Scandinavian Journal of Infectious Diseases, 2014; 46: 704–711
ORIGINAL ARTICLE
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Pneumocystis jirovecii pneumonia in patients with end-stage renal disease: a comparison with the general population
STEFFEN LETH1, SØREN JENSEN-FANGEL1, LARS ØSTERGAARD1, ANDREAS ARENDTSEN ROSTVED2, BENTE JESPERSEN3 & OLE SCHMELTZ SØGAARD1 From the 1Department of Infectious Diseases, Aarhus University Hospital, Aarhus, 2Department of Nephrology P, Rigshospitalet, Copenhagen, and 3Department of Nephrology, Aarhus University Hospital, Aarhus, Denmark
Abstract Background: Data on occurrence and risk factors for pneumocystis pneumonia (PCP) in patients with end-stage renal disease (ESRD) are sparse. Methods: This was a nationwide population-based study assessing occurrence and risk factors for PCP among patients with ESRD and population controls over a 21-year period (1/1 1990 to 31/12 2010). Using Danish registry data, first-time diagnoses of PCP were identified. Results: We identified 13 296 adult patients with ESRD and 244 255 controls, yielding 63 560 and 2 223 660 person-years of follow-up (PYFU), respectively. Fifty-eight first-time diagnoses of PCP were recorded in the ESRD group. Forty-six episodes occurred among renal transplant recipients (RTx) and 12 among haemodialysis patients (HD), yielding incidence rates of 181 (136–242) and 43.1 (24.5–75.9) per 100 000 PYFU. Compared to population controls, we found incidence rate-ratios of 125.9 (78.4–204) among RTx and 29.9 (14.1–59.7) among HD patients. Risk factors for PCP in RTx were age 50–65 years, age ⬎ 65 years, diabetes, polycystic kidney disease and hypertensive kidney disease/nephrosclerosis with an IRR of 2.22 (1.14–4.31), 3.12 (1.35–7.21), 3.44 (1.16–10.2), 4.25 (1.55–11.7) and 3.87 (1.49–10.0), respectively, and more than 36 months of dialysis before transplantation with an IRR of 1.99 (1.03–3.84). Among RTx the risk of PCP was highest during the first 6 months post-transplantation and increased from the beginning (IR1990–94 ⫽ 111 (46.3–267) per 100 000 PYFU) towards the end of the study period (IR2005–10 ⫽ 299 (203–439)). Conclusion: The PCP risk is substantial in RTx within the first 6 months of transplantation, emphasizing the potential benefit of prophylactic treatment in the early post-transplant period. Importantly, we identified subgroups within the RTx group that require more attention.
Keywords: End-stage renal disease, renal transplant recipients, pneumocystis pneumonia, risk factors
Introduction A wide range of infections occur in solid organ transplant recipients, mainly as a result of the iatrogenic immunosuppression, which primarily inhibits T-cell activation and effector functions [1,2]. The resulting non-specific immunosuppression increases the susceptibility to infections. Multiple studies have shown that the incidence of various infection-related cancer types [3], infections such as pneumonia, including pneumocystis pneumonia (PCP) [4], sepsis, herpes zoster and urinary tract infections constitute a considerable burden to renal transplant recipients (RTx) on active immunosuppressive therapy [5–9].
Pneumocystis jirovecii is a ubiquitous organism with a unique tropism for the lungs, normally residing in the alveoli without invading the host; the reservoir of P. jirovecii is strictly human. Symptomatic infection with P. jirovecii occurs primarily in immunosuppressed patients [10]. Subclinical colonization is possible and serological response to P. jirovecii organisms has been detected in healthy children from the age of 2 years [11–13]. De novo infection is probably acquired by person–person aerosol transmission either from immunocompetent to immunocompromised individuals, or among immunocompromised patients, for example, during hospitalization [14–17].
Correspondence: Steffen Leth, Department of Infectious Diseases, Aarhus University Hospital, Brendstrupgaardsvej 100 - 8200 Aarhus N, Denmark. Tel: ⫹ 45 78452824. Fax: ⫹ 45 78452804. E-mail: [email protected] (Received 18 January 2014 ; accepted 1 June 2014 ) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.936492
Pneumocystis jirovecii pneumonia in patients with ESRD The primary objective of this population-based study was to investigate the incidence of PCP among RTx and patients receiving chronic dialysis (peritoneal or haemodialysis) in Denmark. We further aimed to compare the incidence of PCP in patients with end-stage renal disease (ESRD) with the incidence in a matched background population without known renal disease. Potential risk factors for PCP among RTx patients were assessed. Finally, we estimated 30- and 90-day mortality in RTx and dialysis patients and population controls following hospitalization for PCP.
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patient was diagnosed with ESRD. The two cohorts were mutually exclusive. Follow-up Patients were followed from 1 January 1990 or date of first diagnosis of ESRD in the DNR and until date of first PCP diagnosis, death, immigration or 31 December 2010, whichever came first. Population controls were enrolled at the time of their matched ESRD patient.
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Validation of diagnosis of P. jirovecii pneumonia Materials and methods Population, setting and identification In Denmark, there are approximately 650 new cases of ESRD annually on renal replacement therapy defined as renal transplantation or dialysis for more than 90 days. Since 1 January 1990, patients with ESRD on renal replacement therapy have been systematically recorded in the Danish Nephrology Registry (DNR). In August 2010, the DNR contained data from approximately 14 000 patients with ESRD of whom 4100 had had at least one successful renal transplant. Apart from information on the treatment of chronic renal failure, the DNR contains demographic information, transplant waiting list data and tissue types of recipient and donor. Other data sources included the Danish National Patient Registry (DNPR), which contains hospital discharge information from 1977 and onwards. In the DNPR we identified discharge diagnosis of PCP using the International Classification of Diseases (ICD-8) (13600 ⫹ 13603) (1977–1993) and (ICD-10) codes (DB59 Pneumocystosis) (1994 to present). Follow-up information was obtained from the Danish Civil Registration System (CRS), using the unique 10-digit personal registration number assigned at birth or immigration to Denmark. Study design This was a nationwide population-based cohort study including all adult patients (ⱖ 18 years of age) with ESRD in Denmark from 1 January 1990 to 31 December 2010. We categorized patients with ESRD into three groups: (1) peritoneal dialysis (PD); (2) haemodialysis (HD) and (3) renal transplant recipients with a functioning graft (RTx). To estimate the burden of PCP, patients were matched for age and gender with up to 19 background population controls without known chronic renal disease. Controls were sampled from the CRS on the day the index
To validate the PCP diagnosis identified in the DNPR, the medical records from all PCP cases in the ESRD group were reviewed. The diagnosis of PCP was confirmed by documentation of the organism by stained microscopy or by polymerase chain reaction (PCR) using either bronchoalveolar lavage (BAL) fluid or induced sputum/tracheal suction. Further information was collected on recipient status regarding tuberculosis (TB), hepatitis C (HCV), human immunodeficiency virus 1 ⫹ 2 (HIV), clinical presentation and immunosuppressive therapy with the latest discharge regimen before PCP diagnosis. Cytomegalovirus (CMV) status and CMV disease post transplant were also assessed, but not included in the analyses due to incomplete data. Statistical analysis Incidence rates (IRs), incidence rate-ratios (IRRs) and mortality. IRs of first-time hospitalization for PCP were computed for ESRD patients and matched population controls. Further, we used Poisson regression to explore risk factors for first-time admission with PCP in RTx recipients. Finally, 30- and 90-day mortality following hospitalization for PCP was computed using the life table technique. Risk factors. The following variables were considered in a Poisson regression analysis: sex, age, cause of ESRD (glomerulonephritis, diabetes mellitus (DM) type 1 and 2, chronic interstitial nephritis (CIN), hypertensive kidney disease/nephrosclerosis, polycystic kidney disease, vasculitis and others). Treatment era was analysed in four strata (1990–94, 1995–99, 2000–04 and 2005–10); time in dialysis before RTx was analysed in three strata (0–12 months, 13–36 months and ⬎ 36 months); time from RTx diagnosis was analysed in four strata (⬍ 6 months, 6–12 months, 13–24 months and ⬎ 24 months) and finally donor type (deceased, living donor family and living donor not-family) was registered. Differences were considered statistically significant at a p value ⬍ 0.05.
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To identify independent risk factors, an adjusted Poisson regression analysis was conducted including the following variables: live versus diseased donor, age, sex, time from RTx and treatment era. We used Stata software, version 11.0 (StataCorp, College Station, TX, USA) for statistical analyses. The study was approved by the Danish Data Protection Agency.
