Absence of Pneumocystis jiroveci pneumonia in liver transplantation recipients receiving short‐term (3‐month) prophylaxis

Abstract: Pneumocystis jiroveci (formerly known as Pneumocystis carinii) is a fungal pathogen that causes pneumonia (PCP) in liver transplant recipients. Consequently, prophylaxis with trimethoprim–sulfamethoxazole (TMP/SMZ) is typically administered for at least 1 year at most liver transplant programs. At our center we have utilized a short‐term (3‐month) prophylactic regimen with TMP/SMZ for the past decade and report our experience and speculate on the potential widespread application of this approach. Methods. For patients transplanted at our center between January 1997 and January 2007, we recorded all documented PCP infections by review of our liver transplant database and hospital‐based electronic medical records system, both of which record all infections and culture results. Results. We recorded no cases of PCP in any of the liver transplant recipients at our center during the study period. Conclusions. We report the absence of PCP in a large cohort of liver transplant recipients receiving a short‐term (3‐month) prophylaxis with TMP/SMZ. These findings provide a rational basis to consider short‐term (3‐month) PCP prophylaxis or avoidance of prophylaxis altogether in selected low‐risk patients.     

Early onset Pneumocystis carinii pneumonia after allogeneic peripheral blood stem cell transplantation

Pneumocystis carinii (P. carinii) is one of the major opportunistic pathogens responsible for hematopoietic stem cell transplantation (HSCT)-related pneumonias. Although trimethoprim-sulfamethoxazol (TMP/SMX) prophylaxis has been shown to prevent almost all P. carinii infections, 1%-2% of patients may still experience this complication. P. carinii pneumonia (PCP) is usually a late complication in patients receiving TMP/SMX prophylaxis, with most cases occurring later than 2 months post-transplant. We report a patient who developed early onset PCP after allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical sibling donor. On day 12, the patient complained of dyspnea and cough. A chest X ray showed infiltrates in right upper lobe with bilateral pleural effusion. By the findings of Grocott stain on bronchoalveolar lavage fluid obtained on day 14, he was diagnosed as having PCP. Intravenous TMP/SMX failed to improve the lesion. This is the earliest onset PCP in the literature after HSCT despite the prophylactic administration of TMP/SMX before transplant.     

Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia after allogeneic marrow transplantation

Pneumocystis carinii pneumonia (PCP) poses a serious risk to allogeneic bone marrow transplant (BMT) patients, who are often intolerant of trimethoprim‐sulfamethoxazole (TMP‐SMX), the traditional first‐line prophylactic agents. There are limited published data supporting the use of aerosolized pentamidine (AP) prophylaxis in the BMT population. We assessed the effectiveness of AP in BMT recipients by reviewing the experience at our center. We divided our review into four time periods from January 1990 to March 2000, during which approximately 700 BMTs were performed. The first period includes patients receiving AP treatments from January 1990 to July 1997 (baseline), the second from August 1997 to July 1998 (pre‐outbreak), the third from August 1998 to October 1999 (outbreak), and the fourth from November 1999 to March 2000 (post‐outbreak). At our center, TMP‐SMX is the first‐line agent for PCP prophylaxis, which is routinely continued for at least one year, or for the duration of enhanced immunosuppression. During the baseline period, 505 BMTs were performed and 192 patients (38%) received AP for part of their time at risk. Six patients (3%) experienced toxicities requiring discontinuation of AP. Three cases of PCP were diagnosed over 1114 patient‐months of treatment in the baseline period. During the last 42 months of the baseline period, 2/154 patients receiving AP and 2 of an estimated 293 patients receiving exclusively oral prophylaxis developed breakthrough PCP (p = 0.61). During the outbreak period, 9 of 180 patients receiving AP developed PCP compared to none in the group receiving exclusively oral prophylaxis. Either changes in our AP protocol during the pre‐outbreak period or pentamidine resistance may have led to this failure of prophylaxis. There were no further cases during the 5‐month post‐outbreak period. Our observed overall breakthrough rate was 12 cases out of 439 patients (2.7%). Our study shows that AP is an effective and well‐tolerated second‐line agent in preventing PCP post BMT and we recommend its continued use in this regard. However, it should be administered using a well‐studied protocol, and only when TMP‐SMX is not tolerated.     

