Coccidioidomycosis is a fungal infection caused by Coccidioides species, a fungus endemic to the southwestern United States. After inhalation of airborne arthroconidia, as many as 60% of healthy persons experience no symptoms; most of the rest have mild to moderate febrile illness caused by respiratory infection (1). Infrequently, extrapulmonary infection complicates the patient’s clinical course.
In immunocompromised transplant recipients, coccidioidomycosis may be complicated by clinically significant morbidity and mortality (2). A history of coccidioidal infection or positive serologic findings before transplantation are risk factors for coccidioidomycosis after transplantation, which in many cases may be a reactivated infection (2). To minimize the possibility of reactivated infection, we have introduced a program of targeted prophylaxis in our transplant center, with resultant coccidioidal infection rates of 1% to 3% in those patients who have not received any anticoccidioidal prophylaxis (3–5).
Isolated case reports and small case series indicate that oral azoles successfully prevent recurrent coccidioidomycosis after transplantation (6–9). Whether newer immunosuppressants, induction immunosuppression, treatment of rejection, or the presence of cytomegalovirus infection influences the ability of azoles to suppress this infection is not known. We report our experience with the use of azoles as prophylaxis for the first 47 transplant recipients diagnosed with coccidioidomycosis before transplantation.
MATERIALS AND METHODS
We conducted a retrospective review of the medical records of patients with coccidioidomycosis before solid organ transplantation who received their transplant between June 1, 1999, and February 8, 2006, at our tertiary care academic medical institution. Patients were identified through an electronic search of serologic and microbiologic records and departmental databases. This study was approved by the Mayo Foundation Institutional Review Board.
Extracted data included the details of the coccidioidal infection (e.g., date of infection, symptoms, extent of infection, treatment, laboratory studies [serologic, microbiologic, histopathologic, and radiologic findings]), the details of the transplantation (e.g., organ, date of surgery, antifungal prophylaxis, induction, antirejection medication, and maintenance immunosuppression), and outcome of the patient.
We defined coccidioidomycosis as definite when the patient had positive culture or histopathologic finding, regardless of the presence or absence of symptoms or radiographic findings.
In contrast to definite coccidioidomycosis, probable coccidioidomycosis was defined as a compatible clinical illness, plus radiographic changes, plus positive serologic findings.
When a patient had positive serologic findings, but no identifiable clinical illness and normal radiographic studies, neither diagnosis of coccidioidomycosis (definite or probable) was given.
Positive History of Coccidioidomycosis
Patients with a positive history required a physician diagnosis of coccidioidomycosis with appropriate compatible illness, laboratory tests, and radiographic studies. Persons were excluded if they had reported possibly having had coccidioidomycosis, but there was no corroborating physician diagnosis.
Active Coccidioidal Infection at Transplantation
If the patient did not meet the definition for quiescent coccidioidomycosis, the infection was considered active. Quiescent coccidioidomycosis at transplantation required the presence of all of the following: serologic titer findings of less than or equal to 1:4, stable or resolved radiographic findings, and complete resolution of symptoms.
As part of the pretransplantation evaluation, candidates are asked about any history of coccidioidomycosis. Serologic tests are conducted as part of the pretransplantation evaluation and are repeated at transplantation, at annual posttransplantation evaluations, and at any other time as needed.
Multiple methods for identifying coccidioidal serologic findings are used, including the enzyme immunoassay (EIA; immunoglobulin [Ig] M and IgG antibody), the complement fixation (IgG antibody) test, and immunodiffusion (IgM and IgG antibody). The Laboratory Branch complement fixation test of the Centers for Disease Control and Prevention is also used (10, 11). The EIA is performed using a kit produced by Meridian Bioscience, Inc (Cincinnati, Ohio). Before June 2002, the immunodiffusion test was performed using a test kit (Gibson Laboratories, Lexington, Kentucky) with antigen F to detect IgG antibody. Beginning in June 2002, we conducted the immunodiffusion test with a test kit (Meridian Bioscience, Inc) to detect both early (IgM) antibodies and late (IgG) antibodies. Equivocal results are repeated, then sent to the laboratory of D. Pappagianis at the University of California, Davis, for further clarification.
To proceed to transplantation, all persons with coccidioidomycosis required clearance by an infectious diseases physician. Clearance mandates resolution of symptoms, markedly improved serologic findings, and radiographs showing resolution of abnormalities. Before such clearance, patients continue to receive azole prophylaxis. Patients whose coccidioidal infection did not meet the definition of quiescent coccidioidomycosis before transplantation were approved only after discussion with, and approval by, the transplant selection group, and with a frank discussion with the patients of the known and unknown risks of undergoing transplantation with active coccidioidomycosis.
