original article Wien Klin Wochenschr (2014) 126:762–766 DOI 10.1007/s00508-014-0608-3
Pneumocystis pneumonia (PCP) and Pneumocystis jirovecii carriage in renal transplantation patients: a single-centre experience Matthias Maruschke · Diana Riebold · Martha Charlotte Holtfreter · Martina Sombetzki · Steffen Mitzner · Micha Loebermann · Emil Christian Reisinger · Oliver W. Hakenberg
Received: 20 December 2012 / Accepted: 24 August 2014 / Published online: 19 September 2014 © Springer-Verlag Wien 2014
Summary Background The Pneumocystis pneumonia is an increasing problem in transplanted patients: up to 25 % suffer from Pneumocystis pneumonia, occurring during the first 6 months after transplantation. Methods From 2001 to 2009, we investigated 21 patients with pneumonia after renal transplantation for the presence of Pneumocystis jirovecii. The laboratory diagnosis was established by Grocott and Giemsa staining methods and Pneumocystis-specific mitochondrial transcribed large subunit nested polymerase chain reaction (PCR). The PCR was also used for the differentiation of Pneumocystis pneumonia from Pneumocystis carriage. Results Of 21 patients, 7 had a Pneumocystis pneumonia, 6 were Pneumocystis carriers and 8 patients were negative. Four out of seven Pneumocystis pneumonia patients and two out of six patients with Pneumocystis carriage had a delayed graft function. An acute cytomegalovirus infection after transplantation was not detectable in the patients with Pneumocystis pneumonia, but in three patients with Pneumocystis carriage. Conclusions Pneumocystis pneumonia was present in 33.3 % of transplanted patients with suspected pneumonia. An association between acute rejection or coD. Riebold, PhD () · M. C. Holtfreter, PhD · M. Sombetzki, PhD · M. Loebermann, MD · E. C. Reisinger, MD Department of Tropical Medicine and Infectious Diseases, University of Rostock Medical School, Ernst-Heydemann-Str. 6, 18055 Rostock, Germany e-mail: [email protected] M. Maruschke, MD · O. W. Hakenberg, MD Department of Urology, University of Rostock Medical School, Rostock, Germany S. Mitzner, MD Department of Nephrology, University of Rostock Medical School, Rostock, Germany
infections and Pneumocystis pneumonia or carriage in patients after renal transplantation cannot be excluded. In three out of seven Pneumocystis pneumonia patients, an overlapping of hospitalisation times and an onset of Pneumocystis pneumonia 6 months after transplantation was found. Thus, person-to-person transmission seems probable in these cases. Keywords Pneumocystis · PCP · Renal transplantation · Immunosuppression · Pneumonia
Pneumocystis Pneumonie (PCP) und Pneumocystis jirovecii Besiedlung bei Patienten nach Nierentransplantation – Erfahrungen aus einem Transplantationszentrum Zusammenfassung Hintergrund Die Pneumocystis Pneumonie stellt in zunehmendem Maße ein Problem bei Patienten nach Transplantationen dar: bis zu 25 % der Patienten erkranken an einer Pneumocystis Pneumonie, die innerhalb der ersten sechs Monate nach Transplantation auftritt. Methodik Von 2001 bis 2009 wurde bei 21 Patienten nach Nierentransplantation eine Pneumonie durch Pneumocystis jirovecii vermutet. Die Labordiagnostik erfolgte mittels Grocott- und Giemsa-Färbungen sowie Pneumocystis-spezifischer „mitochondrial transcribed large subunit“ nested PCR. Diese PCR wurde zusätzlich zur Differenzierung zwischen einer Pneumocystis Pneumonie und einer Pneumocystis Besiedelung genutzt. Ergebnisse Bei 7/21 Patienten wurde eine Pneumocystis Pneumonie nachgewiesen, 6 waren mit Pneumocystis besiedelt und 8 Patienten waren negativ. 4/7 Pneumocystis Pneumonie Patienten sowie 2/6 Patienten mit Pneumocystis Besiedlung hatten eine verzögerte Transplantat-Funktion. Eine akute Cytomegalie-Virus-Infektion nach Transplantation trat bei keinem der Pneumocystis
762 Pneumocystis pneumonia (PCP) and Pneumocystis jirovecii carriage in renal transplantation patients
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Pneumonie-Fälle und bei drei Patienten mit Pneumocystis Besiedelung auf. Schlussfolgerungen Eine Pneumocystis Pneumonie konnte bei 33,3 % der Patienten nach Nierentransplantation und Verdacht auf Pneumonie nachgewiesen werden. Eine Assoziation zwischen akuter Rejektion oder Koinfektionen und dem Auftreten einer PCP bzw. Besiedelung war nicht auszuschließen. Bei 3/7 Pneumocystis Pneumonie Patienten wurde eine Überschneidung der Hospitalisierungs-Zeiträume mit gleichzeitigem Beginn der Pneumocystis Pneumonie sechs Monate nach Transplantation festgestellt. Eine Übertragung von Person zu Person scheint in diesen Fällen sehr wahrscheinlich. Schlüsselwörter Pneumocystis · PCP · Nierentransplantation · Immunsuppression · Pneumonie
