Pneumocystis Pneumonia in Solid Organ Transplant Recipients

Abstract

Pneumocystis jiroveci, alternatively designated Pneumocystis carinii, remains an important opportunistic pathogen among immunocompromised patient populations in not only the setting of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), but also solid organ transplantation (1Rodriguez M Fishman JA Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients.Clin Microbiol Rev. 2004; 17: 770-782Crossref PubMed Scopus (202) Google Scholar). Pneumocystis spp. are thought to be ubiquitous in nature with serologic studies suggesting that exposure occurs commonly in childhood (2Pifer LL Hughes WT Stagno S Woods D Pneumocystis carinii infection: Evidence for high prevalence in normal and immunosuppressed children.Pediatrics. 1978; 61: 35-41Crossref PubMed Google Scholar). Symptomatic Pneumocystis pneumonia (PCP) is generally limited to individuals with immune deficits. Animal models demonstrate both de novo infection via airborne transmission and by reactivation of previously established latent infections (3Kovacs JA Gill VJ Meshnick S Masur H New insights into transmission, diagnosis, and drug treatment of Pneumocystis carinii pneumonia.JAMA. 2001; 286: 2450-2460Crossref PubMed Scopus (191) Google Scholar). Clusters of infection have been described in medical facilities among renal transplant recipients (4De Boer MG Bruijnesteijn van Coppenraet LE Gaasbeek A 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: 1143-1149Crossref PubMed Scopus (131) Google Scholar, 5Schmoldt S Schuhegger R Wendler T et al.Molecular evidence of nosocomial Pneumocystis jiroveci transmission among 16 patients after kidney transplantation.J Clin Microbiol. 2008; 46: 966-971Crossref PubMed Scopus (96) Google Scholar, 6Hocker B Wendt C Nahimana A Tonshoff B Hauser PM Molecular evidence of Pneumocystis transmission in pediatric transplant unit.Emerg Infect Dis. 2005; 11: 330-332Crossref PubMed Scopus (67) Google Scholar). Based on studies before routine implementation of prophylaxis, the overall incidence of infection among solid organ transplant recipients varied mostly in the range of 5–15% depending on organ type, transplant center and immunosuppressive regimens (7Fishman JA Prevention of infection due to Pneumocystis carinii.Antimicrob Agents Chemother. 1998; 42: 995-1004Crossref PubMed Google Scholar). In older reports before implementation of extensive prophylaxis, the attack rate appeared highest in lung and combined heart–lung transplant recipients with an overall incidence ranging from less than 10% to just over 40%. Among liver and kidney transplant recipients, the incidence appeared to be less at anywhere from close to 2% to 10–15% (1Rodriguez M Fishman JA Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients.Clin Microbiol Rev. 2004; 17: 770-782Crossref PubMed Scopus (202) Google Scholar). The incidence overall may be decreasing with reduction in the routine use of corticosteroids in organ transplantation and the adoption of effective prophylactic measures. Table 1 outlines some risk factors for PCP among non-HIV-infected individuals.Table 1Risk factors for the development of Pneumocystis pneumoniaRisk factorsCommentsImmunosuppressive therapiesCorticosteroidsRetrospective case series in non-HIV patients identified corticosteroids in up to 90%Median dose and duration of therapy in one series of non-HIV patients with PCP was 30 mg/day of prednisone for 12 weeks (8Yale SH Limper AH Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: Associated illness and prior corticosteroid therapy.Mayo Clin Proc. 1996; 71: 5-13Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar)ChemotherapyReports of PCP with numerous chemotherapeutic agents including methotrexate, fluorouracil and bleomycinRisk for infection may be related to subsequent neutropenia (1Rodriguez M Fishman JA Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients.Clin Microbiol Rev. 2004; 17: 770-782Crossref PubMed Scopus (202) Google Scholar)Purine analogs, such as fludarabine and cladribine and the antimetabolite cytarabine may be independent risk factors for PCP (9Byrd JC Hargis JB Kester KE Hospenthal DR Knutson SW Diehl LF Opportunistic pulmonary infections with fludarabine in previously treated patients with low-grade lymphoid malignancies: A role for Pneumocystis carinii pneumonia prophylaxis.Am J Hematol. 