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• W2019417906 abstract "Transplant patients are susceptible to infectious complications due to chronic immunosuppression. We present two cases of persistent fever, weight loss and pancytopenia in kidney transplant recipients (originally concerning for posttransplant lymphoproliferative disease) that were later diagnosed with disseminated histoplasmosis on bone marrow and lymph node biopsy. In both patients, pancytopenia was due to hemophagocytic lymphohistiocytosis (HLH) which has rarely been described in association with histoplasmosis and not previously reported in kidney transplant recipients with this fungal infection. The diagnosis of histoplasmosis can be complex due to nonspecific symptomatology, delays in isolating histoplasma by fungal culture and false‐negative antibody titers in immunocompromised patients. A review of the literature including the clinical features of histoplasmosis in immunosuppressed patients (prevalence, current diagnostic testing and treatment options) as well as the association of HLH in immunocompromised states are discussed. Transplant patients are susceptible to infectious complications due to chronic immunosuppression. We present two cases of persistent fever, weight loss and pancytopenia in kidney transplant recipients (originally concerning for posttransplant lymphoproliferative disease) that were later diagnosed with disseminated histoplasmosis on bone marrow and lymph node biopsy. In both patients, pancytopenia was due to hemophagocytic lymphohistiocytosis (HLH) which has rarely been described in association with histoplasmosis and not previously reported in kidney transplant recipients with this fungal infection. The diagnosis of histoplasmosis can be complex due to nonspecific symptomatology, delays in isolating histoplasma by fungal culture and false‐negative antibody titers in immunocompromised patients. A review of the literature including the clinical features of histoplasmosis in immunosuppressed patients (prevalence, current diagnostic testing and treatment options) as well as the association of HLH in immunocompromised states are discussed. Opportunistic infections with viruses (e.g. EBV, CMV) and fungi (e.g. Candida species, Pneumocystis jirovecii) are a concern for any organ transplant recipient because of chronic immunosuppression, which impairs cellular and humoral immunity (1Dharnidharka VR Harmon WE Management of pediatric post renal transplantation infections.Semin Nephrol. 2001; 21: 521-531Abstract Full Text PDF PubMed Scopus (30) Google Scholar). Our medical center is geographically situated in the Ohio River valley where Histoplasmosis capsulatum is endemic, so our kidney transplant patients are at risk for developing serious infection from this fungus. H. capsulatum exists worldwide but is mainly found in North and Central America; cases have been described in patients with no reported travel to endemic regions (2Kauffman CA Histoplasmosis: A clinical and laboratory update.Clin Microbiol Rev. 2007; 20: 115-132Crossref PubMed Scopus (765) Google Scholar). Histoplasmosis fungal spores are present in soil and are found in large amounts in bat or bird fecal droppings, where spores are aerosolized when infested areas are disturbed such as construction sites. The ‘histoplasma’ pathogenic yeast forms under normal body temperature conditions, such as in human alveoli, after inhalation of mycelial spores. In immunocompetent individuals, inhalation of mycelial spores has no clinical consequence except for a mild, self‐limited respiratory illness whereas immunocompromised hosts can develop disseminated disease, which can be life‐threatening. There are a number of case reports in the literature that document unusual presentations of histoplasmosis in renal transplant recipients (3Trimarchi H Young P Finquelievich J et al.Disseminated histoplasmosis in a kidney transplant patient.Nefrologia. 2008; 28: 571-572PubMed Google Scholar,4McGuinn ML Lawrence ME Proia L Segreti J Progressive disseminated histoplasmosis presenting as cellulitis in a renal transplant recipient.Transplant Proc. 2005; 37: 4313-4314Crossref PubMed Scopus (16) Google Scholar), but this is the first report of disseminated histoplasmosis in kidney transplant recipients that is associated with hemophagocytic lymphohistiocytosis (HLH). HLH is a disorder characterized by excessive cytokine production (IFN‐γ; TNF‐α; IL‐6, IL‐10, IL‐12 and soluble IL‐2 receptor [CD25]), which leads to accumulation of T‐lymphocytes and macrophages in organs such as the liver, spleen and bone marrow. It can be caused by a primary immune deficiency (impaired natural killer cell or cytotoxic T‐cell activity), hematologic malignancies (5Han AR Lee HR Park BB et al.Lymphoma‐associated hemophagocytic syndrome: Clinical features and treatment outcome.Ann Hematol. 