Pneumocystis jiroveci pneumonia (PJP) is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Little is known about PJP infections after HSCT because of the rarity of disease given routine prophylaxis. We report the results of a Center for International Blood and Marrow Transplant Research study evaluating the incidence, timing, prophylaxis agents, risk factors and mortality of PJP after autologous (auto) and allogeneic (allo) HSCT. Between 1995 and 2005, 0.63% allo recipients and 0.28% auto recipients of first HSCT developed PJP. Cases occurred as early as 30 days to beyond a year after allo HSCT. A nested case cohort analysis with supplemental data (n=68 allo cases, n=111 allo controls) revealed that risk factors for PJP infection included lymphopenia and mismatch after HSCT. After allo or auto HSCT, overall survival was significantly poorer among cases vs controls (P=0.0004). After controlling for significant variables, the proportional hazards model revealed that PJP cases were 6.87 times more likely to die vs matched controls (P<0.0001). We conclude PJP infection is rare after HSCT but is associated with high mortality. Factors associated with GVHD and with poor immune reconstitution are among the risk factors for PJP and suggest that protracted prophylaxis for PJP in high-risk HSCT recipients may improve outcomes.
Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PJP), a unicellular fungal infection, is a severe infectious complication in immunocompromised hosts, including hematopoietic stem cell transplant (HSCT) recipients, often leading to fulminant respiratory failure.1, 2, 3 In immunocompromised hosts, PJP disease confers increased mortality, with published historical rates as high as 34–62%,4, 5, 6, 7 although data in the current era are unknown due to the rarity of disease with the implementation of routine PJP prophylaxis. Prior to prophylaxis, PJP disease was reported in 5–37% of HSCT patients.8, 9 However, since the advent of PJP prophylaxis, this incidence has decreased, with recent reports suggesting 1–6%4, 7, 9, 10, 11, 12, 13 and a few reports of no cases in as many as 120 high-risk HSCT recipients.14 However, with this rarity of disease, the actual incidence of PJP after HSCT remains unknown, as the largest number of PJP cases in reports is often under 10, suggesting that these data may overestimate the true incidence due to reporting bias, since cohort studies are often undertaken in the setting of outbreaks.15, 16, 17
Multiple studies have suggested that trimethoprim/sulfamethoxazole (TMP/SMX) is the drug of choice to prevent PJP in immunocompromised patients due to its efficacy against PJP and concurrent prophylaxis against other opportunistic pathogens including Toxoplasma gondii, Nocardia and susceptible bacteria (e.g. Staphylococcus, Streptococcus pneumoniae).1, 5, 8, 10, 18 However, it is not well tolerated in HSCT recipients, with reported intolerance as high as 55% requiring discontinuation of the drug due to rash, marrow suppression and allergy.19, 20, 21, 22, 23 For these TMP/SMX-intolerant patients, PJP prophylaxis alternative agents include aerosolized or IV pentamidine, dapsone, atovaquone, clindamycin and pyrimethamine, though clindamycin and pyrimethamine have been largely abandoned due to lack of efficacy.20, 22, 23, 24, 25 However, there is no consensus regarding efficacy of these agents in HSCT patients, nor an appropriate algorithm for choosing among these second-line agents. PJP breakthrough rates are as high as 9% for aerosolized pentamidine, 7.2% for dapsone, and not well categorized for IV pentamidine and atovaquone, with several anecdotal reports of failures with these agents, although these account for less than 300 total reported patients.26, 27, 28, 29, 30 As a result of these sparse data, the most recent recommendation from the Cochrane Collaboration includes only TMP/SMX and suggests continuation for at least 6 months after HSCT and continuation until discontinuation of immune suppression.10, 31
PJP disease risk and clearance rely upon recovery of lymphocyte numbers and function. Not surprisingly, published factors linked to PJP infection after HSCT are those associated with lymphocyte impairment, including steroids, T-cell depletion in vitro or in vivo, persistent lymphopenia, immunosuppression, GVHD and relapse.4, 11, 32, 33, 34, 35 The highest period of risk for PJP is thought to be from day 80 through day 270 post-HSCT due to impaired lymphocyte function during this time frame, though very early and very late cases have been described.4, 18, 36, 37, 38, 39 While these risk factors are likely determinants of PJP disease, there are conflicting reports, and small sample size limits interpretation.
Since PJP is an uncommon event in the HSCT population, the incidence, timing, risk factors and best prophylaxis regimens may only be addressed in a large registry study, which overcomes the limitation of disease rarity. The reported high mortality underscores the need for these data, to both determine the true mortality in a sufficiently large cohort and reveal the population most at risk, for whom new interventions could be targeted. Thus, we interrogated the largest HSCT database, the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, to identify the incidence of PJP, and then performed a nested case control study to assess risk factors and PJP-associated mortality, and to provide evidence-based data for choice of prophylaxis agents for HSCT recipients.