Pneumocystis jirovecii pneumonia in kidney transplantation

Pneumocystis jirovecii pneumonia (PCP) remains an important cause of morbidity and mortality in immunocompromised renal transplant recipients. In recent years, PCP outbreaks in renal transplant centers have been reported in many countries. Person‐to‐person transmission between PCP patients and other recipients lacking prophylaxis is one of the possible sources of infection. To prevent infection, effective prophylaxis in susceptible patients is recommended. Trimethoprim‐sulfamethoxazole (TMP‐SMX) is the most effective drug for PCP prophylaxis, but its recommended duration of use after transplantation varies among the different guidelines. The European Renal Association recommends a prophylaxis period of 4 months after transplantation, the American Society of Transplantation (AST) 6–12 months, and the Kidney Disease Improving Global Outcomes guidelines 3–6 months. Lifelong prophylaxis with TMP‐SMX is not recommended in renal transplant recipients; however, in many cases, PCP has occurred after the recommended prophylaxis periods after transplantation. In this minireview, we discuss the risk factors including environmental‐nosocomial exposure; state‐of‐the‐art diagnosis, treatment, prophylaxis and isolation; and references to the AST 2009 guidelines with the aim of integrating our experience with PCP outbreaks into recent reports, and we discuss how renal transplant recipients can be protected from PCP.     

A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxazole as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell transplantation.

Pneumonia due to Pneumocystis carinii is an infrequent complication following autologous stem cell transplantation (ASCT) which is associated with a high mortality. Although administration of trimethoprim/sulfa- methoxazole (TMP/SMX) is an effective prophylactic strategy for Pneumocystis carinii pneumonia (PCP), treatment-associated toxicity frequently results in discontinuation of therapy. We have conducted a prospective randomized trial comparing atovaquone, a new anti-Pneumocystis agent, with TMP/SMX for PCP prophylaxis following autologous peripheral blood stem cell (PBSC) transplantation. Thirty-nine patients were studied. Twenty patients received atovaquone suspension and 19 patients received TMP/SMX. The median ages were 44 (range 20-68) and 47 (range 32-63) years, respectively. A similar number of patients with solid tumors (14 vs 15) and hematologic malignancies (five vs five) were treated in each group. Either TMP/SMX (160/800 mg) or atovaquone (1500 mg) was administered daily from transplant day -5 until day -1, discontinued from day 0 to engraftment, then resumed 3 days per week until day +100 post-transplant. The median time to engraftment (ANC >0.5 x 109/l) was similar in both groups. Eighty percent of the patients randomized to atovaquone prophylaxis completed the study. Four atovaquone-treated patients were removed from study; two patients (10%) did not receive a transplant and two patients (10%) were removed due to a protocol violation. None of the 16 patients treated with atovaquone experienced treatment-associated adverse effects. Of the 19 patients randomized to receive TMP/SMX, 55% completed the study. Nine TMP/SMX-treated patients were removed from the study; one patient (5%) did not receive a transplant and eight patients (40%) were removed due to drug intolerance (P < 0.003). The rate of intolerance to TMP/SMX led to the early discontinuation of this randomized trial. Intolerance of TMP/SMX included elevated transaminase levels (n = 1), nausea or vomiting (n = 3), thrombocytopenia (n = 2) and neutropenia (n = 2). All episodes of TMP/SMP intolerance occurred following transplantation after a median duration of 17.5 (range 2-48) days and a median of 7 (range 1-20) doses. Resolution of adverse side-effects occurred in all eight patients within a median of 7 (range 2-20) days following discontinuation of therapy. Neither PCP nor bacterial infections were identified in any of the patients treated. This prospective randomized study demonstrated that atovaquone is well-tolerated for anti-Pneumocystis prophylaxis in autologous PBSC transplant patients intolerant of TMP/SMX.     

Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis

M.G.J. de Boer, F.P. Kroon, S. le Cessie, J.W. de Fijter, J.T. van Dissel. Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis.
Transpl Infect Dis 2011: 13: 559–569. All rights reserved Abstract: Risk stratification‐based duration of trimethoprim‐sulfamethoxazole (TMP‐SMX) chemoprophylaxis to prevent Pneumocystis pneumonia (PCP) in kidney transplant recipients is not a universally adapted strategy and supporting evidence‐based sources are limited. We performed a large retrospective study to identify risk factors for PCP in kidney transplant recipients and to define parameters for use in clinical prophylaxis guidelines. Fifty consecutive patients with confirmed PCP and 2 time‐matched controls per case were enrolled. All patients were participants of the kidney transplantation program of the Leiden University Medical Center, a tertiary care hospital in the Netherlands. Potential risk factors were compared between groups by uni‐ and multivariate matched analyses. At transplantation, age >55 years (adjusted odds ratio [OR] 2.7, 95% confidence interval [CI] 1.3–5.9) and not receiving basiliximab induction therapy (adjusted OR 4.3, 95% CI 1.1–17.1) predicted development of PCP. In the final multivariate analysis, only cytomegalovirus infection (adjusted OR 3.0, 95% CI 1.2–7.9) and rejection treatment (adjusted OR 5.8, 95% CI 1.9–18) were found to be independently associated with PCP. Using the variables identified by the multivariate analyses, effects of different hypothetical chemoprophylaxis strategies were systematically evaluated. Exploring different scenarios showed that chemoprophylaxis in the first 6 months for all renal transplant patients – and during the first year posttransplantation for patients >55 years of age or those treated for rejection – would result in very low PCP incidence and optimal avoidance of TMP‐SMX toxicity. The results provide a rationale for further prospective study on targeted provision of chemoprophylaxis to prevent PCP in kidney transplant patients.     

Switch to atovaquone and subsequent re‐challenge with trimethoprim‐sulfamethoxazole for Pneumocystis prophylaxis in a kidney transplant population

Kidney transplant recipients who are switched to atovaquone (ATO) from trimethoprim‐sulfamethoxazole (TMP/SMX) for Pneumocystis jirovecii pneumonia (PJP) prophylaxis because of adverse events or complications may miss opportunities to be re‐challenged with TMP/SMX, the first‐line agent. This single‐site, retrospective study assessed kidney transplant recipients for documented reasons for switching from TMP/SMX to alternate PJP prophylaxis and outcomes of TMP/SMX re‐challenge. Out of 166 patients, 155 initially received TMP/SMX; of these, 31 were switched to ATO for various reasons. Fourteen patients receiving ATO were re‐challenged with TMP/SMX; all were successfully re‐initiated on TMP/SMX therapy. Most patients switched to ATO post kidney transplant secondary to non‐hypersensitivity reasons should be re‐challenged with TMP/SMX because of the advantages it provides over other agents.     

Comparison of trimethoprim–sulfamethoxazole and aerosolized pentamidine for primary prophylaxis of Pneumocystis jiroveci pneumonia in immunocompromised patients with connective tissue disease

To evaluate the efficacy of primary prophylaxis for Pneumocystis jiroveci pneumonia (PCP) in patients with connective tissue disease (CTD) and immunosuppression, we compared trimethoprim–sulfamethoxazole (TMP-SMZ) with aerosolized pentamidine. Forty-eight CTD patients of Kitasato University Hospital whose CD4+ lymphocyte count in the peripheral blood was less than 300 μl⁻¹ were reviewed from 2002 to 2004. Twenty-seven patients received TMP–SMZ and none of them developed PCP. Among 18 patients receiving aerosolized pentamidine, three patients developed PCP. These data indicate that TMP–SMZ is better for prophylaxis than aerosolized pentamidine.     

