Alimentary Tract Disease in the HIV Patient: Esophageal Diseases and Swallowing Disorders

OVERVIEW: What every practitioner needs to know

The management of HIV infection in the current era is complicated by its heterogeneity. Gastrointestinal symptoms are common in HIV infection, and are found in a majority of patients at some point in the disease. Untreated patients include those with mild, moderate, and severe immune depletion. Treated patients include those who have had a good antiviral response and immune reconstitution, and those with poorer responses due to inadequate adherence or resistant virus, and those who experience treatment toxicity. HIV-infected patients are susceptible to diseases that affect anyone and, especially those accompanying risky behaviors, such as sexually transmitted diseases and viral hepatitis. Patients also may develop symptoms related to the processes of chronic inflammation and “accelerated aging” that have been seen in HIV-infected individuals.

Are you sure your patient has an esophageal disease or swallowing disorder? What should you expect to find?

Several clinical syndromes may affect the gastrointestinal (GI) tract in HIV-infected individuals and may be organized by symptom: swallowing disorders, dyspepsia/vomiting, diarrhea, anorectal diseases, tumors, pancreatic diseases, gastrointestinal bleeding, and the surgical abdomen.
While the specific etiologies underlying GI disease may differ in HIV-infected and HIV-uninfected patients, clinical-pathologic and clinical-pathophysiologic correlations are similar.

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How did the patient develop an esophageal disease or swallowing disorder? What was the primary source from which the infection spread?

Disorders affecting food intake may produce symptoms directly, through local pathology, or indirectly. A wide range of possible etiologies may affect food intake and the swallowing mechanism depending on the specific clinical status of the patient. Disease, host and treatment variables affect the likelihood and specific process affecting food intake.

Which individuals are of greater risk of developing an esophageal disease or swallowing disorder?

There is a characteristic sequence in the appearance of opportunistic infections and tumors during the progression of immune deficiency. Tumors, such as Kaposi’s sarcoma and lymphoma, may occur in patients with a broad range of CD4 values in peripheral blood. Esophageal candidiasis (Figure 1) and tuberculosis are typically found in patients with CD4 values below 250, herpes esophagitis (Figure 2) at a somewhat lower level, and CMV and MAC infections at CD4 levels well under 100.
Patients frequently confuse the symptoms of odynophagia and dysphagia and it is important to question the patient carefully, since different complications produce the two symptoms. Infections typically produce odynophagia while tumors and neurologic problems may produce dysphagia.
Local pathology is most often due to infectious, neoplastic, and inflammatory/ulcerative causes in patients with severe immune depletion. Oral candidiasis affects taste sensation and produces pain on swallowing (odynophagia) without obstruction (dysphagia). Oral candidiasis takes several forms, including pseudomembranous and hyperplastic, which demonstrate white plaques, as well as an atrophic (erythematous) form, and angular cheilitis. Patients may complain of burning, tenderness, pain, and/or increased sensitivity to spicy or other foods. As compared to non-HIV infected patients, a prior course of antibiotic therapy is not the rule. Oral and esophageal candidiasis may coexist or occur separately. Specifically, esophageal candidiasis may occur in the absence of oral lesions, especially in a previously treated patient. Candida albicans is the most common organism isolated from patients, though other species have been recovered, especially in previously treated patients. Other fungal disease, e.g. histoplasmosis rarely affects the esophagus.
Viral infection also may produce swallowing disorders characterized by odynophagia. HIV has been implicated in the production of painful esophageal ulcers during primary infection, but the major viruses causing symptoms in immune deficient patients are the herpes viruses, HSV and CMV. Herpes esophagitis may present as single organ involvement relatively early during the disease course, while CMV esophagitis typically is associated with disease reactivation and multi-system involvement and is a late manifestation of disease.
Idiopathic oral and esophageal ulcers were very commonly seen in the pre-HAART era, and continue to occur in untreated patients. Exceptionally, such ulcers may be large and deep, and may lead to esophageal rupture as well as severe hemorrhage.
There are few reports of bacterial esophagitis. However, tuberculosis may affect the esophagus as a consequence of mediastinal lymph node involvement with secondary extension to the esophageal lumen.
Oral, pharyngeal, and hypopharyngeal tumors may distort the anatomy of the swallowing apparatus, producing dysphagia rather than odynophagia.
Some central nervous system lesions, e.g. toxoplasmosis, progressive multifocal leukoencephalopathy, may cause dysphagia. In such cases, local examination of the esophagus is unrevealing.
Patients with well controlled HIV infection and immune reconstitution are susceptible to the same diseases that affect food intake as non-HIV infected individuals, such as gastroesophageal reflux disease, esophageal cancer, achalasia, eosinophilic esophagitis, functional disorders, etc. Some patients complain of intermittent, transient symptoms affecting swallowing or food intake as a side effect of a medication, such as ritonavir.
Gastrointestinal referral should be sought for alarming symptoms, such as weight loss, fever, severe pain, anemia, or evidence of GI blood loss.