Patients and methods
The CIBMTR is a voluntary working group of more than 450 transplantation centers worldwide that contribute detailed data on consecutive HSCTs to a Statistical Center located at the Medical College of Wisconsin in Milwaukee and the National Marrow Donor Program Coordinating Center in Minneapolis. Participating centers are required to report all transplantations consecutively; compliance is monitored by onsite audits. The CIMBTR maintains an extensive database of detailed patient-, transplant- and disease-related information, and prospectively collects data longitudinally with yearly follow-ups. Observational studies conducted by the CIBMTR are performed in compliance with Health Insurance Portability and Accountability Act of 1996 (HIPAA) regulations as a public health authority and also in compliance with all applicable federal regulations pertaining to the protection of human research participants, as determined by a continuous review by the Institutional Review Boards of National Marrow Donor Program and the Medical College of Wisconsin.
This study includes all patients, irrespective of age, who received HSCT for either malignant or non-malignant indications between 1995 and 2005 and identified with PJP infection within 2 years of transplantation. PJP infection was captured in the CIBMTR data forms either as an infection documented in the post-transplant period or listed as a primary or secondary cause of death. Centers report based upon organism identification and those cases reported as suspected fungal infection were excluded. Those with a history of PJP infection prior to HSCT were excluded. A subsequent analysis was performed to interrogate incidence only using the same inclusion and exclusion criteria from 2006 to 2012.
This is a nested case control cohort study to assess clinical factors impacting the development of PJP and outcomes. Controls were selected 3:1 based on (1) type of transplant (autologous or allogeneic), (2) the same duration of post-HSCT follow-up (ensuring controls are alive at the time of case PJP diagnosis), and (3) the same disease indication for HSCT. A marginal proportional hazards model for clustered data was used for matching.40 Supplemental data forms were requested to evaluate PJP prophylactic agents, concomitant neutrophil and lymphocyte counts, and methods of PJP diagnosis including autopsy, bronchoalveolar lavage and methenamine silver. β-d-Glucan was not included as a diagnostic modality due to the study period evaluated. We received supplemental data on 97 cases (57%) and 236 controls (47%). Data forms were missing PJP prophylaxis data for 14 cases (14%) and 21 controls (9%), and the time of administration of prophylaxis was reported as unknown for 28 cases (29%) and 45 controls (19%). Therefore, detailed prophylaxis medication within the 30 days prior to the diagnosis of PJP was only available for 33% of cases and 34% of controls (Figure 1). Consequently, information on PJP prophylaxis is described but could not be analyzed as a risk factor for PJP.
The effect of PJP infection on overall survival of the entire study population was assessed using a proportional hazards model adjusting for the effect of other significant covariates including time-dependent variables of PJP infection (main effect variable) and GVHD; GVHD was incorporated as a variable in the multivariable model, such that the GVHD event must have occurred prior to the PJP infection to be evaluable. This precludes studying GVHD as an outcome. Interactions between PJP infection and significant covariates were tested. Backward elimination was used to select significant covariates. Analysis was performed using SAS 9.2.
Incidence and timing of PJP infection after HSCT
Between 1995 and 2005, the incidence of PJP was 0.63% in allogeneic recipients (n=177 cases of 27 934 total) and 0.28% in autologous recipients (n=52 cases of 18 525 total). This has not changed with time as the incidence was 0.53% in allo recipients and 0.32% in auto recipients from 2006 to 2012. PJP developed both early (between days 0 and 60) and late (beyond day 270) after allo HSCT. PJP occurred at a median of 120 days (range, 2–620 days), with 26% of cases occurring early (median 31, range 5–56 days), 50% occurring between 60 and 270 days after HSCT (median 120, range 60–265 days) and 24% occurring late (median 342, range 279–587 days) (Figure 2). After auto HSCT, although the numbers were small, a similar trend was observed with 18% prior to day 60, 55% between day 60 and 270, and 27% after day 270. Of those that completed the secondary forms, bronchoalveolar lavage was the most common method of diagnosis for allogeneic and autologous recipients, for allogeneic recipients, this totaled 74%, though autopsy (2%), biopsy (4%), sputum (9%), imaging (9%) and methanamine silver (2%) were also reported.
