Glucocorticoid stimulation of neutrophil donors: a medical, scientific, and ethical dilemma

In this issue of TRANSFUSION, Burch and colleagues1 report results of a multicenter study in which adrenal corticosteroids, given repeatedly to healthy individuals donating apheresis neutrophils (PMNs) for transfusion, were found not to be associated with an increased risk of developing posterior subcapsular cataracts (PSCs). Per study design, 89 pairs of donors—pairs consisted of PMN donors who received corticosteroids and donated 5 to 39 times (mean, 13 donations) matched with a control group of apheresis platelet (PLT) donors who had not received corticosteroids—were examined for PSCs by digital retroillumination infrared photography of both lenses. Photographs were graded by experts who were masked as to donor identity (i.e., PMN or PLT donations). A subset of donors—33 donating PMNs and 30 donating PLTs—were randomly selected at each study site for examination by ophthalmologists, who were masked as to donor identity. The primary outcome was the presence of PSC in at least one lens of an individual donor. A great deal of care was taken to ensure comparability of the PMN and PLT donors enrolled, with the exception of corticosteroid use during PMN donation, and to make detection of PSC as accurate and precise as possible.1 Six of 89 PMN donors (6.7%) and 4 of 89 PLT donors (4.5%) had photographic evidence of PSCs (p = 0.48); 5 of 33 PMN donors (15%) and 3 of 30 PLT donors (10%) had PSCs detected by ophthalmologists (p = 0.54). Two subjects had bilateral eye involvement; both were PMN donors. In all subjects with PSCs, involvement was minimal (i.e., <10 percent of the lens). In PMN donors with PSCs, neither the cumulative dose of corticosteroids taken nor the length of time since the first corticosteroid-stimulated PMN donation were significantly associated with PSCs. Based on study results, Burch and coworkers concluded that corticosteroids given for PMN donation were not a risk factor for developing PSCs and, offering the caveat that their study was not large enough to definitively exclude any possibility of PSC risk with corticosteroid donor stimulation, recommended that no changes be made in the current practice of giving corticosteroids to PMN donors.1 The conclusion and recommendation seem reasonable per their findings and, perhaps in time, will be proven correct by additional studies—but a dilemma arises for those currently collecting apheresis PMN for transfusion when the findings of Burch and colleagues1 are examined in light of an earlier report from Iowa.2 In a small, but well-designed study from Iowa,2 11 donors who received corticosteroids for 17 to 46 PMN donations (mean, 26) were examined by an ophthalmologist using a slit lamp and indirect ophthalmoscopy, and they were compared with a control group of nine apheresis PLT donors—all of whom had donated 15 times and had never donated PMNs with corticosteroid stimulation. The ophthalmologist was masked to donor identity (i.e., PMN or PLT donations). Four of 11 PMN donors (36%) and 0 of 9 PLT donors had PSCs (p = 0.068). Five of 22 PMN donor eyes versus 0 of 18 PLT donor eyes exhibited PSCs (p = 0.040). PSCs were small, and vision was not affected. Cortical and nuclear cataracts were found at similar frequencies in both PMN and PLT donors to suggest that lifestyle factors that might predispose to cataracts, independent of corticosteroid therapy, were comparable. The study was prompted by a long-time PMN donor, who was not part of the study, who reported that he required surgery for PSCs. Because PSCs were found exclusively in PMN donors, all of whom received multiple doses of corticosteroids, and were clinically “silent” (i.e., detected only by formal ophthalmologic examination), the authors urged that additional studies be performed to either confirm or refute their findings.1 Because PMN donors could be developing PSCs without visual complaints, the authors recommended use of granulocyte–colony-stimulating factor (G-CSF) alone to stimulate donors for PMN collection until either the safety of corticosteroid stimulation could be confirmed or the risks be clearly defined. Unfortunately, neither have the findings of the Iowa report been convincingly refuted nor has the safety of corticosteroid stimulation for PMN donation been clearly established by the study of Burch and colleagues.1 Although significant differences were NOT found between matched PMN and PLT donors, worrisome trends “favor” the possible risk for PSCs in PMN donors given corticosteroids.1 A higher percentage of PMN donors versus PLT donors exhibited PSCs both by retroillumination infrared photography and by ophthalmologic examination. Only PMN donors had bilateral involvement. Obviously, the number of PMN donors with PSC in both reports is rather small,1, 2 and a cause-and-effect mechanism for corticosteroids leading to PSCs has not been established in the setting of donor corticosteroid stimulation before PMN donation. Additionally, information is lacking to relate corticosteroid dose, the number of PMN donations with corticosteroid stimulation, or the length of time between the first exposure to corticosteroids to the development of PSCs. Thus, there is no apparent way to avoid the potential risk of PSCs or to accurately advise PMN donors during the informed consent process—should a genuine risk actually exist. If corticosteroids pose a possible risk for development of PSCs, why not follow the Iowa recommendation and use only G-CSF to stimulate donors before PMN collection?2 The problem created by dropping corticosteroids from the combined use of corticosteroid plus G-CSF PMN donor stimulation is reduction of PMN yield by about 25 percent from a mean of 6 × 1010 to 8 × 1010 per collection to 4 × 1010 to 5 × 1010.3, 4 This decrease in PMN dose per transfusion may diminish the efficacy of PMN transfusion therapy for infections in neutropenic patients.4 For decades, it has been presumed that transfusing higher doses of PMNs would improve the antimicrobial effectiveness of PMN transfusions—particularly for severe fungal infections—but randomized clinical trials, in which PMNs from donors stimulated with combined corticosteroid plus G-CSF were transfused, have not been reported. Moreover, case reports and observational studies lacking randomized concurrent control subjects have given mixed results—sometimes with failure of PMN transfusions in severe fungal infections—despite transfusion of high doses of PMNs.4 Thus, it is extremely important to transfuse the highest number of PMNs