2007; 86: 493-498Crossref PubMed Scopus (120) Google Scholar) or secondary to an infectious process (EBV, CMV), which is commonly the case in immunosuppressed patients. Diagnosis of HLH requires five of the following criteria: fever, hepatosplenomegaly, hemophagocytosis, cytopenia in at least two lines, a markedly elevated ferritin, high triglycerides and/or low fibrinogen, high‐soluble IL‐2R/CD25 and little or no natural killer cell activity. Other symptoms include lymphadenopathy, rash and neurological symptoms with CSF changes (6Henter JI Horne A Arico M et al.HLH‐2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.Pediatr Blood Cancer. 2007; 48: 124-131Crossref PubMed Scopus (3265) Google Scholar). In most suspected cases, a bone marrow biopsy will confirm the diagnosis by the presence of hemophagocytosis of red blood cells and other precursor cells in the bone marrow. Treatment of secondary cases of HLH is aimed at treating the underlying infectious cause. Here we present two cases of HLH in kidney transplant recipients, with a clinical presentation similar to posttransplant lymphoproliferative disease (PTLD), which was due to disseminated histoplasmosis infection. A 22‐year‐old female with a history of focal segmental glomerulosclerosis (FSGS) received a living‐related kidney transplant 5 years prior and was on triple immunosuppression consisting of sirolimus 3 mg daily (level of 25.1 ng/mL on admit, range 5.5–7.31 ng/mL previous 6 months), mycophenolate mofetil (MMF) 1000 mg twice daily and prednisone 10 mg daily. Transplant function was stable and there were no recent episodes of rejection. She had been admitted to an outside hospital 1.5 months prior with complaints of fever, headache and nausea/vomiting. An extensive work‐up performed at the outside institution including laboratory serologies for infectious causes (blood cultures, EBV/CMV/BK virus whole blood PCRs), chest X‐ray, spine imaging and a tagged white blood cell scan were all negative. Fever persisted despite antibiotic therapy so she was diagnosed with ‘drug fever’ from empiric trimethoprim‐sulfamethoxasole, which subsided following discontinuation of this medication. She remained well for about 1 month until her symptoms reappeared with fever (38.5°C) and general malaise. She was admitted to our institution for dehydration and an elevated creatinine from a baseline of 1.4 to 2.2 mg/dL. Her only other complaints were sinus headaches, sore throat and mild cough symptoms. On examination, she appeared dehydrated with pallor; small, ulcerated lesions were present on her lip and nares; no rales were appreciated on lung examination. In addition, pancytopenia was present (WBC 2.2 × 103/μL, hemoglobin 6.3 g/dL and platelets 76 × 103/μL). On admission, she was given aggressive IV hydration, which reversed allograft dysfunction (creatinine: 1.5 mg/dL). Blood and urine cultures were sent and she was given intravenous ceftriaxone. She continued to have daily spiking fever (40°C) with no organisms isolated from bacterial cultures. Whole blood PCRs were sent for EBV, CMV, adenovirus, parvovirus, enterovirus and serum BK virus, which were negative. Oral lesions were swabbed for HSV and influenza A/B, which were negative. Fungal blood cultures were obtained at this time. A chest X‐ray showed no infiltrates or lymphadenopathy and a sinus computed tomography (CT) was negative. A high‐resolution chest CT was obtained due to suspicion of sirolimus‐induced pneumonitis and it showed diffuse ground‐glass opacities in the lower lung bases consistent with this diagnosis or an infectious process (7Weiner SM Sellin L Vonend O et al.Pneumonitis associated with sirolimus: Clinical characteristics, risk factors and outcome—a single‐centre experience and review of the literature.Nephrol Dial Transplant. 