Disseminated cryptococcal infection in a patient with glioblastoma multiforme on treatment with lomustine and bevacizumab

Abstract

This case describes a 48-year-old Hispanic man with a history of glioblastoma multiforme on active chemotherapy treatment and corticosteroids who presented to the emergency room with complaints of cough, fever, chills, fatigue, confusion, and somnolence. Workup yielded evidence of disseminated cryptococcal disease. The case highlights the importance of a broad differential in patients with a history of being immunocompromised.

Glioblastoma multiforme is a high-grade glioma and the most common malignant primary brain tumor, with an incidence of 3.19 per 100,000 persons per year.¹ Initial treatment consists of a combination of resection and chemoradiation, as well as corticosteroids to help reduce cerebral edema. Our patient was originally started on temozolomide but was switched to lomustine and bevacizumab once his tumor burden returned. While this dual therapy has not been shown to increase overall survival, it has been shown to improve progression-free survival.² However, addition of these drugs is not without risk of adverse side effects, namely increased susceptibility to opportunistic infections, including disseminated Cryptococcus. This case focuses on the neurologic complications of disseminated cryptococcal infection in a chemotherapy patient with a history of glioblastoma. We believe this is the first case of disseminated cryptococcal infection in a patient on active chemotherapy treatment with lomustine and bevacizumab.

CASE DESCRIPTION

A 48-year-old Hispanic man presented to the hospital with a 3-day duration of cough, fever, chills, and fatigue. He had a past medical history of seizures and of glioblastoma multiforme, which had been treated with debulking, radiation, and chemotherapy with lomustine and bevacizumab. He also took dexamethasone daily. He had never smoked, did not drink alcohol, and denied intravenous drug use. He had no history of recent travel.

At presentation, vitals were normal and he was afebrile. Physical exam was noncontributory aside from right-sided crackles at the base. Initial laboratory results revealed no evidence of leukocytosis, with a normal procalcitonin level and negative SARS-CoV-2 polymerase chain reaction nasal swab. Computed tomography of the chest revealed right lower lobe consolidation and mediastinal lymphadenopathy. He was admitted for community-acquired pneumonia, and pulmonary medicine was consulted for possible bronchoscopy with bronchoalveolar lavage given the atypical findings on imaging.

Despite empiric treatment with cefepime and azithromycin, the patient continued to spike high fevers and around the 48- to 72-hour mark he had altered mental status. Given his somnolence, bronchoscopy was not an option due to the risks of the sedating agents. A neurological workup was initiated, but shortly afterwards the patient’s blood cultures returned positive for yeast. Micafungin was started while a fungal workup was initiated. Cryptococcus neoformans was ultimately identified on blood cultures and serology. Given this new information, the patient was transitioned to liposomal amphotericin B and flucytosine. Additionally, lumbar puncture was ordered to assess for opening pressure and presence of cryptococcal infection in the cerebrospinal fluid. Opening pressure was normal, but C. neoformans was present on fungal culture, meningitis/encephalitis polymerase chain reaction, and cerebrospinal fluid antigen.

With induction therapy, the patient’s somnolence and mentation improved. He was discharged to a skilled nursing facility. His chemotherapy continued to be held.

DISCUSSION

Glioblastoma is the most common intracranial neoplasm in adults, and despite aggressive standard-of-care treatment, median survival from time of diagnosis is still only 14.6 months.³ Since chemotherapeutic regimens decrease cell-mediated immunity, this allows opportunistic infections, like C. neoformans, to cause clinical disease.

C. neoformans is an encapsulated yeast that lives in the environment, often associated with soil, pigeon droppings, and certain trees. C. neoformans usually remains dormant and a host will be clinically asymptomatic until a loss of local immunity occurs, such as with long-term corticosteroid use, HIV infection, transplantation, or malignancies. Cryptococcal meningitis is the main presentation of disseminated disease, and it occurs via hematogenous spread to the central nervous system from primary pulmonary foci.⁴ Prompt recognition is crucial, and it is important to identify signs of both meningitis and increased intracranial pressure, as a cerebrospinal fluid pressure >25 mm Hg can lead to blindness, permanent dementia, and even death. Once identified, serial lumbar punctures, or shunt if severe enough, are necessary.

Treatment for cryptococcal meningitis requires induction, consolidation, and maintenance therapy. The duration depends on the clinical context; however, our patient’s regimen included induction therapy with amphotericin B lipid complex at 500 mg daily plus flucytosine for 6 weeks, followed by consolidation therapy with fluconazole 800 mg monotherapy for 8 weeks, and then fluconazole 400 mg maintenance therapy indefinitely, given the high likelihood for cryptococcal recurrence with active chemotherapy treatment.

There have been two similar case reports of patients with high-grade gliomas on chemotherapy who developed cryptococcal meningitis, one with glioblastoma on temozolomide and one with anaplastic astrocytoma on lomustine.⁵ Our patient had a history of resection and radiation and is on current combined therapy with lomustine, bevacizumab, and corticosteroids. His initial symptoms were concerning for isolated pulmonary disease, but we quickly found evidence of cryptococcal meningitis. This case highlights the fact that in the setting of immunosuppression with chemotherapy and chronic steroid use, physicians should maintain a high index of suspicion for opportunistic infections, including cryptococcosis. Cryptococcal meningitis is potentially treatable if recognized early, but is fatal if missed.