Case Report: Management of Acanthamoeba Rhinosinusitis in a Patient with Chronic Lymphocytic Leukemia

ABSTRACT.

Infections caused by free-living amoebae pose a significant public health threat owing to growing populations of immunocompromised hosts combined with diagnostic delays, treatment difficulties, and high case fatality rates. Nasopharyngeal infections caused by Acanthamoeba are rare and the optimal treatment is not well established. We report a case of Acanthamoeba rhinosinusitis in a patient with chronic lymphocytic leukemia who presented with headaches and chronic rhinosinusitis refractory to multiple courses of antibiotics. A diagnosis of Acanthamoeba rhinosinusitis was established through broad-range polymerase chain reaction testing on sinus tissue. The patient had a favorable response to treatment, which included surgical debridement, cessation of immunosuppressants, and a three-drug regimen consisting of miltefosine, fluconazole, and sulfadiazine.

INTRODUCTION

Acanthamoeba is a ubiquitous free-living organism typically found in soil and freshwater, including lakes, swimming pools, and tap water.¹ Acanthamoeba can cause keratitis in the general population, whereas invasive disease typically occurs in immunocompromised hosts.² Invasive disease may present as granulomatous amebic encephalitis, rhinosinusitis, and cutaneous disease.^1,3 Case fatality rates are high for invasive Acanthamoeba infections, particularly those involving the central nervous system (CNS).

Nasopharyngeal infections caused by Acanthamoeba are rare and found predominantly in people with compromised immune systems, such as those with uncontrolled HIV, hematological malignancy, and solid organ or hematopoietic stem cell transplant recipients.² Infections are characterized by nasal obstruction, nasal crusting, epistaxis, and erythematous mucosa.^3,4 Because of the rarity of disseminated Acanthamoeba infections combined with high mortality, there are little data to guide treatment. We present the successful treatment of a case of Acanthamoeba rhinosinusitis with skull base invasion in a patient with chronic lymphocytic leukemia (CLL).

CASE REPORT

Our patient is an 80-year-old man who lives in central Florida and has a history of CLL and chronic headaches. Around 2019, the patient’s headaches started to become more severe and were attributed to chronic rhinosinusitis. He was treated with amoxicillin–clavulanate for 24 weeks with no improvement. In late 2019, he underwent bilateral functional endoscopic sinus surgery (FESS) and endoscopic septoplasty. Cultures from intraoperative samples grew extended-spectrum beta-lactamase–positive Escherichia coli, Pseudomonas aeruginosa, and normal flora. He started gentamicin and saline nasal sinus rinses for long-term treatment. Surveillance nasal endoscopies throughout 2020 showed well-healed, open sinus cavities with normal mucosa in the sinuses and nasopharynx. In early 2021, he started acalabrutinib (a tyrosine kinase inhibitor) for CLL.

In Fall 2021, the patient developed severe stabbing pain in his left eye and cheek along with sudden-onset left-side hearing loss that did not improve after two courses of oral fluoroquinolones along with oral corticosteroids. A computed tomographic (CT) scan revealed left sphenoid and bilateral ethmoid sinusitis (Figure 1). A flexible fiberoptic and rigid nasal endoscopy was performed mid-December 2021, and revealed mild edema and crusting in the ethmoids. A culture performed on a sample of the ethmoid crust grew only normal flora. Magnetic resonance imaging (MRI) of the trigeminal nerve was obtained subsequently and revealed an infiltrating process in the left nasopharynx, clivus, sphenoid floor, and involvement of the central skull base (Figure 1).

Figure 1.

(A) Coronal computed tomographic (CT) scan, bone window, showing bone destruction of the left sphenoid floor and clivus and vidian nerve canal (arrow). (B) Coronal CT scan, bone window, showing bony erosion at the left skull base and left carotid canal (arrow). (C) Coronal magnetic resonance image, T1-weighted, postcontrast, shows enhancement at the left nasopharynx, eustachian tube, and skull base (arrow).

In early 2022, an extended sphenoidotomy was performed using a drill, which was necessary to access the lesional tissue at the floor of the sphenoid. The anterior face of the sphenoid was drilled away down to the clivus (Figure 2), and a biopsy was performed of the floor of the left sphenoid sinus. Histopathology revealed severe chronic inflammation with focal granulomatous inflammation and acute microabscess formation. No fungal organisms were seen on Grocott’s methenamine silver stain. Aerobic culture grew normal flora, and fungal and acid-fast bacilli cultures were negative. Fixed ethmoid tissue sent for broad-range polymerase chain reaction (PCR) testing to the University of Washington was positive for Acanthamoeba species. Our patient reported no significant fresh- or saltwater exposure aside from nasal sinus irrigation; he used distilled water for irrigation, cleaned the bottle with tap water, and rinsed it again with distilled water.

Figure 2.

(A) Hyperemic mucosa of the left nasopharynx near the eustachian tube orifice prior to biopsy. (B) Submucosal discoloration of the left sphenopalatine foramen prior to biopsy. (C) Abnormal tissue at the lateral floor of the left sphenoid sinus after drilling away bone of the sphenoid face prior to biopsy.