1995; 49: 135-142Crossref PubMed Scopus (102) Google Scholar, 10Sepkowitz KA Pneumocystis carinii pneumonia in patients without AIDS.Clin Infect Dis. 1993; 17: S416-422Crossref PubMed Scopus (133) Google Scholar)Antilymphocyte therapyAntilymphocyte antibodies are linked to the highest risk for PCP in the 1 to 6 month posttransplant period (11Fishman JA Infection in solid-organ transplant recipients.N Engl J Med. 2007; 357: 2601-2614Crossref PubMed Scopus (1387) Google Scholar)Alemtuzumab, a monoclonal antibody with activity against B, T and NK cells may confer the highest risk (12Martin SI Marty FM Fiumara K Treon SP Gribben JG Baden LR Infectious complications associated with alemtuzumab use for lymphoproliferative disorders.Clin Infect Dis. 2006; 43: 16-24Crossref PubMed Scopus (2) Google Scholar)Mycophenolate mofetilThe anti-Pneumocystis effects of mycophenylate mofetil in vitro and in animal models has not been confirmed in prospective clinical trials (13Oz HS Hughes WT Novel anti-Pneumocystis carinii effects of the immunosuppressant mycophenolate mofetil in contrast to provocative effects of tacrolimus, sirolimus, and dexamethasone.J Infect Dis. 1997; 175: 901-904Crossref PubMed Scopus (94) Google Scholar)Calcineurin inhibitorsAt a single institution where cyclosporine A replaced azathioprine in renal transplantation, the incidence of PCP increased from 3 to 9% (14Hardy AM Wajszczuk CP Suffredini AF Hakala TR Ho M Pneumocystis carinii pneumonia in renal-transplant recipients treated with cyclosporine and steroids.J Infect Dis. 1984; 149: 143-147Crossref PubMed Scopus (100) Google Scholar)One retrospective study suggested a higher incidence of PCP among renal transplant recipients on tacrolimus-based regimens compared to cyclosporine A (15Lufft 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: 421-423Crossref PubMed Scopus (80) Google Scholar)SirolimusSirolimus has been associated with interstitial pneumonitis that can be confused with or coexist with PCP (16Morelon E Stern M Kreis H Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients.N Engl J Med. 2000; 343: 225-226Crossref PubMed Scopus (136) Google Scholar)Other clinical factorsCMV diseaseCMV may be an independent risk factor for PCP (17Fishman JA Prevention of infection caused by Pneumocystis carinii in transplant recipients.Clin Infect Dis. 2001; 33: 1397-1405Crossref PubMed Scopus (125) Google Scholar)Coinfection with CMV and PCP may be observed in solid organ transplantation (18Munoz P Munoz RM Palomo J Rodriguez-Creixems M Munoz R Bouza E Pneumocystis carinii infection in heart transplant recipients. Efficacy of a weekend prophylaxis schedule.Medicine (Baltimore). 1997; 76: 415-422Crossref PubMed Scopus (51) Google Scholar, 19Arend SM Westendorp RG Kroon FP et al.Rejection treatment and cytomegalovirus infection as risk factors for Pneumocystis carinii pneumonia in renal transplant recipients.Clin Infect Dis. 1996; 22: 920-925Crossref PubMed Scopus (99) Google Scholar)Allograft rejectionPCP has been related to the intensity of immunosuppression in transplant recipients (15Lufft 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: 421-423Crossref PubMed Scopus (80) Google Scholar)PCP has been linked to treatment and number of episodes of acute rejection (19Arend SM Westendorp RG Kroon FP et al.Rejection treatment and cytomegalovirus infection as risk factors for Pneumocystis carinii pneumonia in renal transplant recipients.Clin Infect Dis. 1996; 22: 920-925Crossref PubMed Scopus (99) Google Scholar)GVHDImmunosuppression therapies for GVHD > 6 months post-HSCT predispose to PCP (20Lyytikainen O Ruutu T Volin L et al.Late onset Pneumocystis carinii pneumonia following allogeneic bone marrow transplantation.Bone Marrow Transplant. 1996; 17: 1057-1059PubMed Google Scholar)Low CD4+ T-cell countsIn HIV infection, the risk for PCP is linked to CD4+T-cell counts <200 cells/mL or <20% of the total circulating lymphocytes (21Masur H Ognibene FP Yarchoan R et al.CD4 counts as predictors of opportunistic pneumonias in human immunodeficiency virus (HIV) infection.Ann Intern Med. 1989; 111: 223-231Crossref PubMed Scopus (408) Google Scholar)PCP has been linked to decreased CD4+T-cell counts in HSCT recipients (22Castagnola E Dini G Lanino E et al.Low CD4 lymphocyte count in a patient with P. carinii pneumonia after autologous bone marrow transplantation.Bone Marrow Transplant. 1995; 15: 977-978PubMed Google Scholar), solid tumor patients receiving chemotherapy (23Sepkowitz KA Brown AE Telzak EE Gottlieb S Armstrong D Pneumocystis carinii pneumonia among patients without AIDS at a cancer hospital.JAMA. 1992; 267: 832-837Crossref PubMed Scopus (260) Google Scholar), autoimmune disease and hematological malignancy patients (24Mansharamani NG Balachandran D Vernovsky I Garland R Koziel H Peripheral blood CD4 + T-lymphocyte counts during Pneumocystis carinii pneumonia in immunocompromised patients without HIV infection.Chest. 