Results
Characteristics of RTx patients with PCP Forty-one (89.1%) patients who developed PCP had not received prophylactic co-trimoxazole. The discharge immunosuppressive regimen leading up to PCP-related hospitalization included steroids in 41 of 46 Rtx patients (89.1%), cyclosporine in 26 patients (56.5%), tacrolimus in 8 (17.4%), mycophenolate mofetil (MMF) in 20 (43.4%) and azathioprine in 17 patients (36.9%) (Table II). Characteristics of the 58 adult patients with ESRD and PCP are shown in Table III.
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Study population We identified 13 296 adult patients with ESRD and 244 255 population controls, contributing 63 560 and 2 223 660 person-years of follow-up (PYFU), respectively. A first-time hospitalization for PCP was identified in 58 patients with ESRD (46 RTx, 0 PD and 12 HD patients) and in 32 matched population controls (Table I). The median age at PCP diagnosis for all PCP cases, background population and HD subgroup was 59.2 years (interquartile range (IQR) 48.4–68.6 years), 68.8 years (IQR 62.8–75.4 years) and 47.4 years (IQR 33.4–63.2 years), respectively. Incidence rates and incidence rate-ratios The IRs of first-time hospitalization for PCP among patients with ESRD and population controls were 87.7 (95% confidence interval (CI): 67.9–114) and 1.43 (95% CI: 1.02–2.04) per 100 000 PYFU, respectively, corresponding to an IRR of 60.9 (95% CI: 39.6–93.9). IRs of first-time hospitalization for PCP in the RTx and HD groups were 181 (95% CI: 136–242) and 43.1 (95% CI: 24.5–75.9) per 100 000 PYFU, respectively, corresponding to an IRR of 126 (95% CI: 78.4–204) and 29.9 (95% CI: 14.0– 59.7) compared to the background population (Table I).
Risk factors for PCP among RTx patients In the 46 RTx patients that developed PCP, the strongest risk factor for PCP in the unadjusted analysis was time since RTx (Table IV). Thirty of the 46 PCP cases among RTx patients occurred within the first 6 months after transplantation. The IR of first PCP dropped from 891 (95% CI: 623–1300) per 100 000 PYFU within the first 6 months to 59.7 (95% CI: 33.1–108) per 100 000 PYFU ⬎ 24 months after RTx (IRR 14.9, 95% CI: 7.47–29.8). The incidence of PCP among RTx patients increased from the beginning towards the end of the study period, with an IR of 111 (95% CI 46.3–267) per 100 000 PYFU in 1990–94, to an IR of 299 (95% CI 203–439) per 100 000 PYFU from 2005 to 2010. In an adjusted analysis of risk factors for PCP among RTx patients the following variables were independent risk factors for PCP: age 50–65 years (IRR 3.44, 95% CI: 1.68–7.06), age ⬎ 65 years (IRR 6.35, 95% CI: 2.42–16.6), time since RTx ⬍ 6 months (IRR 41.4, 95% CI: 19.1–89.7), time from RTx 6–12 months (IRR 9.08, 95% CI: 2.78–29.7) and treatment era 2005–2010 (IRR 4.93, 95% CI: 1.82–13.4). Additionally, 21.7% of patients experienced an episode of rejection followed by treatment with highdose steroids preceding their PCP diagnosis (Table II).
Table I. Incidence rates (IR) and rate-ratios (IRR) of pneumocystis pneumonia (PCP) among persons with end-stage renal disease (ESRD) and population controls.
Group Background controls ESRD Subdivideda PD HD Rtx
No.
No. of PCP
PYFU
IR (95% CI) (per 100 000 person-years)
24 4255 13 296
32 58
2 223 660 63 560
1.43 (1.02–2.04) 87.7 (67.8–113.5)
1 (reference) 60.9 (39.6–93.9) ⬍ 0.001
0 12 46
10 320 27 840 25 400
43.1 (24.5–75.9) 181 (136–242)
29.9 (14.0–59.7) ⬍ 0.001 126 (78.4–204) ⬍ 0.001
IRR (95% CI)
p value
The ESRD group was subdivided into peritoneal dialysis (PD), haemodialysis (HD) and renal transplant recipients with a functioning graft (RTx). aPatients may contribute with risk time in more than one category.
Pneumocystis jirovecii pneumonia in patients with ESRD Table II. Characteristics of 58 adult patients with end-stage renal disease and pneumocystis pneumonia (PCP).
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Characteristic No. Diagnostics Bronchoalveolar lavage (BAL) Microscopy PCR Induced sputum/tracheal suction Microscopy PCR Treatment on clinical presentation Missing data CMV status Donor CMV positive Donor CMV negative Donor CMV status missing Recipient CMV positive Recipient CMV negative Recipient CMV status missing Other transplant factors Tuberculosis positive Hepatitis B positive (HBsAg positive) Discharge immunosuppression leading up to hospitalization due to PCP diagnosis Steroids Sirolimus Mycophenolate mofetil (MMF) Tacrolimus Azathioprine Cyclosporine Everolimus Missing data Anti-rejection medications Steroids Thymoglobulin Muromonab-CD3 (OKT3) PCP prophylaxis Yes No Data missing
PCP in RTx (%)a 46
12
39 (84.8%) 37 (80.4%) 2 (4.3%) 5 (10.8%) 2 (4.3%) 3 (6.5%) 1 (2.2%) 1 (2.2%) 14 11 21 13 22 11
PCP in non-RTx (%)
7 (58.3%)
2 (16.7%)
3 (25.0%)
(30.4%) (23.9%) (45.7%) (28.3%) (47.8%) (23.9%)
1 (2.2%) 1 (2.2%)
41(89.1%) 1 (2.2%) 20 (43.4%) 8 (17.4%) 17 (36.9%) 26 (56.5%) 1 (2.2%)
9 (75.0%)
1 (8.3%) 3 (25.0%)
Table III. Supplementary characteristics of 58 adult patients with end-stage renal disease and pneumocystis pneumonia (PCP).
Characteristic No. Induction therapy Steroids IL-2 receptor antibody Antithymocyte globulin (ATGAM and thymoglobulin) Data missing Discharge immunosuppression leading up to hospitalization due to PCP diagnosis by combinations Cyclosporine, MMF and steroids Cyclosporine, azathioprine and steroids Cyclosporine and steroids Cyclosporine, cyclophosphamide and steroids Tacrolimus, MMF and steroids Tacrolimus and MMF Sirolimus, MMF and steroids Sirolimus and steroids Everolimus, MMF and steroids Data missing Clinical/paraclinical presentation Fever (⬎ 38°C) Fever, data missing Dyspnoea Dyspnoea, data missing Cough Cough, data missing Infiltrates on chest X-ray Infiltrates on chest X-ray, data missing
PCP in RTx (%) 46
PCP in non-RTx (%) 12
1 (2.2%) 16 (34.8%) 4 (8.7%) 25 (54.3%)
12 (26.1%) 18 (39.1%) 2 (4.3%) 1 (2.2%) 7 1 0 1 2
(15.2%) (2.2%)
36 10 40 6 28 18 36 10
(78.3%) (21.7%) (86.9%) (13.0%) (60.9%) (39.1%) (78.3%) (21.7%)
(2.2%) (4.3%)
6 6 8 4 6 6 8 4
(50.0%) (50.0%) (66.7%) (33.3%) (50.0%) (50.0%) (66.7%) (33.3%)
MMF, mycophenolate mofetil.
10 (21.7%) 1 (2.2%) 2 (4.3%) 2 (4.3%) 41 (89.1%) 3 (6.5%)
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2 (16.7%) 8 (66.7%) 2 (16.7%)
aPercentage with one decimal rounded up to the nearest whole number, therefore not all groups add up to 100%.
Mortality following hospitalization for PCP In the RTx group 30-day mortality after hospitalization for PCP was 4.4% (95% CI 1.1–16.3%) compared with 8.3% (95% CI 1.2–46.1%) in the HD group and 28.9% (95% CI 17.2–46.2) in the population controls. Further, 90-day mortality in the RTx, HD and population groups was 8.9% (95% CI 3.4– 21.9%), 50% (95% CI 26.4–79.2%) and 34.2% (95% CI 21.5–51.5%), respectively. Validation of P. jirovecii pneumonia diagnosis According to the DNPR, 59 patients with ESRD had a discharge diagnosis of PCP. Of these, 47 were in
the RTx group and 12 in the non-RTx group. In the RTx group, one patient was misclassified with PCP and one was treated on clinical suspicion without any diagnostic sampling, but was kept in the analysis. A medical record review identified a total of 45 patients with a confirmed PCP diagnosis and 1 was treated on clinical suspicion of PCP. Underlying predisposing conditions for P. jirovecii in the background control population Diagnoses of the 32 cases of PCP in the background population were reviewed and divided into the following groups. Haematologic malignancy, 16 cases (50%); organ transplantation (other than kidney), 2 cases (6.3%); inflammatory conditions, such as rheumatoid arthritis and granulomatosis with polyangiitis (Wegener’s), 4 cases (12.5%); solid tumors, 1 case (3.1%); other miscellaneous conditions, 6 cases (18.7%) and HIV-positive, 3 cases (9.4%). Unfortunately, data on immunosuppressive treatment in the background population was not available.