Introduction Pneumocystis jirovecii (P. jirovecii) causes severe pneumonia in immunocompromised individuals. Up to 45 % of human immunodeficiency virus (HIV) patients suffer from Pneumocystis pneumonia (PCP), but the PCP cases in this patient group are decreasing due to good antiretroviral therapy and PCP prophylaxis [1]. Otherwise, it is an increasing problem in transplanted patients: in the USA, up to 25 % of these patients suffer from a PCP [1, 2]. In Europe, PCP cases are described in 1.1–11.5 % of the transplanted patients, with rising numbers of patients [3]. Problematic is the late onset of PCP after transplantation, which occurs in most cases after 6 months or later. Additionally, due to low Pneumocystis cyst numbers in HIV-negative patients, Pneumocystis staining methods are often negative [1, 4]. In these patients, a diagnosis of PCP is only achievable by sensitive and specific polymerase chain reaction (PCR) methods, which are not the gold standard in most laboratories [5]. The reservoir of P. jirovecii is not finally determined, but it appears to be human derived. Asymptomatic carriage of P. jirovecii is considerably more common than PCP: antibodies against P. jirovecii can be detected in approximately 90 % of the population, and carriage of Pneumocystis was shown to be up to 25 % carriers in different patient groups [2, 6–11]. New studies showed that airborne transmission can occur from PCP patients, but also Pneumocystis carriers, for example health care personnel or other patients [12–14]. We report our experiences with laboratory diagnostics of PCP and Pneumocystis carriage by staining techniques combined with nested PCR in patients following renal transplantation and the necessity of close-meshed controls by PCR.
Patients and methods From 2001 to 2009, 21 out of 270 (7.8 %) renal transplant recipients from the Renal Transplant Unit of the University of Rostock, Germany, suffered from respiratory infec-
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tions. Due to clinical symptoms of fever, dry cough and interstitial infiltrates in thoracic X-ray, a possible PCP was suspected in these 21 patients. The laboratory diagnosis of PCP and Pneumocystis carriage was established from broncho-alveolar lavage (BAL) samples, with parallel examination by specific staining methods with Grocott’s methenamine silver stain (GMS, sensitivity: 60–80 %, specificity: 80 %), Giemsa stain (GS, sensitivity: 40–80 %, specificity: 60–80 %) and nested PCR for the detection of the mitochondrial transcribed large-subunit rRNA gene (mtLSU rRNA nPCR, sensitivity: 93 %, specificity: 95 %) of Pneumocystis spp. [5, 15–17]. Due to the high sensitivity of the PCR and the two-step system, a reliable laboratory differentiation between PCP and P. jirovecii carriage is possible. In our study, the laboratory definition of PCP was a positive GMS or GS stain or a PCR that was positive in both steps. Pneumocystis carriage was defined as staining techniques negative and first PCR step negative, but second step positive. Clinical and follow-up data were retrospectively taken from patient’s files. Primary renal transplant function was defined as a status not requiring more than three haemodialysis sessions after transplantation.
Results Out of 21 renal transplant patients, 7 (33.3 %) had a PCP infection and 6 (28.6 %) had a P. jirovecii carriage. Eight patients (38.1 %) were Pneumocystis negative. The mean ages of the PCP patients, Pneumocystis carriers and negative patients were 63.4, 50.3 and 55.3 years at the time of transplantation. The time between renal transplantation and clinical occurrence of pneumonia ranged from 20.7 months in PCP patients to 72.8 months in patients with P. jirovecii carriage (Table 1). Immunosuppressive regimens are shown in Table 1 according to the Pneumocystis status. The mean steroid dosage of our Pneumocystis-negative patients was significantly higher than in the PCP group (negative patients: 18.1 ± 6.5 mg/day, PCP patients: 10.7 ± 1.9 mg/day; P = 0.0205, Mann–Whitney test), but not in the carrier group (12.5 ± 4.2 mg/day). In six out of seven patients with PCP, the PCR was positive in both steps; in one patient, the diagnosis of PCP was confirmed by staining methods. All patients with PCP received a standard treatment with cotrimoxazole (100 mg/kg body weight/day sulfamethoxazole (SMX) and 20 mg/kg body weight/day trimethoprim (TMP)) for 21 days. Six out of the seven recipients had a positive cytomegalovirus (CMV) antibody status; one patient was CMV antibody negative and received a CMV-negative kidney. Three out of the seven patients with PCP showed pulmonal fungal co-infections (two with Candida spp. pneumonia, one patient with non-differentiated fungal structures in the BAL), and three developed urinary tract infections. In four PCP patients, a delayed graft function was seen, and in one patient, an acute cellular rejection had been diagnosed previously. Two out of the seven PCP patients died immediately after PCP diagnosis (mortality rate: 28.6 %; Table 1).
