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Abstract: Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) is a rare but serious infection that usually occurs within a year after solid organ ...

© 2012 John Wiley & Sons A/S Transplant Infectious Disease, ISSN 1398-2273

Case report

Pneumocystis jirovecii pneumonia 13 years post renal transplant following a recurrent cytomegalovirus infection A.H. Muhammad Iqbal, S.K. Lim, K.P. Ng, L.P. Tan, Y.B. Chong, T.C. Keng. Pneumocystis jirovecii pneumonia 13 years post renal transplant following a recurrent cytomegalovirus infection. Transpl Infect Dis 2012. All rights reserved Abstract: Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) is a rare but serious infection that usually occurs within a year after solid organ transplantation. PCP may occur after 1 year post transplantation, but the rate is reported to be very low. Studies have shown an association between cytomegalovirus (CMV) infection in solid organ transplant patients and an increased risk of opportunistic infection. This increased risk is thought to be a result of the immunomodulatory effects of the CMV infection. We present a case of PCP infection occurring 13 years after a renal transplantation. This occurred following a recurrent CMV infection while the patient was on lowdose immunosuppressants.

A.H. Muhammad Iqbal1, S.K. Lim2, K.P. Ng2, L.P. Tan2, Y.B. Chong2, T.C. Keng2 1

Department of Medicine, Universiti Teknologi MARA (UiTM), Selangor, Malaysia, 2Department of Nephrology, University Malaya Medical Centre, Kuala Lumpur, Malaysia Key words: Pneumocystis carinii; Pneumocystis jirovecii; cytomegalovirus; renal transplantation; immunomodulatory Correspondence to: Dr Muhammad Iqbal Abdul Hafidz, Department of Nephrology, University Malaya Medical Centre, Lembah Pantai, 59100 Kuala Lumpur, Malaysia Tel: 603-79494422 Fax: 603-79562253 E-mail: [email protected]

Received 6 June 2011, revised 9 October 2011, 24 December 2011, accepted for publication 21 January 2012 DOI: 10.1111/j.1399-3062.2012.00738.x Transpl Infect Dis 2012: 0: 1–4

Pneumocystis jirovecii (formerly Pneumocystis carinii) pneumonia (PCP) is a rare but serious infection that usually occurs within a year after solid organ transplantation. Trimethoprim-sulfamethoxazole (TMP-SMX) is given prophylactically for 6 months to a year post transplant to reduce the rate of this infection. PCP may occur after 1 year post transplantation, but the rate is reported to be very low (1). Cytomegalovirus (CMV) is both a common and important cause of infection in a transplant recipient. Studies have shown an association between CMV infection in solid organ transplant patients and an increased risk of opportunistic infection. This increased risk is thought to be a result of the immunomodulatory effects of the CMV infection (2). We present a case of PCP infection occurring 13 years after a renal transplantation, which occurred after a recurrent CMV infection while the patient was on low-dose immunosuppressants.

Case report The patient was a 38-year-old Chinese woman, who developed end-stage renal failure secondary to immunoglobulin (Ig)A nephropathy. She underwent a living-related renal transplant at our center in 1997. The donor was her sister, and both were positive serologically for CMV IgG, but prophylactic CMV therapy was not given, based on the unit protocol at the time. The transplant was successful and she had immediate graft function and no acute rejection. Her immunosuppression consisted of prednisolone, azathioprine, and cyclosporine. The azathioprine was later changed to mycophenolate mofetil (MMF) in 2003, when it was made available at our center, but later changed to the enteric-coated mycophenolate sodium (EC-MPS), as she developed nausea and stomach discomfort from it. She had an allograft biopsy 2 years after her transplant for worsening renal function, but