2007; 22: 3631-3637Crossref PubMed Scopus (92) Google Scholar). She was therefore switched from sirolimus to tacrolimus but her fevers persisted. During her hospitalization, the pancytopenia progressed to nadirs of WBC 1.6 × 103/μL with lymphopenia (3%), hemoglobin 5.7 g/dL and platelets of 46 × 103/μL about a week after admission. She had a reticulocyte count which had dropped from 10.2% to 0.4%, ferritin of 14 094 (normal 3–105 ng/mL), triglycerides of 512 (normal <199 mg/dL) and an LDH of 10 715 (normal 313–618 units/L) with a negative coombs test. Because of a clinical picture suspicious for HLH (persistent fever, high‐serum ferritin and pancytopenia), soluble IL‐2 receptor level was drawn and found to be 28 245 (normal 45–1105 unit/mL). Because of concerns for an infectious or a malignant process, immunosuppression was reduced as follows: MMF reduction by 50%, tacrolimus reduction to achieve levels of (3–5 ng/mL) and the steroid dose was left unchanged. A bone marrow biopsy was performed to look for causes of pancytopenia, which included PTLD and secondary causes of HLH such as EBV/CMV infection that may have been falsely negative (by PCR) in the presence of profound lymphopenia on peripheral blood samples. Unexpectedly, the bone marrow biopsy showed intracellular yeast forms consistent with histoplasmosis along with reactive hemophagocytosis consistent with HLH (Figure 1A). Subsequently, the patient was started on IV liposomal amphotericin and her fever, hematologic abnormalities and oral lesions resolved within several days of treatment. Following 2 weeks of IV amphotericin and clinical improvement, she was switched to oral itraconazole for a 12‐month course. Four days following the identification of histoplasmosis on bone marrow biopsy, a peripheral fungal blood culture was positive for mold (after 10 days in culture) and confirmed to be Histoplasma capsulatum, specifically, after 20 days in culture. Serum histoplasma antibodies were drawn on two occasions during acute histoplasmosis infection and both were negative. The urine histoplasma antigen resulted at 30.16 ng/mL (high positive). Our second patient was an 18‐year‐old male who also received a living‐related kidney transplant 15 months prior due to FSGS. In the immediate posttransplant course, he developed delayed graft function prompting 7 days of Thymoglobulin® (tacrolimus was held). Subsequently, his posttransplant course was stable with no acute rejection episodes on maintenance immunosuppression consisting of tacrolimus 6 mg twice daily (levels 7.0–10.4 ng/mL), MMF 1000 mg twice daily and prednisone 20 mg every other day. One month prior to admission, he developed vomiting and diarrhea, which was attributed to a viral illness. His creatinine remained above baseline at 1.8 mg/dL, despite rehydration, and a biopsy was performed showing chronic allograft nephropathy. Over the next few weeks, he developed fever, malaise, night sweats, pancytopenia and decreased appetite associated with a 10 lb weight loss. Also, a supraclavicular lymph node was palpable on physical exam. Pancytopenia persisted despite discontinuation of MMF, so he was admitted for evaluation of fever of unknown origin with suspicion for PTLD in the presence of ‘B’ symptoms. Upon admission to the hospital, fever persisted (maximum 39°C) associated with a mild cough with normal chest X‐ray findings. Infectious causes were extensively worked‐up and included routine/fungal blood cultures and whole blood EBV/CMV/BK virus PCRs, which were negative; urine histoplasma antigen and serum histoplasma antibodies were sent. Because of concerns for PTLD, a full‐body PET‐CT (with contrast) was performed and showed multiple enlarged lymph nodes throughout the neck, chest and abdomen as well as a markedly enlarged liver and spleen. Subsequently, the patient underwent a simultaneous lymph node and bone marrow biopsy looking for evidence of PTLD. However, the lymph node biopsy unexpectedly showed granulomas and abundant yeast (Figure 1B) with morphology consistent with histoplasmosis. Neither specimen showed signs of PTLD, although hemophagocytosis consistent with HLH was present on the bone marrow biopsy. Laboratory criteria that met the diagnosis of HLH included pancytopenia, a low fibrinogen at 183 mg/dL, an elevated soluble IL‐2 receptor level at 7529 units/mL and elevated ferritin of 899 ng/mL. A fungal culture was sent on the bone marrow aspirate, which confirmed histoplasmosis 21 days later. A urine histoplasma antigen level was 11.63 ng/mL (moderate positive). Similar to Case 1, antihistoplasma antibody was negative at the time of active histoplasmosis infection. Intravenous amphotericin was started and there was improvement in fever and pancytopenia within days of treatment. Following clinical improvement (7 days), he was switched to oral itraconazole for an expected duration of 12 months similar to Case 