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Table 1 Age, time intervals, immunosuppressive therapy and complicating factors of PCP patients, Pneumocystis carriers and negative patients PCP
Carriage
Negative
7
6
8
Female
6
1
4
Male
1
5
4
Age (years) at time of transplantation
63.4 ± 13.6
50.3 ± 10.7
55.3 ± 15.0
N Sex
Age (years) at PCP diagnosis
64.3 ± 13.9
52.2 ± 11.9
59.9 ± 13.0
Time (months) between transplantation and PCP diagnosis
20.7 ± 23.7
72.8 ± 79.6
147.7 ± 161.7
CyA/MMF/prednisolone
5
1
5
Tacrolimus/MMF/prednisolone
2
4
1
Azathioprine
0
1
2
Immunosuppressive therapy
Transplant complications Acute cellular rejection
1
1
0
Delayed graft function
4
2
4
CMV antibody-positive (donor)
6
6
4
CMV antibody-positive (recipient)
6
3
3
Co-infections Urinary tract infection
3
3
1
Candida spp. pneumonia
2
1
2
Aspergillus fumigatus pneumonia
0
1
–
Active CMV infection
0
3
1
No co-infection
4
1
6
Deaths
2
1
1
All time intervals are given as mean ± standard deviation CyA cyclosporine, MMF mycophenolate mofetil, PCP Pneumocystis pneumonia, CMV cytomegalovirus
In the group with Pneumocystis carriage, all six donors but only three of the recipients were CMV antibody positive, and three recipients had an active CMV after transplantation. Two out of six patients with PCP carriage showed pulmonal fungal co-infections (Table 1). Three out of the six patients additionally had urinary tract infections. An episode of acute cellular rejection was also seen in one patient of this group. One Pneumocystis carrier died immediately after the diagnosis of Pneumocystis carriage due to severe Aspergillus fumigatus pneumonia. In three PCP cases, an overlapping of hospitalisation times after renal transplantation at the same ward with an occurrence of PCP approximately 6 months after transplantation was noted. Long-term observation showed that none of our PCP and carrier patients suffered from further PCP infections until 2010. However, one out of the five patients who survived the PCP episode died 2.1 years after transplantation due to myocardial infarction. Additionally, two Pneumocystis carriers died 1.1 and 7.3 years after transplantation due to septicaemia.
Discussion Until now, Pneumocystis diagnostics in Germany use less sensitive staining methods, which can lead to false-negative Pneumocystis results—especially in renal and other transplant patients. Highly sensitive PCR methods are not available by default. In this study, we examined 21 kidney transplant patients for the presence of P. jirovecii and identified 7 (33.3 %) PCP cases and 6 (28.6 %) Pneumocystis carriers with the standard staining methods for P. jirovecii—the GMS and the GS—and additionally with a Pneumocystisspecific mtLSU nPCR [11, 15]. Usually, only low numbers of P. jirovecii cysts are present in the lungs of HIV-negative patients, but onset of symptoms is more sudden [1, 4]. PCR methods with higher sensitivities and specificities should be used in such patients as also shown in our patients: only three out of seven PCP patients were GMS and GS positive and two other patients were only GS positive, while six out of seven patients were positive in the mtLSU nPCR. In one of our PCP patients, the PCR was inhibited, but both staining methods were positive, so the PCP could be confirmed. Although the mtLSU nPCR has a very high sensitivity of 93 % (compared with 60–80 % in the staining methods) [15], inhibitors like haemoglobin or low quantities of the samples used can rarely lead to false-negative PCR results. To avoid inhibition, in our laboratory, all bloody samples are routinely pre-treated with red cell lysis buffer before DNA isolation. However, the low volume of less than 2 ml of BAL in the PCR-negative sample in combination with possible inhibitors could explain the false-negative PCR result in this sample. We recommend the use of at least 3 ml of BAL sample or 5 ml of tracheal secretion or induced sputum for every PCR or staining method [15]. Some clusters of PCP following renal transplantation have been reported in the literature with different intervals and numbers of patients [3, 14, 18–23]. The largest series with 22 PCP patients was reported by de Boer et al. [20]. The risk of PCP infections after renal transplantation is estimated to be 5 % without prophylaxis and can be decreased to less than 2 % when using prophylaxis with TMP-SMX [24, 25]. However, the duration of PCP prophylaxis in renal transplant patients is an important point of discussion. A PCP prophylaxis guideline for these patients does not exist in Germany. Due to potential side effects of TMP-SMX, some centres never prescribed a prophylaxis, while others discontinued the PCP prophylaxis [22]. Two of our patients (28.6 %) died because of severe PCP infection. The mortality rate of patients with PCP after kidney transplantation has been reported as 29–50 % [24, 26]. PCP infections after renal transplantation occur with a postoperative interval of 2–6 months and decline to 0.5 % after 1 year [24]. This can be confirmed by the present series for some cases, but the mean time interval in our series was 20.7 months. Nevertheless, single cases of a “late onset” of PCP were reported by others as well, for example after 5, 11 and 24 years [14, 27–29]. According to this data, the duration of PCP prophylaxis should be
