Pneumocystis jirovecii Pneumonia in Liver Transplant Recipients: A Systematic Review I.D. Kostakis*, G.C. Sotiropoulos, and G. Kouraklis Second Department of Propedeutic Surgery, “Laiko” General Hospital, National and Kapodistrian University of Athens, Medical School, Athens, Greece
ABSTRACT Background. Pneumocystis jirovecii is a fungus that causes pneumonia in immunocompromised patients, such as liver transplant recipients. Methods. We searched the Medline database in September 2013 for articles referring to infections from P. jirovecii in liver transplant recipients, using the terms “liver transplantation” and “pneumocystis.” Our search yielded 60 articles, 35 of which were used for our review. Results. P. jirovecii pneumonia (PJP) has an incidence of 1%e11% in liver transplant recipients without prophylaxis and mortality rates of 7%e88%. Most cases occur within the first 7 months after transplantation. When prophylactic treatment with oral trimethoprimsulfamethoxazole is used, its incidence is only 0%e3%. The duration of its use varies from 3 months to 1 year after the liver transplantation. Conclusions. PJP has relatively high incidence and high mortality rates in liver transplant recipients without prophylactic treatment, which diminishes or even eliminates its occurrence. Therefore, oral trimethoprim-sulfamethoxazole should be used as prophylaxis for 1 year after the liver transplantation in this population.
P
neumocystis jirovecii, formerly known as Pneumocystis carinii, is a fungus that causes pneumonia in immunocompromised patients, such HIV-positive patients, transplant recipients, and patients under immunosuppressive treatment for autoimmune diseases. It is an opportunistic pathogen that may affect patients under immunosuppressive treatment after solid organ transplantation, such as liver transplant recipients [1e3]. Regarding liver transplantations, there is no consensus for the necessity and the duration of prophylactic treatment against P. jirovecii and the clinical trials concerning this group of patients are not many. Here, we review the literature regarding the incidence of P. jirovecii pneumonia (PJP) in liver transplant recipients and the role of the prophylactic therapy against it. METHODS We searched the Medline database in September 2013 for articles referring to infections from P. jirovecii in liver transplant recipients. We used the terms “liver transplantation” and “pneumocystis” combined, and our search yielded 60 articles, corresponding to 40 original articles, 8 case reports, and 12 reviews. We excluded all 12 reviews, 2 of the case reports, and 11 of the original articles to
include 29 original articles and 6 case reports in our review. More details are shown in Fig 1.
RESULTS Clinical and Laboratory Findings of P. jirovecii Pneumonia
Patients may present fever, cough, dyspnea, and fine endinspiratory crackles [4e8], along with diffuse interstitial and intra-alveolar infiltrates in chest X-ray [4e7]. The infection may even cause life-threatening respiratory failure [9e11]. Thoracic computerized tomography typically reveals multifocal, confluent and poorly defined infiltrates with peribronchial distribution [8,12]. Diagnosis is made by positive cytologic or direct microscopic examination of bronchoalveolar lavage (BAL) or induced sputum [5,6,8,10,12e21], but lung biopsy with silver staining of the specimen may be necessary for diagnosis in rare occasions [7,22]. Grocott-Gomori methenamine-silver nitrate and Wright-Giemsa staining methods are used for the cytologic diagnosis of P. jirovecii infection [6,21]. *Address correspondence to Ioannis D. Kostakis, MD, 27 Achridos Street, Kato Patissia, 11144 Athens, Greece. E-mail: [email protected]
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.09.156
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 46, 3206e3208 (2014)
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inhibitorebased monotherapy immunosuppression after liver transplantation [34], and there are several studies reporting cases of concurrent PJP and cytomegalovirus (CMV) infection [4,6,17,23], which has been attributed to the immunosuppressive effect of CMV pneumonia [17]. Time of Presentation of P. jirovecii Pneumonia
The great majority of cases of PJP in liver transplant recipients occur within the 1st 7 months after transplantation [4,5,7e11,13,15,19e21,25,26,28,30,35e37]. The earliest cases of PJP have been reported 4 [37], 17 [11], and 20 days after transplantation [4], and the latest ones usually w16e18 months after the operation [13,20]. However, there are cases manifested 29, 40, 56, and even 60 months after the transplantation [21,30,38]. Treatment and Prophylaxis Against P. jirovecii
Fig 1. Flow chart of the review.