肾移植后患者肺孢子菌肺炎的临床特点分析

目的:探讨肾移植后肺孢子菌肺炎(PCP)的临床特点、诊断及治疗方法。方法:本组7例肾移植后患者PCP均经病原学确诊,具有完整的病例资料,并结合国内外相关报道进行文献复习。结果:7例患者中男性5例,女性2例,年龄28～57岁,平均45岁;临床主要表现为发热、干咳、呼吸困难,而肺部体征较少,其特点为"症征不符";动脉血气表现均为低氧血症,严重者为Ⅰ型呼吸衰竭;静脉血乳酸脱氢酶(LDH)和(1,3)-β-D-葡聚糖(G试验)水平均明显升高;胸部高分辨CT(HRCT)表现为双肺弥散性磨玻璃影(GGO)伴或不伴斑片实变影;5例患者行支气管肺泡灌洗液(BALF)六胺银染色可发现肺孢子菌包囊,另外2例在痰中发现肺孢子菌包囊;痰液及BALF肺孢子菌PCR检测均为阳性。经免疫抑制剂减量、磺胺甲恶唑/甲氧苄啶(SMZ/TMP)治疗、机械通气及支持对症后,5例治愈,1例自愈,1例死亡。结论:肾移植后患者PCP具有较为明显的临床特点,血浆LDH和(1,3)-β-D-葡聚糖等检测有助于早期诊断,痰液或BALF六胺银染色是主要的确诊方法;早期免疫抑制剂减量和SMZ/TMP治疗后患者的预后相对较好。     

Late‐onset Pneumocystis jirovecii pneumonia in solid organ transplant recipients

Anti‐Pneumocystis prophylaxis is recommended for at least 6–12 months after solid organ transplantation, as most cases of Pneumocystis jirovecii pneumonia (PCP) occur during the first year post transplantation. Herein, we report 4 cases of late‐onset PCP (>1 year post transplant). PCP appeared in a range of 50–68 months post transplant. Two cases had history of humoral rejection episodes treated with rituximab, and the other 2 had low CD4+ T‐cell count (<200 cells/mm³) at the time of diagnosis. All 4 patients survived. In conclusion, although the number of cases is low, we must be aware of the possibility of late‐onset PCP in solid organ transplant patients. The role of previous use of rituximab or persistent CD4+ T‐cell lymphopenia should be addressed in future studies.     

Pneumocystis jirovecii pneumonia 13 years post renal transplant following a recurrent cytomegalovirus infection

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 low‐dose immunosuppressants.     

Usefulness of beta-<Emphasis Type="SmallCaps">d</Emphasis> glucan in diagnosing <Emphasis Type="Italic">Pneumocystis carinii</Emphasis> pneumonia and monitoring its treatment in a living-donor liver-transplant recipient

Pneumocystis carinii pneumonia (PCP) is one of the fatal complications encountered after liver transplantation. The diagnosis of PCP is sometimes very difficult, because detection of the bacteria itself is not easy under some conditions, and the serum level of the chemical mediator is not yet considered to be a definitive diagnostic marker. We report a case of PCP that occurred 3 months after transplantation in a living‐donor liver‐transplant recipient; the disease developed during the course of outpatient follow‐up when the patient's condition was stable. The patient was maintained with the usual level of immunosuppressants, using tacrolimus, steroid, and mycophenolate mofetil. The patient had a dry cough with mild fever, and a chest computed tomography (CT) scan showed a reticular shadow in the left lung field. The plasma level of beta‐d glucan was high (135 pg/ml). We suspected an invasive fungal infection, but no pathogen was detected by routine fungal culture and cytology. Finally,P. carinii was detected by polymerase chain reaction (PCR), and we started treatment with trimethoprim‐sulfamethoxazole (TMP/SMX) combined with an antifungal agent. During this period, the level of beta‐d glucan correlated with the patient's clinical symptoms; this marker was very useful for monitoring the treatment of PCP in this living‐donor liver‐transplant recipient.     