1. Disseminated histoplasmosis is an uncommon but serious complication of immunocompromised states, most frequently associated with the rise of the AIDS epidemic. Disease manifestations are varied and include panniculitis (8Bhowmik D Dinda AK Xess I et al.Fungal panniculitis in renal transplant recipients.Transplant Infect Dis. 2008; 10: 286-289Crossref PubMed Scopus (13) Google Scholar), orofacial disease including tongue and nares (9Scully C De Almeida OP Orofacial manifestations of the systemic mycoses.J Oral Pathol Med. 1992; 21: 289-294Crossref PubMed Scopus (72) Google Scholar,10Scully C De Almeida OP Sposto MR The deep mycoses in HIV infection.Oral Dis. 1997; 3: S200-S207Crossref PubMed Scopus (34) Google Scholar), ileal perforation (11Flannery MT Chapman V Cruz‐Gonzales I Rivera M Messina JL Ileal perforation secondary to histoplasmosis in AIDS.Am J Med Sci. 2000; 320: 406-407Abstract Full Text PDF PubMed Scopus (12) Google Scholar,12Guiot HM Bertran‐Pasarell J Tormos LM et al.Ileal perforation and reactive hemophagocytic syndrome in a patient with disseminated histoplasmosis: The role of the real‐time polymerase chain reaction in the diagnosis and successful treatment with amphotericin B lipid complex.Diagn Microbiol Infect Dis. 2007; 57: 429-433Crossref PubMed Scopus (24) Google Scholar), meningitis (13Wheat LJ Musial CE Jenny‐Avital E Diagnosis and management of central nervous system histoplasmosis.Clin Infect Dis. 2005; 40: 844-852Crossref PubMed Scopus (132) Google Scholar) and most commonly pulmonary with disseminated disease (14Gil‐Brusola A Peman J Santos M Salavert M Lacruz J Gobernado M Disseminated histoplasmosis with hemophagocytic syndrome in a patient with AIDS: Description of one case and review of the Spanish literature.Revista Iberoamericana de Micologia. 2007; 24: 312-316Crossref PubMed Google Scholar, 15Paul AY Aldrich S Scott RS Ellis MW Disseminated histoplasmosis in a patient with AIDS: Case report and review of the literature.Cutis. 2007; 80: 309-312PubMed Google Scholar, 16Wheat J Histoplasmosis in the acquired immunodeficiency syndrome.Curr Top Med Mycol. 1996; 7: 7-18PubMed Google Scholar) (including in renal transplant patients [17Behzad Elnollahi ML‐P Lessan‐Pezeshki M Pourfarziani V et al.Invasive fungal infections following renal transplantation: A review of 2410 recipients.Ann Transplant. 2008; 13: 55-58PubMed Google Scholar,18Peddi VR Hariharan S First MR Disseminated histoplasmosis in renal allograft recipients.Clin Transplant. 1996; 10: 160-165PubMed Google Scholar]). Disseminated histoplasmosis has also been reported to present as thrombotic microangiopathy (TMA) in renal transplant recipients (19Dwyre D Bell AM Siechen K Sethi S Raife TJ Histoplasmosis presenting as thrombotic microangiopathy.Transfusion. 2006; 46: 1221-1225Crossref PubMed Scopus (18) Google Scholar,20Thaunat O Delahousse M Fakhouri F et al.Nephrotic syndrome associated with hemophagocytic syndrome.Kidney Int. 2006; 69: 1892-1898Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). In the United States, H. capsulatum is endemic to the Ohio and Mississippi River valleys and anywhere from 5% to 25% of AIDS patients in these areas develop the disease (16Wheat J Histoplasmosis in the acquired immunodeficiency syndrome.Curr Top Med Mycol. 1996; 7: 7-18PubMed Google Scholar,21Histoplasmosis. Available from: http://www.cdc.gov/nczved/dfbmd/disease_listing/histoplasmosis_ti.html. Accessed March 27, 2008.Google Scholar). Dissemination can occur from a primary infection or reactivation of a calcified nodule. In addition, there are rare reports of the transplant organ, itself, transmitting histoplasmosis (22Silveira FP Husain S Fungal infections in solid organ transplantation.Med Mycol. 2007; 45: 305-320Crossref PubMed Scopus (188) Google Scholar). In two multicase reviews of renal transplant patients with histoplasmosis, the incidence was small—5 cases out of 1074 patients over 25 years in the Ohio River valley (18Peddi VR Hariharan S First MR Disseminated histoplasmosis in renal allograft recipients.Clin Transplant. 1996; 10: 160-165PubMed Google Scholar) and another 5 of 1300 patients over 4 years in nonendemic areas (23Davies S Sarosi GA Peterson PK et al.Disseminated histoplasmosis in renal transplant recipients.Am J Surg. 1979; 137: 686-691Abstract Full Text PDF PubMed Scopus (72) Google Scholar). Out of 2410 renal transplant patients reviewed in Iran, histoplasmosis was the least likely fungal infection in that area, representing 1 out of their 21 cases over 10 years (17Behzad Elnollahi ML‐P Lessan‐Pezeshki M Pourfarziani V et al.Invasive fungal infections following renal transplantation: A review of 2410 recipients.Ann Transplant. 