion is ulcerative, with shallow, smooth edges; granular with small mucosal miliary granulomas; or hyperplastic, with fibrosis, luminal narrowing, and stricture formation. Biopsies may show caseating granulomas with or without acid-fast bacilli.

Sputum cultures may grow Mycobacterium tuberculosis even in patients with normal chest x-rays.

An intermediate-strength tuberculin skin test is usually positive and should be compared with other, control antigens.

Treatment. A 9-month course of multidrug regimen including isoniazid, rifampin, and ethambutol hydrochloride has been used to cure esophageal tuberculosis.

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