2000; 118: 712-720Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar)Low CD4+ T-cell counts may reflect viral coinfection or exogenous immunosuppressionTransplant patients with CD4+T-cell lymphopenia are expected to be at risk for PCP (17Fishman JA Prevention of infection caused by Pneumocystis carinii in transplant recipients.Clin Infect Dis. 2001; 33: 1397-1405Crossref PubMed Scopus (125) Google Scholar)NeutropeniaProlonged neutropenia is a potential risk factor for PCP in transplant recipients (17Fishman JA Prevention of infection caused by Pneumocystis carinii in transplant recipients.Clin Infect Dis. 2001; 33: 1397-1405Crossref PubMed Scopus (125) Google Scholar)HIV, human immunodeficiency virus; PCP, Pneumocystis pneumonia; CMV, Cytomegalovirus; HSCT, hematopoietic stem cell transplant; GVHD, Graft versus host disease. Open table in a new tab HIV, human immunodeficiency virus; PCP, Pneumocystis pneumonia; CMV, Cytomegalovirus; HSCT, hematopoietic stem cell transplant; GVHD, Graft versus host disease. Symptomatic progression of PCP in HIV-negative patients can be quite variable but is classically more acute than it is in HIV-infected counterparts. In the setting of transplantation, symptoms often develop over the course of a few days, though evolution over 1–2 weeks may also occur. Use of corticosteroids, calcineurin inhibitors and sirolimus may initially suppress some of the clinical findings early in transplant recipients. The signs and symptoms of infection are outlined in Table 2 and are based on studies from the 1980s when the AIDS epidemic in the United States was just underway (25Kovacs JA Hiemenz JW Macher AM et al.Pneumocystis carinii pneumonia: A comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies.Ann Intern Med. 1984; 100: 663-671Crossref PubMed Scopus (641) Google Scholar). These clinical findings are classically dominated by dyspnea and hypoxemia out of proportion to physical and radiographic findings.Table 2Signs and symptoms of Pneumocystis pneumoniaSign or symptom of PCPIncidenceFever81–87%Dyspnea66–68%Cough71–81%Chest pain23–24%Abnormal lung auscultation on exam30–34%Abnormal chest radiography92–96%Hypoxemia78–91% Open table in a new tab Fever, though common in HIV infection, may be absent in solid organ transplant recipients. Pneumothoraces, although rare overall, are more common in PCP than in other forms of pneumonia. Lymphadenopathy is also uncommon. In children, early signs are nonspecific and include diarrhea, poor feeding and coryza with progression to nasal flaring, intercostal retraction and cyanosis with hypoxemia and respiratory alkalosis. Definitive diagnosis of PCP in the transplant recipient is essential given the need for early therapy to secure a successful outcome and the potential toxicities of most of the agents used to treat infection. Diagnosis of PCP is definitively made by demonstration of organisms in lung tissue or respiratory tract secretions. Chest radiography may be normal or reveal diffuse bilateral interstitial pulmonary infiltrates. Computed tomographic (CT) scans are more sensitive than routine chest radiography. No specific radiological diagnostic pattern exists (26Fujii T Nakamura T Iwamoto A Pneumocystis pneumonia in patients with HIV infection: Clinical manifestations, laboratory findings, and radiological features.J Infect Chemother. 2007; 13: 1-7Abstract Full Text PDF PubMed Scopus (101) Google Scholar). Direct demonstration of the organism is the diagnostic method of choice. Diagnosis can be accomplished using noninvasive or invasive methods. The diagnosis of PCP has been markedly improved by the use of immunofluorescent monoclonal antibody stains against the organism (27Kovacs JA Ng VL Masur H et al.Diagnosis of Pneumocystis carinii pneumonia: Improved detection in sputum with use of monoclonal antibodies.N Engl J Med. 1988; 318: 589-593Crossref PubMed Scopus (255) Google Scholar, 28LaRocque RC Katz JT Perruzzi P Baden LR The utility of sputum induction for diagnosis of Pneumocystis pneumonia in immunocompromised patients without human immunodeficiency virus.Clin Infect Dis. 2003; 37: 1380-1383Crossref PubMed Scopus (29) Google Scholar). Direct staining of samples from either suctioned or induced respiratory tract secretions, or from open lung biopsies, bind to both the cyst and trophozoite forms of Pneumocystis, likely increasing the sensitivity of detecting the organism. Gomori methenamine-silver stains the cyst form while Giemsa and Wright’s stains also stain trophozoites, a common form of the organism. Coinfection with cytomegalovirus (CMV) is common and other respiratory viral infections may precede PCP (1Rodriguez M Fishman JA Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients.Clin Microbiol Rev. 2004; 17: 770-782Crossref PubMed Scopus (202) Google Scholar). PCP has also been observed in concert with abnormal lung changes due to sirolimus. Diagnostic tests are outlined in Table 3.Table 3Diagnostic approaches to Pneumocystis pneumonia in transplantationTestEstimated yieldCommentsRoutine sputumGenerally poorOrgan transplant patients with PCP may have smaller burden of infecting organisms than AIDS patients (29Thomas Jr, CF Limper AH Pneumocystis pneumonia: Clinical presentation and diagnosis in patients with and without acquired immune deficiency syndrome.Semin Respir Infect. 