Discussion
Inadequacy of cellular immunity is a well-established risk factor for development of coccidioidomycosis. Solid organ transplant recipients require lifelong suppression of cell-mediated immunity to prevent organ rejection, thus increasing their risk of coccidioidal infection or other opportunistic infections. This study highlights the serious nature of coccidioidomycosis in the transplant recipient. Among the 15 patients with active infection (12 de novo infection, 2 reactivations and 1 with pretransplantation indeterminate serologic results), 5 had disseminated infection (33%) and 2 (13%) died of active coccidioidomycosis. Therefore, all efforts to limit the effect of this endemic fungal infection are warranted.
Earlier studies have identified several risk factors for the development of coccidioidomycosis posttransplantation. These factors include previous history of coccidioidomycosis, positive coccidioidal serologic results at transplantation and treatment of acute rejection with intravenous corticosteroids. In a previous report, 7 of 10 patients with prior history of coccidioidomycosis who never received antifungal prophylaxis after the solid organ transplantation died of disseminated disease. Therefore, it is standard to offer prophylaxis to patients with seropositivity or a history of prior coccidioidomycosis.
We initially reported our early experience with targeted prophylaxis for liver transplant recipients who had such risk factors for posttransplantation coccidioidomycosis. In the initial report, four patients received targeted prophylaxis and none had reactivated coccidioidomycosis. In addition, de novo coccidioidal infection occurred in 1 of 72 patients (1.4%). At that time, we were unable to identify any patient characteristics that placed the sole patient at increased risk for this infection.
In this study, 12 patients had coccidioidomycosis before transplantation, 11 of whom were asymptomatic at the time of transplantation. Excellent adherence to antifungal prophylaxis continues to predict the lack of active coccidioidomycosis. One of the two patients was not compliant with the posttransplant prophylaxis regimen and had reactivated coccidioidal infection. Except for this one case, no reactivation of the coccidioidomycosis was observed in patients with quiescent infection before transplantation. Our current study supports our initial report, and we continue to advocate the use of and adherence to antifungal prophylaxis for this patient population.
The optimal duration of such antifungal (anticoccidioidal) prophylaxis has not yet been established. As reported in other studies, we observed that nonadherence to antifungal prophylaxis (2 of 12 patients in our study) did not inevitably result in active coccidioidomycosis. However, one recipient with apparently quiescent cavitary lung infection took fluconazole for 4 years, stopped for 1 year, and subsequently had enlargement of the cavitary lesion, which was controlled only with reinstitution of her azole therapy. Although coccidioidal lung nodules and cavities both harbor live fungal organisms, the sputum from patients with cavities are much more frequently culture positive than the sputum from patients with nodules, indicating a greater fungal burden in the cavities. We thus speculate the possibility that a lung cavity may be more likely to reactivate than a nodule when prophylaxis is withdrawn.
Treatment of acute cellular rejection has been reported to be a risk factor for coccidioidomycosis in solid organ transplant recipients. We did not observe this finding in our initial or the present evaluation. In this study, 82 patients required pulsed corticosteroid treatment of acute cellular rejection. Two patients (2%) had pulmonary coccidioidomycosis. No statistically significant association was found between administration of such antirejection therapy and development of coccidioidal illness. However, this cohort did not have any episodes of corticosteroid-resistant rejection and was never treated with antilymphocyte treatments, such as human, monoclonal or chimeric antilymphocyte antibodies or other antirejection regimens. The lack of infection risk seen in this study compared with previous studies may have been due to a lower level of immunosuppression regimens required to reverse the organ rejection.
The liver transplant recipients in our transplantation program have typically resided in and continue to live in the endemic area, putting them at daily risk for de novo infection. In our initial report, 1 (1.4%) of 72 recipients had coccidioidomycosis, compared with 12 (3%) patients in this study (p= 0.70). Within the endemic area, the incidence of de novo coccidioidomycosis in solid organ transplant recipients ranges from 1.4% to 6.9%.