The patient was subsequently admitted to the hospital for expedited workup and treatment. He was started on flucytosine 37.5 mg⋅kg^–1 every 6 hours, miltefosine 50 mg three times daily, fluconazole 800 mg daily, and sulfadiazine 1.5 g every 6 hours after consultation with the CDC, with a plan to continue treatment until clinical and radiographic resolution was achieved. Acalabrutinib was stopped and he was started on monthly intravenous immunoglobulin (IVIG) for hypogammaglobulinemia. A magnetic resonance image of the brain did not show evidence of CNS involvement.

One month after treatment initiation, a head and maxillofacial CT scan showed little interval change. As a result of significant nausea, flucytosine was stopped after 1 month and miltefosine was stopped after 2 months; the patient remained on sulfadiazine and fluconazole. A nasal endoscopy performed 3 months after treatment initiation showed improvement in the left sphenoid and ethmoid sinuses, as well as the nasopharynx, with no crusting. However, follow-up MRI around that time showed marginal progression of the infiltrating process. To confirm the diagnosis of acanthamoebiasis, the patient underwent repeat FESS, and nasopharyngeal tissue was again sent for Acanthamoeba-specific PCR testing at the University of Washington. The tissue again tested positive for Acanthamoeba species. Histopathology demonstrated chronic necrotizing granulomatous inflammation with no cysts or trophozoites visualized. Miltefosine was restarted along with a scheduled daily antiemetic; fluconazole and sulfadiazine were continued. Surveillance MRI done 7 months after treatment initiation demonstrated considerable improvement in the infiltrating process in the central skull base. The patient’s headaches improved with treatment and after a left greater occipital nerve block was performed. Nasal endoscopy in 2023 continues to show normal mucosa in the left nasopharynx as well as the sphenoid sinus. The patient tolerated the three-drug regimen along with IVIG until clinical and radiographic resolution was achieved after 21 months of treatment.

DISCUSSION

Nasopharyngeal infections caused by Acanthamoeba are rare and are found predominantly in immunosuppressed patients. Although most cases of nonkeratitis Acanthamoeba infections were identified historically in people living with HIV, Haston et al.² found that a large proportion of cases in the past 20 years were diagnosed in people with hematological malignancies, particularly leukemia. As a result of poor detection and limited treatment options, fatality rates still exceed 90% for diseases caused by Acanthamoeba species and require immediate treatment.⁵ In most cases of Acanthamoeba infection, tissue diagnosis is used to confirm infection. Histopathological findings of sampled tissue include mucosal tissue necrosis, chronic inflammation, and granulation tissue, and the organism can be cultured on 1.5% agar with an E. coli overlayer.^6,7 Electron microscopy studies may also be used to confirm the presence of cysts and trophozoites.⁷ Metagenomic next-generation sequencing has emerged as a promising tool to diagnose infectious diseases such as Acanthamoeba,⁸ although it has the potential to lead to overdiagnosis of infection. Our patient’s biopsy revealed severe chronic inflammation with focal granulomatous inflammation and acute microabscess formation; however, no trophozoites or cysts were identified.

For disease of the nose and paranasal sinuses, first-line treatment includes surgical intervention, often using a direct visualization and endoscopic approach, with debridement of all necrotic intranasal structures.⁷ After surgery, medical therapy is recommended. Along with reducing immunosuppression, a multidrug antimicrobial approach is favored, although official guidelines for treatment of this specific condition are not available. Drugs that have been used previously in treating infections caused by Acanthamoeba include miltefosine, fluconazole, itraconazole, ketoconazole, sulfadiazine, pentamidine isethionate, trimethoprim–sulfamethoxazole, and 5-fluorocytosine, among others.⁹ Because of the low incidence and high mortality of these infections, optimal treatment duration remains unknown. In addition to stopping acalabrutinib and starting IVIG for hypogammaglobulinemia, sulfadiazine, flucytosine, fluconazole, and miltefosine were chosen initially for our patient as a result of tolerability, availability, and historical use in the literature. Flucytosine and miltefosine were stopped initially as a result of nausea; however, miltefosine was restarted after radiographic findings worsened and repeat PCR testing was again positive for Acanthamoeba. Our patient had radiographic improvement with the three-drug regimen, suggesting the importance of a miltefosine-based regimen.

Despite the rarity of infection, Acanthamoeba is pervasive and found globally, often in freshwater systems. The tap water used to clean the nasal irrigation bottle is the suspected source of exposure for our patient. The ubiquity of Acanthamoeba combined with growing populations of immunosuppressed hosts (secondary to treatments for malignancy, autoimmune conditions, and organ transplantation) poses a significant public health concern. Everyone, but particularly those persons with impaired immunity, should exercise caution with nasal sinus irrigation by using boiled, distilled, or filtered water.¹⁰ More research is needed to develop guidelines for the diagnosis and management of Acanthamoeba infections.