2008; 13: 55-58PubMed Google Scholar). None of these cases mentioned HLH as a part of the clinical presentation. To our knowledge, the only report we could find with disseminated histoplasmosis and HLH in a solid organ transplant was one case in a heart transplant recipient (24Masri K Mahon N Rosario A et al.Reactive hemophagocytic syndrome associated with disseminated histoplasmosis in a heart transplant recipient.J Heart Lung Transplant. 2003; 22: 487-491Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). The true incidence may be underestimated, however, due to the fact that not all patients have a bone marrow biopsy performed to diagnose HLH definitively. In general, EBV, CMV, parvovirus or HIV are the most likely causes for infection‐related secondary HLH in immunocompromised patients. Bacterial and fungal infections may also be implicated as secondary causes of HLH, but far less likely (25Domachowske JB Infectious triggers of hemophagocytic syndrome in children.Pediatr Infect Dis J. 2006; 25: 1067-1068Crossref PubMed Scopus (26) Google Scholar,26Janka GE Familial and acquired hemophagocytic lymphohistiocytosis.Eur J Pediatr. 2007; 166: 95-109Crossref PubMed Scopus (398) Google Scholar). Three out of four kidney transplant patients from Turkey who developed HLH had CMV or EBV (27Gurkan A Yakupoglu U Yavuz A et al.Hemophagocytic syndrome in kidney transplant recipients: Report of four cases from a single center.Acta Haematol. 2006; 116: 108-113Crossref PubMed Scopus (19) Google Scholar). In a review of 17 patients from Paris, eight had CMV, EBV or HHV as the putative cause. Others included Bartonella, lymphoma, TB, Hepatitis C and toxoplasmosis (28Karras A Thervet E Legendre C for the Groupe Cooperatif de transplantation d’Ile de FranceHemophagocytic syndrome in renal transplant recipients: Report of 17 cases and review of literature.Transplantation. 2004; 77: 238-243Crossref PubMed Scopus (148) Google Scholar). Currently, HIV/AIDS is the most frequently described risk factor for developing disseminated histoplasmosis and secondary HLH in endemic areas (12Guiot HM Bertran‐Pasarell J Tormos LM et al.Ileal perforation and reactive hemophagocytic syndrome in a patient with disseminated histoplasmosis: The role of the real‐time polymerase chain reaction in the diagnosis and successful treatment with amphotericin B lipid complex.Diagn Microbiol Infect Dis. 2007; 57: 429-433Crossref PubMed Scopus (24) Google Scholar, 14Gil‐Brusola A Peman J Santos M Salavert M Lacruz J Gobernado M Disseminated histoplasmosis with hemophagocytic syndrome in a patient with AIDS: Description of one case and review of the Spanish literature.Revista Iberoamericana de Micologia. 2007; 24: 312-316Crossref PubMed Google Scholar, 29Sanchez A Celaya AK Victorio A Histoplasmosis‐associated hemophagocytic syndrome: A case report [see comment].AIDS Read. 2007; 17: 496-499PubMed Google Scholar). On review of case reports for solid organ transplant with disseminated histoplasmosis, 9 out of 12 patients had intensified immunosuppression (i.e. rejection or induction therapy) within 6 months of diagnosis (18Peddi VR Hariharan S First MR Disseminated histoplasmosis in renal allograft recipients.Clin Transplant. 1996; 10: 160-165PubMed Google Scholar, 23Davies S Sarosi GA Peterson PK et al.Disseminated histoplasmosis in renal transplant recipients.Am J Surg. 1979; 137: 686-691Abstract Full Text PDF PubMed Scopus (72) Google Scholar, 24Masri K Mahon N Rosario A et al.Reactive hemophagocytic syndrome associated with disseminated histoplasmosis in a heart transplant recipient.J Heart Lung Transplant. 2003; 22: 487-491Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 30Mesa H et al.A case of systemic histoplasmosis diagnosed in a peripheral blood smear.Br J Haematol. 