A Case of Intermittent Fever a Decade After Renal Transplantation

ABSTRACT

Disseminated histoplasmosis is a potentially serious complication after organ transplantation; however, its occurrence is rare, even in endemic regions. Diagnosis can be challenging, particularly in patients with nonspecific symptoms such as intermittent fever or lethargy. We report the case of a man who presented with intermittent fever 10 years after kidney transplantation. His presentation initially raised suspicion for post‐transplant lymphoproliferative disorder (PTLD) but was ultimately diagnosed as disseminated histoplasmosis following mediastinal lymph node biopsy and fungal tissue culture.

Key Clinical Message

Disseminated histoplasmosis is not common among post‐transplant patients, even in endemic regions. However, histoplasmosis should be considered if any post‐transplant patient presents with nonspecific symptoms, irrespective of the duration of the transplant. This will avoid the endless diagnostic dilemmas the patient faces.

1. Introduction

Patients who have undergone organ transplantation are susceptible to several complications, including PTLD, malignancies, viremias (hepatitis viruses, EBV, CMV, BK virus, adenovirus, and parvovirus), as well as bacterial and fungal infections. Among fungal infections in post‐transplant patients, Histoplasma capsulatum is the most common pathogen in endemic regions. Histoplasma capsulatum is a dimorphic fungus endemic to the Midwestern United States along the Mississippi and Ohio River valleys [1]. It is found in soil contaminated with bird and bat droppings and spreads via inhalation of aerosolized microconidia, typically when contaminated soil is disturbed, such as during construction activities [2].

Disseminated histoplasmosis often presents with nonspecific features, including fever, cough, dyspnea, weight loss, and diarrhea. The infection usually involves multiple organs, including the lungs, bone marrow, liver, spleen, gastrointestinal tract, adrenal glands, central nervous system, and skin [3]. Here, we describe the case of a post‐transplant patient admitted with intermittent fever, lethargy, and other nonspecific symptoms initially suspected to represent PTLD, but ultimately diagnosed with disseminated histoplasmosis.

2. Case History/Examination

A 48‐year‐old African–American man with end‐stage kidney disease (ESKD) secondary to focal segmental glomerulosclerosis (FSGS) received a living unrelated kidney transplant in 2013 with alemtuzumab induction, followed by steroid‐free maintenance immunosuppression. His post‐transplant course was complicated by episodes of acute rejection in 2016–2017. In February 2023, he presented with a 2‐week history of fatigue, weakness, intermittent fever, poor appetite, and diarrhea. He also reported shortness of breath with a dry cough but denied chest pain or hemoptysis. Baseline serum creatinine had been 1.6 –1.7 mg/dL. His past medical history was notable for hypertension and type 2 diabetes mellitus. Home medications included losartan 25 mg once daily, insulin glargine, insulin aspart, Envarsus XR (extended‐release tacrolimus) 10 mg once daily, mycophenolic acid EC 540 mg twice daily, and sulfamethoxazole–trimethoprim 400 –80 mg on Monday, Wednesday, and Friday.

On admission, he was alert and oriented to person, place, and time. Supine blood pressure was 124/88 mmHg, pulse 110 beats/min, respiratory rate normal, and oral temperature 102.4°F. He had no palpable peripheral lymphadenopathy, edema, or cyanosis. Lung auscultation was clear without crackles or wheezing. Cardiac examination revealed a regular rhythm without murmurs or gallops. The abdomen was soft and non‐tender with no hepatosplenomegaly or tenderness over the transplanted kidney. There was no muscular or joint tenderness.

3. Differential Diagnosis, Investigations, and Treatment

Nasal swab PCR testing for SARS‐CoV‐2 and influenza, as well as plasma BK virus and CMV PCR, were negative. Plasma Epstein–Barr virus (EBV) PCR was < 500 copies/mL. Inflammatory markers were elevated, with an erythrocyte sedimentation rate of 80 mm/h and C‐reactive protein of 13.7 mg/dL (normal < 0.50 mg/dL). Serial blood cultures, stool gastrointestinal pathogen panel PCR, and QuantiFERON‐TB testing were negative. Complement levels (C3, C4, and CH50) were normal, anti‐neutrophil cytoplasmic antibodies were negative, and ANA IgG was not detected.

Ultrasound of the transplanted kidney demonstrated normal graft size (13.9 × 6.5 × 6.1 cm), normal resistive indices, and no evidence of obstruction, nephrolithiasis, mass, or perinephric collection. Chest radiography was unremarkable. Computed tomography of the chest, abdomen, and pelvis showed no evidence of infection, with an incidental 1.7‐cm indeterminate right adrenal nodule. Transplant kidney biopsy revealed no evidence of acute rejection, inflammation, granuloma formation, or vasculitis.

