Pneumocystis Pneumonia in Solid Organ Transplant Recipients

Authors

  • S. I. Martin,

    Corresponding author
    1. Division of Infectious Diseases and Comprehensive Transplant Center, The Ohio State University Medical Center, Columbus, OH
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  • J. A. Fishman,

    1. Division of Infectious Diseases and Transplantation Center, Massachusetts General Hospital, Boston, MA
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  • the AST Infectious Diseases Community of Practice

    1. Division of Infectious Diseases and Comprehensive Transplant Center, The Ohio State University Medical Center, Columbus, OH
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* Corresponding author: Stanley I. Martin, stanley.martin@osumc.edu

Introduction

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 (1).

Epidemiology and Risk Factors

Pneumocystis spp. are thought to be ubiquitous in nature with serologic studies suggesting that exposure occurs commonly in childhood (2). 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 (3). Clusters of infection have been described in medical facilities among renal transplant recipients (4–6). 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 (7). 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% (1). 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 1.  Risk factors for the development of Pneumocystis pneumonia
Risk factorsComments
  1. HIV, human immunodeficiency virus; PCP, Pneumocystis pneumonia; CMV, Cytomegalovirus; HSCT, hematopoietic stem cell transplant; GVHD, Graft versus host disease.

Immunosuppressive therapies
 CorticosteroidsRetrospective 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 (8)
 ChemotherapyReports of PCP with numerous chemotherapeutic agents including methotrexate, fluorouracil and bleomycin
Risk for infection may be related to subsequent neutropenia (1)
Purine analogs, such as fludarabine and cladribine and the antimetabolite cytarabine may be independent risk factors for PCP (9,10)
 Antilymphocyte therapyAntilymphocyte antibodies are linked to the highest risk for PCP in the 1 to 6 month posttransplant period (11)
Alemtuzumab, a monoclonal antibody with activity against B, T and NK cells may confer the highest risk (12)
 Mycophenolate mofetilThe anti-Pneumocystis effects of mycophenylate mofetil in vitro and in animal models has not been confirmed in prospective clinical trials (13)
 Calcineurin inhibitorsAt a single institution where cyclosporine A replaced azathioprine in renal transplantation, the incidence of PCP increased from 3 to 9% (14)
One retrospective study suggested a higher incidence of PCP among renal transplant recipients on tacrolimus-based regimens compared to cyclosporine A (15)
 SirolimusSirolimus has been associated with interstitial pneumonitis that can be confused with or coexist with PCP (16)
Other clinical factors
 CMV diseaseCMV may be an independent risk factor for PCP (17)
Coinfection with CMV and PCP may be observed in solid organ transplantation (18,19)
 Allograft rejectionPCP has been related to the intensity of immunosuppression in transplant recipients (15)
PCP has been linked to treatment and number of episodes of acute rejection (19)
 GVHDImmunosuppression therapies for GVHD > 6 months post-HSCT predispose to PCP (20)
 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 (21)
PCP has been linked to decreased CD4+T-cell counts in HSCT recipients (22), solid tumor patients receiving chemotherapy (23), autoimmune disease and hematological malignancy patients (24)
Low CD4+ T-cell counts may reflect viral coinfection or exogenous immunosuppression
Transplant patients with CD4+T-cell lymphopenia are expected to be at risk for PCP (17)
 NeutropeniaProlonged neutropenia is a potential risk factor for PCP in transplant recipients (17)

Clinical Presentation

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 (25). These clinical findings are classically dominated by dyspnea and hypoxemia out of proportion to physical and radiographic findings.

Table 2.  Signs and symptoms of Pneumocystis pneumonia
Sign or symptom of PCPIncidence
Fever81–87%
Dyspnea66–68%
Cough71–81%
Chest pain23–24%
Abnormal lung auscultation on exam30–34%
Abnormal chest radiography92–96%
Hypoxemia78–91%

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.

Diagnosis

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 (26).

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 (27,28). 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 (1). PCP has also been observed in concert with abnormal lung changes due to sirolimus. Diagnostic tests are outlined in Table 3.

Table 3.  Diagnostic approaches to Pneumocystis pneumonia in transplantation
TestEstimated yieldComments
  1. AIDS, acquired immunodeficiency syndrome; PCP, Pneumocystis pneumonia; HIV, human immunodeficiency virus; BAL, bronchoalveolar lavage; PCR, polymerase chain reaction; rRNA, ribosomal ribonucleic acid.

Routine sputumGenerally poorOrgan transplant patients with PCP may have smaller burden of infecting organisms than AIDS patients (29)
Induced sputumImproved over routine sputum exam when coupled with antibody staining; yield ≥50% (27)Yield from induced sputum in transplant patients may not reflect that found in HIV-infected patients
 Sensitivity and specificity in transplant patients unknown
 Repeat testing may improve yield (28)
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% (30)
Transbronchial biopsyIncreases yield of routine BAL (1)Multiple biopsies preferred
Open 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 (31,32)
 Cases of missed infection in open lung biopsy also reported (28)
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 rRNAs
Plasma (1→3) β-D-GlucanSome reports after transplantation (33, 34)(1→3) β-D-Glucan is produced in the cyst cell wall (35)
 Clinical trials data lacking

Practice recommendations for the diagnosis of PCP in transplant recipients include:

  • 1Patients 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.
  • 2Clinicians 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.
  • 3Patients undergoing bronchoscopy should be considered for transbronchial biopsies. Increased yield is likely obtained by multiple samples (Grade III).
  • 4Open 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.