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S. Leth et al. Table IV. Risk factors for pneumocystis pneumonia (PCP) among adult renal transplant recipients (n = 3919).
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Variable Sex Female Male Age (years) ⬍ 50 50–65 ⬎ 65 Morbus Glomerulonephritis DM1 DM2 CIN Hypertensive kidney disease/nephrosclerosis Polycystic kidney disease Vasculitis Others Treatment era 1990–94 1995–99 2000–04 2005–10 Time in dialysis before Rtx 0–12 months 13–36 months ⬎ 36 months Time from Rtx ⬎ 24 months 13–24 months 6–12 months ⬍ 6 months Live vs deceased donor Deceased Live donor “not family” Live donor “family”
No. of PCP cases ⫽ 46
Incidence rate (95% CI) (per 100 000 person-years)
Incidence rate ratio (95% CI)
p value
13 33
134 (77.9–231) 210 (149–296)
1 (Reference) 1.57 (0.82–2.97)
0.17
14 23 9
107 (63.6–181) 238 (158–358) 335 (174–643)
1 (Reference) 2.22 (1.14–4.31) 3.12 (1.35–7.21)
0.019 0.008
6 7 1 5 14
70.8 243 374 149 274
1 3.44 5.28 2.10 3.87
(Reference) (1.16–10.2) (0.64–43.9) (0.64–6.88) (1.49–10.0)
0.026 0.12 0.22 0.006
10 2 1
301 (162–560) 349 (87.4–1400) 70.8 (9.97–502)
4.25 (1.55–11.7) 4.93 (0.99–24.6) 0.99 (0.12–8.30)
0.005 0.051 1.00
5 7 8 26
111 125 121 299
1 1.12 1.09 2.69
(Reference) (0.36–3.54) (0.36–3.34) (1.03–7.00)
0.84 0.88 0.04
20 10 16
144 (92.9–223) 168 (90.5–312) 287 (176–468)
1 (Reference) 1.17 (0.55–2.49) 1.99 (1.03–3.84)
0.69 0.04
11 1 4 30
59.7 42.4 319 891
1 0.71 5.34 14.9
37 3 4
190 (138–262) 161 (51.7–498) 99.1 (37.2–264)
(31.8–158) (116–511) (52.7–2700) (61.9–357) (162–462)
(46.3–267) (59.5–262) (60.7–243) (203–439)
(33.1–108) (5.97–301) (120–850) (623–1300)
(Reference) (0.09–5.49) (1.70–16.8) (7.47–29.8)
1 (Reference) 0.85 (0.26–2.74) 0.52 (0.19–1.47)
0.74 0.004 ⬍ 0.001
0.78 0.22
Total person-years of follow-up (PYFU) ⫽ 25400. PCP-specific incidence ratios (IR) and incidence rate-ratios (IRR) during follow-up 1990–2010. CI, confidence interval; CIN, chronic interstitial nephritis; DM, diabetes; IR, incidence rate; IRR, incidence rate ratio; RTx, renal transplant.
Discussion In this nationwide study on PCP in patients with ESRD in Denmark covering a period of 21 years, we found that PCP, although rare, remains a significant opportunistic infection among RTx patients when compared with matched controls without ESRD, occurring primarily within the first 6 months after transplantation. Importantly, we identified specific subgroups within the RTx group that require more attention (Table IV). The majority of patients (89%) received steroids as part of the immunosuppressive regimen in the year leading up to the PCP diagnosis. Thus, these findings add to the current knowledge of PCP in RTx patients and highlight the potential benefit of co-trimoxazole prophylaxis in the first 6 months following transplantation.
The sum of factors affecting the level of immunosuppression includes among others type of immunosuppressive therapy, treatment duration and intensity (including intensification to preserve graft function). Metabolic conditions such as diabetes and uraemia could also contribute to the risk [18]. The upward trend at the end (2005–10) of the 21-year study period is not fully clarified, but could be partially explained by a small coincident nosocomial accumulation in one geographic location [19]. The diagnostic approach has not changed since 2000, where PCR was added as a routine to the diagnostic methods alongside microscopy. Possible explanations could be increased awareness of PCP with intensified diagnostic efforts, for example, BAL with microscopy and/or PCR for PCP on BAL fluid. In the RTx group, we found that 39 (84.7%) of the
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Pneumocystis jirovecii pneumonia in patients with ESRD PCP diagnoses in this study were made on BAL fluid. The diagnostic yield of microscopy with staining on BAL fluid in HIV-positive patients has been shown to be over 90%, but may be lower in HIVnegative patients due to an expected lower organism burden [20]. Further, supplementary PCR on BAL fluid has been shown to increase the diagnostic yield compared with conventional staining alone [21]. However, PCP may be shown by PCR in BAL fluid without being invasive, and there could be a slight over-diagnosis as five cases were diagnosed on PCR alone (two on BAL and three on induced sputum, respectively), which could be false positives or of no clinical significance (Table III). In the RTx group, we found that 89.1% of the combined immunosuppressive therapy included steroids in the year leading up to their PCP diagnosis; this is consistent with previous studies [22,23]. Further, 21.7% had an episode of rejection treated with high-dose steroids preceding their PCP diagnosis; this is also consistent with previous studies [2]. This finding suggests that steroid minimization might be of value in the prevention of PCP, but the fraction of the total population of RTx patients on steroid-free regimens was not available, although one of the Danish transplant centres avoided prednisolone completely in 71% of cases [24]. The lower 30- and 90-day mortality in the RTx group compared with the background population controls may be explained by the increased awareness of pulmonary symptoms and early evaluation in this group leading to faster diagnosis. We had too few non-RTx patients that developed PCP to conduct a separate risk factor analysis. However, it is noteworthy that 75% received steroids as a part of the immunosuppressive treatment in the non-RTx group. The 32 PCP cases in the control population were all well explained by underlying immunosuppressive conditions such as haematologic malignancy and organ transplantation other than RTx. The risk of PCP in RTx recipients is highest between the second and the sixth months after transplantation, with a described attack rate between 0.6 and 14% in transplant recipients not receiving prophylaxis, but has also been described to occur beyond 1 year. This coincides with our data where 12 cases of PCP occurred beyond 1 year [4,25,26]. Although PCP in RTx recipients occurs with the lowest rates compared with other solid organ transplant recipients [27,28], it is a recognized cause of morbidity and mortality in kidney transplant recipients [29]. Additionally, age above 50 years of age is a significant risk factor for PCP in the RTx group, which is consistent with the literature [30]. In HIV-infected individuals, the use of PCP prophylaxis is guided by peripheral blood CD4⫹ T-cell count to assess the
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individual risk of PCP. Unfortunately such a straightforward parameter is still lacking to evaluate the immunological status for patients without HIV infection. However, PCP prophylaxis can be initiated during episodes of high immunosuppressive load such as at transplantation and when initiating rejection therapy. The current international recommendations for PCP prophylaxis are diverse, and during the period of our study PCP prophylaxis was not standard practice at all transplant centres in Denmark. The European Renal Transplant Guidelines now recommend PCP prophylaxis for at least 4 months after RTx; the American Society of Transplantation generally recommends 6–12 months for all solid organ transplant recipients and The Kidney Disease Improving Global Outcomes guideline recommends 3–6 months post transplant [31–33]. In our RTx group, 30 of the 46 patients developed PCP within the first 6 months after transplantation. Among the patients in the present study, 89.1% did not receive PCP prophylaxis before hospitalization for PCP. This study had several strengths, including the possibility to extract data from highly valid registries such as the Danish Civil Registration System, the Danish Nephrology Registry and the Danish National Patient Registry. Further, the long period of follow-up and the use of population-based, nationwide cohorts and the large study sample increased the statistical precision. Additionally, we validated the PCP diagnosis to minimize the possibility of coding errors. Our study also had some limitations. We had no information on immunosuppressive therapy in the remaining ESRD patients, including RTx patients who did not develop PCP. Thus, we could not assess the impact of individual immunosuppressive drugs on the risk of PCP. This information could have provided important information in relation to the risk profile for developing PCP, as indicated in several studies [4,28,34–37]. Finally, we had no data on whether the PCP cases were coinciding at one geographical location as reported in other studies [14,16,17,38–40]. Conclusion In a Danish nationwide study PCP was an increasing problem in RTx recipients over the past two decades. Our findings support the use of PCP prophylaxis in the early post-transplant period. Additionally, our study draws attention to potential subgroups within the RTx group, only scarcely described in the literature, which could benefit from more attention and a longer period of PCP prophylactic treatment.