Beware: there are other diseases that can mimic an esophageal disease or swallowing disorder:

The differential diagnosis in a patient with a swallowing disorder or other problem with food intake includes both local and systemic problems. In addition to gastroesophageal reflux disease, esophageal cancer, achalasia, eosinophilic esophagitis, and other diseases causing local pathology, food intake may be affected indirectly. Anorexia or nausea secondary to medications or other treatments as well as a symptom of a systemic infection or tumor, altered perception of hunger or impaired swallowing mechanism, may be related to central nervous system (CNS) disorders, such as tumors, toxoplasmosis, progressive multifocal leukoencephalopathy, etc. In addition, patients with cerebrovascular disease may present with eating or swallowing disorders.

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

The most important information in relation to developing a differential diagnosis, aside from history and physical examination is the CD4 count and viral load and associated clinical findings. High CD4 counts, especially in a patient on HAART therapy are inconsistent with late stage infections. Conversely, the presence of systemic symptoms, especially fever, in a patient with low CD4 counts is highly suggestive of a systemic infection such as CMV, MAC or histoplasmosis.
Radiologic studies can localize a pathologic process whether diffuse, such as candidiasis, or focal such as an infectious or idiopathic ulcer. However, the techniques are limited for specific etiologic diagnosis.
Radiologic studies, when negative, also can suggest a neurologic or non-esophageal cause for a swallowing disorder.
Non-HIV esophageal diseases, such as achalasia, have a similar appearance in the presence or absence of HIV infection.
Routine laboratory studies lack sensitivity or specificity in diagnosing the cause of a swallowing disorder.

Results that confirm the diagnosis

In the absence of a clinical response to empiric therapy, e.g. in presumed candidiasis, the most appropriate evaluation typically includes tissue diagnosis obtained via endoscopy. The endoscopic appearance of candidiasis is characteristic and appears as whitish plaques that are not easily washed off, and which occur in a background of esophagitis. Herpetic ulcers, both CMV and herpes simplex produce shallow ulcers with slightly raised, frosted edges that grow and coalesce. Idiopathic ulcers are deep and have undermined edges and are clean-based.
Routine histology is helpful in distinguishing the various causes of esophageal disease. Intranuclear inclusions from herpes simplex occur in epithelial cells, while the inclusions of CMV are found mainly in endothelial and mesenchymal cells. Immunohistochemistry can provide a definitive diagnosis. The histologic picture of idiopathic ulcers is one of highly inflamed granulation tissue without viral inclusions or immunohistochemical evidence of viral infection. Occasionally, ‘smudge’ cells are seen suggesting a viral etiology, but patients typically do not improve after herpes virus therapy.
Viral culture usually is not necessary in the evaluation of esophageal disease. The major disadvantage of culture is that endoscopic evaluation is needed to obtain proper tissue specimens and the time course of viral culture is slow, as opposed to other means of making an etiologic diagnosis.

