key: cord-022472-q2qtl26d
authors: Fishman, Jay A.; Ramos, Emilio
title: Infection in Renal Transplant Recipients
date: 2009-05-15
journal: Chronic Kidney Disease, Dialysis, & Transplantation
DOI: 10.1016/b978-1-4160-0158-4.50041-0
sha: 
doc_id: 22472
cord_uid: q2qtl26d

nan

Successful management of infections in the immunocompromised renal transplant recipient is complicated by a variety of factors. 1 These include increased susceptibility to a broad spectrum of infectious pathogens and the difficulty in making a diagnosis of infection in the face of diminished signs and symptoms of infection, an array of noninfectious etiologies of fever (e.g., graft rejection, drug toxicity), and the possibility that multiple processes are present simultaneously. Further, because immunocompromised patients tolerate invasive and established infection poorly with high morbidity and mortality, the urgency for an early and specific diagnosis to guide antimicrobial therapy is increased. Given the primacy of T-lymphocyte dysfunction in transplantation, viral infections in particular are increased and contribute to graft dysfunction, systemic illness, graft rejection, and enhancing the risk for other opportunistic infections (e.g., Pneumocystis and Aspergillus species) and for virally-mediated cancers.

The risk of infection in the renal transplant recipient is determined by the interaction of two factors:

1. The epidemiologic exposures of the patient, including those unrecognized by the patient or distant in time ( 

The prevention and treatment of infection is central to the optimal management of transplant recipients, given the adverse impact of infections on quality of life. Consideration of the epidemiology of infection allows the clinician to establish a differential diagnosis for a given "infectious" presentation and to design the optimal preventive strategy for each patient. Donor and recipient screening are critical components to the post-transplant health maintenance of the patient (Table 37-3) . Of these, consideration should be given to empiric therapy for purified protein derivative (PPD) positive patients, for Strongyloides stercoralis in patients from endemic regions, and for patients known to have received organs from donors with acute bacterial and fungal infections. Specific antiviral strategies stratified according to individual risk should be considered for all kidney recipients.

Exposures of importance can be divided into four overlapping categories: donor-or recipient-derived infections, and community-or nosocomial-acquired exposures.

Infections that are derived from the donor tissues and activated in the recipient are among the most important exposures in transplantation. Some of these are latent while others are the result of bad timing-active infection transmitted at the time of transplantation. All of the known types of infections have been recognized in transplant recipients. The activation of these infections may reflect the intensity of immune suppression or result from the allogeneic response (graft rejection), which activates latent viral pathogens. Three types of infection merit special attention. First, in donors who are bacteremic or fungemic at the time of donation, these infections-staphylococci, pneumococcus, Candida species, Salmonella, E. coli-tend to "stick" to anastamotic sites (vascular, urinary) and may produce leaks or mycotic aneurysms. Second, viral infections, including cytomegalovirus (CMV) and Epstein-Barr virus (EBV), are associated with particular syndromes and morbidity in the immunocompromised population (discussed later in text). The greatest risk of such infections is in recipients who are seronegative (immunologically naïve) and receive infected grafts from seropositive donors (latent viral infection). Third, late, latent infections, including tuberculosis, may activate many years after the initial exposure. Disseminated mycobacterial infection is often difficult to treat once established due largely to interactions between the antimicrobial agents used to treat infection (e.g., rifampin, streptomycin, isoniazid) and the agents used in immune suppressive therapy.

Given the risk of transmission of infection from the organ donor to the recipient, certain infections should be considered relative contraindications to organ donation. Given that renal transplantation is, in general, elective surgery, it is reasonable to avoid donation from individuals with unexplained fever, rash, or infectious syndromes. Some of the common criteria for exclusion of organ donors are listed in Table 37 -4.

Infections in this category are generally latent infections activated in the setting of immune suppression. It is necessary to obtain a careful history of travel and exposures to guide preventive strategies and empiric therapies. Notable among these infections are tuberculosis, strongyloidiasis, viral infections (herpes simplex and Varicella zoster or shingles), histoplasmosis, coccidioidomycosis, hepatitis B or C, and human immunodeficiency virus (HIV). Vaccination status should be evaluated (tetanus, hepatitis B, childhood vaccines, influenza, pneumococcal vaccine). Dietary habits should also be considered, including the use of well water (Cryptosporidia), uncooked meats (Salmonella, Listeria), and unpasteurized dairy products (Listeria).

Common exposures in the community are often related to contaminated food and water ingestion, exposure to infected children or coworkers, or exposures due to hobbies (gardening), travel, or work. Respiratory virus infection due to influenza, respiratory syncytial virus, and adenoviruses and more atypical pathogens (Herpes simplex virus, Herpes zoster virus) carries the risk for viral pneumonia but increased risk for bacterial superinfection. Community (social or transfusion-associated) exposure to CMV and EBV may produce severe primary infection in the nonimmune host. Recent and remote exposures to endemic, geographically restricted systemic mycoses (Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum) and Mycobacterium tuberculosis can result in localized pulmonary, systemic, or metastatic infection. Asymptomatic strongyloides stercoralis infection may activate more than 30 years after initial exposure due to the effects of immunosuppressive therapy. Such reactivation can result in either a diarrheal illness and parasite migration with hyperinfestation syndrome (characterized by hemorrhagic enterocolitis, hemorrhagic pneumonia, or both) or disseminated infection with accompanying (usually) gramnegative bacteremia or meningitis. Gastroenteritis due to Salmonella species, campylobacter jejuni, and a variety of enteric viruses can result in persistent infection, more severe and prolonged diarrheal disease as well as an increased risk of bloodstream invasion and metastatic infection.

Nosocomial infections are of increasing importance because organisms with significant antimicrobial resistance predominate in many centers. These include vancomycin, linezolid and quinupristin/dalfopristin-resistant enterococci, methicillinresistant staphylococci, and fluconazole-resistant Candida species. A single case of nosocomial Aspergillus infection in a compromised host should be seen as an indication of the failure of infection control practices. Antimicrobial abuse has resulted in increased rates of C. difficile colitis. Outbreaks of infections due to Legionella species have been associated with hospital plumbing and contaminated water supplies or ventilation systems. Each nosocomial infection should be investigated to ascertain the source and prevent subsequent infections. Nosocomial spread of P. jiroveci between immunocompromised patients has also been suggested by a variety of case series. Respiratory viral infections may be acquired from medical staff and should be considered among the causes of fever and respiratory decompensation among hospitalized or institutionalized, immunocompromised individuals. 

The net state of immunosuppression is a measure of all of the factors contributing to the patient's risk for infection (Table  37 -2). Among these are:

1. The specific immunosuppressive therapy, including dose, duration, and sequence of agents. 2. Technical problems from the transplant procedure, resulting in leaks (blood, lymph, urine) and fluid collections, devitalized tissue, poor wound healing, and surgical drainage catheters for prolonged periods. 3. Prolonged airway intubation 4. Prolonged use of broad-spectrum antibiotics 5. Renal and/or hepatic dysfunction 6. Prolonged use of vascular access or dialysis catheters Presence of infection with one of the immunomodulating viruses, including CMV, EBV, hepatitis B (HBV) or C (HCV), or HIV.

Specific immunosuppressive agents are associated with increased risk for certain infections (Table 37-5) . Combinations of these agents may enhance this risk or cause toxicity (e.g., nephrotoxicity) and may further enhance risk.

As immunosuppressive regimens have become more standardized, the specific infections that occur most often will vary in a predictable pattern depending on the time elapsed Infection i in R Renal T Transplant R Recipients 683 (Figure 37-1 ). This is a reflection of the changing risk factors (surgery/hospitalization, immune suppression, acute and chronic rejection, emergence of latent infections, and exposures to novel community infections. 1 The pattern of infections will be changed with alterations in the immunosuppressive regimen (pulse dose steroids or intensification for graft rejection), intercurrent viral infection, neutropenia (drug toxicity), graft dysfunction, or significant epidemiologic exposures (travel or food).

