Disseminated histoplasmosis in a patient after orthotopic liver transplantation

Histoplasmosis may cause mild, primarily respiratory disease in endemic areas and only rarely disseminates in an immunocompetent host (1.). However, disseminated histoplasmosis is well documented in immunocompromised patients (2.-10.), including bone marrow (11., 12.) and renal transplant recipients (13.-16.). To date, disseminated histoplasmosis has not been described in liver transplant recipients. We report a case of liver transplant recipient from an endemic area, who developed disseminated histoplasmosis six months after transplantation, and was successfully treated with liposomal amphotericin B. A 42-yr-old Caucasian female with primary sclerosing cholangitis from West Virginia underwent orthotopic liver transplantation in March 1996. Two months after the transplant, she was readmitted to the hospital with cytomegalovirus (CMV) colitis and was treated with I/V ganciclovir. Six months after the transplant, she presented to a local hospital with generalized myalgia, high fever with chills and rigors, nausea and vomiting of 3-4 d duration. On admission, she was pancytopenic and febrile with a temperature of 39°C. All her cultures, serological studies, and chest radiograph were negative. She was transferred to the University of Pittsburgh Medical Center for further evaluation. Her medications on admission included prednisone 5 mg p.o. q.d., tacrolimus (FK-506) 3 mg p.o. q.d., mycophenolate mofetil (MMF) 500 mg p.o. bid, trimethoprim-sulfamethoxazole-single strength 1 tablet p.o. 3 times/wk, and omeprazole 20 mg p.o. q.d. Physical examination was notable for an ill-appearing pale woman in no distress. Her vital signs were remarkable for a temperature of 39°C. There was no icterus, and lymphadenopathy. Chest and cardiovascular exam were unremarkable. Her abdomen revealed mild hepatomegaly (liver span 16 cm in the right midclavicular line) with mild tenderness, and marked splenomegaly. There was no ascites, and bowel sounds were normally active. The remainder of the examination was normal. On admission, the patient was pancytopenic with hematocrit 24.5%, white blood cell count 1100/mm3 (segmented neutrophils 74%, band forms 15%, lymphocytes 8%, atypical lymphocytes 2%, monocyte 1%), and platelet count 34/000/mm3 The clotting studies, electrolytes, renal function and urine analysis were unremarkable. The liver function tests were as follows: total bilirubin 1.0 mg/dL; alkaline phosphatase 737 IU/L (normal level 40-125 IU/L); aspartate aminotransferase (AST) 90 IU/L and alanine aminotransferase (ALT) 90 IU/L (normal levels for AST and ALT: <40 IU/L); γ-glutamyl transpeptidase (γGTP) 967 IU/L (normal 40-125 IU/L). Routine blood cultures and urine cultures were negative and CMV pp65 antigenemia was negative. Histoplasma sérology titer by immunodiffusion method was negative. The chest radiograph was normal. An ultrasound of the abdomen revealed homogeneous liver, low resistive indices with a large velocity gradient of the main hepatic artery, consistent with hepatic artery stenosis. A computerized tomographic (CT) scan of the abdomen revealed mild hepatomegaly with no focal masses, and marked splenomegaly. Celiac and common hepatic angiogram confirmed stenosis of the transplanted hepatic artery which required angioplasty. On admission, the patient was empirically started on intravenous ampicillin and cefotaxime and recombinant G-CSF, and immunosuppression was discontinued. Within 24 h after admission, the patient developed hemorrhagic skin lesions over the forehead and peri-umbilical areas. Empirical I/V aciclovir was started for possible disseminated herpes infection. Tzanck smear and viral culture of the skin biopsy were negative; histopathology showed yeast consistent with Histoplasma capsulatum. A liver biopsy showed lobular inflammation with microabscesses formation; Grocott staining showed small budding intracellular and extracellular yeast consistent with H. capsulatum. Bone marrow biopsy and aspirate showed small yeast and culture grew H. capsulatum which was confirmed. later by DNA probe. An esophagogastroduodenoscopy showed few erythematous indurated lesions involving the prepyloric area, the biopsy of which showed similar yeast. Blood cultures using isolator bottles grew 60 CFU of H. capsulatum. Radioimmunoassay (RIA) of serum and urine for Histoplasma antigen were positive at titres of 24.9 and 22.4, respectively (normal <1.0 RIA units). Because of hypoxemia and development of bilateral pulmonary infiltrates, the patient was placed on mechanical ventilation. Bronchoalveolar lavage (BAL) grew H. capsulatum. Treatment for histoplasmosis was initiated with amphotericin B (AmB) 60 mg/d and a loading dose of itraconazole 200 mg p.o. t.i.d. for 3 d followed by 200 mg b.i.d. After 72 h, AmB was changed to lipophilic AmB (Ablecet) because of oliguria and worsening renal function. The initial dose was at 165 mg/d (3 mg/kg/d) and then increased to 300 mg/d (5 mg/ kg/d). Itraconazole was discontinued after 2 wk of therapy due to allergic urticaria. The patient's hospital course was complicated by adult respiratory distress syndrome, sepsis and renal failure. Repeat BAL, blood cultures, bone marrow and skin biopsies were all negative for H. capsulatum after 2 wk. of Abelcet therapy. Liver biopsy showed few fungal elements and complete resolution of microabscesses. Abelcet was continued for an additional 