Histoplasma-Induced Esophageal Ulcers in HIV/AIDS Patient: A Case Report

Introduction

Dysphagia is a common symptom among patients with human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), and it has been reported in up to 47% of patients with AIDS [1]. The most common cause of dysphagia, in general, in the HIV/AIDS population is esophageal candidiasis [1]. Dysphagia in the HIV/AIDS population is frequently due to opportunistic infections, but it can also be due to opportunistic malignancies, like Kaposi sarcoma and non-Hodgkin lymphoma, or pill-induced esophagitis [2]. Other common causes of dysphagia, unrelated to HIV/AIDS, include inflammation, ulcers, or strictures due to acid reflux, masses, and motility disorders. Patients with HIV/AIDS are at increased risk of opportunistic infections of the esophagus, owing to immune suppression caused by HIV/AIDS. The most common opportunistic infection leading to dysphagia in this patient population is Candida, but viral infections can also cause esophageal pathology, including cytomegalovirus (CMV), herpes simplex virus (HSV), and HIV causing idiopathic ulcers [2]. Bacterial, protozoan and other fungal pathogens leading to esophageal pathology are less common [2].

Case Report

A 58-year-old man presented to Emergency Department with concerns of 4 weeks of progressive dysphagia, with an associated weight loss of 13.6 kg over the same time. The dysphagia progressed quickly over the previous 4 weeks, with the patient initially tolerating most solid foods for the first week of symptoms; however, at presentation, the patient struggled to swallow liquids and was unable to swallow any solid foods. The patient had a history of HIV, diagnosed 40 years prior. His medications included bictegravir/emtricitabine/tenofovir alafenamide daily. He was taking sulfamethoxaszole/trimethoprime daily for pneumocystis jirovecii pneumonia prophylaxis. His HIV disease course was complicated by persistently low CD4 counts and disseminated histoplasmosis (DH) identified 10 years prior to this current presentation, after an ulcerated tongue lesion developed and was found to be histoplasma. The tongue lesion was surgically excised, and he had been maintained on itraconazole 200 mg twice daily for the past 10 years. He admitted that he frequently forgot to take the second dose of itraconazole, but he did take at least 1 dose of itraconazole with his other once-daily medications. He smoked half of a pack of cigarettes daily and intermittently used marijuana. He had a remote history of intravenous drug use but none in the past 30 years, and he denied alcohol use.

On physical examination, the patient was noted to be thin and cachectic, with a weight of 51.7 kg and a height of 162.5 cm. Of note, a weight documented at a routine health maintenance visit 2 months prior was 67.6 kg. Blood pressure was 115/84 mm Hg and pulse was 98 beats per minute. He was afebrile. He was noted to have mild temporal wasting, and mucous membranes were dry; head and neck examinations were otherwise normal. Cardiopulmonary examinations were normal, and abdominal examination revealed a nontender abdomen and no organomegaly. Neurological examination was normal. Skin examination was only significant for decreased turgor. Laboratory data were significant for a white blood cell count of 3.8×103 uL, with a normal differential, positive HIV antibodies, and CD4 count of 32 cells/uL. The remainder of his laboratory data were within the reference range. Computed tomography (CT) scan of his chest, abdomen, and pelvis was significant for diffuse circumferential esophageal wall thickening, with no significant lymphadenopathy. Due to his symptoms and the abnormal CT scan, he had an upper endoscopy, which was notable for large, deeply cratered ulcers in his distal esophagus (Figure 1). Biopsies were obtained, with routine immunohistochemical staining negative for HIV, CMV, yeast or fungal organisms (Figure 2). During hospitalization, he was maintained on his home medications, to include twice daily itraconazole, as well as bictegravir/emtricitabine/tenofovir alafenamide and sulfamethoxaszole/trimethoprime daily. After the findings of the upper endoscopy, he was started on oral pantoprazole 40 mg twice daily for therapy of the esophageal ulcers. Upon discharge, he was maintained on his usual home medications for HIV and DH, including twice-daily itraconazole, daily bictegravir/emtricitabine/tenofovir alafenamide, daily sulfamethoxaszole/trimethoprime, and twice-daily pantoprazole. At discharge, he had minimal symptomatic improvement in dysphagia, but he was tolerating some solid oral intake as well as nutritional supplemental drinks and shakes. One month later, the patient had continued weight loss as well as dysphagia to almost all solids while adherent to acid suppressive therapy. Laboratory test results were significant for subtherapeutic levels of itraconazole therapy, at <0.2 mcg/mL, and he had a positive urine Histoplasma antigen. These laboratory results raised concern for undertreated DH as a possible cause of his esophageal ulcers and led the team to conduct specialized Grocot-Gomori methenamine silver staining on tissue from the esophageal ulcers, which revealed Histoplasma (Figure 3).