What imaging studies will be helpful in making or excluding the diagnosis of an esophageal disease or swallowing disorder?

Endoscopic evaluation is warranted in a patient with odynophagia or dysphagia, or any related symptom in the presence of significant weight loss, anemia or fever. Endoscopy with biopsy is important as tissue diagnosis is necessary for diagnosis for all diseases, with the exception of candida esophagitis. Since candidiasis is the most common esophageal pathogen in an HIV-infected individual, short-term empiric therapy with an azole is cost-effective in an outpatient. Similarly, empiric therapy with a proton pump inhibitor may be considered in an outpatient with dyspepsia and decreased food intake. In these circumstances, a rapid response to therapy would be considered sufficient and no further evaluation would be planned, while the lack of such response would prompt endoscopic evaluation. Anticipating a complete response is important, since many patients with viral or idiopathic ulcers have coexisting candidiasis, and may undergo a partial response to azole therapy. The cost advantages of empiric therapy are limited to the outpatient setting.
The value of radiologic examination is uncertain. The diagnosis of candida esophagitis certainly can be made by barium esophagram or computed tomography (CT) scan, but the empiric therapy approach makes such examinations unnecessary, while the need to follow all other positive X-ray findings with endoscopy and biopsy questions are necessary as a prelude to endoscopy. In some cases, esophageal or mediastinal lesions are incidental findings on X-ray studies performed for other indications. On the other hand, the value of routine endoscopy is limited to luminal pathology, while X-rays, especially cross sectional imaging are far more superior at detecting extraluminal pathology.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

The major consultation service for patients with swallowing disorders is with the gastroenterologist, who is in the best position to make an etiologic diagnosis. Surgical consultation is rarely needed, and usually only needed in a patient with a life-threatening emergency. Nutrition consultation may be required in cases with severe weight loss or with persisting impairment in swallowing.

If you decide the patient has an esophageal disease or swallowing disorder, what therapies should you initiate immediately?

There are several steps in the evaluation and management of patients with swallowing problems or disorders of food intake, including a diet history, and some form of quantitation of caloric intake. If a problem is evident, an offending medication should be sought and discontinued if possible. Local pathology should be sought and treated if possible. If there is no local pathology, the presence of CNS disease or systemic processes affecting food intake should be sought.

If local pathology is detected, an etiologic diagnosis should be possible, and therapy directed specifically to the etiologic agent.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

Empiric therapy is indicated only in the management of odynophagia, especially accompanying or following antibiotic therapy, since candida esophagitis is the most common pathogen. Therapy should include a systemically active agent such as an azole. The symptomatic response to fluconazole or related agents becomes evident within 48 hours in most cases and there is substantial relief within one week. Formal analyses have documented the benefit of empiric treatment for one week with endoscopic evaluation for non-responders or partial responders, the latter reflecting the coexistence of candidiasis and another pathogen, such as cytomegalovirus (CMV) (Table I).

Table I.n

Treatment of Specific Pathogens.

In patients with non-specific symptoms or uncomplicated dyspepsia, symptomatic therapy can be considered for a short period of time, within referral for lack of response to treatment.

In patients with symptoms related to non-HIV conditions, such as gastroesophageal reflux disease, empiric therapy for that condition can be given, with evaluation reserved for non-responding patients.

2. Next list other key therapeutic modalities.

The most important adjunct to the therapy of swallowing disorders is HAART, especially in patients with severe immune depletion. Immune reconstitution may allow for the cessation of therapy as opposed to indefinite maintenance therapy, which was common in the pre-HAART era.
In patients with systemic diseases, especially CNS disorders, clinical diagnosis may provide an adequate explanation for the occurrence of swallowing disorders.
Maintaining appropriate hydration and nutritional status is important in patients with swallowing disorders, since severe wasting or dehydration may lead to hospital admission.