2004; 127: 241Crossref PubMed Scopus (7) Google Scholar). Neither of our patients had recent increases in immunosuppression, except for Case 1, who had a high sirolimus level on admission but had been within a normal range (8–15 ng/mL) on previous clinic visits. Although disseminated histoplasmosis can have a variety of clinical presentations, the key to patient survival lies in rapid diagnosis of this uncommon fungal infection. In both of our patients, the pulmonary symptoms were subtle and chest X‐ray findings were not diagnostic. From a laboratory standpoint, the histoplasmosis antibodies were falsely negative possibly due to HLH or chronic immunosuppression. False‐positives can result from recent rabbit antithymocyte antibodies as well as cross‐reactivity with other fungal infections (e.g. coccidiomycosis and blastomycosis) (2Kauffman CA Histoplasmosis: A clinical and laboratory update.Clin Microbiol Rev. 2007; 20: 115-132Crossref PubMed Scopus (765) Google Scholar). Currently, it is widely held that the most sensitive method for rapid detection of disseminated histoplasmosis is urine antigen testing. Based on data from the AIDS literature, the sensitivity is around 90% with a turn‐around time of 1–2 days. Whichever reference laboratory (MiraVista or ARUP) is chosen to make the diagnosis, it should be the one used for quantitatively following the patient's response to treatment (31Kauffman CA Diagnosis of histoplasmosis in immunosuppressed patients.Curr Opin Infect Dis. 2008; 21: 421-425Crossref PubMed Scopus (114) Google Scholar). Most treatment protocols use intravenous liposomal amphotericin B for the initial 2–6 weeks and, depending on the clinical response, the patient can be switched to oral azole therapy with a total duration of treatment of 6–18 months (22Silveira FP Husain S Fungal infections in solid organ transplantation.Med Mycol. 2007; 45: 305-320Crossref PubMed Scopus (188) Google Scholar). Clinical response to antifungal therapy includes symptom resolution, following monthly urine histoantigens and antifungal drug levels. In addition, we aimed for lower tacrolimus trough levels (3–6 ng/mL) and reduced MMF dose by 50% to ensure complete resolution of histoplasmosis infection. Dose reductions in our two patients were not associated with acute rejection, despite prograf dosing as low as 0.5 mg (Q48 h) to attain trough levels of 3–6 ng/mL (on itraconzole therapy). It is noteworthy that in the AIDS literature, antifungal treatment does not guarantee eradication of infection and patients are on itraconazole prophylaxis indefinitely, which highlights the importance of reducing immunosuppression in solid organ transplants (11Flannery MT Chapman V Cruz‐Gonzales I Rivera M Messina JL Ileal perforation secondary to histoplasmosis in AIDS.Am J Med Sci. 2000; 320: 406-407Abstract Full Text PDF PubMed Scopus (12) Google Scholar,16Wheat J Histoplasmosis in the acquired immunodeficiency syndrome.Curr Top Med Mycol. 1996; 7: 7-18PubMed Google Scholar). Given the high mortality rate of disseminated histoplasmosis, the survival benefit of complete discontinuation of immunosuppression and graft loss should be considered if refractory to antifungal therapy. In summary, disseminated histoplasmosis is more common in immunocompromised populations and may have atypical presentations such as HLH, TMA and soft tissue lesions. A specific history of exposure (i.e. perturbed soil from a construction site) in endemic areas is not needed and recent increases in immunosuppression is a risk factor for developing this opportunistic infection. Urine antigen testing is the most sensitive and rapid testing, but the time lag using a reference laboratory may delay diagnosis. Serum antibodies to histoplasmosis were not reliable indicators of infection in our patients. Fungal cultures are reliable but take several weeks for positive identification. Interestingly, bone marrow and lymph node biopsy (in the presence of pancytopenia) was the most rapid and unequivocal tool to make the diagnosis of disseminated histoplasmosis and HLH at our institution. Treatment involves a combination of antifungal therapy and a reduction in immunosuppression adjusted monthly on the basis of urine histoplasma antigen and antifungal drug levels. Since initial diagnosis 10 months ago, both of our patients are doing well with excellent graft function (at baseline creatinine) and no clinical indications of active histoplasmosis infection. Given the diagnostic difficulties and morbidity/mortality risks in immunocompromised patients, clinical suspicion of disseminated histoplasmosis and HLH must remain high in transplant recipients that present with fever of unknown origin and pancytopenia. This work is supported by Division of Nephrology and Hypertension, Cincinnati Children's Hospital and Medical Center." @default.
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• W2019417906 title "Disseminated Histoplasmosis Associated with Hemophagocytic Lymphohistiocytosis in Kidney Transplant Recipients" @default.
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