Urine antigen-negative disseminated histoplasmosis mimicking post-transplant lymphoproliferative disorder

Background

Histoplasma capsulatum is a dimorphic fungus most prevalent in the USA in the Ohio and Mississippi River valleys, and is the most common of the endemic mycoses in the USA. Exposure occurs via aerosolised microconidia, thought to be associated with soil contaminated by bird and bat guano. In endemic regions it affects an estimated 50%–80% of the population, 90% of whom develop a self-limited asymptomatic infection with the organisms sequestered in calcified granulomas.1 2 In the immunocompromised, or those exposed to a high inoculum, exposure may lead to acute, chronic or disseminated infection.

Disseminated infection presents with a non-specific clinical picture characterised by lymphadenopathy, cytopenias, heterogeneous skin lesions, hepatosplenomegaly, and rheumatological manifestations. This may lead to a significant delay in the diagnosis and treatment of a disease that can reach a 10% mortality rate.2–4 Although antigen testing is most commonly used to identify histoplasmosis, the estimated sensitivity of urine antigen testing is 91%, and in one case series urine antigen was positive in only 79% of patients with disseminated disease.5 6 Thus, false-negative testing can further compound the diagnostic challenge. This case highlights the clinical, diagnostic and therapeutic roadblocks in the management of disseminated H. capsulatum infection in a solid organ transplant recipient.

Case presentation

A 50-year-old woman presented to the hospital with 2 days of generalised abdominal pain at the direction of her primary care physician. In the preceding 6 months she reported recurrent pharyngitis, intermittent fevers, tender cervical lymphadenopathy and 3-5 kg of weight loss. She was seen by her primary care physician numerous times for her recurrent pharyngitis, tested positive for streptococcal pharyngitis, and underwent antibiotic therapy at least twice. She also presented with a new asymptomatic rash to her chest, back and arms that was slowly progressive with new papules appearing every few days, none of which resolved (figures 1 and 2). Two days prior to presentation, she developed generalised abdominal pain for which she presented to her primary care physician, who obtained CT images of her abdomen and pelvis to evaluate her symptoms. She was instructed to present to the emergency department after the imaging identified new retroperitoneal lymphadenopathy and laboratory studies revealed new cytopenias. The remainder of a thorough review of systems was unremarkable. She denied travel outside of her home state of Texas in the last 2 years and had never been to the Ohio or Mississippi River valleys. She also denied bird or bat exposure.

Her relevant previous medical history included a deceased donor kidney transplant performed 3 years ago. Her immunosuppression regimen included tacrolimus 1.5 mg two times per day, mycophenolate mofetil 540 mg two times per day and chronic prednisone 5 mg daily. Her tacrolimus levels had remained within therapeutic range, specified to be 6–8 ng/mL by her nephrologist, in the last year.

Investigations

She was well-appearing, afebrile and haemodynamically stable. Her physical examination revealed a unilateral tonsillar exudate, mild right upper quadrant abdominal tenderness and numerous discrete 2–3 mm violaceous pink papules with a fine scale over her chest and back. The remainder of her examination was unremarkable.

The patient’s primary care physician had initiated a preliminary investigation prior to her presentation to the hospital. Outpatient laboratory studies performed days prior to admission were notable for new cytopenias, with a platelet count of 105×10⁹/L and leukocyte count of 4×10⁹/L, which were lower than her baseline platelet count around 200×10⁹/L and white cell count around 7×10⁹/L. Due to a concern for post-transplant lymphoproliferative disorder, she underwent CT imaging of her chest, abdomen and pelvis which demonstrated extensive retroperitoneal and mediastinal lymphadenopathy (figures 3 and 4). Ground glass opacities were also noted in the right lower lobe of her lung.