Polymerase chain reaction is also used for the diagnosis of P. jirovecii infection through detection of its genome [8,23]. Incidence and Mortality of P. jirovecii Pneumonia
The incidence and mortality of PJP in liver transplant recipients differs among various studies. In recipients without prophylaxis against P. jirovecii, the incidence ranges from 1% to 30% in general [4e6,9e11,13e15,17,19e21,24e27] and from 1% to 11% in studies with large numbers of participants [4,6,11,13e15,19e21], and the mortality rates range from 7% to 88% in most studies [4,6,11,13,15,17,20,21,23,28]. On the other hand, the incidence of PJP is 0%e3% in recipients receiving prophylaxis against P. jirovecii [5,16e18,26,29e33]. In liver transplant recipients, PJP is the underlying disease in w13% of opportunistic pneumonias, in w7% of all pneumonias [6], and in w8% of cases with suspected pulmonary disease [12]. Furthermore, PJP is the underlying disease in w22% of liver transplant recipients with respiratory symptoms who undergo BAL [14]. In adult recipients, the incidence of PJP in those without prophylaxis is 1%e30% in general [4,6,11,15,17,19,21,25e27] and 1%e11% in studies with large numbers of patients [4,6,11,15,19,21], with mortality rates of 7%e88% in most studies [4,6,11,15,17,21,23], whereas the incidence of PJP is 0%e2% in those taking prophylaxis against P. jirovecii [16e18,26,29,33]. In pediatric recipients, the incidence of PJP when they do not receive prophylaxis is 5%e10% [10,13], whereas it is 0%e3% in those under prophylaxis against P. jirovecii [30,32]. A study with 86 pediatric liver transplant recipients not receiving prophylaxis revealed an incidence of 10% and a mortality rate of 11% [13]. In addition, 1 study reports no cases of PJP in recipients without prophylaxis who have received ab initio calcineurin
The standard treatment of PJP consists of intravenous administration of trimethoprim-sulfamethoxazole regimen [4,6,8,10,17,19e22,35,37], usually at a daily dose of 720 mg trimethoprim and 3,600 mg sulfamethoxazole [19,20]. Alternative regimens include pentamidine, either alone or combined with trimethoprim-sulfamethoxazole [4,10,21,35], and the combination of primaquine and clindamycin [21]. Corticosteroids may also be included in the treatment of PJP to reduce the inflammatory response [21]. Owing to the increased incidence of PJP in solid organ transplant recipients, many transplantation centers use the oral trimethoprim-sulfamethoxazole regimen as prophylaxis against P. jirovecii [5,6,13,16e18,23,26,29,32,33], usually at a dose of 80 mg trimethoprim and 400 mg sulfamethoxazole [5,6,16e18,29,33] administered daily [5,16e18,29] or 3 times a week [5,33]. Alternatively, a dosage of 5e10 mg trimethoprim and 30 mg sulfamethoxazole per kg of body weight every 12 hours for 3 days per week has also been proposed [32]. Other proposed regimens include oral combination of 25 mg pyrimethamine and 500 mg sulfadoxine once per week [18], oral atovaquone in a dose of 750 mg once daily or 250 mg 3 times per day [31], per os dapsone [16] and inhaled pentamidine [13,16,29,33] in a dose of 150 mg [13] or 300 mg [33] once per month [13,33]. The duration of prophylaxis varies among different centers, and many authors recommend 3 months [32,33], 6 months [17,18], or even 1 year after the liver transplantation as the appropriate duration of the prophylaxis [5,13,31]. However, other transplantation centers administer oral prophylactic treatment for 1 month after the patient’s discharge from the hospital [6] and others indefinitely [29]. DISCUSSION
PJP is a serious and potentially fatal opportunistic infection that affects liver transplant recipients, like other immunocompromised patients, usually within the first 7 months after the transplantation, whereas later occurrences of PJP are rare [4,5,7e11,13,15,19e21,25,26,28,30,35e37]. It is a relatively common infection among liver transplant recipients, since its incidence is 1%e11% when no prophylaxis is taken