Past studies have shown that in the absence of coccidioidal prophylaxis, approximately 70% of posttransplantation coccidioidomycosis occurs during the first posttransplantation year. In this cohort, despite the institution of a targeted prophylaxis program, we had a similar observation, with eight cases (67%) in the first posttransplantation year; seven of those cases were diagnosed within the first 6 months. In the past, it was hypothesized that the coccidioidal infections occurring early in the posttransplantation period were cases of reactivation and that anticoccidioidal prophylaxis would eliminate these early cases of coccidioidomycosis. Because our high-risk patients already received antifungal prophylaxis, our results indicate a vulnerability to de novo coccidioidomycosis in the early posttransplantation course. A possible explanation for the preponderance of early posttransplantation coccidioidal infection is simply that the patients are at high risk in this early transplantation period because the doses of immunosuppressive medications are highest during this period.
We sought to identify potential risk factors for de novo coccidioidomycosis in liver transplant recipients but found no statistically significant association with respect to numerous patient and transplantation characteristics (Table 4). Therefore, how to further refine targeted prophylaxis is unclear. As a result, we have changed our strategy from targeted to universal prophylaxis for the first year posttransplantation for patients who remain in the endemic area.
Previously, we have strongly advocated the use of targeted prophylaxis for the prevention of coccidioidomycosis in organ transplantation. Unlike our previous studies and recommendations, with the accumulation of 8 years of experience, we conclude that, despite a program of targeted prophylaxis, coccidioidomycosis continues to plague our transplant recipients, and de novo infection accounts for most active cases. Because most liver transplant recipients in our program continue to reside in the endemic area (and thus are at continual risk of acquisition of coccidioidomycosis), we now propose a new strategy of universal prophylaxis of fluconazole of 6–12 months for such patients after transplantation (Table 5). Patients with a history of recent coccidioidomycosis or positive serologic results at transplantation will still receive fluconazole at 400 mg/day for life; however, all other recipients will receive 6–12 months of fluconazole at 200 mg daily. We hypothesize that the addition of fluconazole to treatment of patients at risk for de novo posttransplant coccidioidomycosis will minimize infection risk at the time of maximum immunosuppression. In addition, because the proposed prophylaxis simplifies the prophylaxis construct by applying one of two doses of fluconazole to all recipients for the first year after transplantation, we hope to see improved adherence to the protocol.
How to best approach the care of patients with indeterminate serologic results before transplantation continues to be an unsettled issue. In 11 cases, indeterminate serologic results or an isolated IgM positivity (through EIA) were interpreted as 'negative' by the clinician, such that the patients did not receive anticoccidioidal prophylaxis after transplantation. The EIA IgM test has generated controversy in that some investigators have found this test to be falsely positive when not accompanied by positive results for other serologic markers. Investigators of a recent study argued that the solitary IgM seropositivity with EIA is often a true positive result. In this study, one patient with an indeterminate EIA IgM result 1 month before transplantation had an early posttransplantation course complicated by fatal disseminated coccidioidomycosis. As a result, the subsequent policy at our transplantation center has been to consider any and all indeterminate or positive pretransplantation serologic findings as 'positive' and to recommend prophylaxis for patients as they proceed into a period of high-level immunosuppression.
Our retrospective study has several limitations. As shown, serologic results can be indeterminate, falsely negative, or falsely positive and can be difficult to interpret. Our program has chosen to administer prophylaxis to patients with positive serologic results even though the possibility of false-positives (e.g. potentially the case in patients with autoimmune causes of hepatitis) is present. There was variability of antifungal regimens and immunosuppression, although in our analysis, we could not identify that the variability in the dosage of fluconazole altered the risk of coccidioidal infections. In addition, some patients participated in immunosuppression studies outside our normal protocols; however, such patients did not have an increased risk of coccidioidal infection.
We conclude that coccidioidomycosis continues to challenge transplantation programs within the endemic area. Prospective organ recipients require multidisciplinary evaluation and careful screening and follow-up after transplantation. In the clinical setting of targeted prophylaxis for patients with known risk factors for posttransplantation, de novo infection accounts for most cases of active coccidioidomycosis, most of which occur in the first 6 months after transplantation. We now propose a new strategy of prophylaxis for the first 6–12 months for all recipients who maintain residence in the endemic area. Future studies should assess the efficacy of and adherence to such a strategy.