For treatment of DH, he was admitted for intravenous amphotericin administration for 6 days, which was then transitioned to oral itraconazole 200 mg twice daily. By discharge, he was tolerating soft solid oral intake and liquid oral intake. He was seen in close outpatient follow-up 4 weeks later, with resolution of all swallowing symptoms. He was tolerating a regular diet and had regained 2.7 kg. The itraconazole level, however, remained subtherapeutic. The dosing of itraconazole was subsequently increased to 250 mg twice daily, and the itraconazole levels improved to therapeutic levels of 1.05 mcg/mL. He had follow-up upper endoscopy 13 weeks from index endoscopy and 6 weeks from amphotericin administration, and the esophageal ulcers had resolved (Figure 4).

Discussion

Histoplasmosis is one of the most common endemic mycoses in the United States and is caused by the fungus Histoplasma capsulatum. Geographically, this mycotic infection is found in warmer climates worldwide, with specific areas in the United States being the Ohio and Mississippi River valleys. The fungus is found in soil contaminated with bat and bird excrements [3]. Transmission occurs through inhalation, and symptoms are usually respiratory in nature. Most people exposed to the pathogen remain asymptomatic, with only approximately 1% of those exposed becoming symptomatic. Severity of symptoms depends on the concentration of exposure to the pathogen and the host’s immunity [4]. Once inhaled, T-cell immunity is the prevailing system activated to fend off the pathogen, with macrophage fungicidal activity being the predominate means of attack [5]. In hosts with altered immune response, the macrophages that envelop the pathogen cannot effectively fight off the pathogen and instead get fully laden with the fungus. These fungal-laden macrophages then transport the fungus through the lymphatics, where the organism is then spread throughout the liver, spleen, bone marrow, and lymph system [5]. Symptoms of acute pulmonary histoplasmosis include mild cough, fatigue, and fever [4]. Mild acute pulmonary histoplasmosis usually resolves without any intervention. In certain patient populations, however, such as those with HIV/AIDS, the disease can progress to DH [6]. DH requires anti-fungal therapy, such as itraconazole and amphotericin B [4]. DH is exceedingly rare and accounts for <0.1% of histoplasmosis cases [6]. Symptoms of DH are related to the organ infected and can range from pancytopenia to neurologic changes consistent with central nervous system lesions, and rarely include spread to the gastrointestinal tract, most commonly presenting as abdominal pain [7]. Gastrointestinal infection with DH is rare, but typically occurs in areas rich with lymphoid tissue, such as the ileum and colon [7]. One literature review spanning 20 years of data found only 123 pathologically confirmed cases of gastrointestinal involvement in DH, with most of those patients having HIV/AIDS [7]. The most common clinical presentation was abdominal pain, and the most common pathological finding was ileal and cecal ulcerations [7]. Esophageal histoplasmosis is a rare presentation of DH, somewhat unique to the HIV/AIDS population, and account for 3% of DH cases in patients with HIV/AIDS [7]. One literature review amounted to only 12 cases of esophageal histoplasmosis, 2 of which were fatal [7]. It is postulated that the fungus infects the esophagus through adjacent histoplasmosis mediastinal adenitis [7]. Our patient already had a history of DH, which would in theory increase his risk of DH gastrointestinal tract involvement, although be it very rare.