1998; 13: 289-295PubMed Google Scholar)Induced sputumImproved over routine sputum exam when coupled with antibody staining; yield ≥50% (27Kovacs JA Ng VL Masur H et al.Diagnosis of Pneumocystis carinii pneumonia: Improved detection in sputum with use of monoclonal antibodies.N Engl J Med. 1988; 318: 589-593Crossref PubMed Scopus (255) Google Scholar)Yield from induced sputum in transplant patients may not reflect that found in HIV-infected patientsSensitivity and specificity in transplant patients unknownRepeat testing may improve yield (28LaRocque RC Katz JT Perruzzi P Baden LR The utility of sputum induction for diagnosis of Pneumocystis pneumonia in immunocompromised patients without human immunodeficiency virus.Clin Infect Dis. 2003; 37: 1380-1383Crossref PubMed Scopus (29) Google Scholar)Bronchoalveolar lavage (BAL)Generally ≥70% in non-AIDS immuno-compromised hosts when coupled with antibody stainingOlder data involving immunosuppressed patients with PCP suggested a yield close to 80% (30Stover DE Zaman MB Hajdu SI Lange M Gold J Armstrong D Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host.Ann Intern Med. 1984; 101: 1-7Crossref PubMed Scopus (362) Google Scholar)Transbronchial biopsyIncreases yield of routine BAL (1Rodriguez M Fishman JA Prevention of infection due to Pneumocystis spp. in human immunodeficiency virus-negative immunocompromised patients.Clin Microbiol Rev. 2004; 17: 770-782Crossref PubMed Scopus (202) Google Scholar)Multiple biopsies preferredOpen lung biopsyOften considered to be a gold standard, but early patchy disease may decrease yieldCase reports highlight PCP infections missed on BAL that were subsequently identified from open lung biopsies (31Bondoc AY White DA Granulomatous Pneumocystis carinii pneumonia in patients with malignancy.Thorax. 2002; 57: 435-437Crossref PubMed Scopus (31) Google Scholar, 32Studemeister A Dass S A patient with dyspnea, cough, and fever.Clin Infect Dis. 2006; 43 (1490–1461): 1461-1462Crossref PubMed Google Scholar)Cases of missed infection in open lung biopsy also reported (28LaRocque RC Katz JT Perruzzi P Baden LR The utility of sputum induction for diagnosis of Pneumocystis pneumonia in immunocompromised patients without human immunodeficiency virus.Clin Infect Dis. 2003; 37: 1380-1383Crossref PubMed Scopus (29) Google Scholar)PCR testing of samplesSensitivity and specificity vary depending on manner of sampling (sputum vs. BAL) and assay employedMultiple assays, generally targeting genes for conserved surface glycoproteins or rRNAsPlasma (1→3) β-D-GlucanSome reports after transplantation (33Akamatsu N Sugawara Y Kaneko J Tamura S Makuuchi M Preemptive treatment of fungal infection based on plasma (1 –> 3)beta-D-glucan levels after liver transplantation.Infection. 2007; 35: 346-351Crossref PubMed Scopus (75) Google Scholar, 34Kawagishi N Miyagi S Satoh K Akamatsu Y Sekiguchi S Satomi S 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: 308-311Crossref PubMed Scopus (17) Google Scholar)(1→3) β-D-Glucan is produced in the cyst cell wall (35Yasuoka A Tachikawa N Shimada K Kimura S Oka S (1–>3) beta-D-glucan as a quantitative serological marker for Pneumocystis carinii pneumonia.Clin Diagn Lab Immunol. 1996; 3: 197-199Crossref PubMed Google Scholar)Clinical trials data lackingAIDS, acquired immunodeficiency syndrome; PCP, Pneumocystis pneumonia; HIV, human immunodeficiency virus; BAL, bronchoalveolar lavage; PCR, polymerase chain reaction; rRNA, ribosomal ribonucleic acid. Open table in a new tab AIDS, acquired immunodeficiency syndrome; PCP, Pneumocystis pneumonia; HIV, human immunodeficiency virus; BAL, bronchoalveolar lavage; PCR, polymerase chain reaction; rRNA, ribosomal ribonucleic acid. Practice recommendations for the diagnosis of PCP in transplant recipients include: (1)Patients should undergo initial screening via multiple induced sputum samples (Grade II-2). All respiratory secretions should be stained using antibodies for PCP (immuoflourescent, immunoperoxidase or similar) as well as routine tissue stains (Giemsa, Silver and others) (Grade II-1). Samples should also be stained and cultured for routine bacterial, fungal, mycobacterial and other organisms to rule out other similar or concomitant infections.