Case Presentation: A 32-year-old Human Immunodeficiency Virus (HIV)-negative male presented with one week of headaches, dizziness, blurry vision, nausea, and vomiting. He denied fevers, chills, cough, hemoptysis, neck pain or stiffness, recent travel, sick contacts, photophobia, or phonophobia. He was recently diagnosed with cryptococcal meningitis (CM) and cryptococcal pneumonitis (CP) after presenting previously with 1.5 months of chest pain, cough, headaches, sore throat, nausea, vomiting, malaise, unintentional weight loss, night sweats, and neck swelling. He completed 2 weeks of amphotericin B plus flucytosine followed by an abbreviated 28-day course of fluconazole. On treatment day 26, he presented to our hospital. He is a recent immigrant from Guatemala, works in construction, has no drug use history, and is only sexually active with his wife. Physical exam was normal. Patient was HIV-negative with CD4 count of 1031, CD8 count of 277, and CD4/CD8 ratio of 3.72. Computed Tomography of the head showed multiple parenchymal lesions, surrounding vasogenic edema and mild local mass effect suggestive of recurrent cryptococcal meningitis. A lumbar puncture confirmed the diagnosis. The Infectious Disease team recommended a prolonged course of amphotericin B and flucytosine for 6 weeks followed by a 6-week course of fluconazole with close monitoring for resistance given prior treatment failure. The Immunology team was consulted for a detailed immunodeficiency work-up to assess for other risk factors, including immunoglobulin levels, neutrophil oxidase burst test, T cell/B cell/NK cell panel, lymphocyte antigen and mitogen proliferation panel, Streptococcus pneumoniae antibodies, and IgG (23 serotypes). Immunology labs were completed and all were negative/within normal limits.
Discussion: Cryptococcal meningitis is almost exclusively seen in immunocompromised patients, but can rarely occur in immunocompetent individuals, who may present with non-specific neurological symptoms, as seen in this patient. It is very important for physicians to recognize possible cases in a timely manner and know how to manage them. In a U.S. series of over 300 HIV-negative patients with cryptococcal infection, half had CNS involvement. Of these, 25% had received steroid therapy, 24% had chronic liver, kidney or lung disease, 16% had a malignancy, and 15% had received solid organ transplants. Immunocompromised patients require a prolonged induction course of 4-6 weeks, therefore it is important to determine if an immunodeficiency is present when a patient is diagnosed with cryptococcal meningitis. This patient had no history of steroid therapy, transplanted liver, kidney disease, or lung disease (prior to CP), and had very low suspicion for malignancy. Of note, in the U.S. series, 30% of the patients had no apparent etiology but may have had a rare immunodeficiency, most likely: idiopathic CD4+ lymphopenia (CD4 < 300), pulmonary alveolar proteinosis (auto-antibodies against Granulocyte-macrophage colony-stimulating factor), Job Syndrome, or auto-antibodies against interferon-gamma.
Conclusions: Overall for the hospitalist delayed diagnosis, misdiagnosis, or failure to work up a potential underlying immunodeficient HIV-negative CM can lead to serious complications and high mortality. It is important to search for an underlying immunocompromising condition when a patient presents with an opportunistic infection, which may prompt the involvement of an immunologist and can change treatment duration.