3208
[4,6,11,13e15,19e21]. On the other hand, prophylaxis against P. jirovecii diminishes or even eliminates the occurrence of PJP [5,16e18,26,29e33]. Its mortality rates among the affected liver transplant recipients are high, ranging from 7% to 88% in most studies, despite the administration of adequate treatment [4,6,11,13,15,17,20,21,23,28]. Prophylaxis against P. jirovecii consisted of oral trimethoprim-sulfamethoxazole, or alternatively oral pyrimethamine-sulfadoxine or inhaled pentamidine is recommended by many studies and transplantation centers [5,6,13,16e18,23,26,29,32,33]. In conclusion, we recommend the daily oral trimethoprim-sulfamethoxazole regimen, the oral pyrimethamine-sulfadoxine regimen, or the inhaled pentamidine as prophylaxis against P. jirovecii in liver transplant recipients for the 1st year after transplantation. REFERENCES [1] Helweg-Larsen J. Pneumocystis jirovecii. Applied molecular microbiology, epidemiology and diagnosis. Dan Med Bull 2004;51: 251e73. [2] Morris A, Lundgren JD, Masur H, et al. Current epidemiology of Pneumocystis pneumonia. Emerg Infect Dis 2004;10:1713e20. [3] Wazir JF, Ansari NA. Pneumocystis carinii infection. Update and review. Arch Pathol Lab Med 2004;128:1023e7. [4] Kusne S, Dummer JS, Singh N, et al. Infections after liver transplantation. An analysis of 101 consecutive cases. Medicine (Baltimore) 1988;67:132e43. [5] Barkholt L, Ericzon BG, Tollemar J, et al. Infections in human liver recipients: different patterns early and late after transplantation. Transpl Int 1993;6:77e84. [6] Neumann UP, Langrehr JM, Kaisers U, et al. Simultaneous splenectomy increases risk for opportunistic pneumonia in patients after liver transplantation. Transpl Int 2002;15:226e32. [7] Kleindienst R, Fend F, Prior C, et al. Bronchiolitis obliterans organizing pneumonia associated with Pneumocystis carinii infection in a liver transplant patient receiving tacrolimus. Clin Transplant 1999;13:65e7. [8] Kawagishi N, Miyagi S, Satoh K, et al. Usefulness of beta-D glucan in diagnosing Pneumocystis carinii pneumonia and monitoring its treatment in a living-donor liver-transplant recipient. J Hepatobiliary Pancreat Surg 2007;14:308e11. [9] Rakela J, Perkins JD, Gross Jr JB, et al. Acute hepatic failure: the emerging role of orthotopic liver transplantation. Mayo Clin Proc 1989;64:424e8. [10] Saint-Vil D, Luks FI, Lebel P, et al. Infectious complications of pediatric liver transplantation. J Pediatr Surg 1991;26:908e13. [11] Wang EH, Partovi N, Levy RD, et al. Pneumocystis pneumonia in solid organ transplant recipients: not yet an infection of the past. Transpl Infect Dis 2012;14:519e25. [12] Knollmann FD, Mäurer J, Bechstein WO, et al. Pulmonary disease in liver transplant recipients. Spectrum of CT features. Acta Radiol 2000;41:230e6. [13] Colombo JL, Sammut PH, Langnas AN, et al. The spectrum of Pneumocystis carinii infection after liver transplantation in children. Transplantation 1992;54:621e4. [14] Allen KA, Markin RS, Rennard SI, et al. Bronchoalveolar lavage in liver transplant patients. Acta Cytol 1989;33:539e43. [15] Hayes MJ, Torzillo PJ, Sheil AG, et al. Pneumocystis carinii pneumonia after liver transplantation in adults. Clin Transplant 1994;8:499e503. [16] Singh N, Gayowski T, Wagener M, et al. Pulmonary infections in liver transplant recipients receiving tacrolimus. Changing pattern of microbial etiologies. Transplantation 1996;61:396e401. [17] Torre-Cisneros J, de la Mata M, Lopez-Cillero P, et al. Effectiveness of daily low-dose cotrimoxazole prophylaxis for