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given for a minimum of 6 months [30, 31]. Other authors suggest administering prophylactic TMP-SMX for the first 12 months [27] or an individualised prophylaxis in high-risk patients, e.g. after acute rejection therapy or in patients with poor renal function [22]. New studies indicate that high-dose immunotherapy with a long course of corticosteroids and treatment with anti-lymphocyte antibodies are special risk factors for PCP after renal transplantation [22] in the same manner as coinfections like CMV, tuberculosis and hepatitis C [23, 24, 32, 33]. However, in our cohort, we observed a significantly higher steroid therapy in the negative group than in the PCP patients. In contrast, high numbers of positive CMV antibody status in donors and recipients were seen in all groups of our patients. In our series, there also seemed to be an association between cases with acute rejection or co-infections and PCP or Pneumocystis carriage in transplanted patients. These results coincide with the results of other retrospective studies [22, 34], but also oppositional findings are described [12, 35]. Therefore, the routine prophylaxis for PCP with TMP-SMX as the treatment of choice in all patients with renal transplantation should be a postoperative standard and is now advised unanimously [21, 30, 31]. Routine measuring of CD4 cell counts in transplanted patients can also be a helpful marker for the severity of immunosuppression in these patients. Transmission routes of Pneumocystis jirovecii are also discussed controversially. New molecular studies postulate that transmission occurs not only via smear infection but also by air transmission [36–38]. The primary sources of infection are humans like PCP patients or also healthy carriers, including health personnel [12, 39, 40]. Contradicting this theory, de Boer et al. [20] observed PCP infections only in kidney transplant patients and not in patients after liver transplantation, although both groups used the same outpatient rooms during the same period. In our study, there was an overlap in hospitalisation at the same ward and a clinical onset of the PCP infection 6 months later in three of the patients. Thus, a direct or indirect person-to-person transmission seems to be likely in those cases. Nosocomial PCP infections were also seen in up to 57 % of the renal transplant patients [13, 14, 40–42]. Colonised patients or hospital personnel may play an important role in transmitting the fungus [13]. Therefore, it is recommended that contact of immunosuppressed persons with PCP patients should be avoided. In summary, we suggest that there may be a tendency for higher incidence of PCP infections and Pneumocystis carriage after renal transplantation in patients with a positive CMV status or a reactivation of a CMV infection. These results indicate that CMV status may be an important marker for increased risk of PCP infections or carriage. However, there are relatively small numbers of patients in this series. Thus, statistical analysis of differences could not be extensively explored. Furthermore, a history of treatment of acute rejection may be a potential risk factor [32, 33]. Additionally, we saw a higher number of patients with co-infections in the subgroups with
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significant PCP infections and Pneumocystis carriage. Therefore, all patients with these risk factors should undergo a more careful follow-up with an early diagnosis for P. jirovecii in case of respiratory infections. Since 2001, all immunocompromised patients with suspected pneumonia in our hospital—with focus on HIV-positive and renal transplant patients—were routinely screened by combined staining methods and specific nPCR for the presence of Pneumocystis spp. Additionally, we decided to implement an internal transcribed spacer PCR for the differentiation of Pneumocystis genotypes in positive patients, which can uncover patient-to-patient transmissions. Conflict of interest There are no commercial relationships or conflicts of interests. The authors declare that they did not receive any funding or grants.