Pneumocystis jirovecii pneumonia is rare in renal transplant recipients receiving only one month of prophylaxis

Prophylaxis against Pneumocystis jirovecii pneumonia (PCP) is recommended for at least 4–12 months after solid organ transplant. In our center, renal transplant recipients receive only 1 month of post‐transplant trimethoprim–sulfamethoxazole, which also may provide limited protection against Nocardia. We identified only 4 PCP cases and 4 Nocardia cases in 1352 patients receiving renal and renal‐pancreas transplant from 2003 to 2009 at the University of Michigan Health System. Two PCP cases were identified <1 year after transplant, and 2 PCP cases were identified >1 year after transplant (gross attack rate 4/1352, 0.3%). Two Nocardia cases were identified <1 year after transplant, and 2 cases were identified >1 year after transplant. All identified cases received induction therapy (7 of 8 with anti‐thymocyte globulin), whereas about one‐half of all renal transplant patients received induction therapy at our institution. No patient was treated for rejection within 6 months of PCP; 2 of 4 patients with PCP had recent cytomegalovirus infection. All patients with PCP and 3 of 4 patients with Nocardia survived. The benefits of prolonged PCP prophylaxis should be weighed against the adverse events associated with prolonged use of antimicrobials.     

A dose-escalation regimen of trimethoprim–sulfamethoxazole is tolerable for prophylaxis against Pneumocystis jiroveci pneumonia in rheumatic diseases

Abstract

Objective To investigate the safety and efficacy of a dose-escalation regimen of trimethoprim–sulfamethoxazole (TMP/SMX) for prophylaxis against Pneumocystis jiroveci pneumonia (PCP) in rheumatic diseases.

Methods Data from 41 patients, who received glucocorticoids with or without immunosuppressive agents and prophylactic use of TMP/SMX, were retrospectively analyzed. Thirteen patients were started on a daily dose of 10 % of single-strength (SS) TMP/SMX, which was increased gradually (dose-escalation group), while 28 patients were started on 1 SS tablet daily (routine group).

Results In the dose-escalation group, the retention rate was 100 % at 6 months. In the routine group, 5 patients discontinued TMP/SMX; the retention rate was 82.1 %. Moreover, the retention rate when taking a daily dose of 50 % or more of SS TMP/SMX, or 1 SS tablet thrice-weekly, was significantly higher in the dose-escalation group (100 versus 71.4 %, P = 0.032). No PCP was observed in the dose-escalation group; however, 1 patient in the routine group, who had discontinued TMP/SMX, developed PCP. The rate of adverse effects was less, although nonsignificant, in the dose-escalation group (30.8 versus 46.4 %, P = 0.344).

Conclusions In rheumatic diseases, a dose-escalation regimen of TMP/SMX resulted in a higher retention rate and was safer than the routine regimen.     

Bronchiolitis obliterans organizing pneumonia associated with Pneumocystis jiroveci infection in orthotopic liver transplantation

Abstract: We report a patient who presented 6 months after orthotopic liver transplantation (OLT) with fever, dyspnea, and pulmonary infiltrates with biopsy‐confirmed Pneumocystis jiroveci infection associated with a process of bronchiolitis obliterans organizing pneumonia (BOOP). We present this second case of BOOP associated with P. carinii pneumonia after OLT to highlight the risk of such disease combination in all transplant patients as well as discuss the protective effect of post‐transplant prednisolone with trimethoprim‐sulfamethoxazole prophylaxis and the possible duration of prophylaxis.     