(2)Clinicians should have a low threshold for bronchoscopy with bronchoalveolar lavage (BAL) to obtain diagnostic samples (Grade II-2). This may have the dual advantage of increasing the yield and helping to expedite the diagnosis of other concomitant infections.(3)Patients undergoing bronchoscopy should be considered for transbronchial biopsies. Increased yield is likely obtained by multiple samples (Grade III).(4)Open lung biopsies can be obtained when other diagnostic approaches have been unrevealing or where other concomitant diseases may be a concern (Grade III). Video-assisted thoracoscopic (VATS) biopsies may be appropriate for some patients in this regard. For the established or presumed diagnosis of PCP, therapeutic options are outlined in Table 4.Table 4Therapeutic options for treating Pneumocystis pneumoniaAgentsDosingCommentsTrimethoprim-sulfamethoxazole (TMP-SMX)15–20 mg/kg/day of the TMP component given IV in divided doses every 6–8 h often in combination with corticosteroids (see below);TMP-SMX is the drug of choice and is considered to be the most effective systemic therapy for PCPFor milder disease, two double-strength tablets can be given po bid-tidPentamidine isesthionate4 mg/kg/day IV initially over 1–2 h; dose reduction to 2–3 mg/kg/day if neededPentamidine side effects include pancreatitis, hypoglycemia, hyperglycemia, bone marrow suppression, renal failure and electrolyte disturbancesPancreatic dysfunction may suggest the need for avoidance in pancreas transplantationAtovaquone750 mg po bid (optimal dose uncertain; 1500 bid used anecdotally)Atovaquone is available in an oral suspension onlyAtovaquone has variable oral absorption (best with fatty foods)Atovaquone is approved only for mild and moderate PCPPrimaquine and clindamycinPrimaquine 15–30 mg po qd in combination with clindamycin 600–900 mg IV or po q 6–8 hThis combination has been studied in mild to moderate PCP in AIDSLong-term use of clindamycin can predispose to infection with Clostridium difficilePrimaquine should be avoided in G6PD deficiencyDapsone and trimethoprimDapsone 100 mg po qd used in combination with trimethoprim 15 mg/kg/day po divided tidThis combination has been used with sulfa allergy, though dapsone may elicit sulfa allergies as wellTrimetrexate with folinic acidTrimetrexate 45 mg/m2/day IV (or 1.5 mg/kg/day IV in patients <50 kg) with folinic acid 20 mg/m2 po or IV every 6 h (80 mg/m2 total daily); Folinic acid therapy extends ≥3 days beyond trimetrexate therapyTrimetrexate causes bone marrow suppression without folinic acidOutcomes are inferior to TMP-SMX in AIDSTrimetrexate is no longer commercially available in the United StatesPyrimethamine and sulfadiazinePyrimethamine load of 100–200 mg po, followed by 50–100 mg po qd in combination with sulfadiazine 4 g po qd in divided dosesLimited data available on this regimenIt may also require folinic acid 10mg po qd to reduce bone marrow toxicityMacrolide and SMXMacrolides such as clarithromycin or azithromycin in combination with sulfamethoxazole may be synergistic in vivo (36Fishman JA Treatment of infection due to Pneumocystis carinii.Antimicrob Agents Chemother. 1998; 42: 1309-1314Crossref PubMed Google Scholar)Few clinical data to support the use of this combinationCaspofungin and TMP-SMX70 mg IV loading dose of caspofungin on day one, followed by 50 mg IV daily after in combination with TMP-SMX (dose reduced in the setting of moderate to severe hepatic dysfunction)Echinocandins have activity against Pneumocystis in animal models (37Schmatz DM Romancheck MA Pittarelli LA et al.Treatment of Pneumocystis carinii pneumonia with 1,3-beta-glucan synthesis inhibitors.Proc Natl Acad Sci USA. 1990; 87: 5950-5954Crossref PubMed Scopus (153) Google Scholar, 38Powles MA Liberator P Anderson J et al.Efficacy of MK-991 (L-743,872), a semisynthetic pneumocandin, in murine models of Pneumocystis carinii.Antimicrob Agents Chemother. 1998; 42: 1985-1989Crossref PubMed Google Scholar)Case reports caspofungin use in combination with TMP-SMX for PCP (39Annaloro C Della Volpe A Usardi P Lambertenghi Deliliers G Caspofungin treatment of Pneumocystis pneumonia during conditioning for bone marrow transplantation.Eur J Clin Microbiol Infect Dis. 2006; 25: 52-54Crossref PubMed Scopus (42) Google Scholar, 40Utili R Durante-Mangoni E Basilico C Mattei A Ragone E Grossi P Efficacy of caspofungin addition to trimethoprim-sulfamethoxazole treatment for severe pneumocystis pneumonia in solid organ transplant recipients.Transplantation. 