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Pneumocystis pneumonia (PCP) and Pneumocystis jirovecii carriage in renal transplantation patients: a single-centre experience Matthias Maruschke · Diana Riebold · Martha Charlotte Holtfreter · Martina Sombetzki · Steffen Mitzner · Micha Loebermann · Emil Christian Reisinger · Oliver W. Hakenberg
Received: 20 December 2012 / Accepted: 24 August 2014 / Published online: 19 September 2014 © Springer-Verlag Wien 2014
Summary Background The Pneumocystis pneumonia is an increasing problem in transplanted patients: up to 25 % suffer from Pneumocystis pneumonia, occurring during the first 6 months after transplantation. Methods From 2001 to 2009, we investigated 21 patients with pneumonia after renal transplantation for the presence of Pneumocystis jirovecii. The laboratory diagnosis was established by Grocott and Giemsa staining methods and Pneumocystis-specific mitochondrial transcribed large subunit nested polymerase chain reaction (PCR). The PCR was also used for the differentiation of Pneumocystis pneumonia from Pneumocystis carriage. Results Of 21 patients, 7 had a Pneumocystis pneumonia, 6 were Pneumocystis carriers and 8 patients were negative. Four out of seven Pneumocystis pneumonia patients and two out of six patients with Pneumocystis carriage had a delayed graft function. An acute cytomegalovirus infection after transplantation was not detectable in the patients with Pneumocystis pneumonia, but in three patients with Pneumocystis carriage. Conclusions Pneumocystis pneumonia was present in 33.3 % of transplanted patients with suspected pneumonia. An association between acute rejection or coD. Riebold, PhD () · M. C. Holtfreter, PhD · M. Sombetzki, PhD · M. Loebermann, MD · E. C. Reisinger, MD Department of Tropical Medicine and Infectious Diseases, University of Rostock Medical School, Ernst-Heydemann-Str. 6, 18055 Rostock, Germany e-mail: [email protected] M. Maruschke, MD · O. W. Hakenberg, MD Department of Urology, University of Rostock Medical School, Rostock, Germany S. Mitzner, MD Department of Nephrology, University of Rostock Medical School, Rostock, Germany
infections and Pneumocystis pneumonia or carriage in patients after renal transplantation cannot be excluded. In three out of seven Pneumocystis pneumonia patients, an overlapping of hospitalisation times and an onset of Pneumocystis pneumonia 6 months after transplantation was found. Thus, person-to-person transmission seems probable in these cases. Keywords Pneumocystis · PCP · Renal transplantation · Immunosuppression · Pneumonia
Pneumocystis Pneumonie (PCP) und Pneumocystis jirovecii Besiedlung bei Patienten nach Nierentransplantation – Erfahrungen aus einem Transplantationszentrum Zusammenfassung Hintergrund Die Pneumocystis Pneumonie stellt in zunehmendem Maße ein Problem bei Patienten nach Transplantationen dar: bis zu 25 % der Patienten erkranken an einer Pneumocystis Pneumonie, die innerhalb der ersten sechs Monate nach Transplantation auftritt. Methodik Von 2001 bis 2009 wurde bei 21 Patienten nach Nierentransplantation eine Pneumonie durch Pneumocystis jirovecii vermutet. Die Labordiagnostik erfolgte mittels Grocott- und Giemsa-Färbungen sowie Pneumocystis-spezifischer „mitochondrial transcribed large subunit“ nested PCR. Diese PCR wurde zusätzlich zur Differenzierung zwischen einer Pneumocystis Pneumonie und einer Pneumocystis Besiedelung genutzt. Ergebnisse Bei 7/21 Patienten wurde eine Pneumocystis Pneumonie nachgewiesen, 6 waren mit Pneumocystis besiedelt und 8 Patienten waren negativ. 4/7 Pneumocystis Pneumonie Patienten sowie 2/6 Patienten mit Pneumocystis Besiedlung hatten eine verzögerte Transplantat-Funktion. Eine akute Cytomegalie-Virus-Infektion nach Transplantation trat bei keinem der Pneumocystis
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Pneumonie-Fälle und bei drei Patienten mit Pneumocystis Besiedelung auf. Schlussfolgerungen Eine Pneumocystis Pneumonie konnte bei 33,3 % der Patienten nach Nierentransplantation und Verdacht auf Pneumonie nachgewiesen werden. Eine Assoziation zwischen akuter Rejektion oder Koinfektionen und dem Auftreten einer PCP bzw. Besiedelung war nicht auszuschließen. Bei 3/7 Pneumocystis Pneumonie Patienten wurde eine Überschneidung der Hospitalisierungs-Zeiträume mit gleichzeitigem Beginn der Pneumocystis Pneumonie sechs Monate nach Transplantation festgestellt. Eine Übertragung von Person zu Person scheint in diesen Fällen sehr wahrscheinlich. Schlüsselwörter Pneumocystis · PCP · Nierentransplantation · Immunsuppression · Pneumonie