Initial workup for histoplasmosis includes Histoplasma antigen testing using enzyme immunoassay (EIA) of urine or serum, which has the benefit of high sensitivity and specificity, as well as quick turn-around time [3]. False positives can occur with this method, due to cross reactivity with other fungi [3]. Additional serum antibody testing can be done, which can increase overall diagnostic yield, but is limited by delayed timing of results [3]. Antibody testing is also hampered by the patient’s ability to mount an immune response to the pathogen, as may be the case in the HIV/AIDS population, and antibody testing can remain positive for up to 3 years after a resolved infection [8]. Tissue sampling with visualization of the organism within macrophages under direct microscopy, or via histopathologic examination using special stains such as Grocot-Gomori methenamine silver staining, is definitively diagnostic [3]. Ultimately, tissue culture is the “criterion standard” for diagnosis, but this method is significantly limited by long processing times and need for considerable pathogen burden in tissue [3]. As such, an algorithm for diagnosing histoplasmosis in the HIV/AIDS population would include initial antigen testing with EIA of urine and/or serum, given its accuracy and quick laboratory turnaround time. Cross reactivity with other fungal organisms exists with EIA but this ultimately would not change treatment, as other fungal organisms are treated with the same antifungals as histoplasmosis [3]. EIA testing should be followed by tissue sampling, to allow for microscopy, histopathology, and possibly culture. In patients with HIV/AIDS, antibody testing can be performed, but can be of limited value given an immunocompromised state and potential lack of ability to mount an immune response to the organism. After treatment, EIA urine antigen testing is useful to assess response to therapy [3].

Treatment for histoplasmosis infection centers around itraconazole for mild to moderate infections, and amphotericin B for chronic or severe disseminated infections and for meningitis [8]. Subtherapeutic levels of itraconazole have been noted with concomitant use of drugs that induce the cytochrome P450 pathway and UDP-glucuronosyltransferase enzymes [9], as well as with concomitant use of drugs that can alter its absorption, like proton pump inhibitors [10]. Formulation of the drug, in liquid or capsule formulation, as well as differing manufacturer formulations, have been documented to alter the bioavailability of itraconazole [10]. Additionally, bioavailability can be altered by patient genetic polymorphisms in CYP2C19, as is known to occur among various ethnicities [10]. Finally, patient compliance with taking the medication appropriately plays a central role in subtherapeutic itraconazole levels.

In our patient, his presenting symptom for DH was progressive dysphagia. Dysphagia is a common condition noted in almost half of patients with HIV/AIDS [1]. Dysphagia in HIV/AIDS patients is frequently due to an esophageal opportunistic infection, with esophageal candidiasis being the most common pathogen. Other esophageal opportunistic infections in this patient population include CMV, HSV, idiopathic ulcers related to HIV, bacterial infections, such as various Mycobacterium species, and other non-Candida fungal pathogens, such as histoplasmosis [2]. Patients with HIV/AIDS are also at increased risk for opportunistic malignancies that are a cause of dysphagia, including non-Hodgkin lymphoma and Kaposi sarcoma [2]. Finally, other causes of dysphagia, not unique to HIV/AIDS or immunosuppressed patients, include pill esophagitis, squamous and adenocarcinomas, motility disorders, and inflammation, ulcers, and strictures due to acid reflux. This case report of DH-related esophageal ulcers is novel and important due to the rarity of gastrointestinal esophageal DH.

The limitations of this case report are like the limitations of all such case reports. The rarity of the condition makes it not generalizable to the population at large, causality cannot be inferred, and it puts an emphasis on the rare.

Conclusions

Certainly, there are more common opportunistic infections that cause dysphagia and esophageal ulcers in the HIV/AIDS population. This case, however, underscores Histoplasma capsulatum as a rare but significant cause of esophageal ulceration in patients with HIV/AIDS. A high index of suspicion and proper diagnostic approaches, including specialized staining techniques, are critical when routine examinations fail to identify a pathogen.