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Acknowledgments We would like to thank James Heaf for providing the data from the Danish Nephrology Registry and we would like to thank the Danish Nephrology Society.
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[16]
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. [17]
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References [1] Kelly PA, Burckart GJ, Venkataramanan R. Tacrolimus: a new immunosuppressive agent. Am J Heal Syst Pharm 1995;52: 1521–35. [2] Weir MR, Mulgaonkar S, Chan L, Shidban H, Waid TH, Preston D, et al. Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial. Kidney Int 2011;79:897–907. [3] Van Leeuwen MT, Webster AC, McCredie MRE, Stewart JH, McDonald SP, Amin J, et al. Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study. BMJ 2010; 340:c570. [4] Neff RT, Jindal RM, Yoo DY, Hurst FP, Agodoa LY, Abbott KC. Analysis of USRDS: incidence and risk factors for Pneumocystis jiroveci pneumonia. Transplantation 2009;88: 135–41. [5] Alangaden GJ, Thyagarajan R, Gruber SA, Morawski K, Garnick J, El-Amm JM, et al. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin Transplant 2006;20:401–9. [6] Grimaldi A, Barletta A, Rascente M, Pisani F, Iaria G, Maccarone D, et al. Infectious complications in the renal transplant recipient. Transplant Proc 2005;37:2502–3. [7] Pourmand G, Salem S, Mehrsai A, Taherimahmoudi M, Ebrahimi R, Pourmand MR. Infectious complications after kidney transplantation: a single-center experience. Transpl Infect Dis 2007;9:302–9. [8] Gunst JD, Jensen-Fangel S, Jespersen B, Ostergaard L, Søgaard OS. Central nervous system infections among individuals with and without end-stage renal disease. J Infect 2013;67:19–26. [9] Nielsen LH, Jensen-Fangel S, Jespersen B, Ostergaard L, Søgaard OS. Risk and prognosis of hospitalization for pneumonia among individuals with and without functioning renal transplants in Denmark: a population-based study. Clin Infect Dis 2012;55:679–86. [10] Afessa B. Pulmonary complications of HIV Infection. Chest J 1998;113:1225. [11] Meuwissen JH, Tauber I, Leeuwenberg AD, Beckers PJ, Sieben M. Parasitologic and serologic observations of infection with Pneumocystis in humans. J Infect Dis 1977;136:43–9. [12] Ponce CA, Gallo M, Bustamante R, Vargas SL. Pneumocystis colonization is highly prevalent in the autopsied lungs of the general population. Clin Infect Dis 2010;50:347–53. [13] Vargas SL, Hughes WT, Santolaya ME, Ulloa AV, Ponce CA, Cabrera CE, et al. Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants. Clin Infect Dis 2001;32:855–61. [14] Hirschl MM, Derfler K, Janata O, Heinz G, Sertl K, Balcke P. Accumulation of Pneumocystis carinii pneumonia in
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
patients after kidney transplantation. Clin Nephrol 1992; 37:105. Schmoldt S, Schuhegger R, Wendler T, Huber I, Söllner H, Hogardt M, et al. Molecular evidence of nosocomial Pneumocystis jirovecii transmission among 16 patients after kidney transplantation. J Clin Microbiol 2008;46: 966–71. De Boer MGJ, Bruijnesteijn van Coppenraet LES, Gaasbeek A, Berger SP, Gelinck LBS, van Houwelingen HC, et al. An outbreak of Pneumocystis jiroveci pneumonia with 1 predominant genotype among renal transplant recipients: interhuman transmission or a common environmental source? Clin Infect Dis 2007;44:1143–9. De Boer MGJ, de Fijter JW, Kroon FP. Outbreaks and clustering of Pneumocystis pneumonia in kidney transplant recipients: a systematic review. Med Mycol 2011;49: 673–80. Fishman JA; AST Infectious Diseases Community of Practice. Introduction: infection in solid organ transplant recipients. Am J Transplant 2009;9(Suppl 4):S3–6. Rostved AA, Sassi M, Kurtzhals JA, Sørensen SS, Rasmussen A, Ross C, et al. Outbreak of pneumocystis pneumonia in renal and liver transplant patients caused by genotypically distinct strains of Pneumocystis jirovecii. Transplantation 2013;96:834–42. Shelhamer JH, Gill VJ, Quinn TC, Crawford SW, Kovacs JA, Masur H, et al. The laboratory evaluation of opportunistic pulmonary infections. Ann Intern Med 1996;124:585–99. Azoulay E, Bergeron A, Chevret S, Bele N, Schlemmer B, Menotti J. Polymerase chain reaction for diagnosing pneumocystis pneumonia in non-HIV immunocompromised patients with pulmonary infiltrates. Chest 2009;135: 655–61. Hui M, Kwok WT. Pneumocystis carinii pneumonia in Hong Kong: a 10 year retrospective study. J Med Microbiol 2006; 55:85–8. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis 1989;11:954–63. El-Faramawi M, Rohr N, Jespersen B. Steroid-free immunosuppression after renal transplantation – long-term experience from a single centre. Nephrol Dial Transplant 2006;21: 1966–73. Gordon SM, LaRosa SP, Kalmadi S, Arroliga AC, Avery RK, Truesdell-LaRosa L, et al. Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued? Clin Infect Dis 1999;28:240–6. Rodriguez M, Fishman JA. Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients. Clin Microbiol Rev 2004;17:770–82, table of contents. Gerrard JG. Pneumocystis carinii pneumonia in HIV-negative immunocompromised adults. Med J Aust 1995;162: 233–5. Radisic M, Lattes R, Chapman JF, del Carmen Rial M, Guardia O, Seu F, et al. Risk factors for Pneumocystis carinii pneumonia in kidney transplant recipients: a case-control study. Transpl Infect Dis 2003;5:84–93. Benedetti E, Sileri P, Pursell KJ, Giacomoni A, Tzoracoleftherakis E, Rastellini C, et al. Treatment of severe pneumonia in kidney transplant recipients. Transplant Proc 2001; 33:3652. De Boer MGJ, Kroon FP, le Cessie S, de Fijter JW, van Dissel JT. Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis. Transpl Infect Dis 2011; 13:559–69.
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Pneumocystis jirovecii pneumonia in patients with ESRD [31] Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 2010;77:299–311. [32] European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.7.1 Late infections. Pneumocystis carinii pneumonia. Nephrol Dial Transplant 2002;17(Suppl 4): 36–9. [33] Martin SI, Fishman JA. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant 2013;13(Suppl 4): 272–9. [34] Dominguez J, Mahalati K, Kiberd B, McAlister VC, MacDonald AS. Conversion to rapamycin immunosuppression in renal transplant recipients: report of an initial experience. Transplantation 2000;70:1244–7. [35] Eitner F, Hauser IA, Rettkowski O, Rath T, Lopau K, Pliquett RU, et al. Risk factors for Pneumocystis jiroveci pneumonia (PcP) in renal transplant recipients. Nephrol Dial Transplant 2011;26:2013–7.
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[36] Kahan BD, Julian BA, Pescovitz MD, Vanrenterghem Y, Neylan J. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. Transplantation 1999;68:1526–32. [37] Lufft V, Kliem V, Behrend M, Pichlmayr R, Koch KM, Brunkhorst R. Incidence of Pneumocystis carinii pneumonia after renal transplantation. Impact of immunosuppression. Transplantation 1996;62:421–3. [38] Arichi N, Kishikawa H, Mitsui Y, Kato T, Nishimura K, Tachikawa R, et al. Cluster outbreak of Pneumocystis pneumonia among kidney transplant patients within a single center. Transplant Proc 2009;41:170–2. [39] Bensousan T, Garo B, Islam S, Bourbigot B, Cledes J, Garre M. Possible transfer of Pneumocystis carinii between kidney transplant recipients. Lancet 1990;336:1066–7. [40] Gianella S, Haeberli L, Joos B, Ledergerber B, Wüthrich RP, Weber R, et al. Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients. Transpl Infect Dis 2010;12:1–10.