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this did not reveal any acute rejection. She remained well, with her creatinine ranging from 1.5 to 1.6 mg/dL. She was kept on maintenance immunosuppression consisting of prednisolone 5 mg daily, cyclosporine 50 mg twice daily, and EC-MPS 540 mg twice daily. Her problems started in late 2008, when she developed persistent watery diarrhea for 1 month. She had no fever, but the diarrhea was associated with a loss of appetite and weight loss. A colonoscopy was performed, which showed colitis from the rectum to the splenic flexure. The colonic biopsy was reported as an acute-on-chronic infective colitis. No granulomatous changes were seen to suggest tuberculosis, and a hematoxylin and eosin stain did not reveal any inclusion bodies (anti-CMV immunohistochemical stain was not performed). Her plasma CMV polymerase chain reaction (PCR), however, revealed 98,697 copies of DNA/mL (COBAS Amplicor CMV Monitor Roche Diagnostics, NSW, Australia) and therefore she was treated for CMV colitis. The decision was made to use intravenous ganciclovir, because of the prohibitive cost of valgancyclovir. The dose was adjusted for her renal impairment and was given for a total duration of 6 months. At the same time, her EC-MPS was reduced to 360 mg twice daily. She responded well, as her symptoms resolved and by the end of her treatment, her CMV PCR had dropped to < 600 copies DNA/mL. In March 2010, 6 months after completing her CMV treatment, a surveillance CMV PCR detected 4625 copies of DNA/mL, but she remained asymptomatic for CMV disease. She was therefore recommenced on intravenous ganciclovir. Her CMV PCR continued to be positive despite being on treatment and therefore a decision to withhold her EC-MPS was made. However, in the third month of therapy she developed intermittent fever for 1 week that was associated with lethargy and exertional dyspnea. Physical examination revealed a low-grade fever and hypoxia at rest. The rest of her examination did not reveal anything significant. A chest x-ray was performed that showed bilateral perihilar infiltrates (Fig. 1), and an arterial blood gas showed an arterial oxygen pressure of 74 mmHg. An immunofluorescence staining for Pneumocystis jirovecii oocysts using the Detect IF Pneumocystis (Axis-Shield Diagnostics Limited, Dundee, UK) was found to be positive in her bronchoalveolar lavage. Given the high prevalence of pulmonary TB in our population, an acid-fast bacilli smear and TB culture of the bronchoalveolar lavage fluid were also performed, but they were negative. She was therefore diagnosed as having PCP and was treated with highdose TMP-SMX for 2 weeks without any steroids. The

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Fig. 1. The patient’s initial chest x-ray.

patient made a good recovery with resolution of her chest x-ray changes (Fig. 2). With regard to the CMV infection, the PCR became < 600 copies DNA/mL again, and she is currently being monitored for recurrent CMV infection. She was advised to continue a prophylactic dose of TMP-SMX life-long and her EC-MPS continues to be withheld. Her graft function remained stable after the episode of infection.

Discussion PCP is a serious complication of immunosuppressive therapy in solid organ transplant recipients. It is associated with serious morbidity and mortality to the recipient, and occurs in the first 6–12 months after transplantation

Fig. 2. The patient’s chest x-ray after treatment with trimethoprimsulfamethoxazole.

Muhammad Iqbal et al: Late-onset PCP after CMV

with the incidence reported from 0.6% to 14% (3). Transplant recipients are put on prophylactic TMP-SMX post transplantation, which has been shown to dramatically reduce the rate of PCP infection (4). The risk factors of PCP are related to the degree of immunosuppressive therapy received. Prolonged use of corticosteroid, antilymphocyte therapy, tacrolimus, sirolimus, calcineurin inhibitors, or rituximab has been associated with PCP (5, 6). MMF, on the other hand, has been shown to have an anti-Pneumocystis effects in rats (7). This effect is thought to be a result of the inhibition of the inosine monophosphate dehydrogenase enzyme by MMF, which is able to suppress the growth of Pneumocystis. This finding is also supported by the first few studies comparing the use of MMF as a new immunosuppressant in renal transplant patients. Sollinger (8) showed that, after a 6-month follow-up, no PCP cases occurred in patients on MMF, as compared with 1.2% in patients on azathioprine. A similar study by the Tricontinental MMF Renal Transplant Study Group (9) noted that, after 6 months, the rate of PCP infection in the azathioprine group was higher (1.9%), as compared with the 2 g and 3 g daily MMF groups (< 1% and 0, respectively). In one retrospective study, Azedevedo et al. (10) observed that after 6 months post transplantation, both groups of patients who were on MMF, without any TMP-SMX, and those receiving azathioprine with TMP-SMX, did not develop PCP, thus concluding that patients on MMF may not need PCP prophylaxis. The most recent description of this phenomenon was in a case report by Totet et al. (11), who reported a case of PCP infection acquired within 6 months after discontinuation of MMF. The PCP infection in our patient was diagnosed 3 months after her EC-MPS was discontinued. Could this infection, perhaps, partially be related to withdrawal of mycophenolate? While technically an interesting possibility, this question remains unanswered based on the available data. Late presentation of PCP is rare, with occurrence usually related to the immunosuppression received for an acute rejection. Gordon et al. (1) found that, after the first year, only 1 of 534 renal transplant patients on PCP prophylaxis developed the infection. After a 4-year follow-up of 32,757 renal transplant recipients of the United States Renal Data System (USRDS), there were 142 individual cases of PCP with a cumulative incidence of 0.4%, or 176 cases per 100,000 person years at risk and for the study period. The latest onset of PCP was reported to be at approximately 2 years (median time to development of PCP was 0.80 ± 0.95 years after transplantation) (12). Two cases of PCP occurring nearly 3 years after transplan-