Risk factors for PJP infection after HSCT
Cases and controls were similar in terms of gender, age, Karnofsky score, coexisting endocrine or pulmonary diseases, disease status at the time of transplant, and prior autologous HSCT for both autologous and allogeneic recipients (Table 1). For allogeneic recipients, sex mismatch, intensity of conditioning regimen and CMV mismatch were not significantly different between cases and controls by univariate analysis. After auto HSCT, coexisting autoimmune disease (P<0.05) and lymphopenia (P<0.04) were more likely in cases as compared with controls. Lymphocyte number for the cases was 622 (range 0–1260) vs 1170 in controls (range 0–4758). While recent steroid use was more prevalent in cases than in controls after auto HSCT (16% vs 2% respectively), this did not achieve statistical significance. After allo HSCT, lymphopenia (P<0.001) and use of immunosuppressive agents (P<0.001) were significantly greater in PJP cases vs controls. Lymphocyte numbers were 400 in cases (range 0–7000) vs 810 (range 0–6270) in controls. Relapse was also evaluated as a risk factor after allo HSCT; however, only 14% of patients with malignant indications for HSCT developed PJP after relapse suggesting that this was not a significant factor for the development of PJP disease. Collectively, these data suggest that PJP disease is most likely associated with impaired lymphocyte reconstitution after auto or allo HSCT. In addition, non-Caucasian (P=0.001), peripheral blood stem cell source (P=0.027), administration of GVHD prophylaxis other than tacrolimus/methotrexate (P<0.001) and/or alemtuzumab/ATG (P=0.022), more recent year of transplant (P<0.001) and greater HLA mismatch (P<0.001) were significantly associated with PJP infection compared with controls after allo HSCT (Figure 3).
Association of GVHD with PJP infection after HSCT
For allogeneic recipients, acute and chronic GVHD was higher in PJP cases than controls. Of PJP cases, 27% had grade 3–4 acute GVHD compared with 14% of controls, with 73% of controls experiencing none or grade 1 GVHD vs 57% of cases (Figure 4). Fifty-five percent of cases lacked chronic GVHD vs 61% of controls. However, for patients developing PJP beyond day 270, 79% of cases experienced cGVHD vs 44% of controls. While the transplant time period precluded analysis of severity of chronic GVHD, 33% of cases who developed PJP greater than 270 days after HSCT had been exposed to steroids prior to development of PJP, compared with 0% of controls, which could be a reflection of more significant GVHD.
Association of PJP prophylaxes and risk of PJP infection
Determination of the breakthrough risk of PJP as a function of PJP prophylaxis agents was limited due to both missing and incomplete secondary forms. This large quantity of missing or incomplete data precluded statistical analyses of the association between PJP prophylaxis regimens and the risk of PJP infection. For description, ‘time unknown’ is combined with the known prophylaxis. Despite these limitations, more cases received only inhaled pentamidine for both autologous (10% of cases vs 2% of controls) and allogeneic (20% of cases vs 2% of controls) recipients developing PJP (Figures 5a and b). Additionally, in allogeneic recipients there was a case of IV pentamidine alone and none in controls (Table 2). Allogeneic cases were more likely to be on prophylaxis greater than 60 days after HSCT—likely due to recognition of impaired immune reconstitution, though less likely to receive TMP/SMX prophylaxis. Overall, 14% of cases and 15% of controls were on no prophylaxis in the 30 days prior to the onset of PJP infection.
Mortality after PJP infection
After allo HSCT, overall survival was significantly poorer among PJP cases vs controls (1 year: 41% vs 73% (P<0.0001); 5 year: 25% vs 56% (P<0.0001)) (Figure 6a). Similarly, following auto HSCT, overall survival was lower in cases vs controls (1 year: 42% vs 86% (P=0.0004); 5 year: 13% vs 52% (P=0.0003)) (Figure 6b). Mortality was directly attributable to PJP in nearly a quarter of HSCT recipients (auto, 24%; allo, 23%). For allo HSCT cases, other infections were the largest second contributor to mortality (21%). In auto HSCT cases, recurrent disease accounted for 43% of deaths in PJP cases and 69% of controls. After controlling for significant variables (age, mismatch, race, GVHD prophylaxis, year of HSCT, aGVHD), PJP cases had a 6.87-fold increase in mortality (P<0.0001, 95% CI 4.84–9.75, P<0.0001).