肾移植后并发卡氏肺孢子虫肺炎12例临床研究

目的　探讨肾移植后并发卡氏肺孢子虫 (Pc)肺炎 (PCP)的诊断、治疗和预防方法。　方法　总结12例肾移植后确诊为PCP患者的临床表现、实验室检查、X线胸片及肺部CT、支气管镜检和活检等诊断方法和预防措施。结果　肺泡灌洗液涂片Pc检出率为167%,纤维支气管镜肺组织活检Pc包囊检出率为667%。2例痰标本PCR法检出Pc病原体。X线胸片呈间质性肺炎表现占583% ,CT肺部呈多发毛玻璃样改变占50%,肺泡实变影改变占25%。预防和治疗药物为复方磺胺甲基口恶唑(即磺胺甲基口恶唑SMZ/甲氧苄氨嘧啶TMP)。除1例呼吸衰竭死亡,其余均治愈,肾功能维持正常水平。　结论　肾移植后并发PCP患者早期表现为发热、干咳等非特异症状,实验室检查无明显特异性,X线胸片可提示PCP的存在,CT可帮助对PCP病理改变的进一步理解。支气管镜肺组织活检,查见卡氏肺孢子虫包囊可确诊。SMZ/TMP为首选的综合预防、治疗药物。     

Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued?

Solid organ transplant recipients are at risk for Pneumocystis carinii pneumonia (PCP), but the risk of PCP beyond 1 year is poorly defined. We identified 25 cases of PCP in 1,299 patients undergoing solid organ transplantation between 1987 and 1996 at The Cleveland Clinic Foundation (4.8 cases per 1,000 person transplant-years [PTY]). Ten (36%) of 28 PCP cases (transplantation was performed before 1987 in three cases) occurred > or = 1 year after transplantation, and no patient developed PCP while receiving prophylaxis for PCP. The incidence of PCP during the first year following transplantation was eight times higher than that during subsequent years. The highest rate occurred among lung transplant recipients (22 cases per 1,000 PTY), for whom the incidence did not decline beyond the first year of transplantation. We conclude that the incidence of PCP is highest during the first year after transplantation and differs by type of solid organ transplant. Extending the duration of PCP prophylaxis beyond 1 year may be warranted for lung transplant recipients.     

Hypercalcemia and pneumocystis Pneumonia after kidney transplantation: report of an exceptional case and literature review

C. Chatzikyrkou, C. Clajus, M. Haubitz, C. Hafer. Hypercalcemia and pneumocystis pneumonia after kidney transplantation: report of an exceptional case and literature review.
Transpl Infect Dis 2011: 13: 496–500. xx: 000–000. All rights reserved Abstract: Pneumocystis jirovecii remains an important pathogen in solid organ transplant recipients. Although the overall incidence may be decreasing, after the adoption of effective prophylactic measures, the risk has not been abolished, and pneumocystis pneumonia (PCP) can be observed even many years after successful transplantation. Hypercalcemia develops frequently after renal transplantation and is commonly associated with preexisting secondary hyperparathyroidism. But the pathogenesis of hypercalcemia occurring later in the course of transplantation may be different, and other disease states, such as malignancy and opportunistic infections, must be considered. Hypercalcemia in conjunction with PCP is being increasingly reported in renal transplant patients. In all the cases, respiratory symptoms were prominent, hypercalcemia was of mild‐to‐moderate severity, parathyroid hormone concentration was decreased, and 1,25(OH)₂D levels were extraordinarily or inappropriately high. We report the first case to our knowledge of severe hypercalcemia accompanying PCP, in a patient with previous total parathyroidectomy.     

Cardiac toxoplasmosis after heart transplantation diagnosed by endomyocardial biopsy

We describe a case of cardiac toxoplasmosis diagnosed by routine endomyocardial biopsy in a patient with trimethoprim‐sulfamethoxazole (TMP‐SMX) intolerance on atovaquone prophylaxis. Data are not available on the efficacy of atovaquone as Toxoplasma gondii prophylaxis after heart transplantation. In heart transplant patients in whom TMP‐SMX is not an option, other strategies may be considered, including the addition of pyrimethamine to atovaquone.