What complications could arise as a consequence of an esophageal disease or swallowing disorder?

What should you tell the family about the patient's prognosis?

Swallowing disorders typically are secondary processes, i.e. disease complications as opposed to primary disease processes. As such, they are minimized by effective disease control. HAART therapy is the most important factor that promotes a good long-term outcome.
Adherence to treatment is important in order for the esophageal disease to regress and swallowing to return to normal.
Maintaining nutritional and hydrational status is important in the patient maintaining independence. In severe cases, nutritional assistance such as tube feeding or IV hydration may be necessary, but these interventions typically are temporary.
Occasionally, patients with esophageal disease may require surgery for bleeding, esophageal perforation or esophageal fistula, but these are rare occurrences.

How do you contract an esophageal disease or swallowing disorder and how frequent are these diseases?

The epidemiology and pathogenesis of the various opportunistic infection and tumors vary with the specific etiology, and the reader is referred to the specific chapters covering these conditions for details.

What pathogens are responsible for this disease?

The reader is referred to the individual chapters for detailed discussion of the various etiologic agents.

How do these pathogens cause an esophageal disease or swallowing disorder?

The pathogenesis of esophageal damage does not differ from other affected organs, and the reader is referred to the specific chapters for specific details on pathogenesis.

What other clinical manifestations may help me to diagnose and manage an esophageal disease or swallowing disorder?

The major distinctions for diagnosing swallowing disorders are the distinctions between odynophagia and dysphagia, local versus systemic diseases, mild versus severe immune depletion, and presence versus absence of local pathology. The presence of true dysphagia suggests an organic obstruction as in a mass lesion or a severe neurologic disorder, while odynophagia suggests an inflammatory or ulcerating lesion. The presence of fevers and sweats implies a systemic disorder, such as seen in viral or mycobacterial esophagitis, while its absence suggests local disease, such as candidiasis or an idiopathic ulcer.

Patients with mild immune depletion are more likely to have non-HIV related symptoms, or those from Kaposi’s sarcoma or lymphoma, while patients with severe immune depletion are more likely to have opportunistic infections such as CMV or MAC. The implication of finding local pathology is self-evidence-based and provides a specific target for biopsy. On the other hand, the absence of local pathology is more consistent with an indirect effect, such as a neurologic lesion.

How can an esophageal disease or swallowing disorder be prevented?

The major prevention strategy for esophageal complications is maintenance of immune competence and suppression of HIV viral replication.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

“The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals”. AIDS. vol. 24. 2010. pp. 123-37.

Wilcox, CM, Alexander, LN, Wlark, WS, Thompson, SE. “Fluconazole compared with endoscopy for human immunodeficiency virus-infected patients with esophageal symptoms”. Gastroenterology. vol. 110. 1996. pp. 1803-9.

Pappas, PG, Kauffman, CA, Andes, D. “Clinical practice guidelines for the management of candidiasis, 2009 update by the Infectious diseases Society of America”. Clin Infect Dis. vol. 48. 2009. pp. 503-35.

Wilcox, CM, Rodgers, W, Lazenby, A. “Prospective comparison of brush cytology, viral culture, and histology for the diagnosis of ulcerative esophagitis in AIDS”. Clin Gasrtoenterol Hepatol. vol. 2. 2004. pp. 564-7.

Guidelines on the Treatment of Skin and Oral HIV-Associated Conditions in Children and Adults. 2014. (Well-referenced guide to treatment, particularly relevant in resource-constrained settings.)

Takahashi, Y, Nagata, N, Shimbo, T, Nishijima, T. “Upper Gastrointestinal Symptoms Predictive of Candida Esophagitis and Erosive Esophagitis in HIV and Non-HIV Patients: An Endoscopy-Based Cross-Sectional Study of 6011 Patients”. Medicine (Baltimore). vol. 94. 2015 Nov. pp. e2138(Large prospective study correlating symptoms with diagnoses established by endoscopy.)

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