We have evaluated the incidence, risk factors, timing and mortality for PJP in HSCT recipients using a large HSCT registry. The CIBMTR database included over 50 000 allogeneic recipients at the time of the data query, overcoming common limitations of prior studies, including those of small patient numbers and single institution data. We show that the incidence of PJP following allogeneic and autologous HSCT is much less common than prior publications have suggested. This lower rate is likely due to freedom from publication bias; centers were more likely to publish their findings after an outbreak of PJP, enriching for this rare disease. This suggestion is supported by the fact that large multi-year studies including all infections affecting HSCT recipients often report lower rates of PJP infections as compared with smaller PJP-focused studies (1% vs 2.5–6%).4, 7, 9, 10, 11, 12, 13 This is further supported by the fact that although PJP infections were initially thought to represent an opportunistic event related to chronic colonization, genotyping of P. jiroveci in clusters has confirmed that de novo outbreaks do occur in immunosuppressed patients, and could prompt these publications.1, 15, 16, 17, 41 Interestingly, despite the increased sensitivity of disease detection including the use of β-d-glucan testing,42, 43, 44, 45, 46, 47, 48 and improving survival of severely immunosuppressed patients, the incidence of PJP after HSCT has not increased over time, consistent with the hypothesis that prophylaxes are protective in HSCT patients.8, 20, 26, 49, 50, 51, 52, 53 Notably, our data are unable to assess for a true incidence of PJP in patients on any prophylaxis (i.e. breakthrough PJP) due to the nested case cohort study design. However, since similar numbers of cases and controls (14–15%) within the subset of patients with supplemental data were not on prophylaxis, our estimated overall incidence of PJP following allogeneic and autologous HSCT are a reasonable estimate of the true incidence of PJP after HSCT.
Our data show that PJP infection occurred both early and late after HSCT. Prior reports have often highlighted the period between day 80 and 270 after HSCT as the time of highest risk, with some including up to 1 year.18, 36 In contrast, our data reveal 26% of cases occur before day 60, with the earliest event just 5 days after HSCT.18, 36 Current practice often involves PJP prophylaxis before or during the preparative regimen, to ‘diminish PJP burden’, and re-institution of prophylaxis after counts have recovered due to medication intolerance (e.g. blood count suppression with TMP/SMX, intolerance for inhaled pentamidine) or challenges with oral absorption (atovaquone).31, 54 In addition, while 50% of cases did occur in the period that has been most reported most often previously as the period of highest risk (days 80–270), 24% occurred after day 270, with a median of nearly a year, suggesting that the recommendation of a year of prophylaxis may be insufficient. These data suggest that PJP prophylaxis should be started early and continued late (beyond a year)—at least for patients at highest risk for this disease, with the caveat that these suggestions are limited by the retrospective nature of this study.
This study identifies risk factors for PJP disease, including some of those reported in prior studies such as corticosteroid exposure, in vivo or in vitro T-cell depletion, lymphopenia, immunosuppression and GVHD.4, 11, 32, 33, 34, 35, 39, 55 After auto HSCT, factors associated with ongoing immunosuppression, such as coexisting autoimmune disease and lymphopenia, were higher in PJP patients, although a previously identified risk factor steroids did not achieve statistical significance as a risk factor for PJP disease. This likely reflects the small sample size, as steroids were more common in the PJP diseased cohort. After allo HSCT, factors associated with impaired immune reconstitution (steroid exposure, lymphopenia, neutropenia) and/or GVHD, non-Caucasian decent, peripheral blood stem cell graft, receipt of either GVHD prophylaxis other than tacrolimus/methotrexate and/or alemtuzumab/ATG, and greater HLA mismatch were more common in PJP patients as compared with controls. This is not surprising as PJP eradication relies upon functional CD4 immunity, which is impaired in the setting of GVHD and steroid exposure. As anticipated from these data, lymphopenia as well as both acute and chronic GVHD were greater in recipients developing PJP. Both the aberrant lymphocyte response to infection in patients with GVHD and the effect of immune suppressive therapy likely contribute to the heightened risk for opportunistic infections. In addition, impaired immune reconstitution can occur in the absence of these overt risk factors, due to absence of thymus reconstitution and/or the use of HLA-mismatched grafts, which may demonstrate absent CD4+ cell function with or without normal peripheral counts.56 Together, these data suggest that those HSCT patients with impaired immunity (from GVHD, steroids, T-cell antibody therapy or other factors predictive of T-cell dysfunction) should start PJP prophylaxis early and continue on such prophylaxis until functional immunity is restored—evidenced both by CD4+ cell reconstitution and functional immunity via vaccine response or evidence of thymus reconstitution.