At the time of her presentation to the hospital, her laboratory studies demonstrated a normal complete blood count lacking cytopenias, while her comprehensive metabolic panel was significant for an aspartate transaminase (AST) that peaked at 65 units/L, alanine transaminase (ALT) that peaked at 104 units/L and alkaline phosphatase that peaked at 134 units/L. Her initial serum creatinine was 1.46 mg/dL, elevated from her baseline level of 1.2 mg/dL. Due to the initial concern for post-transplant lymphoproliferative disorder, her initial work-up consisted of Epstein-Barr virus, Cytomegalovirus and BK virus testing which were negative. Additionally, her serum and urine protein electrophoreses did not demonstrate an M-component.7

She began to have fevers on her first day of hospitalisation and was started on broad-spectrum antibiotics which were stopped after her bacterial blood and urine cultures, drawn prior to antibiotic administration, had remained negative for 48 hours. Throughout the hospital course her blood counts gradually declined and she developed pancytopenia with nadirs of leukocyte count as low as 3.8×10⁹/L, haemoglobin of 109 g/L and platelet count of 133×10⁹/L.

Given her evolving hospital course, a broader work-up was commenced. Her bacterial and mycobacterial blood cultures and an interferon-gamma release assay (QuantiFERON-TB Gold) were negative. She had a transthoracic echocardiogram which demonstrated normal valvular function and ejection fraction without evidence of vegetations. HIV testing was also negative.

A biopsy of a skin lesion from her left arm was performed (figures 5 and 6), which demonstrated a diffuse infiltrate with numerous histiocytes and containing small round microorganisms. H. capsulatum was suspected and confirmed by fungal culture of the tissue sample.

Interestingly, while her urine antigen was repeatedly negative, her serum fungal complement fixation panel demonstrated positive Histoplasma serologies at titers of 1:256 for the mycelial phase antigen and 1:16 for the yeast phase antigen. Also included on the fungal panel were Coccidioides and Blastomyces, which were both negative. Serum antigen testing was not done. Fungal blood cultures, drawn after broad spectrum antibiotics but prior to antifungals, demonstrated rare mould growth and identified as Histoplasma, which helped to confirm the diagnosis. Biopsy of an enlarged lymph node was not considered, as the suspicion for a neoplastic process was now lower and the lymphadenopathy was more likely to be secondary to disseminated infection.

Differential diagnosis

Initially, given the non-specific constellation of signs and symptoms, history of transplant, and immunosuppressed state, we maintained a broad differential diagnosis which included bacterial, mycobacterial and fungal infections including opportunistic pathogens, subacute HIV, endocarditis, lymphoma and post-transplant lymphoproliferative disorder. We felt her abdominal imaging with bulky retroperitoneal and mediastinal lymphadenopathy, with several large lymph nodes, was most consistent with post-transplant lymphoproliferative disorder, which served as our initial working diagnosis.

Treatment

After establishing the diagnosis of disseminated histoplasmosis, therapy was initiated with liposomal amphotericin B. However, within 24 hours of the infusion she developed acute renal injury, which is a well-characterised adverse effect of the drug, as well as rising transaminase levels. Her transiently reduced renal function and presumed drug–drug interactions with her immunosuppression caused elevated levels of tacrolimus into the supra-therapeutic range, as high as 16.0 ng/mL. Thus, she was unable to complete the planned induction therapy of amphotericin B for 2 weeks, and instead started liquid itraconazole. The liquid formulation was chosen initially due to its higher bioavailability, but unfortunately her insurance would not approve the liquid formulation.8 She was instead discharged with capsules of itraconazole with the intent to treat for 12 months with close follow-up in the infectious diseases clinic. At the time of discharge, her renal function had begun to recover and her tacrolimus levels returned to within the therapeutic range. Serum itraconazole levels were monitored during the duration of therapy and were consistently within the therapeutic range of >1.0 µg/mL.

Outcome and follow-up

In the months since discharge, the patient continues to follow-up at our infectious diseases clinic and is tolerating itraconazole well. Her complete blood count, liver function tests, and renal function have returned to her baseline. Her symptoms including abdominal pain, fevers, weight loss and anterior cervical lymphadenopathy have resolved. Imaging to assess the retroperitoneal and mediastinal lymphadenopathy since initiating therapy has not been repeated. No fungal studies have been repeated since discharge.