tation were reported, after the administration of rituximab for refractory antibody-mediated rejection (13). Another case reported the onset of PCP 5 years after a renal transplant (14). This patient was on sirolimus and also had a course of monoclonal anti-CD3 antibody for an episode of acute rejection. Late onset PCP 4 years after transplantation has also been reported in a patient whose immunosuppressants consisted of MMF and belatacept, a costimulation blocker (15). This patient interestingly developed CMV disease of the gastrointestinal tract about 6 weeks prior to the PCP infection, after which both the immunosuppressives were then discontinued. Our patient developed PCP while on treatment for a recurrent CMV disease and had already had her EC-MPS discontinued. Both these cases are supportive of studies showing that CMV infection post transplant may have immunomodulating effects on the recipient leading to superinfection with other opportunistic pathogens. CMV is a latent herpesvirus that rarely causes disease in the immunocompetent, but frequently reactivates in a compromised host. It is the most common viral pathogen in any solid organ transplant recipients. In addition to the direct impact of the virus, CMV has indirect effects, which include allograft rejection, decreased graft and patient survival, malignancies, vasculopathy, and post-transplant diabetes (16). The virus also encodes many proteins that can alter the immune environment of the host by modulating molecules involved in immune recognition and inflammation. As a result, CMV is associated with a general non-specific immunosuppressive syndrome, which can lead to higher risk of opportunistic infections like PCP. CMV infection alters host immune responses by a variety of mechanisms, which include the suppression of helper T-cell functions and antigen-presenting cell functions, both of which are critical for PCP resolution (17). Qureshi et al. (18) compared mice that were dually co-infected with CMV and PCP to mice with PCP alone, and found that the dually co-infected mice had more severe PCP disease. The dual-infected mice were found to have a decrease in activated CD4+, CD11c+, and MHC II expressing cells in their lungs, which were important in mounting an immune response toward PCP. The association between post-transplant CMV infection and PCP has been supported by a few observational studies. A case-control study by Arend et al. (19) found that the risk of PCP after a CMV infection post transplant was 5-fold, irrespective of the number of rejection treatments received. The immunosuppressives used in this study were either azathioprine or

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cyclosporine, and no patients were on MMF. In a similar study, Radisic et al. (20) matched 17 PCP cases with 2 controls each, and found that the relative risk for PCP was the same if the patient had never had a CMV infection post transplant, but rose to 2.32 and 13.0 (P = 0.012) if they had 1 and  2 previous or concomitant CMV infection, respectively. A similar finding is seen in our patient, who developed PCP during her second episode of CMV infection. In the USRDS analysis, patients who were co-infected with CMV had a higher percentage of PCP compared with those without CMV (20.4% vs. 8.8% P < 0.001). However, they did not find any temporal relationship between CMV infection and PCP infection. It is interesting to note, however, that both the Radisic study and the USRDS analysis associated the use of MMF with an increased risk of developing PCP. This is, to our knowledge, the first report in the literature of a case of PCP occurring more than 13 years after renal transplantation. Our patient’s episode of PCP seemed to have a temporal relationship with the CMV infection. Because of reports suggesting that MMF might have anti-PCP activity, we are unable to comment on the role that discontinuation of MMF played in the development of PCP in our patient, but CMV is known to be immunosuppressive. Hence, we recommend that physicians have a high suspicion for PCP in renal transplant patients with previous or concurrent CMV infection presenting with fever, with or without respiratory symptoms.

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Conclusion CMV has indirect effects on renal transplant recipients, which include susceptibility to other opportunistic infections, such as PCP. The very late onset of PCP following a CMV infection seen in our patient is in agreement with previous reports in which CMV infection was found to increase the risk of PCP by itself. It may thus be justifiable to start PCP prophylaxis in these groups of patients, especially if the CMV disease is a recurrence.

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