The patient is a 66-year-old Caucasian female who presented to our hospital with three weeks history of fever of unknown origin with no specific pattern, associated with nausea, vomiting, fatigue, and pruritus. The patient was already admitted twice to an outside hospital within the last month and underwent extensive diagnostic workup. She had a bronchoscopy with BAL studies as well as lung biopsy of an incidental 1.6 cm right lower lobe lung nodule, seen on imaging studies, with no definite diagnosis.
Her past medical history is significant for 16 years history of rheumatoid arthritis, for which she has been on methotrexate for the last 8 years and infliximab for the last 6 years. At the outside hospital, she was found to have elevated liver enzymes with subsequent discontinuation of methotrexate and infliximab. The patient was started on prednisone at a dose of 40 mg daily.
Upon arrival to our hospital, the patient was found to have a fever of 103 F with chills and tachycardia, along with painless jaundice, fatigue, nausea, and vomiting.
She denies any history of sick contacts, unpasteurized milk, or undercooked meat intake. Upon further questioning, she reports that her fever started only two days after a long road trip with her husband, from Michigan to Florida. On their way, and 11 days prior to her symptoms started, they stopped at Pittsburg, Kansas, where they stayed for 6 days. The patient endorsed horseback riding in Pittsburg but, however, denied any sick contacts.
Her examination was notable for an awake, alert, and oriented patient with icteric sclerae. Her respiratory rate was 18 breaths per minute and was saturating 98% on room air. There was no hepatosplenomegaly or abdominal tenderness and the rest of the examination was normal.
Laboratory examination revealed hemoglobin of 12.3 g/dL, white cell count of 7.9 with 40% granulocytes, 43% lymphocytes and 7% monocytes, and platelets of 230. Liver function tests revealed alanine aminotransferase 252 IU/L (0-60 IU/L), aspartate aminotransferase 173 IU/L (0-46 IU/L), alkaline phosphatase of 375 IU/L (44-147 IU/L), total bilirubin 4.2 mg/dL (0-1 mg/dL), corrected calcium 8.7 mg/dL (8.5-10.5 mg/dL), PT 11.4 (9-12.5 sec), total protein of 7 mg/dL, and an albumin of 2.5 mg/dL. Autoimmune markers, including serum antimitochondrial antibodies, were negative, except for RF and anti-CCP. Blood cultures and urine culture remained negative.
Ultrasound of the abdomen was normal. The chest X-ray again revealed a right lower lobe pulmonary nodule. Computed tomography (CT) of the chest showed a 1.3 cm right lower lobe pulmonary nodule which corresponds to the abnormality seen on chest X-ray. CT of the abdomen showed normal appearance and size of liver, pancreas, spleen, and adrenals.
Outside records were reviewed and bronchial washings had grown only Candida albicans on routine bacterial and fungal cultures. Cytology was consistent with mixed inflammatory cells with no evidence of microorganism on Grocott's methenamine silver (GMS) stain. Right lower lobe nodule CT guided needle biopsy was only consistent with focal acute and chronic inflammation, along with scattered yeast elements consistent with candida species, with no evidence of granulomas or tumor.
CMV PCR and hepatitis serologies were negative. EBV blood PCR came back positive with 1959 copies/cc (IgG VCA positive, IgM VCA negative). Serum RPR and QuantiFERON test for tuberculosis were negative. Serum cryptococcal antigen from outside hospital was negative.
Empiric antibiotics consisting of vancomycin and piperacillin-tazobactam were discontinued after final blood cultures reported no growth and patient remained febrile. Transthoracic echocardiogram was compatible with grade 1 diastolic dysfunction, normal ejection fraction, and no vegetation. An ultrasound guided liver biopsy, done on hospital day two, was consistent with granulomatous hepatitis with negative acid fast stain, and subsequently steroids were restarted. Cryptococcal antigen and Brucella, Bartonella and Q fever serologies were all negative. Liver biopsy immunohistochemical stain with in situ hybridization studies was also negative for EBV. On hospital day five, after additional stains on liver specimen were performed, pathological examination reported that fungal organism was identified within areas of granulomatous inflammation, largely within histiocytes on hematoxylin and eosin staining. They were further described as round to ovoid 2-4 micrometers narrow based budding fungal organisms on GMS staining suggestive of histoplasmosis (Figure 1). Three days later, serum histoplasma antigen, by quantitative MVista Histoplasma antigen enzyme immunoassay (EIA) detection test, reported strongly positive with titers above the limit of quantification, above 19 ng/mL.
Meanwhile, patient clinical condition deteriorated and progressed into a respiratory failure with bilateral interstitial infiltrates on chest imaging requiring mechanical ventilation. Intravenous liposomal amphotericin B at a dose of 3 mg/kg q 24 hrs was ultimately started. Fungal culture from bronchoalveolar lavage eventually grew Histoplasma capsulatum. The patient became afebrile on day five of amphotericin and her jaundice started to resolve. Her chest X-ray cleared and was extubated. The patient was switched on day seven to itraconazole secondary to acute kidney injury. Antifungal therapy was subsequently switched to voriconazole once she developed a bleeding peptic ulcer disease requiring intravenous proton pomp inhibitor while being on itraconazole.
Patient's liver function tests completely normalized in six weeks.