KOSTAKIS, SOTIROPOULOS, AND KOURAKLIS Pneumocystis carinii pneumonia in liver transplantationdan open clinical trial. Transplantation 1996;62:1519e21. [18] Torre-Cisneros J, de la Mata M, Pozo JC, et al. Randomized trial of weekly sulfadoxine/pyrimethamine vs daily low-dose trimethoprim-sulfamethoxazole for the prophylaxis of Pneumocystis carinii pneumonia after liver transplantation. Clin Infect Dis 1999;29:771e4. [19] Akamatsu N, Sugawara Y, Kaneko J, et al. Preemptive treatment of fungal infection based on plasma (1/3)beta-D-glucan levels after liver transplantation. Infection 2007;35:346e51. [20] Ohkubo T, Sugawara Y, Takayama T, et al. The risk factors of fungal infection in living-donor liver transplantations. J Hepatobiliary Pancreat Sci 2012;19:382e8. [21] Sarwar S, Carey B, Hegarty JE, et al. Low incidence of Pneumocystis jirovecii pneumonia in an unprophylaxed liver transplant cohort. Transpl Infect Dis 2013;15:510e5. [22] Almaslmani M, Derbala MF, Albozom I, et al. Bronchiolitis obliterans organizing pneumonia associated with Pneumocystis jiroveci infection in orthotopic liver transplantation. Transpl Infect Dis 2008;10:339e42. [23] Rostved AA, Sassi M, Kurtzhals JA, et al. Outbreak of Pneumocystis pneumonia in renal and liver transplant patients caused by genotypically distinct strains of Pneumocystis jirovecii. Transplantation 2013;96:834e42. [24] Afessa B, Gay PC, Plevak DJ, et al. Pulmonary complications of orthotopic liver transplantation. Mayo Clin Proc 1993;68:427e34. [25] Heurlin N, Brattström C, Lönnqvist B, et al. Aetiology of pulmonary diseases in immunocompromised patients. Eur Respir J 1991;4:10e8. [26] Watson CJ, Friend PJ, Jamieson NV, et al. Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 1999;67:505e9. [27] Jiménez-Pérez M, Lozano Rey JM, Marín García D, et al. Efficacy and safety of monotherapy with mycophenolate mofetil in liver transplantation. Transplant Proc 2006;38:2480e1. [28] Paya CV, Hermans PE, Washington 2nd JA, et al. Incidence, distribution, and outcome of episodes of infection in 100 orthotopic liver transplantations. Mayo Clin Proc 1989;64:555e64. [29] Singh N, Gayowski T, Wagener MM, et al. Pulmonary infiltrates in liver transplant recipients in the intensive care unit. Transplantation 1999;67:1138e44. [30] Ryckman FC, Alonso MH, Bucuvalas JC, et al. Long-term survival after liver transplantation. J Pediatr Surg 1999;34:845e9. [31] Meyers B, Borrego F, Papanicolaou G. Pneumocystis carinii pneumonia prophylaxis with atovaquone in trimethoprimsulfamethoxazole-intolerant orthotopic liver transplant patients: a preliminary study. Liver Transpl 2001;7:750e1. [32] Wiesmayr S, Stelzmueller I, Mark W, et al. Experience with the use of piperacillin-tazobactam in pediatric nonrenal solid organ transplantation. Pediatr Transplant 2007;11:38e48. [33] Trotter JF, Levi M, Steinberg T, et al. Absence of Pneumocystis jiroveci pneumonia in liver transplantation recipients receiving short-term (3-month) prophylaxis. Transpl Infect Dis 2008;10:369e71. [34] Orlando G, Tariciotti L, Manzia TM, et al. Ab initio calcineurin inhibitorebased monotherapy immunosuppression after liver transplantation reduces the risk for Pneumocystis jirovecii pneumonia. Transpl Infect Dis 2010;12:11e5. [35] Dummer JS, Erb S, Breinig MK, et al. Infection with human immunodeficiency virus in the Pittsburgh transplant population. A study of 583 donors and 1043 recipients, 1981-1986. Transplantation 1989;47:134e40. [36] Norris S, Crosbie O, McEntee G, et al. Orthotopic liver transplantation for veno-occlusive disease complicating autologous bone marrow transplantation. Transplantation 1997;63:1521e4. [37] Reyes J, Todo S, Green M, et al. Graft-versus-host disease after liver and small bowel transplantation in a child. Clin Transplant 1997;11:345e8. [38] Starzl T, Porter KA, Schroter G, et al. Autopsy findings in a long-surviving liver recipient. N Engl J Med 1973;289:82e4.