possible, if and when properly designed clinical trials are performed to investigate the efficacy of PMN transfusions. How best to advise PMN donors of the possible risk, if any actually exists, during the informed consent process is the dilemma discussed in the following section. The decision whether to disclose the possible association of adrenal corticosteroid use with the development of PSCs to PMN donors who will receive corticosteroids presents a difficult dilemma for facilities following such a protocol. The dilemma is a textbook example of a significant ethical tension inherent in all blood donation . . . ensuring an adequate supply of blood and components for patients in need, while protecting the safety of the donors. Although the report of the Iowa study recommended the use of G-CSF alone to induce neutrophilia in PMN donors,2 the possibility that this course of action could gravely diminish the efficacy of PMN therapy for patients in need does not, perhaps, strike the appropriate balance between risk and benefit. The continued use of adrenal corticosteroids to stimulate PMN donors, however, leads to the question of disclosure of the possibility of this adverse reaction in the informed consent process. Legal, as well as ethical, considerations underpin the requirement to disclose risks to mainstream donors, as well as those who participate in research protocols. Laws and regulations for the protection of both regular donors and human research subjects require that these individuals be provided, among other information, a description of any reasonably foreseeable harms or risks, other than minimal risks, associated with the donation process. In the research setting, a human research subject must also be provided a description of the benefits to the research participant.5 Given the results of the recent study by Burch and coworkers, a decision not to inform PMN donors stimulated with corticosteroids of the possible risk of PSCs is legally defensible. No study has demonstrated that the risk of developing PSCs was increased in a significant way through the administration of corticosteroids.1, 2 In the Iowa study subjects, the lens involvement was less than 10 percent, and in the PMN donors with PSCs, there was no demonstrated association of PSCs with cumulative dose or duration of the steroid therapy.2 Further, the existing information available for disclosure may not be particularly helpful to an individual making a decision whether to take adrenal corticosteroids to become a PMN donor. Without a statistical association between adrenal corticosteroid use and the development of PSCs, a donor is left with information about a worrisome, but not significant, trend in the development of PSCs in some donors who received adrenal corticosteroids, but no definitive relationship between the development of PSCs and the dose or duration of steroid use. Still, there are aspects of these two studies and the specific context of this ethical dilemma that are concerning and that could lead a facility to a different decision. Ethical decision making involves the balancing of four fundamental principles, respect for autonomy (the right of an individual to make choices about his or her personal matters), beneficence (the principle of doing good), nonmaleficence (the principle of doing no harm), and justice (the principle of fairness and equality).6 Although all of these principles are at play in the decision whether to stimulate donors with corticosteroids, the ethical obligation to inform the donors about a possible risk is based on the principle of respect for that individual's autonomy. At the heart of individual autonomy is the donor's right to balance the risks and benefits of participation. Although the risk of this particular adverse reaction may seem minimal, remote, or unproven, balancing the risk against the benefit on behalf of a donor participant is not an easy task, particularly in situations where the only benefit may be a sense of well-being about helping others. The ethical question in this setting is who makes the determination? Burch and associates report that any decision regarding disclosure of risk must take into account the donor's perspective. In this case, given the relative risks and benefits, the principle of autonomy dictates not only that the donor's perspective be taken into account, but also that the donor, rather than a facility, should make this balance. Neither dose nor duration of therapy appears to be associated with the development of PSCs. There are data, not relating to PMN donors, however, which support some relationship between corticosteroid use and the development of PSCs7 and that PSCs may resolve spontaneously after drug withdrawal.8 Certainly the presumption of safety of corticosteroid therapy for donors is reinforced by the lack of reports of adverse steroid effects in PMN donors, but the silent nature of the risk and the fact that it may not be detected except by ophthalmologic examination suggest that this is a problem that may not be found without an affirmative action by the donor, specifically, ophthalmologic examination. Without knowledge about the potential for this risk, many donors would not receive such an examination. Moreover, the demonstrated efficacy of corticosteroid stimulation and the growing efficacy of PMN therapy mean that the use of this procedure, and with it more donor exposure to adrenal corticosteroids, will only increase, underscoring the importance of a careful approach to the disclosure question. Burch and coworkers concluded that further studies would be necessary to confirm their conclusions that the use of corticosteroids in PMN donors is unlikely to increase the risk of developing clinically significant PSCs over the lifetime of a donor. The question for every facility following this protocol is whether the lack of a conclusive study excluding any PSC risk associated with this use of corticosteroids mandates the disclosure of less or more information. As those responsible for protecting the well-being of donors in both operational and research settings, perhaps the best course of action and the one that best serves the principle of autonomy is disclosure about the possible relationship between corticosteroids therapy and PSCs and the study conclusions. While not an easy message to formulate, information about the underlying association of corticosteroid use and PSCs, the results of the two studies specific to adrenal corticosteroid-stimulated donors, and the role of ophthalmologic examination in eye care are excellent starting points.