2007; 84: 685-688Crossref PubMed Scopus (65) Google Scholar)Clinical efficacy compared to TMP-SMX alone remains unknownAdjunctive agentsCorticosteroids40 mg-60 mg of prednisone (or equivalent) po bid with taper after 5–7 days over a period of 1–2 weeksCorticosteroids are best administered within 72 h in the setting of hypoxia (pAO2 < 70 mmHg)Not well studied in transplantationMay require prolonged taper to avoid immune reconstitution pneumonitisColony-stimulating factorsIdeal dosing unknownUse of GM-CSF as an adjuvant has been studied in animal models (41Mandujano JF D’Souza NB Nelson S Summer WR Beckerman RC Shellito JE Granulocyte-macrophage colony stimulating factor and Pneumocystis carinii pneumonia in mice.Am J Respir Crit Care Med. 1995; 151: 1233-1238PubMed Google Scholar)No clinical data in humans availableTMP-SMX, trimethoprim-sulfamethoxazole; PCP, Pneumocystis pneumonia; AIDS, acquired immunodeficiency syndrome; G6PD, glucose-6-phosphate dehydrogenase; GM-CSF, granulocyte/macrophage colony stimulating factor. Open table in a new tab TMP-SMX, trimethoprim-sulfamethoxazole; PCP, Pneumocystis pneumonia; AIDS, acquired immunodeficiency syndrome; G6PD, glucose-6-phosphate dehydrogenase; GM-CSF, granulocyte/macrophage colony stimulating factor. Practice recommendations regarding the treatment of PCP in transplant recipients include: (1)Trimethoprim-sulfamethoxazole (TMP-SMX) is the first-line agent and drug of choice (Grade I). No agent has been shown to have outcomes superior to TMP-SMX.(2)In severe infections, intravenous pentamidine probably remains the second-line agent after TMP-SMX (Grade II-1). Although it is effective, its use can be complicated by numerous toxicities outlined in Table 4. Most experts recommend avoiding it altogether in pancreas transplant recipients because of the potential for islet cell necrosis (Grade III).(3)In patients with hypoxemia (pAO2 < 70 mmHg on room air), adjunctive corticosteroids should be administered with antimicrobial therapy, ideally within 72 h of initiating antimicrobial therapy for maximum benefit (Grade II-1). Though the optimal dose of corticosteroids has not been well established, recommendations of 40–60 mg of prednisone (or equivalent) given twice daily for 5–7 days before being tapered over a period of another 7–14 days is often recommended (Grade III).(4)Duration of antimicrobial therapy should be extended for at least 14 days, though longer courses may be required in severe infections (Grade III).(5)Consider reducing pharmacological immunosuppression when feasible (Grade III). This is not well studied enough to know when it is an absolute necessity or to know which agents are better to hold or reduce in dosing. This approach has to be weighed in each individual patient and balanced with the risk for rejection and immune reconstitution. Routine anti-Pneumocystis prophylaxis is recommended for most centers with an incidence of PCP of at least 3–5% among transplant recipients (17Fishman JA Prevention of infection caused by Pneumocystis carinii in transplant recipients.Clin Infect Dis. 2001; 33: 1397-1405Crossref PubMed Scopus (125) Google Scholar). With widespread use of prophylaxis and diverse immunosuppressive regimens, the true incidence of posttransplant PCP is unknown. The benefits of TMP-SMX prophylaxis are significant and may also include the prevention of most infections due to Toxoplasma and Listeria species, common respiratory, urinary and gastrointestinal pathogens. For those patients who have risk factors such as the need for increasing immunosuppression in the face of rejection, recurrent or chronic active infection with CMV, prolonged courses of higher-dose corticosteroid therapy (e.g. >20 mg daily of prednisone for at least 2 weeks), prolonged neutropenia or flares of autoimmune disease, prophylaxis is generally indicated. Lung transplant recipients are always considered at high risk for PCP. In any transplant population, the risk is considered highest within the first 6 months posttransplant, though features outlined above may prolong that risk. For patients receiving immunosuppressive drugs or corticosteroids pretransplant (as in the case of certain autoimmune diseases), the risk for PCP may be acute after transplant, occurring in the first few weeks rather than after 1 month. In general, anti-Pneumocystis prophylaxis is recommended for all solid organ transplant recipients for at least 6–12 months posttransplant (Grade III). For lung and small bowel transplant recipients, as well as any transplant patient with a history of prior PCP infection or chronic CMV disease, lifelong prophylaxis may be indicated (Grade III). Lifelong prophylaxis is also often used in the setting of heart and liver transplantation depending on perceived overall risk and intensity of