The time line reflects three overlapping periods of risk for infection: (1) the perioperative period to approximately 4 weeks after transplantation; (2) the period 1 to 6 months after transplantation (depending on the rapidity of taper of immune suppression and the type and dosing of antilymphocyte "induction" that may persist); and (3) the period beyond the first year after transplantation. These periods reflect the changing major risk factors associated with infection: (1) surgery and technical complications; (2) intensive immune suppression with viral activation; and (3) community-acquired exposures with the return of normal activities.

The time line may be used in a variety of ways: (1) to establish a differential diagnosis for the transplant patient suspected of having infection; (2) as a clue to the presence of an excessive environmental hazard for the individual, either within the hospital or in the community; and (3) as a guide to the design of preventive antimicrobial strategies. Infections occurring outside the usual period or of unusual severity suggest either excessive epidemiologic hazard or excessive immunosuppression. The prevention of infection must be linked to the risk for infection at various times after transplantation. Routine preventive strategies from the Massachusetts General Hospital are outlined in Table 37 -6. It should be noted that such strategies serve only to delay the onset of infection in the face of epidemiologic pressure. The use of antibiotic prophylaxis, vaccines, and behavioral modifications (e.g., routine hand washing or advice against digging in gardens without masks) may only result in a "shift to the Transplantation 684 (1) a combination of atovaquone 1500 mg po with meals once daily plus levofloxacin (or equivalent fluoroquinolone without anti-anaerobic spectrum) 250 mg once daily; (2) pentamidine (300 mg iv or inhaled q 3-4 weeks); and (3) Dapsone (100 mg po qd to biweekly) +/− pyrimethamine. Each of these agents has toxicities that must be considered, including hemolysis in G6PD-deficient hosts with dapsone. None of these alternative programs offer the same broad protection of TMP-SMX. Continued right" of the infection time line, unless the intensity of immune suppression is reduced or immunity develops.

During the first month after transplantation, three types of infection occur.

The first type of infection is that present in the recipient prior to transplantation, was inadequately treated, and now has emerged in the setting of surgery, anesthesia, and immunosuppression. Pre-transplantation pneumonia and vascular access infections are common examples of this type of infection. Colonization of the recipient with resistant organisms is also common (e.g., MRSA). The first rule of successful transplant infectious disease is the eradication of all infection possible prior to transplantation.

The second type of early infection was present in the donor before transplantation. This is often a nosocomial-acquired organism (resistant gram-negative bacilli and S. aureus or Candida species) due to (1) systemic infection in the donor (e.g., line infection) or (2) contamination during the organ procurement process. The end result is a high risk of infection of vascular suture lines with resultant mycotic aneurysm. Uncommonly, infections have been transmitted from donor to recipient, including tuberculosis or fungal (e.g., histoplasmosis) infection that may emerge earlier in the time line than would be predicted (i.e., in the first month).

The third type and the most common source of infections in this period are related to the complex surgical procedure of transplantation. These include surgical wound infections, pneumonia (aspiration), bacteremia due to vascular access or surgical drainage catheters, urinary tract infections, or infections of fluid collections-leaks of vascular or urinary Transplantation 686 Table 3 37-6 Renal Transplantation Antimicrobial Protocols at the Massachusetts General Hospital, Boston, Massachusetts-cont'd

Prophylaxis is achieved with 50% of the therapeutic dose of ganciclovir or valganciclovir (corrected for renal function). In some patients, intravenous immune globulin (IvIG or hyperimmune globulin) is used as an adjunctive therapy for prophylaxis. Certain subgroups merit routine prophylaxis. These include:

• Solid organ transplant recipients who are naïve (seronegative) and receive an organ from a seropositive donor (D+/R−) • Solid organ transplant recipients who are seropositive (R+) and receive antilymphocyte antibodies or other intensive immune suppression (e.g., for graft rejection) Symptoms, fever/neutropenia mo (or valacyclovir 500 bid or acyclovir 400 tid) Use of CMV-negative or leukocyte-filtered blood Status unknown with ALS Intravenous ganciclovir 5mg/kg iv for first dose and QD (corrected for renal function) until sero-status determined.

Neutropenia: The dose of antiviral and antibacterial therapies ARE NOT, in general, reduced for neutropenia. Consider other options first! + ALS: Antilymphocyte antibodies include any of the lytic, lymphocyte-depleting antisera *Note: Not FDA approved at these doses

Prevention of mucocutaneous infection can be accomplished with oral clotrimazole (may increase CyA levels) or nystatin 2 to 3 times per day at times of steroid therapy or in the face of antibacterial therapy. Fluconazole, at a dose of 200-400 mg/day for 10-14 days is utilized in the treatment of prophylaxis failures. Routine prophylaxis with fluconazole is used for pancreas transplants.

anastamoses or of lymphoceles. These are nosocomial infections and, as such, are due to the same bacteria and Candida infections observed in nonimmunosuppressed patients undergoing comparable surgery. However, given the immune suppression, the signs of infection may be subtle and the severity or duration may be greater. The technical skill of the surgeons and meticulous postoperative care (i.e., wound care, endotracheal tubes, vascular access devices, and drainage catheters) are the determinants of risk for these infections. Also among the common infections is C. difficile colitis. Limited perioperative antibiotic prophylaxis (i.e., from a single dose to 24 hours of an antibiotic such as cefazolin) is usually adequate with additional coverage only for known risk factors (e.g., prior colonization with MRSA). For pancreas transplantation, perioperative prophylaxis against yeasts with fluconazole is used in addition, bearing in mind the interactions between azole antifungal agents and calcineurin inhibitors and sirolimus (levels may be increased significantly). Notable by their absence in the 1st month after transplantation are opportunistic infections, even though the daily doses of immunosuppressive drugs are at their highest during this time. The implications of this observation are important: The net state of immunosuppression is not great enough to support the occurrence of opportunistic infections unless an exposure has been excessive; this observation suggests that it is not the daily dose of immunosuppressive drugs that is of importance but rather the sustained administration of these drugs, the "area under the curve," in determining the net state of immunosuppression. Thus, the occurrence of a single case of opportunistic infection in this period should trigger an epidemiologic investigation for an environmental hazard.

Infection in the transplant recipient 1 to 6 months after transplantation has one of three causes:

1. Lingering infection from the peri-surgical period, including relapsed C. difficile colitis, inadequately treated pneumonia, or infection related to a technical problem (e.g., urine leak, lymphocele, hematoma). Fluid collections require drainage. 2. Viral infections, including CMV, HSV, shingles (VZV), human herpesvirus 6 or 7, EBV, relapsed hepatitis (HBV, HCV), and HIV. This group of viruses is unique: lifelong infection; tissue-associated (often transmitted with the allograft from seropositive donors); immunomodulating-systemically immune suppressive and, potentially, predisposing to graft rejection. It is also notable that the herpesviruses are prominent due to the attenuated ability of T cells to control these infections. Among the other viral pathogens of this period must be included BK polyomavirus in association with allograft dysfunction and community-acquired respiratory viruses (adenovirus, influenza, parainfluenza, respiratory syncytial virus, metapneumovirus). The suppression of antibody production (e.g., using tacrolimus and mycophenylate mofetil or with lymphopenia) may predispose to other infections. 3. Opportunistic infection due to P. jiroveci, Listeria monocytogenes, T. gondii, Nocardia species, Aspergillus species, and other agents.

In this period, the stage is also set for the emergence of a subgroup of patients, the "chronic ne'er-do-wells"-individuals who require higher than average immune suppression to maintain graft function or who have prolonged untreated viral infections and other opportunistic infections, predicting long-term susceptibility to many other infections (third phase, discussed later). Such individuals may merit prolonged (lifelong) prophylaxis (antibacterial and/or antiviral) to prevent life-threatening infection.