PET‐CT demonstrated hepatosplenomegaly with avid fluorodeoxyglucose (FDG) uptake in mediastinal lymph nodes, spleen, and bone marrow (Figure 1). Peripheral blood smear showed normocytic, normochromic anemia. Bone marrow biopsy revealed erythroid and megakaryocytic hyperplasia without morphologic evidence of lymphoma or high‐grade myeloid neoplasm; acid‐fast bacilli and Grocott methenamine silver (GNS) stains were negative. An aggressive lymphoma fluorescence in situ hybridization panel was negative.

FIGURE 1.

Positron Emission Tomography (PET) scan revealed avid fluorodeoxyglucose (FDG) uptake in mediastinal lymph nodes, spleen, and bone marrow.

Endobronchial ultrasound (EBUS)‐guided bronchoscopy demonstrated left hilar and mediastinal lymphadenopathy. Fine‐needle aspiration and biopsy revealed granulomas without evidence of malignancy. Tissue cultures grew Histoplasma capsulatum, Actinomyces species, rare Rothia mucilaginosa , and rare Streptococcus parasanguinis . Spleen biopsy demonstrated non‐necrotizing granulomas with negative acid‐fast bacilli and fungal stains.

Urine Blastomyces antigen by enzyme immunosorbent assay was elevated at 20.83 U/mL, while serum Blastomyces antibody testing was negative. EBV viral load subsequently increased to 1952 copies/mL, and leukopenia developed with a white blood cell count of 3400/mm³. Lumbar puncture to evaluate for asymptomatic central nervous system involvement was discussed but declined by the patient.

During the hospital course, he maintained a mild hyponatremia and hypobicarbonatemia, mild hyperkalemia, and tachycardia with a tendency to be hypotensive, suggesting salt wasting syndrome, most probably due to hypoaldosteronism (Table 1). His heart rate was 100–110 beats/min, and his supine blood pressures were 90–110/70 –80 mmHg, responding well to normal saline infusion. His oral temperature was fluctuating; the highest recorded was 102.4°F. His high temperatures were more prominent during the afternoons and early morning hours.

TABLE 1.

Laboratory results.

Lab test	Result	Reference range/notes
Sodium (Na)	132 mmol/L	135–145 mmol/L
Potassium (K)	4.5 mmol/L	3.5–5.0 mmol/L
Total CO2	15 mmol/L	22–29 mmol/L
Anion gap	19 mmol/L	8–16 mmol/L
Serum creatinine (Cr)	2.80 mg/dL	0.6–1.3 mg/dL
Blood urea nitrogen (BUN)	32 mg/dL	7–20 mg/dL
eGFR	27 mL/min/1.73 m2	≥ 60 mL/min/1.73 m2
Glucose	219 mg/dL	70–100 mg/dL (fasting)
Hemoglobin A1c	10.8%	< 5.7%
Alkaline phosphatase	124 U/L	44–147 U/L
ALT	35 U/L	7–56 U/L
AST	24 U/L	10–40 U/L
Albumin	3.7 g/dL	3.5–5.0 g/dL
D‐dimer	1.87 mcg/mL	< 0.50 mcg/mL
WBC	5400/mm3	4000–11,000/mm3
Hemoglobin	10.7 g/dL	13.5–17.5 g/dL (male)
Platelets	195,000/mm3	150,000–450,000/mm3
Tacrolimus level	11.8 ng/mL	Goal trough 5–7 ng/mL
ESR	80 mm/h	0–20 mm/h
CRP	13.7 mg/dL	< 0.50 mg/dL
EBV PCR	< 500 copies/mL (initial), 1952 copies/mL (later)	—
Random urine sodium	70 mmol/L	—
Random urine potassium Random urine creatinine	15.4 mmol/L 148 mg/dL	—
Morning serum cortisol	1.5 mcg/dL (initial), 14.3 mcg/dL (repeat)	5–23 mcg/dL
Cosyntropin stimulation	18.5 μg/dL (40 min), 19.2 μg/dL (80 min)	≥ 18 μg/dL adequate

The envarsus XR dose was reduced to 6 mg daily, lowering the trough to 5.4 ng/mL. The mycophenolic acid EC was discontinued, and oral prednisone was initiated at 5 mg daily, reducing the recorded highest temperature to 100.1°F. Sulfamethoxazole–trimethoprim was discontinued, and intravenous ampicillin–sulbactam 3 g every 6 h was administered for Actinomyces, Rothia, and Streptococci viridans, later transitioned to oral amoxicillin–clavulanate 875/125 mg twice daily for 14 days. Itraconazole 200 mg thrice daily for three days, followed by 200 mg twice daily for one year, was initiated for disseminated histoplasmosis. Outpatient monthly urine Histoplasma/galactomannan antigen tests remained negative.