immunosuppression. Agents used for prophylaxis are outlined in Table 5.Table 5Specific prophylactic agents for prevention of PneumocystisAgentsDosingCommentsTrimethoprim-sulfamethoxazole (TMP-SMX, cotrimoxazole)Can be given at 80 mg TMP/400 mg SMX or 160 mg TMP/800 mg SMX po (single or double strength) daily or three times weeklyTMP-SMX remains the drug of choice for PCP prophylaxis (42Ioannidis JP Cappelleri JC Skolnik PR Lau J Sacks HS A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens.Arch Intern Med. 1996; 156: 177-188Crossref PubMed Google Scholar)Daily regimens may be required to have efficacy for other forms of posttransplant infectionsDapsone50–100 mg po qdDapsone is considered a second-line agent for the prophylaxis of PCP (43Hughes WT Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: A review.Clin Infect Dis. 1998; 27: 191-204Crossref PubMed Scopus (103) Google Scholar)Side effect profile of dapsone may be more common among solid organ transplant recipients (44Lee I Barton TD Goral S et al.Complications related to dapsone use for Pneumocystis jiroveci pneumonia prophylaxis in solid organ transplant recipients.Am J Transplant. 2005; 5: 2791-2795Crossref PubMed Scopus (42) Google Scholar)Atovaquone1500 mg po qdClinical trial data in HIV patients who could not tolerate TMP-SMX showed atovaquone to be equivalent to dapsone in preventing PCP (45El-Sadr WM Murphy RL Yurik TM et al.Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group.N Engl J Med. 1998; 339: 1889-1895Crossref PubMed Scopus (148) Google Scholar)Data in solid organ transplant recipients show it to be well tolerated (17Fishman JA Prevention of infection caused by Pneumocystis carinii in transplant recipients.Clin Infect Dis. 2001; 33: 1397-1405Crossref PubMed Scopus (125) Google Scholar)Failures of atovaquone have been reported at doses of 1000 mg or less daily (17Fishman JA Prevention of infection caused by Pneumocystis carinii in transplant recipients.Clin Infect Dis. 2001; 33: 1397-1405Crossref PubMed Scopus (125) Google Scholar, 46Rodriguez M Sifri CD Fishman JA Failure of low-dose atovaquone prophylaxis against Pneumocystis jiroveci infection in transplant recipients.Clin Infect Dis. 2004; 38: e76-e78Crossref PubMed Scopus (37) Google Scholar)Pentamidine300 mg administered through aerosolized nebulizer q 3–4 weeksPentamidine requires administration by experienced personnel with a nebulizer producing droplets of 1–3 μPentamidine is well tolerated with minimal side effects other than cough and bronchospasmThere is a higher incidence of breakthrough infection compared to TMP-SMX or dapsoneReports of disseminated infection involving the thyroid in HIV cases receiving inhaled pentamidine as prophylaxis (47Zavascki AP Maia AL Goldani LZ Pneumocystis jiroveci thyroiditis: Report of 15 cases in the literature.Mycoses. 2007; 50: 443-446Crossref PubMed Scopus (15) Google Scholar)Clindamycin and pyrimethamineUp to 300 mg of clindamycin po qd with 15 mg of pyrimethamine po qd (some clinicians have administered this regimen three times weekly instead of daily)Somewhat efficacious in AIDS, though less effective than TMP-SMX or dapsone (48Barber BA Pegram PS High KP Clindamycin/primaquine as prophylaxis for Pneumocystis carinii pneumonia.Clin Infect Dis. 1996; 23: 718-722Crossref PubMed Scopus (28) Google Scholar)Failure rate higher than for aerosolized pentamidineGastrointestinal intolerance may be limitingTMP-SMX, trimethoprim-sulfamethoxazole; PCP, Pneumocystis pneumonia; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome. Open table in a new tab TMP-SMX, trimethoprim-sulfamethoxazole; PCP, Pneumocystis pneumonia; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome. Practice recommendations regarding prophylaxis include TMP-SMX as the drug of choice for prophylaxis of PCP (Grade I). All other prophylactic agents should be considered second-line agents due to breadth of coverage, drug intolerances, cost and efficacy issues that are not favorable compared to TMP-SMX. TMP-SMX may also have the advantage of preventing other opportunistic pathogens after transplantation. The side effects of TMP-SMX dosing in prophylaxis are less common than with therapy, but may include bone marrow suppression that can be potentiated by concomitant administration of other myelosuppressive agents. Rash may occur, spanning the gamut of benign reactions to Stevens-Johnson syndrome. Other potential adverse effects include hepatitis, interstitial nephritis, aseptic meninigits and pancreatitis. Trimethoprim has the capacity to inhibit potassium and creatinine secretion in the renal tubules, resulting in hyperkalemia and an elevation of serum creatinine that does not necessarily reflect true