The specific opportunistic infections that occur, reflect the specific immunosuppressive regimen used and the presence or absence of immunomodulating viral infection. Viral pathogens (and rejection) are responsible for the majority of febrile episodes that occur in this period. During this period, anti-CMV strategies and trimethoprim-sulfamethoxazole prophylaxis are effective in decreasing the risk of infection. Trimethoprim-sulfamethoxazole prophylaxis eliminates P. jiroveci pneumonia (PCP) and reduces the incidence of urinary tract infection and urosepsis, L. monocytogenes meningitis, Nocardia species infection, and Toxoplasma gondii.

Transplant recipients who are more than 6 months past the procedure can be divided into three groups in terms of infection risk.

The first group consists of the majority of transplant recipients (70%-80%) who had a technically good procedure with satisfactory allograft function, reduced and maintenance immunosuppression, and absence of chronic viral infection. These patients resemble the general community in terms of infection risk, with community-acquired respiratory viruses constituting their major risk. Occasionally, such patients will develop primary CMV infection (socially acquired) or infections related to underlying diseases (e.g., skin infections in diabetes).

The second group (~10% of patients) suffers chronic viral infection, which, in the absence of effective therapy, will lead inexorably to one of three results:

• End organ damage (e.g., BK polyomavirus nephropathy, cryoglobulinemia, or cirrhosis from HCV-HBV being relatively well managed at present) • Malignancy (post-transplantation lymphoproliferative disease [PTLD] due to EBV, skin, or anogenital cancer due to papilloma viruses) • Acquired immunodeficiency syndrome (HIV/AIDS) The third group of patients (~10% of all recipients) has less than satisfactory allograft function and requires excessive amounts of immunosuppressive therapy for recurrent graft rejection. This may be associated with chronic viral infection. This is the subgroup of transplant recipients, often termed the "chronic ne'er-do-wells," who are at highest risk for opportunistic infection with such pathogens as P. jiroveci, L. monocytogenes, N. asteroides, and Cryptococcus neoformans. It is our practice to give these patients lifetime maintenance trimethoprim-sulfamethoxazole prophylaxis and to consider the use of fluconazole prophylaxis. Also, this group is susceptible to organisms more often associated with immune dysfunction of AIDS (Bartonella, Rhodococcus, Cryptosporidium, and Microsporidium species) and invasive fungal pathogens (Aspergillus, Zygomycetes, and the Dematiaceae, or pigmented, molds). Minimal signs or symptoms merit careful evaluation in this group of "high-risk" individuals.

Guidelines for pre-transplant screening have been the subject of several recent publications including a consensus conference of the Immunocompromised Host Society (ICHS), the American Society for Transplantation (AST) Clinical Practice Guidelines on the evaluation of renal transplant candidates, and the ASTP Clinical Practice Guidelines on the evaluation of living renal transplant donors. [2] [3] [4] [5] [6] [7] [8] [9] The Transplant Donor

The critical feature of screening for deceased donors is time limitation. A useful organ must be procured and implanted before some microbiologic assessments have been completed. Thus, major infections must be excluded and appropriate cultures and stored samples obtained for future reference. As a result, bacteremia or fungemia may not be detected until after the transplant has occurred. Such infections have not generally resulted in transmission of infection as long as the infection has been adequately treated, both in terms of use of antimicrobial agents to which the organism is susceptible and time. In recipients of tissues from 95 bacteremic donors, a mean of 3.8 days of effective therapy post-transplantation appeared adequate to prevent transmission; longer courses of therapy in the recipient are preferred, targeting known potential pathogens from the donor. 10 Bacterial meningitis must also be treated with antibiotics that penetrate the CSF before procurement. Similarly, due to the limited time for testing, certain acute infections (CMV, EBV, HIV, HBV, or HCV) may be undetected in the period prior to antibody formation, and viral DNA detection is preferred. As a result, the donor's clinical, social, and medical histories are essential to reducing the risk of such infections. However, in the presence of known infection, such infections must be treated prior to procurement, if possible. Major exclusion criteria are outlined in Table 37 -4.

The differences in screening of the living donor and the cadaver donor are largely based on the different time frames during which this screening takes place. The living donor procedure should be considered elective-and, thus, evaluation completed and infections treated prior to such procedures. An interim history must be taken at the time of surgery to assess the presence of new infections since the initial donor evaluation. Intercurrent infections (flu-like illness, headache, confusion, myalgia, cough) might be the harbinger of important infection (West Nile Virus, SARS, rabies, Trypanosoma cruzi).

Live donors undergo a battery of serologic tests (Table 37-3) as well as PPD skin test and, if indicated, chest radiograph.

The testing must be individualized based on unique risk factors (e.g., travel). Of particular importance to the renal transplant recipient is the exclusion of urinary tract infection. Whether focal infections in the donor outside the procured organs merit therapy remains unresolved.

Mycobacterium tuberculosis. This bacterium from the donor represented approximately 4% of reported post-transplant TB cases in a review of 511 patients by Singh and colleagues. 11 Active disease should be excluded in PPD positive donors, including chest radiograph, sputum cultures, and chest CT, if the chest radiograph is abnormal. Urine AFB cultures may be useful in the PPD-positive kidney donor. Isoniazid prophylaxis of the recipient should be considered for untreated, PPDpositive donors. 12 Factors mitigating towards prophylaxis include donor from endemic region, use of high-dose steroid regimen, or high-risk social environment.

Chagas' disease (T. cruzi). This parasitic disease has been transmitted by transplantation in endemic areas and recently in the United States. Schistosomiasis and infection by Strongyloides stercoralis are generally recipient-derived problems.

Epstein-Barr virus. The risk for post-transplant lymphoproliferative disease (PTLD) is greatest in the EBV seronegative recipient of an EBV seropositive allograft (i.e., D+/R−). This is most common in pediatric transplant recipients and in adults coinfected with CMV or on higher levels of immune suppression. Monitoring should be considered for at-risk individuals using a quantitative, molecular assay (e.g., PCR) for EBV. 13, 14 EBV is also a cofactor for other lymphoid malignancies. Varicella screening should be used to identify seronegative individuals (no history of chicken pox or shingles) for vaccination prior to transplantation. HSV screening is performed by most centers despite the use of antiviral prophylaxis during the post-transplant period. VZV serologic status is particularly important in children who may be exposed at school (for antiviral or varicella immune globulin prophylaxis) and in adults with atypical presentations of infection (pneumonia or GI disease). Other herpesviruses may reactivate with HHV-6 and HHV-7 serving as cofactors for CMV and fungal infections and in endemic regions, Kaposi's sarcoma-associated herpesvirus (HHV-8/KSHV) causing malignancies.

Hepatitis B virus (HBV). HBsAg and HBV core antibody (HBcAb) are used for screening purposes with HBsAb positivity indicating either vaccination or prior infection. HBcAb-IgM positivity suggests active HBV infection, whereas IgG positivity suggests a more remote or persistent infection. The HBsAg negative, HBcAb-IgG positive donor may have viral DNA in the liver but may be appropriate as a donor for HBVinfected renal recipients. Quantitative assays for HBV should be obtained to guide further therapy. The presence of HBsAg negative, HBcAb-IgG positive assays may be a false-positive or reflect true, latent HBV infection.

Hepatitis C virus (HCV) infection will generally progress more rapidly with immune suppression and with CMV coinfection. HCV seropositive renal transplant candidates are more likely to develop cirrhosis and complications of liver failure. There is no good therapy for HCV infection; management is by quantitative molecular viral assays.

HIV-infected donors have not been utilized. The progression of disease is rapid and outweighs the benefits of transplantation. Donors may be excluded based on historic evidence of "high-risk" behavior for HIV infection. Western blot testing and molecular assays (PCR) should be obtained prior to the use of tissues from any HIVseropositive donor.