4. Conclusions and Results

Disseminated histoplasmosis is uncommon in post‐transplant patients, even in endemic areas. This case illustrates the diagnostic challenges in a patient 10 years post‐transplant presenting with nonspecific symptoms. Histoplasmosis should be considered in post‐transplant patients from endemic regions, regardless of transplant duration, to avoid prolonged diagnostic uncertainty. 5. Discussion.

The patient presented with nonspecific symptoms—intermittent fever, fatigue, weakness, and diarrhea—prompting consideration of PTLD and opportunistic infections such as CMV, EBV, and fungal pathogens. The intermittent pattern of fever, peaking in the evenings and late at night, initially suggested PTLD. EBV is a major risk factor for PTLD early post‐transplant, affecting 3%–10% of solid organ recipients [4]. Admission EBV PCR was < 500 copies/mL, rising later to 1952 copies/mL. PET‐CT findings also suggested PTLD.

Screening for CMV, M. tuberculosis , C. difficile , Cryptococcus, influenza, and BK virus was negative. PET‐CT‐guided biopsies of bone marrow, mediastinal lymph nodes, and spleen showed no evidence of PTLD. Both mediastinal lymph node and spleen biopsies revealed non‐caseating granulomas, and EBUS tissue culture grew Histoplasma capsulatum. Blastomyces urine antigen was positive, likely reflecting cross‐reactivity, consistent with prior reports [5].

Histoplasmosis is the most common post‐transplant invasive fungal infection in endemic regions, but its overall incidence remains low. At the University of Wisconsin, 14 of 128 fungal infections in kidney transplant patients over 20 years were histoplasmosis [6]. Other reports from endemic areas show either zero among 586 post‐transplant cases after a mean follow‐up exceeding 16 months or one case per 1000 patient‐years [7, 8]. Median time to histoplasmosis diagnosis post‐transplant ranges from 17 to 27 months [8, 9], with one‐third diagnosed within the first year [9]. Our patient developed disseminated histoplasmosis 10 years post‐transplant—a rare occurrence, previously reported only in two cases at 8 and 20 years post‐transplant [9, 10].

During hospitalization, PET‐CT showed increased FDG uptake in the bone marrow, but biopsy revealed no histoplasmosis; uptake was attributed to anemia. Literature reports 25% bone marrow involvement, 6% CNS involvement, 12% splenic involvement, and 80% pulmonary involvement in post‐transplant histoplasmosis [9]. Adrenal involvement may cause adrenal insufficiency. Our patient showed clinical signs of mild hypoaldosteronism, though cosyntropin testing was normal [11, 12, 13, 14].

Definitive diagnosis of disseminated histoplasmosis relies on histopathology and culture, which may show yeast in granulomas. Non‐caseating granulomas, as seen in our patient, are not specific and can mimic sarcoidosis. GMS stains were negative, but Calcofluor White staining and culture confirmed H. capsulatum. Cultures can take 4 –6 weeks, delaying diagnosis [15]. Urine or serum antigen testing is faster (≈7 days) [16], though sensitivities vary, urine 80%–97%, serum 50%–89% [9, 17, 18]. Antibody detection is less sensitive (≈28%) in immunosuppressed patients [9]. Cross‐reactivity with other fungi, notably Blastomyces dermatitidis, is common [15].

Treatment per IDSA (Infectious Diseases Society of America) guidelines for severe disseminated histoplasmosis includes liposomal amphotericin B (3 mg/kg daily for 1–2 weeks), followed by oral itraconazole 200 mg thrice daily for 3 days, and then 200 mg twice daily for ≥ 12 months; lifelong therapy may be required in immunosuppressed patients [19]. Mild‐to‐moderate disease can be treated with oral itraconazole 200 mg twice daily for ≥ 12 months [1]. Azole antifungals inhibit CYP3A4 and significantly raise tacrolimus levels; doses must be adjusted and monitored closely.

Author Contributions

Merazul Islam Ony: writing – original draft. Baris Afsar: writing – review and editing. Bahar Bastani: writing – review and editing.

Funding

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The authors have nothing to report.