While missing data preclude full analysis of the relative efficacy of PJP prophylaxis agents, our data do provide some possible insights into this important question. Most surprisingly, approximately 15% of cases and controls were on no agent for PJP prophylaxis following allogeneic HSCT. This could suggest either patients did not adhere to the recommended regimen or because physician practice did not include PJP prophylaxis, which would be particularly important in high-risk patients at high-risk time frames after HSCT. Not surprisingly, after auto HSCT, more controls were on no prophylaxis, likely reflecting remission, and/or absence of immune suppression. In both auto and allo patients, there were more cases with PJP vs controls receiving pentamidine, which has been previously suggested in one of the largest investigations of PJP disease in allo HSCT recipients.23 Data from non-HSCT diseases have shown higher breakthrough rates for pentamidine as well, leading to recommendations of greater than the third-line choice for pentamidine for PJP prophylaxis.31, 34 Although one single center study suggests that IV pentamidine may provide efficacy, this was published during an outbreak of cases (with cases occurring despite known adherence to the pentamidine regimen), with unclear generalizability or efficacy in light of the rarity we report here. Further, data show that the IV route does not result in high intra-alveolar concentrations of drug, providing poor protection for high-risk patients.57, 58 In our study, there were similar cases and controls on dapsone (though small numbers), which may reflect the high rate of intolerance of this agent (greater than 40%) and concern regarding toxicities such as aplastic anemia and agranulocytosis, precluding interpretation of efficacy.21, 22, 27, 59 There were no cases or controls on atovaquone, though this may simply reflect the era of evaluation, given that atovaquone has only recently been incorporated in recommendations and requires fatty foods and oral absorption, limiting its use in HSCT patients.31 Breakthroughs were also observed with the best prophylaxis agent, TMP/SMX, which may reflect decreased adherence, frequency of dosing or resistance of the organism, which is difficult to prove and often unknown.60, 61 Emerging, albeit anecdotal data have recently reported the activity of caspofungin against PJP,62 though after the time frame of the current analysis. In summary, while these data are limited due to missing or incomplete secondary forms, our data would support that of prior publications that TMP/SMX be strongly recommended and careful consideration regarding cessation as no other alternative agent has been shown to be equally effective. Before stopping this medication for count suppression or rashes, perhaps, we recommend that TMP/SMX prophylaxis should be reconsidered in high-risk patients with growth factor support or desensitization utilized whenever possible, as has been recommended by the recent international guidelines for PJP prophylaxis.19, 31
Mortality was high in patients with PJP disease, with nearly seven-fold increased risk of death compared with matched controls. The absolute overall survival matches that previously published for early time points, approximately 40% at 2 years4, 5 and decreased with time to <25% at 5 years after allogeneic HSCT, and even lower for autologous recipients at 5 years. While this is compelling data that PJP portends poor survival, it is possible that PJP is a surrogate marker for other high-risk predictors of mortality due to impaired immunity or relapse as well.
There were several notable limitations to our study. The analyses addressing mortality, timing and associated risk factors including therapeutic prevention were limited by missing data due to secondary forms that were incomplete or not returned. Furthermore, limitations to our data include those of all registry studies, where data rely upon accurate capture of events into the database and that only a small proportion is audited for accuracy, thus possibly resulting in underestimation of the true incidence especially as time from HSCT increases and visits to the primary HSCT center decline. This could lead to intentional or accidental under-reporting, either from a desire to report positive results or due to missed data that was not captured, though one would postulate that both the anonymity of these data and the onus to responsibly report would drive accurate reporting and minimize this risk. Because the transplant center is more likely to be contacted for sick patients than for healthy controls, there may be increasing selection bias with longer time from transplantation as well.
In summary, our data demonstrate that the incidence of PJP disease is very low in autologous and allogeneic HSCT recipients, and most common among recipients with poor immune reconstitution, including those with mismatched grafts and GVHD. Our data demonstrate that PJP infection may occur at any time after HSCT and confers a high risk of mortality. In addition, these data suggest that TMP/SMX remains the most effective prophylactic drug. We provide guidance about duration of prophylaxis during periods of immune compromise, including very early and very late after HSCT.
Gilroy SA, Bennett NJ . Pneumocystis pneumonia. Semin Respir Crit Care Med 2011; 32: 775–782.
Wakefield AE, Peters SE, Banerji S, Bridge PD, Hall GS, Hawksworth DL et al. Pneumocystis carinii shows DNA homology with the ustomycetous red yeast fungi. Mol Microbiol 1992; 6: 1903–1911.
Gluck T, Geerdes-Fenge HF, Straub RH, Raffenberg M, Lang B, Lode H et al. Pneumocystis carinii pneumonia as a complication of immunosuppressive therapy. Infection 2000; 28: 227–230.
Tuan IZ, Dennison D, Weisdorf DJ . Pneumocystis carinii pneumonitis following bone marrow transplantation. Bone Marrow Transplant 1992; 10: 267–272.
Wazir JF, Ansari NA . Pneumocystis carinii infection. Update and review. Arch Pathol Lab Med 2004; 128: 1023–1027.
Torres HA, Chemaly RF, Storey R, Aguilera EA, Noqueras GM, Safdar A et al. Influence of type of cancer and hematopoietic stem cell transplantation on clinical presentation of Pneumocystis jiroveci pneumonia in cancer patients. Eur J Clin Microbiol Infect Dis 2006; 25: 382–388.
Yoo JH, Lee DG, Choi SM, Choi JH, Park YH, Kim YJ et al. Infectious complications and outcomes after allogeneic hematopoietic stem cell transplantation in Korea. Bone Marrow Transplant 2004; 34: 497–504.