Introduction Pneumocystis jirovecii (P. jirovecii) causes severe pneumonia in immunocompromised individuals. Up to 45 % of human immunodeficiency virus (HIV) patients suffer from Pneumocystis pneumonia (PCP), but the PCP cases in this patient group are decreasing due to good antiretroviral therapy and PCP prophylaxis [1]. Otherwise, it is an increasing problem in transplanted patients: in the USA, up to 25 % of these patients suffer from a PCP [1, 2]. In Europe, PCP cases are described in 1.1–11.5 % of the transplanted patients, with rising numbers of patients [3]. Problematic is the late onset of PCP after transplantation, which occurs in most cases after 6 months or later. Additionally, due to low Pneumocystis cyst numbers in HIV-negative patients, Pneumocystis staining methods are often negative [1, 4]. In these patients, a diagnosis of PCP is only achievable by sensitive and specific polymerase chain reaction (PCR) methods, which are not the gold standard in most laboratories [5]. The reservoir of P. jirovecii is not finally determined, but it appears to be human derived. Asymptomatic carriage of P. jirovecii is considerably more common than PCP: antibodies against P. jirovecii can be detected in approximately 90 % of the population, and carriage of Pneumocystis was shown to be up to 25 % carriers in different patient groups [2, 6–11]. New studies showed that airborne transmission can occur from PCP patients, but also Pneumocystis carriers, for example health care personnel or other patients [12–14]. We report our experiences with laboratory diagnostics of PCP and Pneumocystis carriage by staining techniques combined with nested PCR in patients following renal transplantation and the necessity of close-meshed controls by PCR.
Patients and methods From 2001 to 2009, 21 out of 270 (7.8 %) renal transplant recipients from the Renal Transplant Unit of the University of Rostock, Germany, suffered from respiratory infec-
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tions. Due to clinical symptoms of fever, dry cough and interstitial infiltrates in thoracic X-ray, a possible PCP was suspected in these 21 patients. The laboratory diagnosis of PCP and Pneumocystis carriage was established from broncho-alveolar lavage (BAL) samples, with parallel examination by specific staining methods with Grocott’s methenamine silver stain (GMS, sensitivity: 60–80 %, specificity: 80 %), Giemsa stain (GS, sensitivity: 40–80 %, specificity: 60–80 %) and nested PCR for the detection of the mitochondrial transcribed large-subunit rRNA gene (mtLSU rRNA nPCR, sensitivity: 93 %, specificity: 95 %) of Pneumocystis spp. [5, 15–17]. Due to the high sensitivity of the PCR and the two-step system, a reliable laboratory differentiation between PCP and P. jirovecii carriage is possible. In our study, the laboratory definition of PCP was a positive GMS or GS stain or a PCR that was positive in both steps. Pneumocystis carriage was defined as staining techniques negative and first PCR step negative, but second step positive. Clinical and follow-up data were retrospectively taken from patient’s files. Primary renal transplant function was defined as a status not requiring more than three haemodialysis sessions after transplantation.
Results Out of 21 renal transplant patients, 7 (33.3 %) had a PCP infection and 6 (28.6 %) had a P. jirovecii carriage. Eight patients (38.1 %) were Pneumocystis negative. The mean ages of the PCP patients, Pneumocystis carriers and negative patients were 63.4, 50.3 and 55.3 years at the time of transplantation. The time between renal transplantation and clinical occurrence of pneumonia ranged from 20.7 months in PCP patients to 72.8 months in patients with P. jirovecii carriage (Table 1). Immunosuppressive regimens are shown in Table 1 according to the Pneumocystis status. The mean steroid dosage of our Pneumocystis-negative patients was significantly higher than in the PCP group (negative patients: 18.1 ± 6.5 mg/day, PCP patients: 10.7 ± 1.9 mg/day; P = 0.0205, Mann–Whitney test), but not in the carrier group (12.5 ± 4.2 mg/day). In six out of seven patients with PCP, the PCR was positive in both steps; in one patient, the diagnosis of PCP was confirmed by staining methods. All patients with PCP received a standard treatment with cotrimoxazole (100 mg/kg body weight/day sulfamethoxazole (SMX) and 20 mg/kg body weight/day trimethoprim (TMP)) for 21 days. Six out of the seven recipients had a positive cytomegalovirus (CMV) antibody status; one patient was CMV antibody negative and received a CMV-negative kidney. Three out of the seven patients with PCP showed pulmonal fungal co-infections (two with Candida spp. pneumonia, one patient with non-differentiated fungal structures in the BAL), and three developed urinary tract infections. In four PCP patients, a delayed graft function was seen, and in one patient, an acute cellular rejection had been diagnosed previously. Two out of the seven PCP patients died immediately after PCP diagnosis (mortality rate: 28.6 %; Table 1).