ABSTRACT Background. Pneumocystis jirovecii is a fungus that causes pneumonia in immunocompromised patients, such as liver transplant recipients. Methods. We searched the Medline database in September 2013 for articles referring to infections from P. jirovecii in liver transplant recipients, using the terms “liver transplantation” and “pneumocystis.” Our search yielded 60 articles, 35 of which were used for our review. Results. P. jirovecii pneumonia (PJP) has an incidence of 1%e11% in liver transplant recipients without prophylaxis and mortality rates of 7%e88%. Most cases occur within the first 7 months after transplantation. When prophylactic treatment with oral trimethoprimsulfamethoxazole is used, its incidence is only 0%e3%. The duration of its use varies from 3 months to 1 year after the liver transplantation. Conclusions. PJP has relatively high incidence and high mortality rates in liver transplant recipients without prophylactic treatment, which diminishes or even eliminates its occurrence. Therefore, oral trimethoprim-sulfamethoxazole should be used as prophylaxis for 1 year after the liver transplantation in this population.
P
neumocystis jirovecii, formerly known as Pneumocystis carinii, is a fungus that causes pneumonia in immunocompromised patients, such HIV-positive patients, transplant recipients, and patients under immunosuppressive treatment for autoimmune diseases. It is an opportunistic pathogen that may affect patients under immunosuppressive treatment after solid organ transplantation, such as liver transplant recipients [1e3]. Regarding liver transplantations, there is no consensus for the necessity and the duration of prophylactic treatment against P. jirovecii and the clinical trials concerning this group of patients are not many. Here, we review the literature regarding the incidence of P. jirovecii pneumonia (PJP) in liver transplant recipients and the role of the prophylactic therapy against it. METHODS We searched the Medline database in September 2013 for articles referring to infections from P. jirovecii in liver transplant recipients. We used the terms “liver transplantation” and “pneumocystis” combined, and our search yielded 60 articles, corresponding to 40 original articles, 8 case reports, and 12 reviews. We excluded all 12 reviews, 2 of the case reports, and 11 of the original articles to
include 29 original articles and 6 case reports in our review. More details are shown in Fig 1.
RESULTS Clinical and Laboratory Findings of P. jirovecii Pneumonia
Patients may present fever, cough, dyspnea, and fine endinspiratory crackles [4e8], along with diffuse interstitial and intra-alveolar infiltrates in chest X-ray [4e7]. The infection may even cause life-threatening respiratory failure [9e11]. Thoracic computerized tomography typically reveals multifocal, confluent and poorly defined infiltrates with peribronchial distribution [8,12]. Diagnosis is made by positive cytologic or direct microscopic examination of bronchoalveolar lavage (BAL) or induced sputum [5,6,8,10,12e21], but lung biopsy with silver staining of the specimen may be necessary for diagnosis in rare occasions [7,22]. Grocott-Gomori methenamine-silver nitrate and Wright-Giemsa staining methods are used for the cytologic diagnosis of P. jirovecii infection [6,21]. *Address correspondence to Ioannis D. Kostakis, MD, 27 Achridos Street, Kato Patissia, 11144 Athens, Greece. E-mail: [email protected]
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.09.156
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3206
Transplantation Proceedings, 46, 3206e3208 (2014)
P. JIROVECII PNEUMONIA IN LIVER TRANSPLANTATIONS
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inhibitorebased monotherapy immunosuppression after liver transplantation [34], and there are several studies reporting cases of concurrent PJP and cytomegalovirus (CMV) infection [4,6,17,23], which has been attributed to the immunosuppressive effect of CMV pneumonia [17]. Time of Presentation of P. jirovecii Pneumonia
The great majority of cases of PJP in liver transplant recipients occur within the 1st 7 months after transplantation [4,5,7e11,13,15,19e21,25,26,28,30,35e37]. The earliest cases of PJP have been reported 4 [37], 17 [11], and 20 days after transplantation [4], and the latest ones usually w16e18 months after the operation [13,20]. However, there are cases manifested 29, 40, 56, and even 60 months after the transplantation [21,30,38]. Treatment and Prophylaxis Against P. jirovecii
Fig 1. Flow chart of the review.
