Case Presentation: A 57 years old man with a history of prediabetes and Lyme disease diagnosed two months prior to admission and treated with doxycycline for three weeks, was transferred from another hospital to our institution for recurrent high grade fevers and shaking chills for two months. Originally from Guatemala, he had lived in America for more than ten years, and worked as a construction worker. He underwent extensive workup for the fever of unknown origin including blood cultures which were all negative; lumbar puncture negative for infection, TEE negative for any vegetations; Brucella, Bartonella, Parvovirus B19 and Listeria serologies were negative, AFB culture was negative; HIV and TB gold interferon negative. VDRL, serology for CMV and EBV were negative. Other tickborne illnesses, including Babesia, were negative. He had normocytic anemia, with a hemoglobin of 7. 7 and MCV of 83. Bone marrow biopsy showed no leukemia or granuloma. He was transferred to our institution for further evaluation. Rheumatological workup was negative. SPEP was normal. Iron was 14 and TIBC was 258. A CT scan showed tree in bud opacity in left lower lobe, splenomegaly to 16 cm, and hilar and mediastinal lymphadenopathy. He underwent bronchoscopy with EBUS and FNA which was unrevealing but a BAL culture was positive for Cryptococcus neoformans. VATS biopsy of a mediastinal lymph node was positive for diffuse large B cell lymphoma. He was treated with rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin.

Discussion: Fever of unknown origin (FUO) is not an uncommon diagnosis in the hospital. We present a rare case of cryptococcal pneumonia in an immunocompromised patient with newly diagnosed diffuse large B cell lymphoma (DLBCL). Cryptococcus accounts for 1.5-3% of invasive fungal infections in all hematologic malignancies, but a review of the literature shows that it has been rarely reported in DLBCL prior to initiation of any chemotherapies.
Inhalation of Cryptococcus neoformans, a yeast found in soil contaminated with bird dropping, may result in pulmonary infections or meningitis. Risk factors include immunosuppression due to lymphoma, AIDS, and chronic steroid use. Cryptococcal pneumonia and disseminated infection in the setting of lymphoproliferative disorders can carry a mortality rate approaching 50%, so early recognition can be key to improving outcomes. Our patient was treated with fluconazole after he developed side effect of encephalopathy from amphotericin B. CSF was negative for cryptococcal antigen.

Conclusions: There are four general categories of fever of unknown origin: infection, malignancy, autoimmune, and miscellaneous etiologies. This case illustrates how the diagnosis can be more challenging when these categories intersect. The CT of the chest and abdomen was helpful because it showed splenomegaly and mediastinal lymphadenopathy. Although the bone marrow biopsy and fine needle aspiration on bronchoscopy were unrevealing, a video assisted thoracoscopic surgery with lymph node excisional biopsy revealed the diagnosis of diffuse large B cell lymphoma. Although invasive, biopsy of lymph node may be helpful to rule out lymphoma in some patients with fever of unknown origin.