A 52-year-old man with a history of RA presented to the emergency department with a one-week history of fevers, chills, headache, nausea, vomiting, and diarrhea. He also reported having a nonproductive cough, fatigue, and one month of night sweats.
His therapy for RA comprised weekly methotrexate, daily hydroxychloroquine, and sulfasalazine. His symptoms were well-controlled on this regimen. He also gave a history of receipt of rituximab for a year prior to presentation.
Our patient is originally from Mexico but has lived in the United States for over forty years. Prior to moving to Colorado, he gave a history of residence in Ohio. He works as a truck driver and his route involves the Midwest states. He also gave a history of travel to California nearly a year ago. About one month before admission, he unloaded his truck in Kansas City during a rainstorm and shortly thereafter began having night sweats and a nonproductive cough. No known history of exposure to tuberculosis.
On admission, he was afebrile but was found to have an oxygen saturation of 85% on room air and required 2-3 liters/minute of supplemental oxygen. Initial laboratory studies revealed a normal white blood cell count. Liver enzymes were elevated above his baseline (AST 74 U/L, ALT 60 U/L, and alkaline phosphatase 170 U/L). An abdominal ultrasound showed mild hepatosplenomegaly, and a chest X-ray showed a diffuse reticulonodular density with hilar lymphadenopathy. He received one dose of intravenous (IV) ceftriaxone and azithromycin and was started on empiric treatment with IV ceftriaxone, doxycycline, and metronidazole for community-acquired pneumonia. Additional negative studies included a respiratory viral PCR, Histoplasma urine antigen, Streptococcus pneumoniae urine antigen, Legionella urine antigen, human immunodeficiency virus (HIV) 4th generation antibody/antigen assay, acute hepatitis panel, serum herpes simplex virus (HSV) PCR, serum cytomegalovirus (CMV PCR), Mycobacterium tuberculosis (MTB) quantiferon gold, and sputum Pneumocystis jirovecii pneumonia (PJP) direct fluorescent antibody (DFA). Rheumatology recommended continuing hydroxychloroquine and stopping methotrexate and sulfasalazine in the setting of possible infection.
A CT chest interstitial lung disease (ILD) showed diffuse micronodularity in all five pulmonary lobes in a perilymphatic and centrilobular distribution and few scattered calcified granulomas that suggested disseminated infection. The CT chest scan also showed mediastinal and hilar lymphadenopathy as well as splenomegaly (Figure 1). Diffuse micronodules had not been seen on previous CT chest scans six years prior and one month prior to presentation. His imaging findings suggested a miliary pattern. This combined with his clinical symptoms and environmental exposure history was concerning for an invasive fungal infection or tuberculosis (TB). Three sputum AFB cultures were collected and were smear negative. An MTB complex nucleic acid amplification test (NAAT) was performed on one of his AFB sputum samples and was not detectable.
He underwent bronchoscopy and findings were notable for endobronchial nodules and plaques in the left upper lobe. Multiple biopsies were done and sent for standard aerobic, AFB and fungal cultures. An Aspergillus galactomannan antigen and PJP DFA in bronchoalveolar lavage fluid (BAL) were negative. Since all cultures remained negative, his antibiotics were stopped after 3 days. Infectious Diseases was consulted and recommended starting empiric anidulafungin and posaconazole combination therapy given concern for a fungal infection. Empiric combination therapy with an azole + echinocandin was chosen to cover possible endemic fungi and invasive aspergillosis. Posaconazole was chosen over voriconazole for the addition of Mucorales coverage. Assays for serum Histoplasma antigen enzyme immunoassay (EIA), urine Histoplasma galactomannan antigen quantitative EIA, serum Aspergillus galactomannan antigen, and serum Cryptococcus neoformans/gattii antigen were negative. T-SPOT interferon-gamma release assay was negative. Aspergillus fumigatus IgG was elevated at 13.03 U/mL. Pathology from bronchoscopy biopsy showed necrotizing granulomatous inflammation suggestive of infectious etiology. Acid-fast bacilli (AFB) and Grocott-Gomori methenamine silver (GMS) stains were negative. Periodic acid- Schiff (PAS) stain and hematoxylin and eosin (HE) stain were not done. Five days after bronchoscopy, Coccidioides antibody by complement fixation (CF) assay returned positive at 1 : 8, Coccidioides IgM by enzyme-linked immunosorbent assay (ELISA) was positive, and Coccidioides IgG by ELISA was negative. Coccidioides immitis antibody by immunodiffusion (ID) demonstrated a partial identity reaction indicating the presence of two different types of antibodies. One antibody was identical to the positive control, and the other antibody was unrelated and could be a cross-reactive antibody due to infection with other systemic fungi. His Coccidioides immitis antibody was repeated three days later and was reported as detectable. This pattern of serological data suggested active coccidioidomycosis. He was started on liposomal amphotericin B. Posaconazole and anidulafungin were discontinued. After one week of liposomal amphotericin B treatment, he was transitioned to oral fluconazole 400 mg daily. His hypoxia resolved, and he was discharged home.
Nine days after discharge, our microbiology lab reported growth of mold from fungal lung tissue cultures. The isolate was preliminarily identified as Histoplasma capsulatum based on morphology (Figure 2) and was sent to a reference laboratory where it tested positive for Histoplasma capsulatum by DNA probe. A Histoplasma capsulatum DNA probe sent from his left upper lobe tissue culture was positive. On follow-up visit in the Infectious Diseases clinic, he was switched from fluconazole to itraconazole for the treatment of pulmonary histoplasmosis. A repeat chest CT showed improvement in the size and number of bilateral lung micronodules. One month after discharge, he reported resolution of shortness of breath. However, he described worsening of pain from RA in his shoulders, knees, wrists, and ankles. He was restarted on sulfasalazine and methotrexate after he had been on treatment for histoplasmosis for more than two months. Approximately eight months after presentation, his CT imaging continued to display multiple bilateral pulmonary nodules. Histoplasma antibodies by CF were checked and were negative (<1 : 8). He has been continued on his oral itraconazole treatment with plans to treat for at least one year.