2 wk (cumulative dose 8.5 g) and then was discontinued. The patient was then given AmB 35 mg/daily (0.5 mg/kg/d) for 2 wk and then started on AmB 50 mg/d twice a wk as maintenance regimen for 61 months. Immunosuppression was resumed with prednisone 5 mg p.o. q.d. and FK-506 1 mg p.o. q.d. The patient continued to improve with complete resolution of pancytopenia and near normalization of liver function. H. capsulatum antigen. titres declined and became negative after 15 wk of therapy with AmB. Histoplasmosis, is the most common endemic systemic mycoses in the USA and is endemic in the Ohio and Mississippi river valley. Most infections. cause asymptomatic or self-limited febrile illness, and in immunocompetent individuals, disseminated histoplasmosis is uncommon (1.). However, over recent years, H. capsulatum has emerged as opportunistic fungal pathogen. Individuals with altered cell immunity such as transplant recipients on immunosuppressive medication, patients on corticosteroids and cytotoxic drugs, patients with. acquired immune deficiency states, elderly people, and patients with comorbid conditions, are susceptible to a disseminated form of the disease (2.-16.) and may have a fatal outcome. In the Indianapolis outbreak, disseminated disease developed in 73.8% of immunocomprised patients infected with H. capsulatum but in only 6.5% of immunocompetent patients (1.). The reported mortality from histoplasmosis in the immunocompromised population ranges from zero to 73%. A high index of suspicion must be maintained. for histoplasmosis, especially, if there is a history of pre-transplantation endemic exposure, hilar calcification together with negative PPD. Although our patient lives in an endemic area, there were no calcified lesions noted on the chest radiograph. Transplant recipients may develop histoplasmosis as a result of primary infection, reactivation of prior infection or direct transmission with an infected allograft (17.-19.). The mechanism of infection in our patient most likely appears to be a primary acquired infection in the light of negative serology for H. capsulatum, although serology can be falsely negative in an immunosuppressed patient (20.). The diagnosis of disseminated histoplasmosis depends on either demonstration of intracellular yeast forms by histopathologic study or a positive culture of blood, bone marrow, lymph node, skin or mucus membrane, liver, lung, or other involved sites. Demonstrations of the fungus in bone marrow aspirate and biopsy is often the earliest means of diagnosing histoplasmosis in the immunosuppressed patients, since the fungus may take up to 2 wk to grow. Serum and urine for H. capsulatum antigen have been confirmed as a sensitive method for the diagnosis of disseminated infection and overcomes many of the limitations of the other tests (21., 22.). Follow-up Histoplasma antigen titers may be also useful in monitoring response to antifungal therapy, and helpful in detection of relapse (23., 24.). In our patient, histopathologic examination of liver, bone marrow, skin and BAL provided rapid presumptive diagnosis, and results of positive blood cultures and H. capsulatum antigen confirmed the diagnosis. Serology, although useful in immunocompetent patients, may be less useful in immunosuppressed patients. In three previous studies of immunosuppressed patients with histoplasmosis (4., 11., 13.), complement fixing antibodies to H. capsulatum were absent in 54%, but in a study by Wheat et al, all renal transplant recipients. had complement fixation titres greater than 1:8 (14.). For patients with severe, life-threatening disease, AmB is the drug of choice, and is effective in treating disseminated histoplasmosis (4., 8., 14., 16., 23., 24.). However, in patients with neutropenia and renal failure, conventional form of AmB may be poorly tolerated. Encapsulating AmB into liposomes or binding of AmB to other lipid carriers results in a significant reduction of toxicity of AmB and possibly an increased therapeutic index (25., 26.). Our patient was initially started on AmB and then switched over to Abelcet because of renal failure. Once renal failure resolved, it was changed back to AmB. Intravenous AmB (total dose, 1.0- 2.0 grams) is used to reduce the organism load, and is followed by long-term maintenance or suppressive therapy with either weekly or twice weekly AmB (1 mg/kg) or an oral antifungal azole, given daily. Among the azole drugs, itraconazole, appears to be the most promising therapy for immunosuppressed patients (27., 28.), and has been. shown to be effective maintenance therapy for prevention of relapse of histoplasmosis in AIDS patients (29., 30.). Our patient initially received itraconazole for several days before it was withheld because of drug rash (erythema multiforme). The rash resolved when the drug was held and recurred when the drug was reinstituted about 4 wk later. Therefore, the patient was given maintenance therapy with AmB. The incidence of drug rash with itraconazole is about 8%, however, it tends to occur more frequently in immunocompromised patients (27.-30.). In rare instances, angioedema, anaphylaxis, and Stevens-Johnson syndrome, have also been reported (27., 28.). In conclusion, histoplasmosis should be considered in immunosuppressed transplant patients. from endemic areas who present with a febrile illness. Prompt recognition of this disease will permit timely institution of appropriate therapy.