ORIGINAL ARTICLE
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Pneumocystis jirovecii pneumonia in patients with end-stage renal disease: a comparison with the general population
STEFFEN LETH1, SØREN JENSEN-FANGEL1, LARS ØSTERGAARD1, ANDREAS ARENDTSEN ROSTVED2, BENTE JESPERSEN3 & OLE SCHMELTZ SØGAARD1 From the 1Department of Infectious Diseases, Aarhus University Hospital, Aarhus, 2Department of Nephrology P, Rigshospitalet, Copenhagen, and 3Department of Nephrology, Aarhus University Hospital, Aarhus, Denmark
Abstract Background: Data on occurrence and risk factors for pneumocystis pneumonia (PCP) in patients with end-stage renal disease (ESRD) are sparse. Methods: This was a nationwide population-based study assessing occurrence and risk factors for PCP among patients with ESRD and population controls over a 21-year period (1/1 1990 to 31/12 2010). Using Danish registry data, first-time diagnoses of PCP were identified. Results: We identified 13 296 adult patients with ESRD and 244 255 controls, yielding 63 560 and 2 223 660 person-years of follow-up (PYFU), respectively. Fifty-eight first-time diagnoses of PCP were recorded in the ESRD group. Forty-six episodes occurred among renal transplant recipients (RTx) and 12 among haemodialysis patients (HD), yielding incidence rates of 181 (136–242) and 43.1 (24.5–75.9) per 100 000 PYFU. Compared to population controls, we found incidence rate-ratios of 125.9 (78.4–204) among RTx and 29.9 (14.1–59.7) among HD patients. Risk factors for PCP in RTx were age 50–65 years, age ⬎ 65 years, diabetes, polycystic kidney disease and hypertensive kidney disease/nephrosclerosis with an IRR of 2.22 (1.14–4.31), 3.12 (1.35–7.21), 3.44 (1.16–10.2), 4.25 (1.55–11.7) and 3.87 (1.49–10.0), respectively, and more than 36 months of dialysis before transplantation with an IRR of 1.99 (1.03–3.84). Among RTx the risk of PCP was highest during the first 6 months post-transplantation and increased from the beginning (IR1990–94 ⫽ 111 (46.3–267) per 100 000 PYFU) towards the end of the study period (IR2005–10 ⫽ 299 (203–439)). Conclusion: The PCP risk is substantial in RTx within the first 6 months of transplantation, emphasizing the potential benefit of prophylactic treatment in the early post-transplant period. Importantly, we identified subgroups within the RTx group that require more attention.
Keywords: End-stage renal disease, renal transplant recipients, pneumocystis pneumonia, risk factors
Introduction A wide range of infections occur in solid organ transplant recipients, mainly as a result of the iatrogenic immunosuppression, which primarily inhibits T-cell activation and effector functions [1,2]. The resulting non-specific immunosuppression increases the susceptibility to infections. Multiple studies have shown that the incidence of various infection-related cancer types [3], infections such as pneumonia, including pneumocystis pneumonia (PCP) [4], sepsis, herpes zoster and urinary tract infections constitute a considerable burden to renal transplant recipients (RTx) on active immunosuppressive therapy [5–9].
Pneumocystis jirovecii is a ubiquitous organism with a unique tropism for the lungs, normally residing in the alveoli without invading the host; the reservoir of P. jirovecii is strictly human. Symptomatic infection with P. jirovecii occurs primarily in immunosuppressed patients [10]. Subclinical colonization is possible and serological response to P. jirovecii organisms has been detected in healthy children from the age of 2 years [11–13]. De novo infection is probably acquired by person–person aerosol transmission either from immunocompetent to immunocompromised individuals, or among immunocompromised patients, for example, during hospitalization [14–17].
Correspondence: Steffen Leth, Department of Infectious Diseases, Aarhus University Hospital, Brendstrupgaardsvej 100 - 8200 Aarhus N, Denmark. Tel: ⫹ 45 78452824. Fax: ⫹ 45 78452804. E-mail: [email protected] (Received 18 January 2014 ; accepted 1 June 2014 ) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2014.936492
Pneumocystis jirovecii pneumonia in patients with ESRD The primary objective of this population-based study was to investigate the incidence of PCP among RTx and patients receiving chronic dialysis (peritoneal or haemodialysis) in Denmark. We further aimed to compare the incidence of PCP in patients with end-stage renal disease (ESRD) with the incidence in a matched background population without known renal disease. Potential risk factors for PCP among RTx patients were assessed. Finally, we estimated 30- and 90-day mortality in RTx and dialysis patients and population controls following hospitalization for PCP.
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patient was diagnosed with ESRD. The two cohorts were mutually exclusive. Follow-up Patients were followed from 1 January 1990 or date of first diagnosis of ESRD in the DNR and until date of first PCP diagnosis, death, immigration or 31 December 2010, whichever came first. Population controls were enrolled at the time of their matched ESRD patient.
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Validation of diagnosis of P. jirovecii pneumonia Materials and methods Population, setting and identification In Denmark, there are approximately 650 new cases of ESRD annually on renal replacement therapy defined as renal transplantation or dialysis for more than 90 days. Since 1 January 1990, patients with ESRD on renal replacement therapy have been systematically recorded in the Danish Nephrology Registry (DNR). In August 2010, the DNR contained data from approximately 14 000 patients with ESRD of whom 4100 had had at least one successful renal transplant. Apart from information on the treatment of chronic renal failure, the DNR contains demographic information, transplant waiting list data and tissue types of recipient and donor. Other data sources included the Danish National Patient Registry (DNPR), which contains hospital discharge information from 1977 and onwards. In the DNPR we identified discharge diagnosis of PCP using the International Classification of Diseases (ICD-8) (13600 ⫹ 13603) (1977–1993) and (ICD-10) codes (DB59 Pneumocystosis) (1994 to present). Follow-up information was obtained from the Danish Civil Registration System (CRS), using the unique 10-digit personal registration number assigned at birth or immigration to Denmark. Study design This was a nationwide population-based cohort study including all adult patients (ⱖ 18 years of age) with ESRD in Denmark from 1 January 1990 to 31 December 2010. We categorized patients with ESRD into three groups: (1) peritoneal dialysis (PD); (2) haemodialysis (HD) and (3) renal transplant recipients with a functioning graft (RTx). To estimate the burden of PCP, patients were matched for age and gender with up to 19 background population controls without known chronic renal disease. Controls were sampled from the CRS on the day the index
To validate the PCP diagnosis identified in the DNPR, the medical records from all PCP cases in the ESRD group were reviewed. The diagnosis of PCP was confirmed by documentation of the organism by stained microscopy or by polymerase chain reaction (PCR) using either bronchoalveolar lavage (BAL) fluid or induced sputum/tracheal suction. Further information was collected on recipient status regarding tuberculosis (TB), hepatitis C (HCV), human immunodeficiency virus 1 ⫹ 2 (HIV), clinical presentation and immunosuppressive therapy with the latest discharge regimen before PCP diagnosis. Cytomegalovirus (CMV) status and CMV disease post transplant were also assessed, but not included in the analyses due to incomplete data. Statistical analysis Incidence rates (IRs), incidence rate-ratios (IRRs) and mortality. IRs of first-time hospitalization for PCP were computed for ESRD patients and matched population controls. Further, we used Poisson regression to explore risk factors for first-time admission with PCP in RTx recipients. Finally, 30- and 90-day mortality following hospitalization for PCP was computed using the life table technique. Risk factors. The following variables were considered in a Poisson regression analysis: sex, age, cause of ESRD (glomerulonephritis, diabetes mellitus (DM) type 1 and 2, chronic interstitial nephritis (CIN), hypertensive kidney disease/nephrosclerosis, polycystic kidney disease, vasculitis and others). Treatment era was analysed in four strata (1990–94, 1995–99, 2000–04 and 2005–10); time in dialysis before RTx was analysed in three strata (0–12 months, 13–36 months and ⬎ 36 months); time from RTx diagnosis was analysed in four strata (⬍ 6 months, 6–12 months, 13–24 months and ⬎ 24 months) and finally donor type (deceased, living donor family and living donor not-family) was registered. Differences were considered statistically significant at a p value ⬍ 0.05.
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To identify independent risk factors, an adjusted Poisson regression analysis was conducted including the following variables: live versus diseased donor, age, sex, time from RTx and treatment era. We used Stata software, version 11.0 (StataCorp, College Station, TX, USA) for statistical analyses. The study was approved by the Danish Data Protection Agency.
Results
Characteristics of RTx patients with PCP Forty-one (89.1%) patients who developed PCP had not received prophylactic co-trimoxazole. The discharge immunosuppressive regimen leading up to PCP-related hospitalization included steroids in 41 of 46 Rtx patients (89.1%), cyclosporine in 26 patients (56.5%), tacrolimus in 8 (17.4%), mycophenolate mofetil (MMF) in 20 (43.4%) and azathioprine in 17 patients (36.9%) (Table II). Characteristics of the 58 adult patients with ESRD and PCP are shown in Table III.