Rodriguez M, Fishman JA . Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients. Clin Microbiol Rev 2004; 17: 770–782.
Tasaka S, Tokuda H . Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies. J Infect Chemother 2012; 18: 793–806.
Green H, Paul M, Vidal L, Leibovici L . Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev 2007; 3: CD005590.
De Castro N, Neuville S, Sarfati C, Ribaud P, Derouin F, Gluckman E et al. Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study. Bone Marrow Transplant 2005; 36: 879–883.
Mikaelsson L, Jacobsson G, Andersson R . Pneumocystis pneumonia—a retrospective study 1991-2001 in Gothenburg, Sweden. J Infect 2006; 53: 260–265.
Kruger W, Russmann B, Kroger N, Salomon C, Ekopf N, Elsner HA et al. Early infections in patients undergoing bone marrow or blood stem cell transplantation—a 7 year single centre investigation of 409 cases. Bone Marrow Transplant 1999; 23: 589–597.
Tomonari A, Takahashi S, Ooi J, Tsukada N, Konuma T, Kato S et al. No occurrence of Pneumocystis jiroveci (carinii) pneumonia in 120 adults undergoing myeloablative unrelated cord blood transplantation. Transpl Infect Dis 2008; 10: 303–307.
Chapman JR, Marriott DJ, Chen SC, MacDonald PS . Post-transplant Pneumocystis jirovecii pneumonia—a re-emerged public health problem? Kidney Int 2013; 84: 240–243.
Nankivell BJ, Firacative C, Kable K, Chen SC, Meyer W . Molecular epidemiology linking multihospital clusters of opportunistic Pneumocystis jirovecii pneumonia. Clin Infect Dis 2013; 57: 1058–1059.
Morris A, Norris KA . Colonization by Pneumocystis jirovecii and its role in disease. Clin Microbiol Rev 2012; 25: 297–317.
Dykewicz CA . Preventing opportunistic infections in bone marrow transplant recipients. Transpl Infect Dis 1999; 1: 40–49.
Fontanet ACY, Roosnek E, Mohty B, Passweg JR . Cotrimoxazole myelotoxicity in hematopoietic SCT recipients: time for reappraisal. Bone Marrow Transplant 2011; 46: 1272–1273.
Colby C, McAfee S, Sackstein R, Finkelstein D, Fishman J, Spitzer T . 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. Bone Marrow Transplant 1999; 24: 897–902.
Fishman JA . Prevention of infection caused by Pneumocystis carinii in transplant recipients. Clin Infect Dis 2001; 33: 1397–1405.
Sangiolo D, Storer B, Nash R, Corey L, Davis C, Flowers M et al. Toxicity and efficacy of daily dapsone as Pneumocystis jiroveci prophylaxis after hematopoietic stem cell transplantation: a case-control study. Biol Blood Marrow Transplant 2005; 11: 521–529.
Marras TK, Sanders K, Lipton JH, Messner HA, Conly J, Chan CK . Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia after allogeneic marrow transplantation. Transpl Infect Dis 2002; 4: 66–74.
Ramesh M, Chandrasekar PH . Effective alternates to trimethoprim-sulfamethoxazole as antimicrobial prophylaxis in stem cell recipients: are there any? Pediatr Transplant 2008; 12: 823–826.
Utili R, Durante-Mangoni E, Basilico C, Mattei A, Ragone E, Grossi P . Efficacy of caspofungin addition to trimethoprim-sulfamethoxazole treatment for severe pneumocystis pneumonia in solid organ transplant recipients. Transplantation 2007; 84: 685–688.
Rodriguez M, Sifri CD, Fishman JA . Failure of low-dose atovaquone prophylaxis against Pneumocystis jiroveci infection in transplant recipients. Clin Infect Dis 2004; 38: e76–e78.
Maltezou HC, Petropoulos D, Choroszy M, Gardner M, Mantzouranis EC, Rolston KV et al. Dapsone for Pneumocystis carinii prophylaxis in children undergoing bone marrow transplantation. Bone Marrow Transplant 1997; 20: 879–881.
Vasconcelles MJ, Bernardo MV, King C, Weller EA, Antin JH . Aerosolized pentamidine as pneumocystis prophylaxis after bone marrow transplantation is inferior to other regimens and is associated with decreased survival and an increased risk of other infections. Biol Blood Marrow Transplant 2000; 6: 35–43.
Souza JP, Boeckh M, Gooley TA, Flowers ME, Crawford SW . High rates of Pneumocystis carinii pneumonia in allogeneic blood and marrow transplant recipients receiving dapsone prophylaxis. Clin Infect Dis 1999; 29: 1467–1471.
Afessa B, Peters SG . Major complications following hematopoietic stem cell transplantation. Semin Respir Crit Care Med 2006; 27: 297–309.
