A resurgence of Pneumocystis in aggressive lymphoma treated with R-CHOP-14: the price of a dose-dense regimen?

Pneumocystis is one of the more frequent infections seen in immune-compromised patients, and usually manifests as a disseminated and life-threatening pneumonia (PCP). Because of this, consideration of prophylaxis is important for these patients. Understanding more about the infectious agent, Pneumocystis, and the disease it causes, may add much in the successful treatment and more importantly in prevention of the infection in these patients [1].

Recently, a number of studies on the biology and immunology of the organism have been reported, and new concepts in relation to Pneumocystis are emerging [2,3]. First, it is now recognized that each mammalian host is infected by a specific organism, which does not infect another host. Furthermore, it is worth recalling that the infective organism, Pneumocystis carinii, which causes the infection in humans, has been renamed Pneumocystis jirovecii, after Otto Jirovec, who is credited with first describing the microbe in humans [4]. Second, new evidence suggests that PCP is not really a result of reactivation of a dormant infection occurring during immune suppression, as always believed, but rather a re-infection from an as yet unidentified human or environmental source [3]. The third, and most intriguing recent observation, relates to the fact that immunity to Pneumocystis is no longer regarded just as a single arm response, restricted only to CD4+ T-lymphocytes, but in fact consists of a dynamic interplay between every arm of the immune system, involving the innate immunity within the pulmonary environment, where alveolar macrophages play a central role, and the adaptive immune response, in which activated alveolar macrophages stimulate both cellular and antibody responses [3]. Consequently, a low CD4 count (<200 cells/mm³) is probably not the only criterion that should be used in deciding whether a particular patient is at risk for PCP and requires prophylaxis therapy.

It is indeed possible that Pneumocystis infection may once again be emerging out of the shadows, as in the 1980s when human immunodeficiency virus (HIV) infection became widespread, and PCP infections became common.

In this issue of Leukemia and Lymphoma, Kamel et al. report that among 47 patients with aggressive B-cell lymphoma treated with R-CHOP-14 (biweekly rituximab, cyclophosphamide, adriamycin, vincristine, prednisone), five (11% of patients) developed microbiologically proven PCP during therapy [5]. This phenomenon is notable, because in patients receiving other CHOP schedules (CHOP-21 or R-CHOP-21, given 3-weekly); the risk of PCP is negligible [6,7]. Others have also reported opportunistic infections using dose-intense R-CHOP-14 therapy [6] and variants, including R-CHOEP-14 (R-CHOP combination with etoposide) [7]. In most of these patients the number of CD4+ T-lymphocytes was above 200 cells/mm³, and immunoglobulin levels were within the normal range [5–7].

What is the most likely cause for the increased risk of PCP in patients receiving the R-CHOP-14 based regimens? As Kamel et al. suggest, it seems most likely that the reason for the increased risk for PCP is the increased intensity of corticosteroid exposure, as well as the cumulative dose of the drug [5]. On the other hand, other possibilities should be kept in mind. Might the B-cell depletion caused by rituximab play a role? The German non-Hodgkin lymphoma (NHL) study group compared CHOP-21 to CHOP-14 (and CHOEP-21 to CHOEP-14), without rituximab, and did not record an increased rate of PCP in the intensified protocols [8,9]. This observation, in retrospect, suggests that in NHL, rituximab may well be implicated or contribute to the development of interstitial pneumonitis and other respiratory tract infections [10] when given together with combination chemotherapy, or even as monotherapy [10]. This risk appears to be heightened when an intensive schedule of rituximab is employed, so prophylactic antibiotics have been suggested in that setting [11]. However, case reports have even described the association of the use of rituximab as a single agent and the development of PCP [12–14]. Taking this into consideration, it is hard to exclude the possibility that rituximab may contribute to the risk of PCP development, when used in the context of a steroid-dense R-CHOP-14 schedule. Notably, recent reports suggest that standard R-CHOP-21 is just as effective as R-CHOP-14, and perhaps less toxic [15].

In conclusion, we indeed appear to be dealing with a phenomenon that looks like a reappearance of a relatively small number of ‘reactivated’ cases of an already controlled infectious disease caused by Pneumocystis. Clinicians should take note, and consider prophylaxis in appropriate settings. In the future, the therapeutic options may also include a vaccine against Pneumocystis [3]. This development would bring with it the hope for better control of PCP, or even for eliminating Pneumocystis infection completely.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.