Oroesophageal Candidiasis in a Patient With AIDS

The patient is a 47-year-old HIV-positive man who has been out of medical care for several years. He presented recently with severe thrush, profound dysphagia, and a 30-lb weight loss. His CD4⁺ cell count was 21/µL. He was initially treated with fluconazole. Antiretroviral therapy was restarted and prophylaxis against Pneumocystis jiroveci pneumonia and Mycobacterium avium complex infection was started.

The patient underwent an upper endoscopy with biopsies. Severe esophagitis was seen; biopsy specimens revealed unspeciated Candida (Figure).

The patient missed 2 subsequent follow-up appointments. He returned to the office a few months later with the same problem. He claimed he had taken his medications but had not ordered refills.
 
The patient was again treated with fluconazole; a follow-up appointment was scheduled, which the patient missed. He presented for a third time with recurrent thrush and was hospitalized and treated. This time it took longer for the infection to resolve.

An HIV genotype returned pansensitive; the patient’s high HIV viral load never decreased. It was clear that the patient was not taking his antiretroviral medications.

On his fourth presentation-18 months after the initial one-the severe oral candidiasis did not improve with fluconazole. Instead the patient was given amphotericin B, which cleared his infection within a day. He was discharged with a prescription for oral itraconazole. Shortly after the discharge, the patient called the clinic and said the itraconazole was not working. Voriconazole was prescribed.

The patient returned several more times to the hospital. Each time he had thick, clotting wads of candidal lesions lining his oral cavity and throat. Despite admonishments, he rarely took out his dentures, gave flimsy excuses for missing his appointments, and claimed he took his medications while the pharmacists noted that his prescriptions went unfilled.

Amphotericin B worked well the first few times it was given, but it soon failed to afford any improvement. The patient began to appear in the GI clinic unannounced, asking for someone to dilate his esophagus. He lost weight and eventually agreed to a percutaneous endoscopic gastrostomy (PEG) feeding tube, which he used at night to stave off further weight loss.

Candida
Oral candidiasis is the most common fungal infection, and the HIV epidemic caused its incidence to rise considerably. During the 1980s, nearly 90% of patients with HIV infection had oral candidiasis at some point during their illness. Candida may spread down into the esophagus when the CD4⁺ cell count falls below 100/µL. Opportunistic fungal infections are a consequence of other immunosuppressive states, including organ transplant, cancer chemotherapy, indwelling catheters, and parenteral nutrition.

In the post-HAART era, the development of opportunistic infections-including esophageal candidiasis-became less common. In patients with poorly controlled or uncontrolled HIV infection, however, the risk of this infection remains.

There are numerous strains of Candida species, of which Candida albicans is the most common. (It is isolated in more that 80% of oral lesions.) Other strains that affect the oral mucosa include Candida glabrata, Candida krusei, Candida parapsilosis, and Candida tropicalis. These all have different invasive qualities and antifungal susceptibilities. Of note, C albicans is markedly sensitive to the azoles (fluconazole, voriconazole, itraconazole) but C glabrata and C krusei are not.

With the HIV epidemic, there was a marked increase in the use of fluconazole-an easy, well-tolerated treatment that was commonly prescribed in intermittent doses for recurrent outbreaks. As a result, there was also a rise in the incidence of non-albicansCandida species, particularly C krusei and C glabrata.

Treatment
Topical treatment for oral candidiasis is not as effective when there is esophageal involvement (Table). Topical treatments include nystatin, amphotericin B solution, and miconazole tablets. Systemic therapy given orally includes the azoles, of which fluconazole remains the most effective commonly prescribed agent.

Voriconazole is effective against some resistant strains of Candida.

The newer class of drugs, echinocandins, are glucan synthesis inhibitors, which inhibit cell wall synthesis. Caspofungin, micafungin, and anidulafungin are the 3 approved echinocandins. All 3 are available only as intravenous treatments. Amphotericin B has been the standard against which all antifungals have been measured. Its adverse effects and toxicity continue to make it a difficult drug to administer. Newer formulations, liposomal amphotericin B (LAmB) and amphotericin B lipid complex (ABLC), are better tolerated.

Conclusion
This patient’s advanced HIV disease made him vulnerable to the dramatic growth of Candida in his esophagus. The intermittent fluconazole treatment may have wiped out C albicans and allowed other, more resistant strains to emerge. It is also possible that the C albicans that was originally identified eventually became resistant. Amphotericin B was initially effective but the organism soon became resistant to that as well. Successive azoles did not afford any degree of disease management, and the patient was unable or unwilling to keep follow-up appointments or adhere to medication regimens, for both his esophagitis and his HIV disease. He eventually received an indwelling intravenous line for treatment with caspofungin and then micafungin. The efficacy of both was short-lived. While his PEG feeding tube prevented further weight loss, the patient’s infection continued to worsen. He was hospitalized on multiple occasions and eventually went to a skilled nursing facility where he died of disseminated fungal disease.

For more information
• Farah CS, Lynch N, McCullough MJ. Aust Dent J. 2010;55(suppl 1):48-54.
• Giannini PJ, Shetty KV. Diagnosis and management of oral candidiasis. Otolaryngol Clin North Am. 2011;44:231-240.
• Pappas PG. Invasive candidiasis. Infect Dis Clin North Am. 2006;20:485-506.
• Rautemaa R, Ramage G. Oral candidiasis-clinical challenges of a biofilm disease. Crit Rev Microbiol. 2011;37:328-336.

Table. Topical treatment
Nystatin
Amphotericin B solution
Micafungin tablets

Oral systemic treatment
Fluconazole
Voriconazole
Itraconazole
Ketoconazole

Systemic intravenous therapy
Fluconazole
Echinocandins
• Caspofungin
• Micafungin
Amphotericin B