Human T-lymphotropic virus I (HTLV-I) is endemic in the Caribbean and parts of Asia (Japan) and can progress to HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or to adult T cell leukemia/lymphoma (ATL). HTLV-II is similar to HTLV-I serologically but is less clearly associated with disease. Use of organs from such donors is generally avoided. 15, 16 West Nile virus (WNV) is a flavivirus associated with viral syndromes and meningoencephalitis and may be transmitted by blood transfusion and organ transplantation. 17, 18 Routine screening of donors is not advocated other than in areas with endemic infection of the blood supply. Donors with unexplained changes in mental status or recent viral illness with neurologic signs should be avoided.

SARS (Severe Acute Respiratory Syndrome) is a recently described coronavirus, thought to be associated with exposure to civets or other animals common to the diet of certain regions of China. Tissue persistence is prolonged and infection of transplant recipients appears to be severe and often symptomatic. Organ procurement should exclude patients with recent acute illnesses meeting SARS criteria.

The pre-transplant period is useful for a thorough travel, animal, and environmental and exposure history; updating immunizations; and counseling of the recipient regarding travel, food, and other infection risks. Ongoing infection must be eradicated prior to transplantation. Two forms of infection pose a special risk:

1. Bloodstream infection: This is related to vascular access, including that for dialysis and pneumonia, which puts the patient at high risk for subsequent lung infection with nosocomial organisms. Infected ascites or peritoneal dialysis fluid must also be cleared prior to surgery. Urinary tract infection (UTI) must be eliminated prior to transplantation with antibiotics with or without nephrectomy. Similarly, skin disease that threatens the integrity of this primary defense against infection should be corrected before transplantation, even if doing so requires the initiation of immunosuppression prior to transplantation (e.g., the initiation of immune suppression to treat psoriasis or eczema). Finally, the history of more than one episode of diverticulitis should initiate an evaluation to determine whether sigmoid colectomy should be carried out prior to transplantation. 2. Tuberculosis: Both the incidence of active disease and the occurrence of disseminated infection due to M. tuberculosis are far higher in the transplant recipient than in the general population. Active tuberculous disease must be eradicated prior to transplantation. The major antituberculous drugs are potentially hepatotoxic, and significant drug interactions are common between the anti-TB agents and the agents of immune suppression. In patients with active infection, from endemic regions or with high risk exposures, TB therapy should be initiated in all PPD positive individuals prior to transplantation. Some judgment may be used as to the optimal timing of treatment in individuals without evidence of active or pleuropulmonary disease. Greater risk may include:

• Previously active tuberculosis or significant signs of old tuberculosis on chest radiograph • Recent tuberculin reaction conversion • Known exposure to active disease • Protein-calorie malnutrition, cirrhosis, or other immune deficiency • Living in a shelter or other group housing AIDS For those benefiting from HAART, AIDS has been converted from a progressively fatal disease to a chronic infection controlled by complex regimens of antiviral agents. HAART has been associated with reduced viral loads, improved CD4 lymphocyte counts, and reduced susceptibility to opportunistic infections. In the pre-HAART era, organ transplantation was generally associated with a rapid progression of AIDS. As a result, HIV-infected individuals have been excluded at most transplantation centers. However, prolonged disease-free survival with HAART has lead to a reconsideration of this policy. Renal transplantation in HIV has been associated with good outcomes in individuals with controlled HIV infection and in the absence of HCV co-infection. 19 Management requires some sophistication regarding both the immune suppressive agents and the various HAART regimens.

The spectrum of infection in the immunocompromised host is quite broad. Given the toxicity of antimicrobial agents and the need for rapid interruption of infection, early, specific diagnosis is essential in this population. Advances in diagnostic modalities (CT or MRI scanning, molecular microbiologic techniques) may greatly assist in this process. However, the need for invasive diagnostic tools cannot be overemphasized. Given the diminished immune responses of the host and the frequency of multiple simultaneous processes, invasive diagnosis is often the only method for optimal care. The initial therapy will, by necessity, be broad with a rapid narrowing of the antimicrobial spectrum as data become available. The first choice of therapy is to reduce the intensity of immune suppression. The risk of such an approach is that of graft rejection. The selection of the specific reduction may depend upon the organisms isolated. Similarly, reversal of some immune deficits (neutropenia, hypogammaglobulinemia) may be possible with adjunctive therapies (colony stimulating factors or IgG). Co-infection with virus (CMV) is common and merits additional therapy.

CMV is the single most important pathogen in transplant recipients, having a variety of direct and indirect effects. 1, 27 The direct effects include:

• Fever and neutropenia syndrome with features of infectious mononucleosis, including hepatitis, nephritis, leukopenia, and/or thrombocytopenia • Pneumonia • Gastrointestinal invasion with colitis, esophagitis, gastritis, ulcers, bleeding, or perforation • Hepatitis, pancreatitis, chorioretinitis With the exception of chorioretinitis, the direct clinical manifestations of CMV infection usually occur 1 to 4 months after transplantation; chorioretinitis usually does not begin until later in the transplant course.

Although CMV is the most common cause of clinical infectious disease syndromes, its "indirect effects" are often more important. CMV infection produces a profound suppression of a variety of host defenses, predisposing to secondary invasion by such pathogens as P. jiroveci, Candida and Aspergillus species, and some bacterial infections. CMV also contributes to the risk for graft rejection, PTLD, HHV6, and HHV7 infections. The mechanisms for this effect are complex, including altered T-cell subsets and MHC synthesis, and the elaboration of an array of pro-inflammatory cytokines, chemokines, and growth factors.

Transmission of CMV in the transplant recipient occurs in one of three patterns: primary infection, reactivation infection, and superinfection. 1 

Virus may be reactivated in the setting of an allograft from a seropositive donor transplanted into a seropositive recipient (D+R+).

Control of CMV infection is via MHC-restricted, virusspecific, cytotoxic T lymphocyte response (CD8+ cells) controlled by CD4+ lymphocytes. Seroconversion is a marker for the development of host immunity. Thus, the major effector for activation of virus is the nature of the immunosuppressive therapy being administered. The lytic antilymphocyte antibodies, both polyclonal and monoclonal, are direct activators of viral infection (mimicking the alloimmune response) and also provoke the elaboration of TNF and the other pro-inflammatory cytokines that enhance viral replication. Cyclosporine, tacrolimus, sirolimus, and prednisone (other than pulse doses) have limited ability to reactivate latent CMV while azathioprine, mycophenolate, and cyclophosphamide are moderately potent in terms of promoting viral reactivation. These agents perpetuate infection once established.

Allograft rejection is a major stimulus for CMV activation and vice versa. Thus, the CMV infection has been linked to a diminished outcome of renal and other allografts. As a result, Reinke and colleagues 27 showed that 17 of 21 patients for whom biopsy revealed evidence of "late acute rejection" demonstrated a response to antiviral therapy. Further, Lowance and colleagues 28 demonstrated that the prevention of CMV infection also resulted in a lower incidence of graft rejection.

Clinical management of CMV, both prevention and treatment, is of great importance for the transplant recipient. It is based on a clear understanding of the causes of CMV activation and the variety of diagnostic techniques available. CMV cultures are generally too slow and insensitive for clinical utility. Further, a positive CMV culture (or shell vial culture) derived from respiratory secretions or urine is of little diagnostic value-many patients secrete CMV in the absence of invasive disease. Serologic tests are useful prior to transplantation to predict risk but are of little value after transplantation in defining clinical disease (this statement includes measurements of anti-CMV immunoglobulin M [IgM] levels). Should a patient seroconvert to CMV, this is evidence that the patient has been exposed to CMV and has developed some degree of immunity. However, seroconversion in transplantation is generally delayed and, thus, not useful for clinical diagnosis. The demonstration of CMV inclusions in tissues in the setting of a compatible clinical presentation is the "gold standard" for diagnosis.