The dose and duration of prophylaxis for coccidioidomycosis was based on the patient’s history of coccidioidal infection. Seronegative patients with no history of coccidioidomycosis did not receive prophylaxis. Seropositive patients with no evidence of active infection at transplantation received lifelong fluconazole, with an initial dose of 400 mg/day for the first year after transplantation that was then halved to 200 mg/day. Patients with acute coccidioidal illness manifesting within 1 year of evaluation and transplantation received 400 mg/day for 1 year, then consideration for 200 mg/day thereafter. For seronegative patients with a physician-confirmed history of coccidioidomycosis more than a year before transplantation, fluconazole 200 mg/day was administered for 6 to 12 months, then discontinued.
Kidney and Pancreas Immunosuppression
Before July 2003, kidney transplant recipients did not receive induction therapy. Maintenance immunosuppression was with tacrolimus, mycophenolate mofetil (MMF), and corticosteroids. After July 2003, all recipients received induction with either rabbit antithymocyte globulin (target dose, 6 mg/kg, in divided doses) or basiliximab (20 mg) on the day of surgery, then repeated 4 days later. Maintenance immunosuppression was generally with tacrolimus and MMF with steroid avoidance. Sixty percent of the recipients who had either a kidney transplant alone or simultaneous kidney and pancreas transplants were steroid-free after the first posttransplantation week. Biopsy-proven acute rejection was treated with methylprednisolone sodium succinate 500 mg for 3 doses. Patients with more severe acute rejection (Banff grade 2B or greater) received rabbit antithymocyte globulin.
Standard immunosuppression for liver recipients is tacrolimus with intravenous methylprednisolone at transplantation, followed by oral prednisone, which is tapered off within 4 months. For patients with mild renal insufficiency, MMF is added to allow for lower tacrolimus levels. Patients with moderate to severe renal insufficiency are considered for conversion to sirolimus, depending on the specific clinical situation.
Mild to moderate cellular rejection is treated with three 1-g doses of methylprednisolone by intravenous infusion every other day. Steroid-resistant rejection is rarely encountered in liver transplant recipients but is treated either with monoclonal murine anti-CD3 antibody or with rabbit antithymocyte globulin.
Between June 1, 1999, and February 8, 2006, our program performed solid organ transplants in 820 patients (471 kidney, 306 liver, and 43 pancreas). Of these 820 patients, 46 (5.6%) had evidence of coccidioidomycosis before transplantation. One additional patient who received all of her transplant and coccidioidomycosis-related health care at our institution was included in this cohort, for a total of 47 patients, although she had received a pancreas transplantation at another institution.
Table 1 summarizes the clinical characteristics of these 47 patients. At transplantation, 44 patients (94%) had quiescent coccidioidal infection and three had active coccidioidomycosis.
Of the three patients with active coccidioidomycosis at transplantation, one patient was not diagnosed until afterward when the results of serologic studies drawn before transplantation were reported (12). At that point, a few hours after surgery, coccidioidal prophylaxis was begun; disseminated infection nonetheless developed. The patient required debridement of coccidioidal tenosynovitis in a finger. She was treated orally with fluconazole, which resolved the infection, and she continues to do well taking lifelong fluconazole.
The second patient had a cavitated pulmonary nodule associated with symptoms that had been documented about 1.5 years before transplantation. His initial complement fixation was 1:512, and he had positive EIA and immunodiffusion serologic responses. Extrapulmonary coccidioidomycosis was not recognized despite clinical and radiographic evaluation. At transplantation, the risk of death from underlying liver disease (i.e., documented hepatocellular carcinoma) was considered greater than the risk of death from fungal disease. Both the patient and his family were informed about the potential risk of dissemination or death due to coccidioidomycosis, and they elected to proceed with the transplant operation. The patient received fluconazole 400 mg as prophylaxis before, during, and after transplantation. Histopathologic evaluation of the explanted liver identified spherules of Coecidiodes species on the serosal surface of the peritoneum. At 9-month follow-up, he had no reactivated coccidioidal illness.
The third patient had a complement fixation of 1:16 during evaluation for liver transplantation that increased to 1:32 in subsequent testing during pretransplantation monitoring. He had no symptoms, and radiologic examination showed only a 5-mm uncalcified nodule in one lung. Before transplantation, he was treated with fluconazole, which was later changed to itraconazole because of his intolerance to fluconazole. At transplantation, he had a titer of 1:8, which did not meet the criteria for quiescent coccidioidomycosis.
Forty-four patients began coccidioidal prophylaxis according to protocol. Three did not receive prophylaxis for unclear reasons but had no recurrent infection, and four patients admitted that they discontinued (either completely or intermittently) their prophylaxis against medical advice (Table 2).