Polymerase chain reaction is also used for the diagnosis of P. jirovecii infection through detection of its genome [8,23]. Incidence and Mortality of P. jirovecii Pneumonia
The incidence and mortality of PJP in liver transplant recipients differs among various studies. In recipients without prophylaxis against P. jirovecii, the incidence ranges from 1% to 30% in general [4e6,9e11,13e15,17,19e21,24e27] and from 1% to 11% in studies with large numbers of participants [4,6,11,13e15,19e21], and the mortality rates range from 7% to 88% in most studies [4,6,11,13,15,17,20,21,23,28]. On the other hand, the incidence of PJP is 0%e3% in recipients receiving prophylaxis against P. jirovecii [5,16e18,26,29e33]. In liver transplant recipients, PJP is the underlying disease in w13% of opportunistic pneumonias, in w7% of all pneumonias [6], and in w8% of cases with suspected pulmonary disease [12]. Furthermore, PJP is the underlying disease in w22% of liver transplant recipients with respiratory symptoms who undergo BAL [14]. In adult recipients, the incidence of PJP in those without prophylaxis is 1%e30% in general [4,6,11,15,17,19,21,25e27] and 1%e11% in studies with large numbers of patients [4,6,11,15,19,21], with mortality rates of 7%e88% in most studies [4,6,11,15,17,21,23], whereas the incidence of PJP is 0%e2% in those taking prophylaxis against P. jirovecii [16e18,26,29,33]. In pediatric recipients, the incidence of PJP when they do not receive prophylaxis is 5%e10% [10,13], whereas it is 0%e3% in those under prophylaxis against P. jirovecii [30,32]. A study with 86 pediatric liver transplant recipients not receiving prophylaxis revealed an incidence of 10% and a mortality rate of 11% [13]. In addition, 1 study reports no cases of PJP in recipients without prophylaxis who have received ab initio calcineurin
The standard treatment of PJP consists of intravenous administration of trimethoprim-sulfamethoxazole regimen [4,6,8,10,17,19e22,35,37], usually at a daily dose of 720 mg trimethoprim and 3,600 mg sulfamethoxazole [19,20]. Alternative regimens include pentamidine, either alone or combined with trimethoprim-sulfamethoxazole [4,10,21,35], and the combination of primaquine and clindamycin [21]. Corticosteroids may also be included in the treatment of PJP to reduce the inflammatory response [21]. Owing to the increased incidence of PJP in solid organ transplant recipients, many transplantation centers use the oral trimethoprim-sulfamethoxazole regimen as prophylaxis against P. jirovecii [5,6,13,16e18,23,26,29,32,33], usually at a dose of 80 mg trimethoprim and 400 mg sulfamethoxazole [5,6,16e18,29,33] administered daily [5,16e18,29] or 3 times a week [5,33]. Alternatively, a dosage of 5e10 mg trimethoprim and 30 mg sulfamethoxazole per kg of body weight every 12 hours for 3 days per week has also been proposed [32]. Other proposed regimens include oral combination of 25 mg pyrimethamine and 500 mg sulfadoxine once per week [18], oral atovaquone in a dose of 750 mg once daily or 250 mg 3 times per day [31], per os dapsone [16] and inhaled pentamidine [13,16,29,33] in a dose of 150 mg [13] or 300 mg [33] once per month [13,33]. The duration of prophylaxis varies among different centers, and many authors recommend 3 months [32,33], 6 months [17,18], or even 1 year after the liver transplantation as the appropriate duration of the prophylaxis [5,13,31]. However, other transplantation centers administer oral prophylactic treatment for 1 month after the patient’s discharge from the hospital [6] and others indefinitely [29]. DISCUSSION
PJP is a serious and potentially fatal opportunistic infection that affects liver transplant recipients, like other immunocompromised patients, usually within the first 7 months after the transplantation, whereas later occurrences of PJP are rare [4,5,7e11,13,15,19e21,25,26,28,30,35e37]. It is a relatively common infection among liver transplant recipients, since its incidence is 1%e11% when no prophylaxis is taken