Quantitation of the intensity of CMV infection has been linked to the risk for infection in transplant recipients. [29] [30] [31] [32] [33] Two types of quantitative assays have been developed: the molecular assays and the antigen detection assays. The antigenemia assay is a semiquantitative fluorescent assay in which circulating neutrophils are stained for CMV early antigen (pp65), which is taken up nonspecifically as a measure of the total viral burden in the body. The molecular assays (direct DNA PCR, hybrid capture, amplification assays) are highly specific and sensitive for the detection of viremia. Most commonly used assays include plasma-based PCR testing and the whole-blood hybrid capture assay, noting that whole blood and plasma-based assays cannot be directly compared. The highest viral loads are often associated with tissue-invasive disease with the lowest in asymptomatic CMV infection. Viral loads in the CMV syndrome are variable. Either assay can be used in management.

The advent of quantitative assays for the diagnosis and management of CMV infection has allowed noninvasive diagnosis in many patients with two important exceptions:

1. Neurologic disease, including chorioretinitis 2. Gastrointestinal disease, including invasive colitis and gastritis.

In these syndromes, the CMV assays are often negative and invasive (biopsy) diagnosis may be needed. The central role of assays is illustrated by the approach to prevention and treatment of CMV (Table 37-6). The schedule for screening is linked to the risk for infection. Thus, in the high risk patient (D+/R− or R+ with antilymphocyte globulin) after the completion of prophylaxis, monthly screening is performed to assure the absence of infection for 3 to 6 months. In the patient being treated for CMV infection, the assays provide an end point (zero positivity) for therapy and the initiation of prophylaxis.

Prevention of CMV infection must be individualized for immunosuppressive regimens and the patient. Two strategies are commonly used for CMV prevention: (1) universal prophylaxis and (2) preemptive therapy. Universal prophylaxis involves giving antiviral therapy to all "at-risk" patients beginning at or immediately post-transplant for a defined time period. In preemptive therapy, quantitative assays are used to monitor patients at predefined intervals to detect early disease. Positive assays result in therapy. Preemptive therapy incurs extra costs for monitoring and coordination of outpatient care while reducing the cost of drugs and the inherent toxicities. Prophylaxis has the possible advantage of preventing not only CMV infection during the period of greatest risk, but also diminishing infections due to HHV6, HHV7, and EBV. Further, the indirect effects of CMV (i.e., graft rejection, opportunistic infection) may also be reduced by routine prophylaxis. In practice neither strategy is perfect. Both breakthrough disease and ganciclovir resistance have been observed in both approaches.

Given the risk for invasive infection, patients at risk for primary infection (CMV D+/R−) are generally given prophylaxis for 3 to 6 months after transplantation. We utilize 6 months of prophylaxis in patients receiving lytic antilymphocyte antibodies. Other groups are candidates for preemptive therapy if an appropriate monitoring system is in place and patient compliance is good.

The standard of care for treating CMV disease is 2 to 3 weeks of intravenous ganciclovir (5 mg/kg twice daily, with dosage adjustments for renal dysfunction). In patients slow to respond to therapy and who are seronegative, the addition of 3 months of CMV hyperimmune globulin in seronegative individuals (150 mg/kg/dose iv) may be useful. Relapse does occur, primarily in those not treated beyond the achievement of a negative quantitative assay. Therefore, we treat intravenously until viremia has been cleared and following it with prophylaxis with 2 to 4 months of oral ganciclovir (1 g two or three times daily) or valganciclovir (based on creatinine clearance). This approach has resulted in rare symptomatic relapses and appears to prevent the emergence of antiviral resistance.

A number of issues remain. First, the role of oral valganciclovir in treatment has not been well studied. This agent provides good bioavailability but is not approved for this indication. Further, some relapses occur in GI disease because the assays used to follow disease are not reliable in this setting. Thus, repeat endoscopy should be considered to assure the clearance of infection. The optimum dosing of valganciclovir for prophylaxis in renal transplant recipients is also unclear. Many centers use 450 mg/day po (given reduced creatinine clearance) although the FDA approved dosing 900 mg/day. It is worth measuring the creatinine clearance to ensure appropriate dosing.

Alternative therapies are available in intravenous form only. These include foscarnet and cidofovir. Foscarnet has been used extensively for therapy of CMV in AIDS patients. It is active against most ganciclovir-resistant strains of CMV, although we prefer combination therapy (ganciclovir and foscarnet) for such individuals, given the toxicities of each agent and the antiviral synergy demonstrated. Cidofovir has been used in renal transplant recipients, often with nephrotoxicity. Both foscarnet and cidofovir may exhibit synergistic nephrotoxicity with calcineurin inhibitors. A newer class of agents (leflunamide) has been approved for immune suppression and treatment of rheumatologic diseases but also appears to have useful activity against CMV (and possibly BK polyomavirus).

EBV is a ubiquitous herpesvirus (the majority of adults are infected) that has B-lymphocytes as a primary target for infection. In immunosuppressed transplant recipients, primary EBV infection (and relapses in the absence of antiviral immunity) causes a mononucleosis-type syndrome, generally presenting as a lymphocytosis (B-cells) with or without lymphadenopathy or pharyngitis. Meningitis, hepatitis, and pancreatitis may also be observed. Remitting-relapsing EBV infection is common in children and may reflect the interplay between evolving antiviral immunity and immune suppression. This syndrome should suggest relative over-immune suppression.

EBV also plays a central role in the pathogenesis of posttransplant lymphoproliferative disorder or PTLD. [34] [35] [36] [37] The most clearly defined risk factor for PTLD is primary EBV infection that increases the risk for PTLD by 10-to 76-fold. PTLD may occur, however, in the absence of EBV infection or in seropositive patients. Post-transplant non-Hodgkin's lymphoma (NHL) is a common complication of solid organ transplantation. Lymphomas comprise up to 15% of tumors among adult transplant recipients (51% in children) with mortality of 40% to 60%. Many deaths are associated with allograft failure after withdrawal of immune suppression during treatment of malignancy. Compared with the general population, PTLD has increased extranodal involvement, poor response to conventional therapies, and poor outcomes. The spectrum of disease ranges from benign polyclonal, B-cell infectious mononucleosis-like disease to malignant, monoclonal lymphoma. 38 The majority is of B-cell origin, although T-cell, NK-cell and null cell tumors are described. It should be noted that EBV-negative PTLD has been described and that T-cell PTLD has been demonstrated in allografts, confused with graft rejection or other viral infection. PTLD late (more than 1-2 years) after transplantation is more often EBV-negative in adults.

The clinical presentations of EBV-associated PTLD vary:

1. Unexplained fever (fever of unknown origin) 2. A mononucleosis-type syndrome, with fever, malaise, with or without pharyngitis or tonsillitis (often diagnosed incidentally in tonsillectomy specimens); often no lymphadenopathy is observed. 3. Gastrointestinal bleeding, obstruction, perforation 4. Abdominal mass lesions 5. Infiltrative disease of the allograft 6. Hepatocellular or pancreatic dysfunction 7. Central nervous system disease Diagnosis Serologic testing is not useful for the diagnosis of acute EBV infection or PTLD in transplantation. Thus, quantitative EBV viral load testing is required for the diagnosis and management of PTLD. [39] [40] [41] [42] Serial assays are more useful in an individual patient than specific viral load measurements. These assays are not standardized and cannot be directly compared between centers. There are some data to suggest that assays using unfractionated whole blood are preferable to plasma samples for EBV viral load surveillance.

Clinical management depends on the stage of disease. In the polyclonal form, particularly in children, reestablishment of immune function may suffice to cause PTLD to regress. At this stage, it is possible that antiviral therapy might have some utility given the viremia and role of EBV as an immune suppressive agent. With the progression of disease to extra-nodal and monoclonal malignant forms, reduction in immune suppression may be useful, but alternate therapies are often required. In renal transplantation, the failure to regress with significant reductions in immune suppression may suggest the need to sacrifice the allograft for patient survival. Combinations of anti-B-cell therapy (anti-CD20 rituximab), chemotherapy (CHOP), and/or adoptive immunotherapy with stimulated T cells have been utilized. [43] [44] [45] [46] Polyomaviruses Polyomaviruses have been identified in transplant recipients in association with nephropathy and ureteral obstruction (BK virus) and in association with demyelinating disease of the brain (JC virus) similar to that in AIDS. Polyomaviruses are small nonenveloped viruses with covalently closed, circular, double-stranded DNA genomes. Adult levels of seroprevalence are 65% to 90%. BK virus appears to achieve latency in renal tubular epithelial cells. JC virus has also been isolated from renal tissues but appears to have preferred tropism for neural tissues. Reactivation occurs with immune deficiency and suppression and tissue injury (e.g., ischemia-reperfusion).