renal function. Dapsone is often used as a second-line agent for PCP prophylaxis. Some reports of daily dapsone use have included it in combination with pyrimethamine at 25–50 mg once weekly. Dapsone may also be an effective agent for prevention of T. gondii (42Ioannidis JP Cappelleri JC Skolnik PR Lau J Sacks HS A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens.Arch Intern Med. 1996; 156: 177-188Crossref PubMed Google Scholar). Although it may be tolerated in transplant patients who cannot receive TMP-SMX, it is generally not recommended in those who suffer severe TMP-SMX reactions such as desquamation, neutropenia, interstitial nephritis or hepatitis. It is also generally contraindicated in those patients with documented glucose-6-phosphate dehydrogenase (G6PD) deficiencies. The most commonly associated side effects of dapsone include hemolytic anemia and methemoglobinemia. Classically these symptoms are associated with G6PD enzyme deficiency, though G6PD deficiency is not a prerequisite (44Lee I Barton TD Goral S et al.Complications related to dapsone use for Pneumocystis jiroveci pneumonia prophylaxis in solid organ transplant recipients.Am J Transplant. 2005; 5: 2791-2795Crossref PubMed Scopus (42) Google Scholar). Atovaquone is well studied in the HIV population and has also been studied in small prospective trials of solid organ transplant recipients (17Fishman JA Prevention of infection caused by Pneumocystis carinii in transplant recipients.Clin Infect Dis. 2001; 33: 1397-1405Crossref PubMed Scopus (125) Google Scholar). Available only in a suspension, atovaquone acts by inhibiting mitochondrial electron transport in susceptible Pneumocystis. Absorption is enhanced by fatty foods and decreased in the setting of diarrhea. Rash and gastrointestinal complaints are the most common side effects. Increased hepatic transaminases are rarely noted. Although ideal dosing may be unclear, breakthrough infections have been documented in patients taking 1000 mg or less daily (17Fishman JA Prevention of infection caused by Pneumocystis carinii in transplant recipients.Clin Infect Dis. 2001; 33: 1397-1405Crossref PubMed Scopus (125) Google Scholar, 46Rodriguez M Sifri CD Fishman JA Failure of low-dose atovaquone prophylaxis against Pneumocystis jiroveci infection in transplant recipients.Clin Infect Dis. 2004; 38: e76-e78Crossref PubMed Scopus (37) Google Scholar). Atovaquone may also have activity against the bradyzoites of toxoplasmosis similar to TMP-SMX and dapsone. Pneumocystis jiroveci is generally not considered a nosocomial infection, though nosocomial transmission has been documented (4De Boer MG Bruijnesteijn van Coppenraet LE Gaasbeek A 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: 1143-1149Crossref PubMed Scopus (131) Google Scholar, 5Schmoldt S Schuhegger R Wendler T et al.Molecular evidence of nosocomial Pneumocystis jiroveci transmission among 16 patients after kidney transplantation.J Clin Microbiol. 2008; 46: 966-971Crossref PubMed Scopus (96) Google Scholar, 6Hocker B Wendt C Nahimana A Tonshoff B Hauser PM Molecular evidence of Pneumocystis transmission in pediatric transplant unit.Emerg Infect Dis. 2005; 11: 330-332Crossref PubMed Scopus (67) Google Scholar, 49Thomas Jr, CF Limper AH Current insights into the biology and pathogenesis of Pneumocystis pneumonia.Nat Rev Microbiol. 2007; 5: 298-308Crossref PubMed Scopus (196) Google Scholar). Older studies have shown that Pneumocystis can be detected in air samples from hospital patient care rooms using polymerase chain reaction (PCR) techniques (50Bartlett MS Vermund SH Jacobs R et al.Detection of Pneumocystis carinii DNA in air samples: Likely environmental risk to susceptible persons.J Clin Microbiol. 1997; 35: 2511-2513Crossref PubMed Google Scholar, 51Olsson M Lidman C Latouche S et al.Identification of Pneumocystis carinii f. sp. hominis gene sequences in filtered air in hospital environments.J Clin Microbiol. 1998; 36: 1737-1740Crossref PubMed Google Scholar). Some authors recommend strict hospital segregation of immunocompromised patients with PCP and the use of facemask filtering to prevent transmission among infected individuals (5Schmoldt S Schuhegger R Wendler T et al.Molecular evidence of nosocomial Pneumocystis jiroveci transmission among 16 patients after kidney transplantation.J Clin Microbiol. 2008; 46: 966-971Crossref PubMed Scopus (96) Google Scholar). However, effective prophylaxis in susceptible patients is effective at preventing infection. Without definitive data, formal recommendations regarding infection control in the hospital cannot yet be made. Martin S.I.: The author has nothing to disclose. Fishman, J.A.: Scientific Advisor, Primera, Inc.