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[4,6,11,13e15,19e21]. On the other hand, prophylaxis against P. jirovecii diminishes or even eliminates the occurrence of PJP [5,16e18,26,29e33]. Its mortality rates among the affected liver transplant recipients are high, ranging from 7% to 88% in most studies, despite the administration of adequate treatment [4,6,11,13,15,17,20,21,23,28]. Prophylaxis against P. jirovecii consisted of oral trimethoprim-sulfamethoxazole, or alternatively oral pyrimethamine-sulfadoxine or inhaled pentamidine is recommended by many studies and transplantation centers [5,6,13,16e18,23,26,29,32,33]. In conclusion, we recommend the daily oral trimethoprim-sulfamethoxazole regimen, the oral pyrimethamine-sulfadoxine regimen, or the inhaled pentamidine as prophylaxis against P. jirovecii in liver transplant recipients for the 1st year after transplantation. REFERENCES [1] Helweg-Larsen J. Pneumocystis jirovecii. Applied molecular microbiology, epidemiology and diagnosis. Dan Med Bull 2004;51: 251e73. [2] Morris A, Lundgren JD, Masur H, et al. Current epidemiology of Pneumocystis pneumonia. Emerg Infect Dis 2004;10:1713e20. [3] Wazir JF, Ansari NA. Pneumocystis carinii infection. Update and review. Arch Pathol Lab Med 2004;128:1023e7. [4] Kusne S, Dummer JS, Singh N, et al. Infections after liver transplantation. An analysis of 101 consecutive cases. Medicine (Baltimore) 1988;67:132e43. [5] Barkholt L, Ericzon BG, Tollemar J, et al. Infections in human liver recipients: different patterns early and late after transplantation. Transpl Int 1993;6:77e84. [6] Neumann UP, Langrehr JM, Kaisers U, et al. Simultaneous splenectomy increases risk for opportunistic pneumonia in patients after liver transplantation. Transpl Int 2002;15:226e32. [7] Kleindienst R, Fend F, Prior C, et al. Bronchiolitis obliterans organizing pneumonia associated with Pneumocystis carinii infection in a liver transplant patient receiving tacrolimus. Clin Transplant 1999;13:65e7. [8] Kawagishi N, Miyagi S, Satoh K, et al. Usefulness of beta-D glucan in diagnosing Pneumocystis carinii pneumonia and monitoring its treatment in a living-donor liver-transplant recipient. J Hepatobiliary Pancreat Surg 2007;14:308e11. [9] Rakela J, Perkins JD, Gross Jr JB, et al. Acute hepatic failure: the emerging role of orthotopic liver transplantation. Mayo Clin Proc 1989;64:424e8. [10] Saint-Vil D, Luks FI, Lebel P, et al. Infectious complications of pediatric liver transplantation. J Pediatr Surg 1991;26:908e13. [11] Wang EH, Partovi N, Levy RD, et al. Pneumocystis pneumonia in solid organ transplant recipients: not yet an infection of the past. Transpl Infect Dis 2012;14:519e25. [12] Knollmann FD, Mäurer J, Bechstein WO, et al. Pulmonary disease in liver transplant recipients. Spectrum of CT features. Acta Radiol 2000;41:230e6. [13] Colombo JL, Sammut PH, Langnas AN, et al. The spectrum of Pneumocystis carinii infection after liver transplantation in children. Transplantation 1992;54:621e4. [14] Allen KA, Markin RS, Rennard SI, et al. Bronchoalveolar lavage in liver transplant patients. Acta Cytol 1989;33:539e43. [15] Hayes MJ, Torzillo PJ, Sheil AG, et al. Pneumocystis carinii pneumonia after liver transplantation in adults. Clin Transplant 1994;8:499e503. [16] Singh N, Gayowski T, Wagener M, et al. Pulmonary infections in liver transplant recipients receiving tacrolimus. Changing pattern of microbial etiologies. Transplantation 1996;61:396e401. [17] Torre-Cisneros J, de la Mata M, Lopez-Cillero P, et al. Effectiveness of daily low-dose cotrimoxazole prophylaxis for