Gea-Banacloche J, Masur H, Arns da Cunha C, Chiller T, Kirchhoff LV, Shaw P et al. Regionally limited or rare infections: prevention after hematopoietic cell transplantation. Bone Marrow Transplant 2009; 44: 489–494.
Sepkowitz KA, Brown AE, Telzak EE, Gottlieb S, Armstrong D . Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital. JAMA 1992; 267: 832–837.
Russian DA, Levine SJ . Pneumocystis carinii pneumonia in patients without HIV infection. Am J Med Sci 2001; 321: 56–65.
Roux A, Gonzalez F, Roux M, Mehrad M, Menotti J, Zahar JR et al. Update on pulmonary Pneumocystis jirovecii infection in non-HIV patients. Med Mal Infect 2014; 44: 185–198.
Worth LJ, Dooley MJ, Seymour JF, Mileshkin L, Slavin MA, Thursky KA . An analysis of the utilisation of chemoprophylaxis against Pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer hospital. Br J Cancer 2005; 92: 867–872.
Ahuja J, Kanne JP . Thoracic infections in immunocompromised patients. Radiol Clin North Am 2014; 52: 121–136.
Saito T, Seo S, Kanda Y, Shoji N, Ogasawara T, Murakami J et al. Early onset Pneumocystis carinii pneumonia after allogeneic peripheral blood stem cell transplantation. Am J Hematol 2001; 67: 206–209.
Bjorklund A, Aschan J, Labopin M, Remberger M, Ringden O, Winiarski J et al. Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation. Bone Marrow Transplant 2007; 40: 1055–1062.
Roblot F, Le Moal G, Kauffmann-Lacroix C, Bastides F, Boutoille D, Verdon R et al. Pneumocystis jirovecii pneumonia in HIV-negative patients: a prospective study with focus on immunosuppressive drugs and markers of immune impairment. Scand J Infect Dis 2014; 46: 210–214.
Lee EW, Wei LJ, Amato DA Cox-type regression analysis for large numbers of small groups of correlated failure time observations". In: Klein JP and Goel PK (eds). Survival Analysis: State of the Art. Kluwer Academic Publishers: Dordrecht, Netherlands, 1992 pp 237–247.
Olsson M, Eriksson BM, Elvin K, Strandberg M, Wahlgren M . Genotypes of clustered cases of Pneumocystis carinii pneumonia. Scand J Infect Dis 2001; 33: 285–289.
Damiani C, Le Gal S, Da Costa C, Virmaux M, Nevez G, Totet A . Combined quantification of pulmonary Pneumocystis jirovecii DNA and serum (1->3)-beta-D-glucan for differential diagnosis of pneumocystis pneumonia and Pneumocystis colonization. J Clin Microbiol 2013; 51: 3380–3388.
Esteves F, Lee CH, de Sousa B, Badura R, Seringa M, Fernandes C et al. (1-3)-Beta-D-glucan in association with lactate dehydrogenase as biomarkers of Pneumocystis pneumonia (PcP) in HIV-infected patients. Eur J Clin Microbiol Infect Dis 2014; 33: 1173–1180.
Fan LC, Lu HW, Cheng KB, Li HP, Xu JF . Evaluation of PCR in bronchoalveolar lavage fluid for diagnosis of Pneumocystis jirovecii pneumonia: a bivariate meta-analysis and systematic review. PloS ONE 2013; 8: e73099.
Maillet M, Maubon D, Brion JP, Francois P, Molina L, Stahl JP et al. Pneumocystis jirovecii (Pj) quantitative PCR to differentiate Pj pneumonia from Pj colonization in immunocompromised patients. Eur J Clin Microbiol Infect Dis 2014; 33: 331–336.
Matsumura Y, Ito Y, Yamamoto M, Matsushima A, Nagao M, Takakura S et al. Pneumocystis polymerase chain reaction and blood (1—>3)-beta-D-glucan assays to predict survival with suspected Pneumocystis jirovecii pneumonia. J Infect Chemother 2014; 20: 109–114.
Olsson M, Stralin K, Holmberg H . Clinical significance of nested polymerase chain reaction and immunofluorescence for detection of Pneumocystis carinii pneumonia. Clin Microbiol Infect 2001; 7: 492–497.
Tasaka S, Tokuda H . Recent advances in the diagnosis of Pneumocystis jirovecii pneumonia in HIV-infected adults. Expert Opin Med Diagn 2013; 7: 85–97.
Coyle PV, McCaughey C, Nager A, McKenna J, O'Neill H, Feeney SA et al. Rising incidence of Pneumocystis jirovecii pneumonia suggests iatrogenic exposure of immune-compromised patients may be becoming a significant problem. J Med Microbiol 2012; 61: 1009–1015.