BK virus is associated with a range of clinical syndromes in immunocompromised hosts: viruria and viremia, ureteral ulceration and stenosis, and hemorrhagic cystitis. [47] [48] [49] [50] [51] [52] [53] [54] Active infection of renal allografts has been associated with progressive loss of graft function (BK nephropathy) in some individuals. This may be referred to as polyomavirus-associated nephropathy or PVAN. BK nephropathy is rarely recognized in recipients of nonrenal organs. The clinical presentation of disease is usually as sterile pyuria, reflecting shedding of infected tubular and ureteric epithelial cells. These cells contain sheets of virus and are detected by urine cytology as "decoy cells." In most cases, such cells are not detected and the patient presents with diminished renal allograft function or with ureteric stenosis and obstruction. In such patients, the etiologies of decreased renal function must be carefully evaluated (e.g., mechanical obstruction, drug toxicity, pyelonephritis, rejection, thrombosis, recurrent disease), and choices must be made between increasing immune suppression to treat suspected graft rejection and reducing immune suppression to allow the immune system to control infection. Patients with BK nephropathy treated with increased immune suppression have a high incidence of graft loss. Reduced immune suppression may stabilize renal allograft function but risks graft rejection. Polyoma-associated nephropathy manifested by characteristic histologic features and renal dysfunction is found in about 1% to 8% of renal transplant patients.

Risk factors for nephropathy are poorly defined. Nickeleit and colleagues 51, 52 found that cellular rejection occurred more commonly in patients with BK nephropathy than in controls. Other studies have implicated high dose immunosuppression (particularly tacrolimus and mycophenolate mofetil), pulse dose steroids, severe ischemia-reperfusion injury, exposure to antilymphocyte antibody therapy, increased number of HLA mismatches between donor and recipient, cadaver renal transplants, and presence and degree of viremia in the pathogenesis of disease. The role of specific immunosuppressive agents has not been confirmed.

The use of urine cytology to detect the presence of infected decoy cells in the urine has approximately 100% sensitivity for BK virus infection but a low (29%) predictive value. 53, 54 It is, therefore, a useful screening tool but cannot establish a firm diagnosis. The use of molecular techniques to screen blood or urine has also been advocated but is more useful in management of established cases (viral clearance with therapy) than in specific diagnosis. [55] [56] [57] [58] [59] [60] Hirsch and colleagues 53 showed that patients with BK nephropathy have a plasma viral load statistically significantly higher (>7700 BK virus copies per mL of plasma, p<.001, 50% positive predictive value, 100% negative predictive value) when compared to patients without such disease. 53 Given the presence of viremia in renal allograft recipients, it is critical to reduce immune suppression when possible. However, the possible coexistence of rejection with BK infection makes renal biopsy essential for the management of such patients. Renal biopsies will demonstrate cytopathic changes in renal epithelial cells without cellular infiltration with the gradual evolution of cellular infiltration consistent with the diagnosis of interstitial nephritis. Fibrosis is often prominent occasionally with calcification. Immunostaining for cross reacting SV40 virus demonstrates patchy staining of viral particles within tubular cells.

There is no accepted treatment for PVAN other than a marked reduction in the intensity of immune suppression. It is possible to monitor the response to such maneuvers using urine cytology (decoy cells) and viral load measures in blood and/or urine. The greatest incidence of BK nephropathy is at centers with the most intensive immune suppressive regimens. Thus, it is unclear whether reduction of calcineurin inhibitors or antimetabolites should be considered first. Given the toxicity of calcineurin inhibitors for tubular cells and the role of injury in the activation of BK virus, as well as the need for anti-BK T-cell activity, we have generally reduced these agents first. Other centers have selected reduction of the antimetabolite first. Regardless of the approach, renal function, drug levels, and viral loads must be monitored carefully.

Some centers advocate the use of cidofovir for BK nephropathy in low doses (0.25-1 mg/kg every 2 weeks). [61] [62] [63] [64] Significant renal toxicity may be observed with this agent, especially in combination with the calcineurin inhibitors. Retransplantation has been achieved in such patients with failed allografts, possibly as a reflection of immunity developing subsequent to reduction in immune suppression. 65 

Infection of the central nervous system by JC polyomavirus has been observed uncommonly in renal allograft recipients as progressive multifocal encephalopathy. This infection generally presents with focal neurologic deficits or seizures and may progress to death following extensive demyelination. PML may be confused with calcineurin neurotoxicity; both may respond to a reduction in drug levels. It is thought that these are distinct entities, but further studies are underway.

In addition to the endemic mycoses, transplant recipients are at risk for opportunistic infection with a variety of fungal agents, the most important of which are Candida species, Aspergillus species, and C. neoformans.

The most common fungal pathogen in these patients is Candida, with C. albicans and C. tropicalis accounting for 90% of the infections and C. glabrata for most of the rest. Mucocutaneous candidal infection (e.g., oral thrush, esophageal infection, cutaneous infection at intertriginous sites, candidal vaginitis) occurs particularly when candidal overgrowth is promoted by the presence of high levels of glucose and glycogen in tissues and fluids (e.g., with poorly controlled diabetes, high-dose steroid therapy) and by broad-spectrum antibacterial therapy). These infections are usually treatable through correction of the underlying meta-bolic abnormality and topical therapy with clotrimazole or nystatin. More difficult to manage is candidal infection occurring in association with the presence of foreign bodies that violate the mucocutaneous surfaces of the body (e.g., vascular access catheters, surgical drains, and bladder catheters). Optimal management of these infections requires removal of the foreign body and systemic antifungal therapy with either fluconazole or amphotericin.

A special problem in renal transplant recipients is candiduria, even if the patient is asymptomatic. Particularly in individuals with poor bladder function, obstructing fungal balls can develop at the ureteropelvic junction, resulting in obstructive uropathy, ascending pyelonephritis, and the possibility of systemic dissemination. A single positive culture result for Candida species from a blood specimen necessitates systemic antifungal therapy, because this finding carries a risk of visceral invasion of more than 50% in this population. Fluconazole (400-600 mg/day, with adjustment for renal dysfunction), because of its better safety profile, is usually used as initial therapy, unless the patient is critically ill or a fluconazole-resistant species (e.g., C. glabrata or C. krusei) is present. In these instances, therapy is with caspofungin or amphotericin B, usually in a lipid preparation. Flucytosine may be useful as an adjunctive therapy in resistant infections but must be guided by drug levels and attention to hematopoietic toxicity.

Invasive aspergillosis is a medical emergency in the transplant recipient, with the portal of entry being the lungs and sinuses in more than 90% of patients and the skin in most of those remaining. Two species, A. fumigatus and A. flavum, account for most of these infections, although amphotericin-resistant isolates (A. terreus) are occasionally recognized. The pathologic hallmark of invasive aspergillosis is blood vessel invasion, which accounts for the three clinical characteristics of this infection: tissue infarction, hemorrhage, systemic dissemination with metastatic invasion. Early in the course of transplantation, central nervous system involment with fungal infection is most often due to Aspergillus species; more than 1 year after transplantation, other fungi (zygomycetes, dematiaceous fungi) are increasingly prominent.

The drug of choice for this infection is probably voriconazole, noting the intense interactions between this agent and the calcineurin inhibitors and sirolimus. Liposomal amphotericin is a reasonable alternative, and combination therapies are under study. Of note, surgical debridement is often essential for the successful clearance of such invasive infections.