Treatment

For the established or presumed diagnosis of PCP, therapeutic options are outlined in Table 4.

Table 4.  Therapeutic options for treating Pneumocystis pneumonia
AgentsDosingComments
  1. TMP-SMX, trimethoprim-sulfamethoxazole; PCP, Pneumocystis pneumonia; AIDS, acquired immunodeficiency syndrome; G6PD, glucose-6-phosphate dehydrogenase; GM-CSF, granulocyte/macrophage colony stimulating factor.

Trimethoprim-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 PCP
For milder disease, two double-strength tablets can be given po bid-tid 
Pentamidine 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 disturbances
 Pancreatic dysfunction may suggest the need for avoidance in pancreas transplantation
Atovaquone750 mg po bid (optimal dose uncertain; 1500 bid used anecdotally)Atovaquone is available in an oral suspension only
 Atovaquone has variable oral absorption (best with fatty foods)
 Atovaquone is approved only for mild and moderate PCP
Primaquine 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 AIDS
 Long-term use of clindamycin can predispose to infection with Clostridium difficile
 Primaquine should be avoided in G6PD deficiency
Dapsone 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 well
Trimetrexate 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 acid
 Outcomes are inferior to TMP-SMX in AIDS
 Trimetrexate is no longer commercially available in the United States
Pyrimethamine 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 regimen
 It may also require folinic acid 10mg po qd to reduce bone marrow toxicity
Macrolide and SMXMacrolides such as clarithromycin or azithromycin in combination with sulfamethoxazole may be synergistic in vivo (36)Few clinical data to support the use of this combination
Caspofungin 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 (37,38)
 Case reports caspofungin use in combination with TMP-SMX for PCP (39,40)
 Clinical efficacy compared to TMP-SMX alone remains unknown
Adjunctive agents
 Corticosteroids40 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 transplantation
 May require prolonged taper to avoid immune reconstitution pneumonitis
 Colony-stimulating factorsIdeal dosing unknownUse of GM-CSF as an adjuvant has been studied in animal models (41)
 No clinical data in humans available

Practice recommendations regarding the treatment of PCP in transplant recipients include:

  • 1Trimethoprim-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.
  • 2In 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).
  • 3In 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).
  • 4Duration of antimicrobial therapy should be extended for at least 14 days, though longer courses may be required in severe infections (Grade III).
  • 5Consider 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.

Prophylaxis

Routine anti-Pneumocystis prophylaxis is recommended for most centers with an incidence of PCP of at least 3–5% among transplant recipients (17). 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 5.  Specific prophylactic agents for prevention of Pneumocystis
AgentsDosingComments
  1. TMP-SMX, trimethoprim-sulfamethoxazole; PCP, Pneumocystis pneumonia; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome.

Trimethoprim-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 (42)
 Daily regimens may be required to have efficacy for other forms of posttransplant infections
Dapsone50–100 mg po qdDapsone is considered a second-line agent for the prophylaxis of PCP (43)
 Side effect profile of dapsone may be more common among solid organ transplant recipients (44)
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 (45)
 Data in solid organ transplant recipients show it to be well tolerated (17)
 Failures of atovaquone have been reported at doses of 1000 mg or less daily (17,46)
Pentamidine300 mg administered through aerosolized nebulizer q 3–4 weeksPentamidine requires administration by experienced personnel with a nebulizer producing droplets of 1–3 μ
 Pentamidine is well tolerated with minimal side effects other than cough and bronchospasm
 There is a higher incidence of breakthrough infection compared to TMP-SMX or dapsone
 Reports of disseminated infection involving the thyroid in HIV cases receiving inhaled pentamidine as prophylaxis (47)
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 (48)
 Failure rate higher than for aerosolized pentamidine
 Gastrointestinal intolerance may be limiting

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 (42). 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 (44).

Atovaquone is well studied in the HIV population and has also been studied in small prospective trials of solid organ transplant recipients (17). 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 (17,46). Atovaquone may also have activity against the bradyzoites of toxoplasmosis similar to TMP-SMX and dapsone.

Infection Control Issues

Pneumocystis jiroveci is generally not considered a nosocomial infection, though nosocomial transmission has been documented (4–6,49). Older studies have shown that Pneumocystis can be detected in air samples from hospital patient care rooms using polymerase chain reaction (PCR) techniques (50,51). Some authors recommend strict hospital segregation of immunocompromised patients with PCP and the use of facemask filtering to prevent transmission among infected individuals (5). 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.

Disclosure

Martin S.I.: The author has nothing to disclose. Fishman, J.A.: Scientific Advisor, Primera, Inc.

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