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CASE REPORT
Fever of Unknown Origin in a Renal Transplant Recipient: Lactate Dehydrogenase as an Important Clue to Diagnosis

Histoplasmosis is a rare disease in nonendemic areas. We report a case of a 23-year-old male patient who presented with fever of unknown origin, cytopenias, organomegaly, and allograft dysfunction 4 months after renal transplant with father as donor. Bone marrow examination showed intracellular budding yeast cells, which was confirmed as histoplasmosis by culture of bone marrow biopsy sample. The patient was treated with intravenous liposomal amphotericin and responded well.


Key words : Bicytopenia, Histoplasmosis, Immuno-suppression

Introduction

Histoplasmosis is a rare infection in the post-transplant period. According to statistics from the Transplant-Associated Infection Surveillance Network, the 12-month cumulative incidence rate of histoplasmosis among solid-organ transplant recipients was 0.1%.1 Here, we present a case that highlights the point that clinicians should consider and investigate histoplasmosis as a differential diagnosis of fever of unknown origin when it presents with organomegaly, cytopenias, and elevated lactate dehydrogenase levels in renal transplant recipients.

Case Report

A 23-year-old male patient from the Jammu region in India, who had undergone kidney transplant 4 months earlier with father as donor, presented on day 0 with fever of 25 days duration. On presen-tation, his immunosuppressive drug regimen consisted of tacrolimus, mycophenolate mofetil, and low-dose methylprednisolone. Graft function had been stable until presentation with a baseline serum creatinine of 1.3 mg/dL. On presentation, the patient had bicytopenia (leukopenia showing 3800/mm3, thrombocytopenia showing 96 000/mm3), hepato-splenomegaly, elevated serum creatinine level of 1.9 mg/dL, and elevated lactate dehydrogenase level (2389 U/L; reference range is 240-480 U/L).

Work-up for fever included blood and urine cultures, thick and thin smears for malaria, dengue serology, leptospira serology, scrub typhus poly-merase chain reaction, and cytomegalovirus DNA polymerase chain reaction. All tests were negative. In view of bicytopenia and fever of unknown origin, we conducted a bone marrow biopsy, which revealed yeast forms of histoplasma in the cytoplasm of histiocytes along with hemophagocytosis. These were further confirmed on bone marrow culture as histoplasma capsulatum (Figure 1). Contrast-enhanced computed tomography scans of chest revealed multiple military nodules in bilateral lung fields, which were likely pulmonary histoplasmosis. Hence, a diagnosis of acute disseminated histoplasmosis was made.

The patient was subsequently started on liposomal amphotericin B, and mycophenolate mofetil was stopped. After starting amphotericin therapy, the patient became afebrile and cytopenias improved. Serum creatinine and lactate dehydrogenase measurements showed a decreasing trend. After 2 weeks of induction therapy, the patient was given 12 months of oral itraconazole maintenance therapy. Graft function remained stable thereafter, with a serum creatinine level of 1.5 mg/dL. Our plan is to continue suppressive itraconazole therapy for the patient’s entire life.

Discussion

Fever of unknown origin was defined by Petersdorf and Beeson as fever > 101°F lasting for at least 3 weeks that remains undiagnosed after a thorough inpatient or outpatient work-up.2 Histoplasmosis is a rare infection in renal transplant recipients, even in those residing in endemic areas. In a study by Gupta spanning 23 years (1977-2000), of 850 patients undergoing renal transplant during that period, only 2 patients developed histoplasmosis.3 Clinical manifestations are of 3 types: acute primary, chronic cavitary, and progressive disseminated. The disseminated form usually presents with fever of unknown origin, cytopenias, hepatosplenomegaly, and weight loss. In India, most cases have been reported from the eastern (West Bengal) and northeastern states (Assam), a fact attributed to the large rivers flowing through these states.4 Our patient was from Jammu, a nonendemic area for histoplasmosis.

In our country, where tuberculosis prevalence is high, histoplasmosis is not clinically suspected in patients who present with fever of unknown origin and is often misdiagnosed as tuberculosis. Lactate dehydrogenase is a useful noninvasive laboratory clue that can help the clinician to suspect dis-seminated histoplasmosis at an early stage. Serum lactate dehydrogenase levels more than 600 IU/mL at admission in a patient of fever of unknown origin supports histoplasmosis rather than tuberculosis.5

Conclusions

A high index of suspicion is required in immuno-suppressed patients presenting with fever of unknown origin to allow diagnosis of this rare fungal infection.


References:

  1. Kauffman CA, Freifeld AG, Andes DR, et al. Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET). Transpl Infect Dis. 2014;16(2):213-224.
    CrossRef - PubMed
  2. Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore). 1961;40:1-30.
    CrossRef - PubMed
  3. Gupta KL. Fungal infections and the kidney. Indian J Nephrol. 2001;11:147-154.
  4. Sanyal M, Thammayya A. Histoplasma capsulatum in the soil of Gangetic Plain in India. Indian J Med Res. 1975;63(7):1020-1028.
    PubMed
  5. Butt AA, Michaels S, Greer D, Clark R, Kissinger P, Martin DH. Serum LDH level as a clue to the diagnosis of histoplasmosis. AIDS Read. 2002;12(7):317-321.
    PubMed


DOI : 10.6002/ect.2018.0380


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From the 1Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, the 2Department of Nephrology, Apollo Gleneagles Hospital, Kolkata, the 3Institute of Liver and Biliary Sciences, New Delhi, and the 4Department of Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Krishan Lal Gupta, Department of Nephrology, PGIMER, Chandigarh, India
Phone: +91 172 7087009732
E-mail: klgupta@hotmail.com