Central nervous system (CNS) infection in the transplant recipient is an important differential for the clinician. The spectrum of causative organisms is broad and must be considered in terms of the timeline for infection in this population. Many infections are metastatic to the CNS, often from the lungs. Thus, a "metastatic workup" is a component of evaluation of CNS lesions, including those due to Aspergillus, Cryptococcus, Nocardia, or Strongyloides stercoralis. Viral infections include cytomegalovirus (nodular angiitis), herpes simplex meningoencephalitis, JC virus (PML), and varicella zoster virus. Common bacterial infections include Listeria monocytogenes, mycobacteria, Nocardia, and occasionally Salmonella species. Brain abscess and epidural abscess may be observed with methicillin-resistant staphylococcus, penicillin resistant pneumococcus and quinolone-resistant streptococci problematic. Metastatic fungi include Aspergillus and Cryptococcus but also spread from sinuses (Mucoraceae), skin (Dematiaceae), and bloodstream (Histoplasma and Pseudoallescheria/Scedosporium, Fusarium species). Parasites include Toxoplasma gondii and Strongyloides. Given the spectrum of etiologies, precise diagnosis is essential. In particular, empiric therapy must "cover" Listeria (ampicillin), Cryptococcus (fluconazole or amphotericin), and herpes simplex virus (acyclovir) while awaiting data from lumbar puncture, blood cultures, and radiographic studies. Included in the differential diagnosis are noninfectious etiologies, including calcineurin inhibitor toxicity and lymphoma, as well as metastatic cancer. Biopsy is often needed for a firm diagnosis.

Cryptococcal infection is rarely seen in the transplant recipient until more than 6 months after transplantation. In the relatively intact transplant recipient, the most common presentation of cryptococcal infection is that of an asymptomatic pulmonary nodule, often with active organisms present. In the "chronic ne'er-do-well" patient, pneumonia and meningitis are common with skin involvement at sites of tissue injury (catheters) also being observed.

Cryptococcosis should be suspected in transplant recipients present with unexplained headaches (especially when accompanied by fevers), decreased state of consciousness, failure to thrive, or unexplained focal skin disease (which requires biopsy for culture and pathologic evaluation) more than 6 months after transplantation. Diagnosis is often achieved by serum cryptococcal antigen detection, but all such patients should have lumbar puncture for cell counts and cryptococcal antigen studies. Initial treatment is probably best with amphotericin and 5-flucytosine followed by high dose fluconazole until the cryptococcal antigen is cleared from blood and cerebrospinal fluid. Scarring and hydrocephalus may be observed.

The spectrum of potential pathogens of the lungs in transplantation is too broad for this discussion. However, some general concepts are worth mentioning. As for all infections in transplantation, invasive diagnostic techniques are often necessary in these hosts. The depressed inflammatory response of the immunocompromised transplant patient may greatly modify or delay the appearance of a pulmonary lesion on radiograph. Focal or multifocal consolidation of acute onset will quite likely be caused by bacterial infection. Similar multifocal lesions with subacute to chronic progression are more likely secondary to fungi, tuberculosis, or nocardial infections. Large nodules are usually a sign of fungal or nocardial infection, particularly if they are subacute to chronic in onset. Subacute disease with diffuse abnormalities, either of the peri-bronchovascular type or miliary micronodules, are usually caused by viruses (especially CMV) or Pneumocystis jiroveci. 66, 67 Additional clues can be found by examining pulmonary lesions for cavitation; cavitation suggests such necrotizing infections as those caused by fungi (Aspergillus or Mucoraceae), Nocardia, Staphylococcus, certain gram-negative bacilli, most commonly with Klebsiella pneumoniae and Pseudomonas aeruginosa. [68] [69] [70] CT of the chest is useful when the chest radiograph is negative or when the radiographic findings are subtle or nonspecific. CT is also essential to the definition of the extent of the disease process, the possibility of multiple simultaneous processes (superinfection), and to the selection of the optimal invasive technique to achieve microbiologic diagnosis.

The risk of infection with Pneumocystis is greatest in the first 6 months after transplantation and during periods of increased immune suppression. 1, 66, 67 The natural reservoir of infection remains unknown. Aerosol transmission of infection has been demonstrated by a number of investigators in animal models, and clusters of infections have developed in clinical settings, including between HIV-infected persons and renal transplant recipients. Activation of latent infection remains a significant factor in the incidence of disease in immunocompromised hosts. In the solid organ transplant recipient, chronic immune suppression that includes corticosteroids is most often associated with pneumocystosis. Bolus corticosteroids, cyclosporine, or co-infection with CMV may also contribute to the risk for Pneumocystis pneumonia.

In patients not receiving trimethoprim-sulfamethoxazole (or alternative drugs) as prophylaxis, most transplant centers report an incidence of Pneumocystis jiroveci pneumonia of approximately 10% in the first 6 months post-transplant. There is a continued risk of infection in three overlapping groups of transplant recipients: (1) those who require higher than normal levels of immune suppression for prolonged periods of time due to poor allograft function or chronic rejection; (2) those with chronic cytomegalovirus infection; and (3) those undergoing treatments that increase the level of immune deficiency, such as cancer chemotherapy or neutropenia due to drug toxicity. The expected mortality due to Pneumocystis pneumonia is increased in patients on cyclosporine when compared to other immunocompromised hosts. The hallmark of infection due to P. jiroveci is the presence of marked hypoxemia, dyspnea, and cough with a paucity of physical or radiologic findings. In the transplant recipient, Pneumocystis pneumonia is generally acute to subacute in development. Atypical Pneumocystis infection (radiographically or clinically) may be seen in patients who have coexisting pulmonary infections or who develop disease while receiving prophylaxis with second choice agents (e.g., pentamidine or atovaquone). Patients outside the usual period of greatest risk for PCP may present with indolent disease confused with heart failure. In such patients, diagnosis often has to be made by invasive procedures. The role of sirolimus therapy in the clinical presentation is unknown. A number of patients have been identified with interstitial pneumonitis while receiving sirolimus; it is not known whether this syndrome is directly attributable to sirolimus or reflects concomitant infection.

The characteristic hypoxemia of Pneumocystis pneumonia produces a broad alveolar-arterial PO 2 gradient. The level of serum lactic dehydrogenase (LDH) is elevated in most patients with Pneumocystis pneumonia (>300 international units [IU]/mL). However, many other diffuse pulmonary processes also raise serum LDH levels.

Like many of the "atypical" pneumonias (pulmonary infection without sputum production), no diagnostic pattern exists for Pneumocystis pneumonia on routine chest radiograph. The chest radiograph may be entirely normal or develop the classical pattern of perihilar and interstitial "ground glass" infiltrates. Microabscesses, nodules, small effusions, lymphadenopathy, asymmetry, and linear bands are common. Chest computerized tomography (CT-scans) will be more sensitive to the diffuse interstitial and nodular pattern than routine radiographs. The clinical and radiologic manifestations of P. jiroveci pneumonia are virtually identical to those of CMV. Indeed, the clinical challenge is to determine whether both pathogens are present. Significant extrapulmonary disease is uncommon in the transplant recipient.

Identification of P. jiroveci as a specific etiologic agent of pneumonia in an immunocompromised patient should lead to successful treatment. A distinction should be made between the diagnosis of Pneumocystis infection in AIDS and in non-AIDS patients. The burden of organisms in infected AIDS patients is generally greater than that of other immunocompromised hosts and noninvasive diagnosis (sputum induction) more often achieved. In general, noninvasive testing should be attempted to make the initial diagnosis, but invasive techniques should be used when clinically feasible. The diagnosis of P. jiroveci infection has been improved by the use of induced sputum samples and of immunofluorescent monoclonal antibodies to detect the organism in clinical specimens. These antibodies bind both cysts and trophozoites. The cyst wall can be displayed by a variety of staining techniques; of these, the Gomori's methenamine-silver nitrate method (which stains organisms brown or black) is most reliable, even though it is susceptible to artifacts. Sporozoites and trophozoites are stained by polychrome stains, particularly the Giemsa stain.