KOSTAKIS, SOTIROPOULOS, AND KOURAKLIS Pneumocystis carinii pneumonia in liver transplantationdan open clinical trial. Transplantation 1996;62:1519e21. [18] Torre-Cisneros J, de la Mata M, Pozo JC, et al. Randomized trial of weekly sulfadoxine/pyrimethamine vs daily low-dose trimethoprim-sulfamethoxazole for the prophylaxis of Pneumocystis carinii pneumonia after liver transplantation. Clin Infect Dis 1999;29:771e4. [19] Akamatsu N, Sugawara Y, Kaneko J, et al. Preemptive treatment of fungal infection based on plasma (1/3)beta-D-glucan levels after liver transplantation. Infection 2007;35:346e51. [20] Ohkubo T, Sugawara Y, Takayama T, et al. The risk factors of fungal infection in living-donor liver transplantations. J Hepatobiliary Pancreat Sci 2012;19:382e8. [21] Sarwar S, Carey B, Hegarty JE, et al. Low incidence of Pneumocystis jirovecii pneumonia in an unprophylaxed liver transplant cohort. Transpl Infect Dis 2013;15:510e5. [22] Almaslmani M, Derbala MF, Albozom I, et al. Bronchiolitis obliterans organizing pneumonia associated with Pneumocystis jiroveci infection in orthotopic liver transplantation. Transpl Infect Dis 2008;10:339e42. [23] Rostved AA, Sassi M, Kurtzhals JA, et al. Outbreak of Pneumocystis pneumonia in renal and liver transplant patients caused by genotypically distinct strains of Pneumocystis jirovecii. Transplantation 2013;96:834e42. [24] Afessa B, Gay PC, Plevak DJ, et al. Pulmonary complications of orthotopic liver transplantation. Mayo Clin Proc 1993;68:427e34. [25] Heurlin N, Brattström C, Lönnqvist B, et al. Aetiology of pulmonary diseases in immunocompromised patients. Eur Respir J 1991;4:10e8. [26] Watson CJ, Friend PJ, Jamieson NV, et al. Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 1999;67:505e9. [27] Jiménez-Pérez M, Lozano Rey JM, Marín García D, et al. Efficacy and safety of monotherapy with mycophenolate mofetil in liver transplantation. Transplant Proc 2006;38:2480e1. [28] Paya CV, Hermans PE, Washington 2nd JA, et al. Incidence, distribution, and outcome of episodes of infection in 100 orthotopic liver transplantations. Mayo Clin Proc 1989;64:555e64. [29] Singh N, Gayowski T, Wagener MM, et al. Pulmonary infiltrates in liver transplant recipients in the intensive care unit. Transplantation 1999;67:1138e44. [30] Ryckman FC, Alonso MH, Bucuvalas JC, et al. Long-term survival after liver transplantation. J Pediatr Surg 1999;34:845e9. [31] Meyers B, Borrego F, Papanicolaou G. Pneumocystis carinii pneumonia prophylaxis with atovaquone in trimethoprimsulfamethoxazole-intolerant orthotopic liver transplant patients: a preliminary study. Liver Transpl 2001;7:750e1. [32] Wiesmayr S, Stelzmueller I, Mark W, et al. Experience with the use of piperacillin-tazobactam in pediatric nonrenal solid organ transplantation. Pediatr Transplant 2007;11:38e48. [33] Trotter JF, Levi M, Steinberg T, et al. Absence of Pneumocystis jiroveci pneumonia in liver transplantation recipients receiving short-term (3-month) prophylaxis. Transpl Infect Dis 2008;10:369e71. [34] Orlando G, Tariciotti L, Manzia TM, et al. Ab initio calcineurin inhibitorebased monotherapy immunosuppression after liver transplantation reduces the risk for Pneumocystis jirovecii pneumonia. Transpl Infect Dis 2010;12:11e5. [35] Dummer JS, Erb S, Breinig MK, et al. Infection with human immunodeficiency virus in the Pittsburgh transplant population. A study of 583 donors and 1043 recipients, 1981-1986. Transplantation 1989;47:134e40. [36] Norris S, Crosbie O, McEntee G, et al. Orthotopic liver transplantation for veno-occlusive disease complicating autologous bone marrow transplantation. Transplantation 1997;63:1521e4. [37] Reyes J, Todo S, Green M, et al. Graft-versus-host disease after liver and small bowel transplantation in a child. Clin Transplant 1997;11:345e8. [38] Starzl T, Porter KA, Schroter G, et al. Autopsy findings in a long-surviving liver recipient. N Engl J Med 1973;289:82e4.
