The required use of immunosuppressive regimens after organ transplantation is recognized as increasing the risk that the recipient will acquire an opportunistic infection. Before routine prophylaxis, Pneumcystis jirovecii pneumonia (PJP) was common (5%–15%) in transplant recipients. Prophylactic regimens after organ transplantation have become routine for recipients to reduce the risk, not only for Pneumocystis jirovecii but also for other common pathogens such as cytomegalovirus (CMV), hepatitis B and C, mycobacterium, Nocardia, toxoplasmosis, and others, depending upon prevalence and perceived risk. While prophylaxis against a variety of pathogens is routine immediately after the induction immunosuppression phase of transplant care, it is common to discontinue these regimens when the risk is lower. Most centers adhere to the American Society of Transplantation Infectious Diseases (AST ID) Community of Practice (COP) recommendations for PJP prophylaxis: it is given to all organ transplant recipients for 6–12 months (when the incidence of PJP is at least 3%–5%), and prolonged courses should be administered to lung and small bowel recipients with higher levels of immunosuppression and individuals with prior PJP infection or chronic CMV.1 The ID COP also made the recommendation in their article that clarity of high-risk periods for reinstitution of prophylaxis needed to be made. The meta-analysis by Permpalung et al2 is a response to that need. Their meta-analyses demonstrated that PJP risk increased during periods when cellular immunity was significantly disrupted, conditions such as antibody treatment for rejection (polyclonal or rituximab), BK and CMV-associated disease (rather than asymptomatic viremia), host characteristics associated with significant lymphopenia, and perhaps an HLA mismatch of >3 (although the authors queried whether this could be epiphenomena associated with increased need for alloimmunosuppression). Under these conditions, the authors recommended reinstitution of PJP prophylaxis be considered.
This is sound advice. However, good clinical decision making requires that an intervention weigh the degree of increased risk, the effectiveness and duration of the proposed therapy, and adverse events associated with the intervention. The benefit to the individual recipient needs to outweigh the risk. The AST ID COP recommended that PJP prophylaxis be given when the risk of disease was higher than 3%–5%. This may or may not be the “correct” threshold, but the risk of infectious complications is not uniform after transplantation. What clinical trigger determines when the risk of disease acquisition is sufficient to reinstitute a prophylactic treatment? An increased hazard ratio (HR) for an uncommon event associated with a specific finding may not be sufficient to warrant initiation of treatment. How long after a specific identified event (antilymphocyte therapy) does the increased risk (HR) last? The literature used for this meta-analysis does not address many of the clinically relevant events that lead recommendation for the use of PJP prophylaxis.
Current understanding of the risk for opportunistic infections has been greatly influenced through the lens of the HIV experience. The lower the CD4 number,3 the greater the risk and the more diverse the types of opportunistic pathogens. From the transplant meta-analysis, it was noted that CD4 numbers are infrequently used in the transplant literature to assess risk, requiring usage of clinical and laboratory surrogates. However, the direct comparison of transplant and HIV patients may also need further discrimination, as the immunosuppressed transplant recipient becomes immunosuppressed via a fundamentally different pathway from the HIV patient. Polyclonal antilymphocyte antibodies will reduce CD4 numbers and other circulating populations, but transiently. Anti-CD20 for B-cell lineage is administered in the context of other disease states (ie, post transplant lymphoproliferative disease, chronic antibody rejection, or Epstein-Barr virus infection) that have many points of impact upon the immune system. While not specifically mentioned in this analysis, one should also assume that alemtuzumab (anti-CD52) administration would induce a higher risk. The lymphopenia/immunosuppression associated with chronic DNA viral diseases (CMV and BKV) or other pharmacological immunosuppressive interventions used in transplantation are not necessarily the same as those associated with chronic HIV (RNA) infection.
So what does this meta-analysis tell the transplant community? Importantly, PJP remains an opportunistic infection that persists in transplant patients and requires a strategy that addresses the impact. However, from here on, it becomes murky. It may or may not be warranted to start preventive therapies for disease acquisition when the conditions described in this article are recognized. The risk of disease acquisition is given in HRs and not absolute risk. If the risk increases from 0.1% to 0.3% (HR, 3.0), does that warrant reinitiation of prophylaxis when the guidance from the AST ID COP was to consider prophylaxis when the absolute risk of disease development was >3%? The transplant clinician must factor the duration and magnitude of clinical risk, adverse events, and inconvenience of any proposed therapy. The primary recommended treatment for PJP prevention is trimethoprim-sulfa, a cheap and effective regimen that reduces the clinical frequency of the disease to <1%. In most instances, this is easy and cheap to administer, making the risk/benefit calculation easy in favor of the administration. However, when trimethoprim-sulfa is not an option, one needs to assess the “absolute” risk of PJP disease with the efficiency of the prophylactic therapy, side effects, and the associated costs of the alternative regimens. Alternative agents, such as pentamidine and atovaquone, can be very expensive or complicated to administer. Dapsone may elicit allergic reactions in patients who are sulfa allergic. To discern when to administer PJP prophylaxis and for what duration, it is necessary to address the magnitude of the risk and whether prophylaxis is effective enough to outweigh the side effects, adherence, and cost. This analysis does not provide guidance on when one should stop prophylaxis after restarting. For example, the impact of antilymphocyte therapy upon circulating cells can be short or protracted. Is risk modified by duration of lymphopenia? There may be a place for routine measurement of CD4 cells and not just lymphocyte numbers. There is a need to consolidate knowledge from the HIV literature with the transplant and cancer literature. Additionally, a relevant question is the assessment of overall pharmacological immunosuppression and nutritional state associated with chronic viral infections. At present, few specific measures can predict sufficient alloimmunosuppression for graft function while preserving capacity for antiviral/fungal immunologic containment. With an aging and increasingly frail population of transplant candidates for all organs, the problem of opportunistic infections within the context of alloimmunity attenuation is going to continue to exist. The changing immune environment provoked within the organ transplant recipient suggests that there is still be much work to do.
1. Fishman JA, Gans H; AST Infectious Diseases Community of Practice. Pneumocystis jiroveci in solid organ transplantation: guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33:e13587.
2. Permpalung N, Kittipibul V, Mekraksakit P, et al. A comprehensive evaluation of risk factors for Pneumocystis jirovecii pneumonia in adult solid organ transplant recipients: a systematic review and meta-analysis. Transplantation. [Epub ahead of print. December 14, 2020]. doi: 10.1097/TP.0000000000003576
3. Summers NA, Armstrong WS. Management of advanced HIV disease. Infect Dis Clin North Am. 2019;33:743–767.