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Study population We identified 13 296 adult patients with ESRD and 244 255 population controls, contributing 63 560 and 2 223 660 person-years of follow-up (PYFU), respectively. A first-time hospitalization for PCP was identified in 58 patients with ESRD (46 RTx, 0 PD and 12 HD patients) and in 32 matched population controls (Table I). The median age at PCP diagnosis for all PCP cases, background population and HD subgroup was 59.2 years (interquartile range (IQR) 48.4–68.6 years), 68.8 years (IQR 62.8–75.4 years) and 47.4 years (IQR 33.4–63.2 years), respectively. Incidence rates and incidence rate-ratios The IRs of first-time hospitalization for PCP among patients with ESRD and population controls were 87.7 (95% confidence interval (CI): 67.9–114) and 1.43 (95% CI: 1.02–2.04) per 100 000 PYFU, respectively, corresponding to an IRR of 60.9 (95% CI: 39.6–93.9). IRs of first-time hospitalization for PCP in the RTx and HD groups were 181 (95% CI: 136–242) and 43.1 (95% CI: 24.5–75.9) per 100 000 PYFU, respectively, corresponding to an IRR of 126 (95% CI: 78.4–204) and 29.9 (95% CI: 14.0– 59.7) compared to the background population (Table I).
Risk factors for PCP among RTx patients In the 46 RTx patients that developed PCP, the strongest risk factor for PCP in the unadjusted analysis was time since RTx (Table IV). Thirty of the 46 PCP cases among RTx patients occurred within the first 6 months after transplantation. The IR of first PCP dropped from 891 (95% CI: 623–1300) per 100 000 PYFU within the first 6 months to 59.7 (95% CI: 33.1–108) per 100 000 PYFU ⬎ 24 months after RTx (IRR 14.9, 95% CI: 7.47–29.8). The incidence of PCP among RTx patients increased from the beginning towards the end of the study period, with an IR of 111 (95% CI 46.3–267) per 100 000 PYFU in 1990–94, to an IR of 299 (95% CI 203–439) per 100 000 PYFU from 2005 to 2010. In an adjusted analysis of risk factors for PCP among RTx patients the following variables were independent risk factors for PCP: age 50–65 years (IRR 3.44, 95% CI: 1.68–7.06), age ⬎ 65 years (IRR 6.35, 95% CI: 2.42–16.6), time since RTx ⬍ 6 months (IRR 41.4, 95% CI: 19.1–89.7), time from RTx 6–12 months (IRR 9.08, 95% CI: 2.78–29.7) and treatment era 2005–2010 (IRR 4.93, 95% CI: 1.82–13.4). Additionally, 21.7% of patients experienced an episode of rejection followed by treatment with highdose steroids preceding their PCP diagnosis (Table II).
Table I. Incidence rates (IR) and rate-ratios (IRR) of pneumocystis pneumonia (PCP) among persons with end-stage renal disease (ESRD) and population controls.
Group Background controls ESRD Subdivideda PD HD Rtx
No.
No. of PCP
PYFU
IR (95% CI) (per 100 000 person-years)
24 4255 13 296
32 58
2 223 660 63 560
1.43 (1.02–2.04) 87.7 (67.8–113.5)
1 (reference) 60.9 (39.6–93.9) ⬍ 0.001
0 12 46
10 320 27 840 25 400
43.1 (24.5–75.9) 181 (136–242)
29.9 (14.0–59.7) ⬍ 0.001 126 (78.4–204) ⬍ 0.001
IRR (95% CI)
p value
The ESRD group was subdivided into peritoneal dialysis (PD), haemodialysis (HD) and renal transplant recipients with a functioning graft (RTx). aPatients may contribute with risk time in more than one category.
Pneumocystis jirovecii pneumonia in patients with ESRD Table II. Characteristics of 58 adult patients with end-stage renal disease and pneumocystis pneumonia (PCP).
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Characteristic No. Diagnostics Bronchoalveolar lavage (BAL) Microscopy PCR Induced sputum/tracheal suction Microscopy PCR Treatment on clinical presentation Missing data CMV status Donor CMV positive Donor CMV negative Donor CMV status missing Recipient CMV positive Recipient CMV negative Recipient CMV status missing Other transplant factors Tuberculosis positive Hepatitis B positive (HBsAg positive) Discharge immunosuppression leading up to hospitalization due to PCP diagnosis Steroids Sirolimus Mycophenolate mofetil (MMF) Tacrolimus Azathioprine Cyclosporine Everolimus Missing data Anti-rejection medications Steroids Thymoglobulin Muromonab-CD3 (OKT3) PCP prophylaxis Yes No Data missing
PCP in RTx (%)a 46
12
39 (84.8%) 37 (80.4%) 2 (4.3%) 5 (10.8%) 2 (4.3%) 3 (6.5%) 1 (2.2%) 1 (2.2%) 14 11 21 13 22 11
PCP in non-RTx (%)
7 (58.3%)
2 (16.7%)
3 (25.0%)
(30.4%) (23.9%) (45.7%) (28.3%) (47.8%) (23.9%)
1 (2.2%) 1 (2.2%)
41(89.1%) 1 (2.2%) 20 (43.4%) 8 (17.4%) 17 (36.9%) 26 (56.5%) 1 (2.2%)
9 (75.0%)
1 (8.3%) 3 (25.0%)
Table III. Supplementary characteristics of 58 adult patients with end-stage renal disease and pneumocystis pneumonia (PCP).
Characteristic No. Induction therapy Steroids IL-2 receptor antibody Antithymocyte globulin (ATGAM and thymoglobulin) Data missing Discharge immunosuppression leading up to hospitalization due to PCP diagnosis by combinations Cyclosporine, MMF and steroids Cyclosporine, azathioprine and steroids Cyclosporine and steroids Cyclosporine, cyclophosphamide and steroids Tacrolimus, MMF and steroids Tacrolimus and MMF Sirolimus, MMF and steroids Sirolimus and steroids Everolimus, MMF and steroids Data missing Clinical/paraclinical presentation Fever (⬎ 38°C) Fever, data missing Dyspnoea Dyspnoea, data missing Cough Cough, data missing Infiltrates on chest X-ray Infiltrates on chest X-ray, data missing
PCP in RTx (%) 46
PCP in non-RTx (%) 12
1 (2.2%) 16 (34.8%) 4 (8.7%) 25 (54.3%)
12 (26.1%) 18 (39.1%) 2 (4.3%) 1 (2.2%) 7 1 0 1 2
(15.2%) (2.2%)
36 10 40 6 28 18 36 10
(78.3%) (21.7%) (86.9%) (13.0%) (60.9%) (39.1%) (78.3%) (21.7%)
(2.2%) (4.3%)
6 6 8 4 6 6 8 4
(50.0%) (50.0%) (66.7%) (33.3%) (50.0%) (50.0%) (66.7%) (33.3%)
MMF, mycophenolate mofetil.
10 (21.7%) 1 (2.2%) 2 (4.3%) 2 (4.3%) 41 (89.1%) 3 (6.5%)
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2 (16.7%) 8 (66.7%) 2 (16.7%)
aPercentage with one decimal rounded up to the nearest whole number, therefore not all groups add up to 100%.
Mortality following hospitalization for PCP In the RTx group 30-day mortality after hospitalization for PCP was 4.4% (95% CI 1.1–16.3%) compared with 8.3% (95% CI 1.2–46.1%) in the HD group and 28.9% (95% CI 17.2–46.2) in the population controls. Further, 90-day mortality in the RTx, HD and population groups was 8.9% (95% CI 3.4– 21.9%), 50% (95% CI 26.4–79.2%) and 34.2% (95% CI 21.5–51.5%), respectively. Validation of P. jirovecii pneumonia diagnosis According to the DNPR, 59 patients with ESRD had a discharge diagnosis of PCP. Of these, 47 were in
the RTx group and 12 in the non-RTx group. In the RTx group, one patient was misclassified with PCP and one was treated on clinical suspicion without any diagnostic sampling, but was kept in the analysis. A medical record review identified a total of 45 patients with a confirmed PCP diagnosis and 1 was treated on clinical suspicion of PCP. Underlying predisposing conditions for P. jirovecii in the background control population Diagnoses of the 32 cases of PCP in the background population were reviewed and divided into the following groups. Haematologic malignancy, 16 cases (50%); organ transplantation (other than kidney), 2 cases (6.3%); inflammatory conditions, such as rheumatoid arthritis and granulomatosis with polyangiitis (Wegener’s), 4 cases (12.5%); solid tumors, 1 case (3.1%); other miscellaneous conditions, 6 cases (18.7%) and HIV-positive, 3 cases (9.4%). Unfortunately, data on immunosuppressive treatment in the background population was not available.