Early therapy, preferably with trimethoprim-sulfamethoxazole (TMP-SMZ) is preferred; few renal transplant patients will tolerate full-dose TMP-SMZ for prolonged periods of time. This reflects both the elevation of creatinine due to trimethoprim (competing for secretion in the kidney) and the toxicity of sulfa agents for the renal allograft. Hydration and the gradual initiation of therapy may help. Alternate therapies are less desirable but have been used with success, including: intravenous pentamidine, atovaquone, clindamycin with primaquine or pyrimethamine, and trimetrexate. Although a reduction in the intensity of immune suppression is generally considered a part of anti-infective therapy in transplantation, the use of short courses of adjunctive steroids with a gradual taper is sometimes used in transplant recipients (as in AIDS patients) with severe respiratory distress associated with PCP.

The importance of preventing Pneumocystis infection cannot be overemphasized. Low dose trimethoprim-sulfamethoxazole is well tolerated and should be used in the absence of concrete data demonstrating true allergy. Alternative prophylactic strategies including dapsone, atovaquone, inhaled or intravenous pentamidine, are less effective than trimethoprim-sulfamethoxazole but useful in the patient with significant allergy to sulfa drugs. TMP-SMX is the most effective agent for prevention of infection due to P. jiroveci. The advantages of TMP-SMX include increased efficacy, lower cost, the availability of oral preparations, and possible protection against other organisms, including Toxoplasma gondii, Isospora belli, Cyclospora cayetanensis, Nocardia asteroides, and common urinary, respiratory, and gastrointestinal bacterial pathogens. It should be noted that alternative agents lack this spectrum of activity.

Due to concerns about the efficacy of vaccines following transplantation, patients should complete vaccinations at least 4 weeks beforehand to allow time for an optimal immune response and resolution of subclinical infection from live vaccines. Vaccinations should include pneumococcal vaccine (if not vaccinated in last 3-5 years), documentation of tetanus and MMR (measles, mumps, rubella) and polio status, as well as vaccines for hepatitis B and Varicella zoster (if no history of chickenpox or shingles) (see also . After transplant, influenza vaccination should be performed yearly or as per local guidelines. Recommended schedules and doses for routine vaccinations can be obtained from the United States Centers for Disease Control and Prevention (CDC) at www.immunize.org or the CDC Immunization Information Hotline, (800) 232-2522. 

Infection in organ-transplant recipients

Pretransplant evaluation for infections in donors and recipients of solid organs

Prophylactic measures in the solid-organ recipient before transplantation

Organ donor screening for infectious diseases: Review of practice and implications for transplantation

Cadaver donor screening for infectious agents in solid organ transplantation

Recipient screening prior to solid-organ transplantation

American Society of Transplantation. The evaluation of renal transplant candidates: Clinical practice guidelines

Ad Hoc Clinical Practice Guidelines Subcommittee of the Patient Care and Education Committee of the American Society of Transplant Physicians

Report of the Crystal City meeting to maximize the use of organs recovered from the cadaver donor

Outcome of transplantation of organs procured from bacteremic donors

Mycobacterium tuberculosis infection in solid-organ transplant recipients: Impact and implications for management

Isoniazid hepatotoxicity in renal transplant recipients

Diagnosis and management of posttransplant lymphoproliferative disorder in solid-organ transplant recipients

Serial measurement of Epstein-Barr viral load in peripheral blood in pediatric liver transplant recipients during treatment for posttransplant lymphoproliferative disease

Guidelines for counseling persons infected with human Tlymphotropic virus type I (HTLV-I) and type II (HTLV-II)

Long-term results in human T-cell leukemia virus type 1-positive renal transplant recipients

Update: Investigations of West Nile virus infections in recipients of organ transplantation and blood transfusion

Update: Investigations of West Nile virus infections in recipients of organ transplantation and blood transfusion? Michigan

Transplantation for patients infected with human immunodeficiency virus: no longer experimental, but not yet routine

Clinical presentation and outcome of tuberculosis in kidney, liver and heart transplant recipients in Spain

Mycobacterial infections in renal allograft recipients

Mycobacterial infections in renal transplant recipients: Report of five cases and review of the literature

Mycobacterial infections in renal transplant recipients: Seven cases and a review of the literature

Mycobacterial infections after renal transplantation: Report of fourteen cases and review of the literature

Typical and atypical mycobacterium

Mycobacterium tuberculosis infection in solid-organ transplant recipients: Impact and implications for management

Late-acute renal allograft rejection and symptomless cytomegalovirus infection

Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group

Comparison of quantitative cytomegalovirus (CMV) PCR in plasma and CMV antigenemia assay: Clinical utility of the prototype AMPLICOR CMV MONITOR test in transplant recipients

Cytomegalovirus (CMV) virus load kinetics to predict recurrent disease in solidorgan transplant patients with CMV disease

Multicenter comparison of the digene hybrid capture CMV DNA assay (version 2.0), the pp65 antigenemia assay, and cell culture for detection of cytomegalovirus viremia

Prevention of cytomegalovirus disease in recipients of solid-organ transplants

New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients

Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients

Epstein-Barr virus-induced posttransplant lymphoproliferative disorders

The diverse pathology of posttransplant lymphoproliferative disorders: Importance of a standardized approach

Guidelines for the diagnosis and management of post transplant lymphoproliferative disorder in solid organ transplant recipients

Posttransplant lymphoproliferative disorders (PTLD) pathology and genetics: Tumours of haematopoietic and lymphoid tissues

Management of Epstein-Barr virus-induced posttransplant lymphoproliferative disease in recipients of solid organ transplantation

Quantitation of Epstein-Barr virus DNA in the blood of adult liver transplant recipients

Epstein-Barr viral load as a tool to diagnose and monitor post-transplant lymphoproliferative disease

Epstein-Barr virus load monitoring: Its role in the prevention and management of PTLD

Immunotherapy for post-transplant lymphoproliferative disease

Anti-B cell and anti-cytokine therapy for the treatment of PTLD: Past, present and future

Treatment of Epstein-Barrvirus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells

Interferon and cytotoxic chemotherapy for the treatment of post transplant lymphoproliferative disorder

The persistence of papovavirus BK DNA sequences in normal human renal tissue

BK virus: Discovery, epidemiology, and biology

BK virus in solid organ transplant recipients: An emerging syndrome

Human polyoma virus-associated interstitial nephritis in the allograft kidney

BK-virus nephropathy in renal transplants-tubular necrosis, MHC-class II expression and rejection in a puzzling game

Polyomavirus infection of renal allograft recipients: From latent infection to manifest disease

Prospective study of polyomavirus type BK replication and nephropathy in renaltransplant recipients

BK virus nephropathy? polyomavirus adding insult to injury

Morphological spectrum of polyoma virus disease in renal allografts: Diagnostic accuracy of urine cytology

Prospective study of the human polyomaviruses BK and JC and cytomegalovirus in renal transplant recipients

Clinical course of polyoma virus nephropathy in 67 renal transplant patients

BK virus infection in a kidney allograft diagnosed by needle biopsy

Polyomavirus reactivation in native kidneys of pancreas alone allograft recipients

BK virus nephropathy diagnosis and treatment: Experience at the University of Maryland Renal Transplant Program

The use of vidarabine in the treatment of human polyomavirus associated acute haemorrhagic cystitis

Activities of various compounds against murine and primate polyomaviruses

Clinical pharmacokinetics of cidofovir in human immunodeficiency virus-infected patients

Quantitative viral load monitoring and cidofovir therapy for the management of BK virusassociated nephropathy in children and adults

Successful retransplantation following renal allograft loss to polyoma virus interstitial nephritis

Prevention of infection caused by Pneumocystis carinii in transplant recipients

Prevention of infection due to Pneumocystis carinii

Nocardiosis in transplant recipients

Recurrent nocardiosis in a renal transplant recipient

Central venous catheter-associated Nocardia bacteremia: An unusual manifestation of nocardiosis