Two patients had disseminated nonmeningeal infection before transplantation. One of these two patients had culture-proven bilateral pulmonary infiltrates and biopsy-proven coccidioidal nodules in a hepatic allograft shortly after liver transplantation. The infection was controlled with fluconazole, which has been continued for life. Then 2.5 years after liver transplantation, this patient underwent kidney transplantation. She has had no recurrence of coccidioidomycosis in the 5 years since receiving the transplant.
The second patient who received a pancreas transplant after having had extrapulmonary coccidioidomycosis was a patient with an earlier kidney transplant who sustained coccidioidal tenosynovitis in his arm that required debridement and fluconazole therapy. He then underwent a pancreas transplantation, and in the subsequent 2-year follow-up since receiving his pancreas transplant, he has had no recurrence of coccidioidomycosis.
Cell-mediated immunity is critical to the control of coccidioidomycosis (13). Solid organ transplantation requires the use of iatrogenic immunosuppression designed to decrease the activity of such immunity; thus, it is not surprising that organ transplant recipients have a decreased ability to control coccidioidomycosis, resulting in substantial morbidity and mortality (2). Between 1960 and 2000, 9 publications (6, 9, 14–20) reported the outcomes of 21 patients with coccidioidomycosis followed by organ transplantation; these cases were previously reviewed as a group (2). Of the 11 who received posttransplantation coccidioidomycosis prophylaxis, nine had no coccidioidal infection after transplantation. Two experienced recurrent coccidioidomycosis after discontinuation of prophylaxis. Of the 10 who either did not receive prophylaxis or for whom no details of such intervention were given, seven died, one from pneumonia (pathogenesis not reported) and six from disseminated coccidioidomycosis. Three of the 10 had no coccidioidomycosis after transplantation (2). From these historical case reports, an actual incidence of reactivated coccidioidomycosis after transplantation cannot be calculated, due to a lack of denominator (patients at risk). Among all transplant recipients within the endemic area, the highest risk of posttransplantation coccidioidomycosis is among those who have a history of coccidioidal infection or positive serologic findings at transplantation (6–9, 14). Antifungal prophylaxis attenuates the risk (2, 9).
The present study is the first review of a cohort of transplant candidates with prior coccidioidomycosis who subsequently underwent solid organ transplantation. Several findings are worth highlighting. As suggested by anecdotal reports, patients with a history of coccidioidomycosis before solid organ transplantation may be able to avoid reactivation of infection with azole prophylaxis. Indeed, in our study, only one transplant recipient had active coccidioidomycosis while taking azole prophylaxis. However, the pretransplantation coccidioidomycosis in this patient was not identified until after transplantation, and prophylaxis was therefore not initiated until after the procedure.
Our review did include three patients for whom prophylaxis was intended but not begun, and four patients who did not take prophylaxis as instructed (Table 2). The three patients whose prophylaxis was not begun had no evidence of active disease at transplantation, and two of the three had a remote history of coccidioidomycosis but negative serologic results. The outcome for the four patients who discontinued prophylaxis against medical advice was mixed: one patient who had mild chest symptoms and mild enlargement of the coccidioidal cavity subsequently resumed prophylaxis; one patient took prophylaxis intermittently; and the other two patients completely discontinued medication. None of these last three had apparent sequelae. These limited findings indicate that not all patients (even if seropositive) require lifelong prophylaxis after transplantation, but there were no distinguishing characteristics to determine which candidates would require prophylaxis.
In the face of a patient’s need for an organ transplant, we have found that achieving control of the patient’s coccidioidomycosis may be slow, difficult, or incomplete, even with azole therapy. In some instances, resection of a pulmonary mass or an enlarging nodule has resulted in enough improvement to allow a patient to proceed with transplantation.
Three of our patients underwent organ transplantation despite active coccidioidomycosis of varying degrees. Two of these patients were taking azole prophylaxis and have thus far not had reactivation. The one patient who underwent transplantation with unbeknownst active coccidioidomycosis had dissemination shortly after the procedure, despite institution of antifungal treatment within hours of surgery.
A decision to pursue transplantation when a patient has active coccidioidomycosis should be made only after careful consideration and discussion with the patient and all members of the transplant team. When we knowingly performed transplantation in two such patients, we did so only after deciding that the risk without the transplant procedure outweighed the risk of coccidioidomycosis after transplantation. We still strongly recommend achieving complete control of coccidioidal infection beforehand. In the rare circumstance of transplantation despite active coccidioidomycosis, the patient and family members should be advised of risks, including the possibility of active coccidioidomycosis, possible dissemination, and even death.
Our examination of the medical records of 47 patients who had prior coccidioidomycosis followed by solid organ transplantation shows that such procedures should be accompanied by azole prophylaxis to prevent recrudescent coccidioidomycosis after organ transplantation. The optimal dose and duration, and the identification of which patients would best benefit from such prophylaxis, are all topics for future study.
Editing, proofreading, and reference verification were provided by the Section of Scientific Publications, Mayo Clinic.
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