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S. Leth et al. Table IV. Risk factors for pneumocystis pneumonia (PCP) among adult renal transplant recipients (n = 3919).
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Variable Sex Female Male Age (years) ⬍ 50 50–65 ⬎ 65 Morbus Glomerulonephritis DM1 DM2 CIN Hypertensive kidney disease/nephrosclerosis Polycystic kidney disease Vasculitis Others Treatment era 1990–94 1995–99 2000–04 2005–10 Time in dialysis before Rtx 0–12 months 13–36 months ⬎ 36 months Time from Rtx ⬎ 24 months 13–24 months 6–12 months ⬍ 6 months Live vs deceased donor Deceased Live donor “not family” Live donor “family”
No. of PCP cases ⫽ 46
Incidence rate (95% CI) (per 100 000 person-years)
Incidence rate ratio (95% CI)
p value
13 33
134 (77.9–231) 210 (149–296)
1 (Reference) 1.57 (0.82–2.97)
0.17
14 23 9
107 (63.6–181) 238 (158–358) 335 (174–643)
1 (Reference) 2.22 (1.14–4.31) 3.12 (1.35–7.21)
0.019 0.008
6 7 1 5 14
70.8 243 374 149 274
1 3.44 5.28 2.10 3.87
(Reference) (1.16–10.2) (0.64–43.9) (0.64–6.88) (1.49–10.0)
0.026 0.12 0.22 0.006
10 2 1
301 (162–560) 349 (87.4–1400) 70.8 (9.97–502)
4.25 (1.55–11.7) 4.93 (0.99–24.6) 0.99 (0.12–8.30)
0.005 0.051 1.00
5 7 8 26
111 125 121 299
1 1.12 1.09 2.69
(Reference) (0.36–3.54) (0.36–3.34) (1.03–7.00)
0.84 0.88 0.04
20 10 16
144 (92.9–223) 168 (90.5–312) 287 (176–468)
1 (Reference) 1.17 (0.55–2.49) 1.99 (1.03–3.84)
0.69 0.04
11 1 4 30
59.7 42.4 319 891
1 0.71 5.34 14.9
37 3 4
190 (138–262) 161 (51.7–498) 99.1 (37.2–264)
(31.8–158) (116–511) (52.7–2700) (61.9–357) (162–462)
(46.3–267) (59.5–262) (60.7–243) (203–439)
(33.1–108) (5.97–301) (120–850) (623–1300)
(Reference) (0.09–5.49) (1.70–16.8) (7.47–29.8)
1 (Reference) 0.85 (0.26–2.74) 0.52 (0.19–1.47)
0.74 0.004 ⬍ 0.001
0.78 0.22
Total person-years of follow-up (PYFU) ⫽ 25400. PCP-specific incidence ratios (IR) and incidence rate-ratios (IRR) during follow-up 1990–2010. CI, confidence interval; CIN, chronic interstitial nephritis; DM, diabetes; IR, incidence rate; IRR, incidence rate ratio; RTx, renal transplant.
Discussion In this nationwide study on PCP in patients with ESRD in Denmark covering a period of 21 years, we found that PCP, although rare, remains a significant opportunistic infection among RTx patients when compared with matched controls without ESRD, occurring primarily within the first 6 months after transplantation. Importantly, we identified specific subgroups within the RTx group that require more attention (Table IV). The majority of patients (89%) received steroids as part of the immunosuppressive regimen in the year leading up to the PCP diagnosis. Thus, these findings add to the current knowledge of PCP in RTx patients and highlight the potential benefit of co-trimoxazole prophylaxis in the first 6 months following transplantation.
The sum of factors affecting the level of immunosuppression includes among others type of immunosuppressive therapy, treatment duration and intensity (including intensification to preserve graft function). Metabolic conditions such as diabetes and uraemia could also contribute to the risk [18]. The upward trend at the end (2005–10) of the 21-year study period is not fully clarified, but could be partially explained by a small coincident nosocomial accumulation in one geographic location [19]. The diagnostic approach has not changed since 2000, where PCR was added as a routine to the diagnostic methods alongside microscopy. Possible explanations could be increased awareness of PCP with intensified diagnostic efforts, for example, BAL with microscopy and/or PCR for PCP on BAL fluid. In the RTx group, we found that 39 (84.7%) of the
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Pneumocystis jirovecii pneumonia in patients with ESRD PCP diagnoses in this study were made on BAL fluid. The diagnostic yield of microscopy with staining on BAL fluid in HIV-positive patients has been shown to be over 90%, but may be lower in HIVnegative patients due to an expected lower organism burden [20]. Further, supplementary PCR on BAL fluid has been shown to increase the diagnostic yield compared with conventional staining alone [21]. However, PCP may be shown by PCR in BAL fluid without being invasive, and there could be a slight over-diagnosis as five cases were diagnosed on PCR alone (two on BAL and three on induced sputum, respectively), which could be false positives or of no clinical significance (Table III). In the RTx group, we found that 89.1% of the combined immunosuppressive therapy included steroids in the year leading up to their PCP diagnosis; this is consistent with previous studies [22,23]. Further, 21.7% had an episode of rejection treated with high-dose steroids preceding their PCP diagnosis; this is also consistent with previous studies [2]. This finding suggests that steroid minimization might be of value in the prevention of PCP, but the fraction of the total population of RTx patients on steroid-free regimens was not available, although one of the Danish transplant centres avoided prednisolone completely in 71% of cases [24]. The lower 30- and 90-day mortality in the RTx group compared with the background population controls may be explained by the increased awareness of pulmonary symptoms and early evaluation in this group leading to faster diagnosis. We had too few non-RTx patients that developed PCP to conduct a separate risk factor analysis. However, it is noteworthy that 75% received steroids as a part of the immunosuppressive treatment in the non-RTx group. The 32 PCP cases in the control population were all well explained by underlying immunosuppressive conditions such as haematologic malignancy and organ transplantation other than RTx. The risk of PCP in RTx recipients is highest between the second and the sixth months after transplantation, with a described attack rate between 0.6 and 14% in transplant recipients not receiving prophylaxis, but has also been described to occur beyond 1 year. This coincides with our data where 12 cases of PCP occurred beyond 1 year [4,25,26]. Although PCP in RTx recipients occurs with the lowest rates compared with other solid organ transplant recipients [27,28], it is a recognized cause of morbidity and mortality in kidney transplant recipients [29]. Additionally, age above 50 years of age is a significant risk factor for PCP in the RTx group, which is consistent with the literature [30]. In HIV-infected individuals, the use of PCP prophylaxis is guided by peripheral blood CD4⫹ T-cell count to assess the
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individual risk of PCP. Unfortunately such a straightforward parameter is still lacking to evaluate the immunological status for patients without HIV infection. However, PCP prophylaxis can be initiated during episodes of high immunosuppressive load such as at transplantation and when initiating rejection therapy. The current international recommendations for PCP prophylaxis are diverse, and during the period of our study PCP prophylaxis was not standard practice at all transplant centres in Denmark. The European Renal Transplant Guidelines now recommend PCP prophylaxis for at least 4 months after RTx; the American Society of Transplantation generally recommends 6–12 months for all solid organ transplant recipients and The Kidney Disease Improving Global Outcomes guideline recommends 3–6 months post transplant [31–33]. In our RTx group, 30 of the 46 patients developed PCP within the first 6 months after transplantation. Among the patients in the present study, 89.1% did not receive PCP prophylaxis before hospitalization for PCP. This study had several strengths, including the possibility to extract data from highly valid registries such as the Danish Civil Registration System, the Danish Nephrology Registry and the Danish National Patient Registry. Further, the long period of follow-up and the use of population-based, nationwide cohorts and the large study sample increased the statistical precision. Additionally, we validated the PCP diagnosis to minimize the possibility of coding errors. Our study also had some limitations. We had no information on immunosuppressive therapy in the remaining ESRD patients, including RTx patients who did not develop PCP. Thus, we could not assess the impact of individual immunosuppressive drugs on the risk of PCP. This information could have provided important information in relation to the risk profile for developing PCP, as indicated in several studies [4,28,34–37]. Finally, we had no data on whether the PCP cases were coinciding at one geographical location as reported in other studies [14,16,17,38–40]. Conclusion In a Danish nationwide study PCP was an increasing problem in RTx recipients over the past two decades. Our findings support the use of PCP prophylaxis in the early post-transplant period. Additionally, our study draws attention to potential subgroups within the RTx group, only scarcely described in the literature, which could benefit from more attention and a longer period of PCP prophylactic treatment.