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Table 1 Age, time intervals, immunosuppressive therapy and complicating factors of PCP patients, Pneumocystis carriers and negative patients PCP
Carriage
Negative
7
6
8
Female
6
1
4
Male
1
5
4
Age (years) at time of transplantation
63.4 ± 13.6
50.3 ± 10.7
55.3 ± 15.0
N Sex
Age (years) at PCP diagnosis
64.3 ± 13.9
52.2 ± 11.9
59.9 ± 13.0
Time (months) between transplantation and PCP diagnosis
20.7 ± 23.7
72.8 ± 79.6
147.7 ± 161.7
CyA/MMF/prednisolone
5
1
5
Tacrolimus/MMF/prednisolone
2
4
1
Azathioprine
0
1
2
Immunosuppressive therapy
Transplant complications Acute cellular rejection
1
1
0
Delayed graft function
4
2
4
CMV antibody-positive (donor)
6
6
4
CMV antibody-positive (recipient)
6
3
3
Co-infections Urinary tract infection
3
3
1
Candida spp. pneumonia
2
1
2
Aspergillus fumigatus pneumonia
0
1
–
Active CMV infection
0
3
1
No co-infection
4
1
6
Deaths
2
1
1
All time intervals are given as mean ± standard deviation CyA cyclosporine, MMF mycophenolate mofetil, PCP Pneumocystis pneumonia, CMV cytomegalovirus
In the group with Pneumocystis carriage, all six donors but only three of the recipients were CMV antibody positive, and three recipients had an active CMV after transplantation. Two out of six patients with PCP carriage showed pulmonal fungal co-infections (Table 1). Three out of the six patients additionally had urinary tract infections. An episode of acute cellular rejection was also seen in one patient of this group. One Pneumocystis carrier died immediately after the diagnosis of Pneumocystis carriage due to severe Aspergillus fumigatus pneumonia. In three PCP cases, an overlapping of hospitalisation times after renal transplantation at the same ward with an occurrence of PCP approximately 6 months after transplantation was noted. Long-term observation showed that none of our PCP and carrier patients suffered from further PCP infections until 2010. However, one out of the five patients who survived the PCP episode died 2.1 years after transplantation due to myocardial infarction. Additionally, two Pneumocystis carriers died 1.1 and 7.3 years after transplantation due to septicaemia.
Discussion Until now, Pneumocystis diagnostics in Germany use less sensitive staining methods, which can lead to false-negative Pneumocystis results—especially in renal and other transplant patients. Highly sensitive PCR methods are not available by default. In this study, we examined 21 kidney transplant patients for the presence of P. jirovecii and identified 7 (33.3 %) PCP cases and 6 (28.6 %) Pneumocystis carriers with the standard staining methods for P. jirovecii—the GMS and the GS—and additionally with a Pneumocystisspecific mtLSU nPCR [11, 15]. Usually, only low numbers of P. jirovecii cysts are present in the lungs of HIV-negative patients, but onset of symptoms is more sudden [1, 4]. PCR methods with higher sensitivities and specificities should be used in such patients as also shown in our patients: only three out of seven PCP patients were GMS and GS positive and two other patients were only GS positive, while six out of seven patients were positive in the mtLSU nPCR. In one of our PCP patients, the PCR was inhibited, but both staining methods were positive, so the PCP could be confirmed. Although the mtLSU nPCR has a very high sensitivity of 93 % (compared with 60–80 % in the staining methods) [15], inhibitors like haemoglobin or low quantities of the samples used can rarely lead to false-negative PCR results. To avoid inhibition, in our laboratory, all bloody samples are routinely pre-treated with red cell lysis buffer before DNA isolation. However, the low volume of less than 2 ml of BAL in the PCR-negative sample in combination with possible inhibitors could explain the false-negative PCR result in this sample. We recommend the use of at least 3 ml of BAL sample or 5 ml of tracheal secretion or induced sputum for every PCR or staining method [15]. Some clusters of PCP following renal transplantation have been reported in the literature with different intervals and numbers of patients [3, 14, 18–23]. The largest series with 22 PCP patients was reported by de Boer et al. [20]. The risk of PCP infections after renal transplantation is estimated to be 5 % without prophylaxis and can be decreased to less than 2 % when using prophylaxis with TMP-SMX [24, 25]. However, the duration of PCP prophylaxis in renal transplant patients is an important point of discussion. A PCP prophylaxis guideline for these patients does not exist in Germany. Due to potential side effects of TMP-SMX, some centres never prescribed a prophylaxis, while others discontinued the PCP prophylaxis [22]. Two of our patients (28.6 %) died because of severe PCP infection. The mortality rate of patients with PCP after kidney transplantation has been reported as 29–50 % [24, 26]. PCP infections after renal transplantation occur with a postoperative interval of 2–6 months and decline to 0.5 % after 1 year [24]. This can be confirmed by the present series for some cases, but the mean time interval in our series was 20.7 months. Nevertheless, single cases of a “late onset” of PCP were reported by others as well, for example after 5, 11 and 24 years [14, 27–29]. According to this data, the duration of PCP prophylaxis should be