Maini R, Henderson KL, Sheridan EA, Lamagni T, Nichols G, Delpech V et al. Increasing Pneumocystis pneumonia, England, UK, 2000-2010. Emerg Infect Dis 2013; 19: 386–392.
Madden RM, Pui CH, Hughes WT, Flynn PM, Leung W . Prophylaxis of Pneumocystis carinii pneumonia with atovaquone in children with leukemia. Cancer 2007; 109: 1654–1658.
Meyers B, Borrego F, Papanicolaou G . Pneumocystis carinii pneumonia prophylaxis with atovaquone in trimethoprim-sulfamethoxazole-intolerant orthotopic liver transplant patients: a preliminary study. Liver Transpl 2001; 7: 750–751.
Shankar SM, Nania JJ . Management of Pneumocystis jiroveci pneumonia in children receiving chemotherapy. Paediatr Drugs 2007; 9: 301–309.
Neumann S, Krause SW, Maschmeyer G, Schiel X, von Lilienfeld-Toal M . Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematological malignancies and solid tumors: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2013; 92: 433–442.
Overgaard UM, Helweg-Larsen J . Pneumocystis jiroveci pneumonia (PCP) in HIV-1-negative patients: a retrospective study 2002-2004. Scand J Infect Dis 2007; 39: 589–595.
Williams KM, Hakim FT, Gress RE . T cell immune reconstitution following lymphodepletion. Semin Immunol 2007; 19: 318–330.
Kim SY, Dabb AA, Glenn DJ, Snyder KM, Chuk MK, Loeb DM . Intravenous pentamidine is effective as second line Pneumocystis pneumonia prophylaxis in pediatric oncology patients. Pediatr Blood Cancer 2008; 50: 779–783.
Debs RJ, Straubinger RM, Brunette EN, Lin JM, Lin EJ, Montgomery AB et al. Selective enhancement of pentamidine uptake in the lung by aerosolization and delivery in liposomes. Am Rev Respir Dis 1987; 135: 731–737.
Williams S, MacDonald P, Hoyer JD, Barr RD, Athale UH . Methemoglobinemia in children with acute lymphoblastic leukemia (ALL) receiving dapsone for pneumocystis carinii pneumonia (PCP) prophylaxis: a correlation with cytochrome b5 reductase (Cb5R) enzyme levels. Pediatr Blood Cancer 2005; 44: 55–62.
Queener SF, Cody V, Pace J, Torkelson P, Gangjee A . Trimethoprim resistance of dihydrofolate reductase variants from clinical isolates of Pneumocystis jirovecii. Antimicrob Agents Chemother 2013; 57: 4990–4998.
Caselli D, Petris MG, Rondelli R, Carraro F, Colombini A, Muggeo P et al. Single-day trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis pneumonia in children with cancer. J Pediatr 2014; 164: 389–392 e1.
Link H, Vohringer HF, Wingen F, Bragas B, Schwardt A, Ehninger G . Pentamidine aerosol for prophylaxis of Pneumocystis carinii pneumonia after BMT. Bone Marrow Transplant 1993; 11: 403–406.
The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA076518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U10HL069294 from NHLBI and NCI; a contract HHSH250201200016C with Health Resources and Services Administration (HRSA/DHHS); two grants N00014-13-1-0039 and N00014-14-1-0028 from the Office of Naval Research; and grants from *Actinium Pharmaceuticals; Allos Therapeutics, Inc.; *Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; *Blue Cross and Blue Shield Association; *Celgene Corporation; Chimerix, Inc.; Fred Hutchinson Cancer Research Center; Fresenius-Biotech North America, Inc.; *Gamida Cell Teva Joint Venture Ltd; Genentech, Inc.;*Gentium SpA; Genzyme Corporation; GlaxoSmithKline; Health Research, Inc. Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Jeff Gordon Children’s Foundation; Kiadis Pharma; The Leukemia & Lymphoma Society; Medac GmbH; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; *Milliman USA, Inc.; *Miltenyi Biotec, Inc.; National Marrow Donor Program; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; Perkin Elmer, Inc.; *Remedy Informatics; *Sanofi US; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; St. Baldrick’s Foundation; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; *Tarix Pharmaceuticals; *TerumoBCT; *Teva Neuroscience, Inc.; *THERAKOS, Inc.; University of Minnesota; University of Utah; and *Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense, Health Resources and Services Administration (HRSA) or any other agency of the U.S. Government.
The authors declare no conflict of interest.
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Williams, K., Ahn, K., Chen, M. et al. The incidence, mortality and timing of Pneumocystis jiroveci pneumonia after hematopoietic cell transplantation: a CIBMTR analysis. Bone Marrow Transplant 51, 573–580 (2016). https://doi.org/10.1038/bmt.2015.316
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