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Acknowledgments We would like to thank James Heaf for providing the data from the Danish Nephrology Registry and we would like to thank the Danish Nephrology Society.
[15]
[16]
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. [17]
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References [1] Kelly PA, Burckart GJ, Venkataramanan R. Tacrolimus: a new immunosuppressive agent. Am J Heal Syst Pharm 1995;52: 1521–35. [2] Weir MR, Mulgaonkar S, Chan L, Shidban H, Waid TH, Preston D, et al. Mycophenolate mofetil-based immunosuppression with sirolimus in renal transplantation: a randomized, controlled Spare-the-Nephron trial. Kidney Int 2011;79:897–907. [3] Van Leeuwen MT, Webster AC, McCredie MRE, Stewart JH, McDonald SP, Amin J, et al. Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study. BMJ 2010; 340:c570. [4] Neff RT, Jindal RM, Yoo DY, Hurst FP, Agodoa LY, Abbott KC. Analysis of USRDS: incidence and risk factors for Pneumocystis jiroveci pneumonia. Transplantation 2009;88: 135–41. [5] Alangaden GJ, Thyagarajan R, Gruber SA, Morawski K, Garnick J, El-Amm JM, et al. Infectious complications after kidney transplantation: current epidemiology and associated risk factors. Clin Transplant 2006;20:401–9. [6] Grimaldi A, Barletta A, Rascente M, Pisani F, Iaria G, Maccarone D, et al. Infectious complications in the renal transplant recipient. Transplant Proc 2005;37:2502–3. [7] Pourmand G, Salem S, Mehrsai A, Taherimahmoudi M, Ebrahimi R, Pourmand MR. Infectious complications after kidney transplantation: a single-center experience. Transpl Infect Dis 2007;9:302–9. [8] Gunst JD, Jensen-Fangel S, Jespersen B, Ostergaard L, Søgaard OS. Central nervous system infections among individuals with and without end-stage renal disease. J Infect 2013;67:19–26. [9] Nielsen LH, Jensen-Fangel S, Jespersen B, Ostergaard L, Søgaard OS. Risk and prognosis of hospitalization for pneumonia among individuals with and without functioning renal transplants in Denmark: a population-based study. Clin Infect Dis 2012;55:679–86. [10] Afessa B. Pulmonary complications of HIV Infection. Chest J 1998;113:1225. [11] Meuwissen JH, Tauber I, Leeuwenberg AD, Beckers PJ, Sieben M. Parasitologic and serologic observations of infection with Pneumocystis in humans. J Infect Dis 1977;136:43–9. [12] Ponce CA, Gallo M, Bustamante R, Vargas SL. Pneumocystis colonization is highly prevalent in the autopsied lungs of the general population. Clin Infect Dis 2010;50:347–53. [13] Vargas SL, Hughes WT, Santolaya ME, Ulloa AV, Ponce CA, Cabrera CE, et al. Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants. Clin Infect Dis 2001;32:855–61. [14] Hirschl MM, Derfler K, Janata O, Heinz G, Sertl K, Balcke P. Accumulation of Pneumocystis carinii pneumonia in
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
patients after kidney transplantation. Clin Nephrol 1992; 37:105. Schmoldt S, Schuhegger R, Wendler T, Huber I, Söllner H, Hogardt M, et al. Molecular evidence of nosocomial Pneumocystis jirovecii transmission among 16 patients after kidney transplantation. J Clin Microbiol 2008;46: 966–71. De Boer MGJ, Bruijnesteijn van Coppenraet LES, Gaasbeek A, Berger SP, Gelinck LBS, van Houwelingen HC, et al. An outbreak of Pneumocystis jiroveci pneumonia with 1 predominant genotype among renal transplant recipients: interhuman transmission or a common environmental source? Clin Infect Dis 2007;44:1143–9. De Boer MGJ, de Fijter JW, Kroon FP. Outbreaks and clustering of Pneumocystis pneumonia in kidney transplant recipients: a systematic review. Med Mycol 2011;49: 673–80. Fishman JA; AST Infectious Diseases Community of Practice. Introduction: infection in solid organ transplant recipients. Am J Transplant 2009;9(Suppl 4):S3–6. Rostved AA, Sassi M, Kurtzhals JA, Sørensen SS, Rasmussen A, Ross C, et al. Outbreak of pneumocystis pneumonia in renal and liver transplant patients caused by genotypically distinct strains of Pneumocystis jirovecii. Transplantation 2013;96:834–42. Shelhamer JH, Gill VJ, Quinn TC, Crawford SW, Kovacs JA, Masur H, et al. The laboratory evaluation of opportunistic pulmonary infections. Ann Intern Med 1996;124:585–99. Azoulay E, Bergeron A, Chevret S, Bele N, Schlemmer B, Menotti J. Polymerase chain reaction for diagnosing pneumocystis pneumonia in non-HIV immunocompromised patients with pulmonary infiltrates. Chest 2009;135: 655–61. Hui M, Kwok WT. Pneumocystis carinii pneumonia in Hong Kong: a 10 year retrospective study. J Med Microbiol 2006; 55:85–8. Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis 1989;11:954–63. El-Faramawi M, Rohr N, Jespersen B. Steroid-free immunosuppression after renal transplantation – long-term experience from a single centre. Nephrol Dial Transplant 2006;21: 1966–73. Gordon SM, LaRosa SP, Kalmadi S, Arroliga AC, Avery RK, Truesdell-LaRosa L, et al. Should prophylaxis for Pneumocystis carinii pneumonia in solid organ transplant recipients ever be discontinued? Clin Infect Dis 1999;28:240–6. Rodriguez M, Fishman JA. Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients. Clin Microbiol Rev 2004;17:770–82, table of contents. Gerrard JG. Pneumocystis carinii pneumonia in HIV-negative immunocompromised adults. Med J Aust 1995;162: 233–5. Radisic M, Lattes R, Chapman JF, del Carmen Rial M, Guardia O, Seu F, et al. Risk factors for Pneumocystis carinii pneumonia in kidney transplant recipients: a case-control study. Transpl Infect Dis 2003;5:84–93. Benedetti E, Sileri P, Pursell KJ, Giacomoni A, Tzoracoleftherakis E, Rastellini C, et al. Treatment of severe pneumonia in kidney transplant recipients. Transplant Proc 2001; 33:3652. De Boer MGJ, Kroon FP, le Cessie S, de Fijter JW, van Dissel JT. Risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients and appraisal of strategies for selective use of chemoprophylaxis. Transpl Infect Dis 2011; 13:559–69.
Scand J Infect Dis 2014.46:704-711. Downloaded from informahealthcare.com by Kainan University on 04/19/15. For personal use only.
Pneumocystis jirovecii pneumonia in patients with ESRD [31] Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 2010;77:299–311. [32] European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.7.1 Late infections. Pneumocystis carinii pneumonia. Nephrol Dial Transplant 2002;17(Suppl 4): 36–9. [33] Martin SI, Fishman JA. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant 2013;13(Suppl 4): 272–9. [34] Dominguez J, Mahalati K, Kiberd B, McAlister VC, MacDonald AS. Conversion to rapamycin immunosuppression in renal transplant recipients: report of an initial experience. Transplantation 2000;70:1244–7. [35] Eitner F, Hauser IA, Rettkowski O, Rath T, Lopau K, Pliquett RU, et al. Risk factors for Pneumocystis jiroveci pneumonia (PcP) in renal transplant recipients. Nephrol Dial Transplant 2011;26:2013–7.
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[36] Kahan BD, Julian BA, Pescovitz MD, Vanrenterghem Y, Neylan J. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group. Transplantation 1999;68:1526–32. [37] Lufft V, Kliem V, Behrend M, Pichlmayr R, Koch KM, Brunkhorst R. Incidence of Pneumocystis carinii pneumonia after renal transplantation. Impact of immunosuppression. Transplantation 1996;62:421–3. [38] Arichi N, Kishikawa H, Mitsui Y, Kato T, Nishimura K, Tachikawa R, et al. Cluster outbreak of Pneumocystis pneumonia among kidney transplant patients within a single center. Transplant Proc 2009;41:170–2. [39] Bensousan T, Garo B, Islam S, Bourbigot B, Cledes J, Garre M. Possible transfer of Pneumocystis carinii between kidney transplant recipients. Lancet 1990;336:1066–7. [40] Gianella S, Haeberli L, Joos B, Ledergerber B, Wüthrich RP, Weber R, et al. Molecular evidence of interhuman transmission in an outbreak of Pneumocystis jirovecii pneumonia among renal transplant recipients. Transpl Infect Dis 2010;12:1–10.