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given for a minimum of 6 months [30, 31]. Other authors suggest administering prophylactic TMP-SMX for the first 12 months [27] or an individualised prophylaxis in high-risk patients, e.g. after acute rejection therapy or in patients with poor renal function [22]. New studies indicate that high-dose immunotherapy with a long course of corticosteroids and treatment with anti-lymphocyte antibodies are special risk factors for PCP after renal transplantation [22] in the same manner as coinfections like CMV, tuberculosis and hepatitis C [23, 24, 32, 33]. However, in our cohort, we observed a significantly higher steroid therapy in the negative group than in the PCP patients. In contrast, high numbers of positive CMV antibody status in donors and recipients were seen in all groups of our patients. In our series, there also seemed to be an association between cases with acute rejection or co-infections and PCP or Pneumocystis carriage in transplanted patients. These results coincide with the results of other retrospective studies [22, 34], but also oppositional findings are described [12, 35]. Therefore, the routine prophylaxis for PCP with TMP-SMX as the treatment of choice in all patients with renal transplantation should be a postoperative standard and is now advised unanimously [21, 30, 31]. Routine measuring of CD4 cell counts in transplanted patients can also be a helpful marker for the severity of immunosuppression in these patients. Transmission routes of Pneumocystis jirovecii are also discussed controversially. New molecular studies postulate that transmission occurs not only via smear infection but also by air transmission [36–38]. The primary sources of infection are humans like PCP patients or also healthy carriers, including health personnel [12, 39, 40]. Contradicting this theory, de Boer et al. [20] observed PCP infections only in kidney transplant patients and not in patients after liver transplantation, although both groups used the same outpatient rooms during the same period. In our study, there was an overlap in hospitalisation at the same ward and a clinical onset of the PCP infection 6 months later in three of the patients. Thus, a direct or indirect person-to-person transmission seems to be likely in those cases. Nosocomial PCP infections were also seen in up to 57 % of the renal transplant patients [13, 14, 40–42]. Colonised patients or hospital personnel may play an important role in transmitting the fungus [13]. Therefore, it is recommended that contact of immunosuppressed persons with PCP patients should be avoided. In summary, we suggest that there may be a tendency for higher incidence of PCP infections and Pneumocystis carriage after renal transplantation in patients with a positive CMV status or a reactivation of a CMV infection. These results indicate that CMV status may be an important marker for increased risk of PCP infections or carriage. However, there are relatively small numbers of patients in this series. Thus, statistical analysis of differences could not be extensively explored. Furthermore, a history of treatment of acute rejection may be a potential risk factor [32, 33]. Additionally, we saw a higher number of patients with co-infections in the subgroups with
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significant PCP infections and Pneumocystis carriage. Therefore, all patients with these risk factors should undergo a more careful follow-up with an early diagnosis for P. jirovecii in case of respiratory infections. Since 2001, all immunocompromised patients with suspected pneumonia in our hospital—with focus on HIV-positive and renal transplant patients—were routinely screened by combined staining methods and specific nPCR for the presence of Pneumocystis spp. Additionally, we decided to implement an internal transcribed spacer PCR for the differentiation of Pneumocystis genotypes in positive patients, which can uncover patient-to-patient transmissions. Conflict of interest There are no commercial relationships or conflicts of interests. The authors declare that they did not receive any funding or grants.
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