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Saudi Journal of Kidney Diseases and Transplantation
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ARTICLES Table of Contents   
Year : 2005  |  Volume : 16  |  Issue : 4  |  Page : 453-497
Infectious Complications in Kidney Transplant Recipients: Review of the Literature


Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri, USA

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   Abstract 

Since the initial successful kidney transplantation in humans, the field of renal transplantation has made significant progress. Patient survival and graft survival have improved tremendously. Our armamentarium of immunosuppressive drugs and antimicrobial agents has expanded, as our understanding of their effects and proper utilization. Enhanced surgical techniques also improved the overall survival of kidney recipients. However, infectious complications remain a major cause of morbidity and mortality in this patient population. In this article, we provide an overview of infections in kidney transplant recipients, a detailed illustration of specific infectious agents with a focus on cytomegalovirus, and finally we lay some general principles for limiting the burden of infectious complications in kidney transplants through proper infection control measures.

Keywords: Kidney Transplantation, Infection Control, Graft Survival, Patient Survival, Cytomegalovirus, Immunization.

How to cite this article:
Khoury JA, Brennan DC. Infectious Complications in Kidney Transplant Recipients: Review of the Literature. Saudi J Kidney Dis Transpl 2005;16:453-97

How to cite this URL:
Khoury JA, Brennan DC. Infectious Complications in Kidney Transplant Recipients: Review of the Literature. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2017 Feb 20];16:453-97. Available from: http://www.sjkdt.org/text.asp?2005/16/4/453/32840

   Introduction Top


Since the first failed attempt at a human renal transplantation by the Ukrainian surgeon Yu Yu Voronoy in 1933 and the first successful renal transplantation in the United States in the early 1950's, kidney transplantation has made significant progress. Overall graft and patient survival have improved due to several factors including enhanced surgical techniques, a better selection and use of immunosuppressive drugs and improved diagnostic, preventive and therapeutic measures for infectious complications.

During the first decades of the renal trans­plantation era, a serious infectious complication developed in up to 70% of patients following transplantation, resulting in fatal outcomes in as many as 11% to 40% of cases. In the late 90's, the incidence of infections had declined to 15%- 44% with a mortality rate of less than 5%. [1] Despite improved outcomes in kidney transplant patients over the years, infectious complications remain a significant cause of morbidity and mortality in this population. Several studies have shown that allograft and patient survival were reduced at one and three years after transplantation in recipients with infection and febrile episodes, and even in the current era infection remains the third largest cause of death in renal transplant recipients. [2],[3] Although several factors influence the risk of infections following transplantation, key factors include the degree of human leuko­cyte antigens (HLA) mismatch, the net state of immunosuppression, early renal function, early rejection episodes, and donor kidney source.

Most infections occur early in the post­transplantation course with about two-thirds of renal transplant recipients (RTR) expe­riencing an infectious-related complication in the first year after transplantation. [4] Approxi­mately 70% of severe bacterial, fungal and viral infections occur within 3 months of transplantation.

After the first 6 months from transplantation, the kidney transplant function becomes the main predictor of risk for infections. [5] About 75% of patients have excellent allograft function and require low maintenance immunosuppre­ssive therapy; these develop infections at a frequency comparable to that in the general population. Fifteen percent have a moderate graft function and have a higher incidence of viral infections. [6] The remaining 10% with poor allograft function and frequent episodes of acute and chronic rejections carry the highest risk for development of opportunistic infections. [7]

Deceased donor kidney transplant recipients are more prone to infectious complications than living related RTR because of a higher risk of HLA mismatching and increased requirements for immunosuppression. [8] Accord­ing to data from the United Network for Organ Sharing (UNOS) for 2001, the one-year adjusted graft survival for recipients of deceased donor kidneys was 89.2% with a 96.1% patient survival. The one-year adjusted graft survival for recipients of kidneys from living relatives was 96.1% and the one-year patient survival was 98.3%. [9]

The optimal approach to address infections in RTR is prevention. This could be achieved with pre-transplantation evaluation of both recipient and donor for latent or active infect­ions, immunization of susceptible individuals, antimicrobial prophylaxis and adequate surveillance for opportunistic infections.


   Timing of Infections Post-Transplantation Top


The post-transplantation period has tradi­tionally been divided into three time frames in relation to the incidence and type of infectious complications: the first month, the second through the sixth months, and the late post­transplantation period beyond the sixth month. Infections in the first month post-transplant­ation are mostly similar in pattern to post­surgical infections in non-immunocompromised individuals. These include urinary tract infections, wound infections, pneumonia and line sepsis and are mostly caused by bacteria and Candida species. [10] Technical or anatomic problems related to the allograft such as perigraft hematoma, lymphocele or urinary leak may increase the risk of infection. [11] Common viral infections that reactivate in the first month are herpes viruses types 1 and 2. Other infections that occur in the first month are untreated infections in the recipient that may be exacerbated by immunosuppression, or infections related to contamination of the allograft from an infection in the donor or during organ procurement or preservation. [7]

The second to the sixth month post trans­plantation is the period where opportunistic infections are most common such as cyto-megalovirus (CMV), Pneumocystis jiroveci (PCP), Nocardia, Listeria and others. Also, latent infections that were present in the recipient or transmitted from the donor may be reactivated or become clinically apparent in this period. Examples include tuberculosis (TB) and viral hepatitis. [11]

Beyond the sixth month, the type of infection is mostly dictated by the allograft function and the degree of immunosuppression, with increased risk of opportunistic infections in patients with poor allograft function and those with repeated episodes of acute rejection requiring increased immunosuppressive therapy. One possible explanation for late infections with allograft dysfunction is unrecognized increased immunosuppression from reduced clearance associated with renal insufficiency. For example, mycophenolate mofetil (MMF) accumulates with renal insufficiency. 12 A viral infection commonly seen during this period is reactivated Varicella Zoster Virus (VZV) manifesting as herpes zoster. [11] Chronic viral infections such as hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodefi­ciency virus (HIV), Epstein-Barr virus (EBV) and CMV chorioretinitis are apparent in 10­15% of patients in this time period. [7]


   Infectious Considerations in Certain Populations of Kidney Transplant Recipients Top


African-Americans

When compared with Caucasian RTR, African­American (AA) renal transplant recipients have a tendency to experience more acute rejection episodes and have a shorter graft survival; moreover, an AA race was found to confer a 70% increased risk of chronic allograft failure independent of acute rejection. The reason for this disparity is not entirely clear as pharmaco­kinetics of the major maintenance immuno­suppression agents do not differ by race or gender. [13] The risk of infectious death, however, has been reported to be lower in AA compared to Caucasians, suggesting that AA RTR may tolerate the risk of greater immunosuppression to improve the allograft survival. [14]

Impact of Diabetes

Approximately 30% of patients with end-stage renal disease (ESRD) who undergo transplant­ation developed renal failure as a result of their long-standing diabetes mellitus. [15] Diabetes mellitus (DM) increases the risk of invasive fungal infections such as mucormycoses and other infections. [16] Corticosteroid therapy and infection can both lead to hyperglycemia and DM, making wound healing and clearing of infections more difficult. How DM increases the risk of infections is unclear, and the contri­bution of the metabolic abnormalities of diabetes to the net state of immunosuppression is debatable. The response of monocytes and granulocytes to chemotactic stimuli is impaired but cell-mediated immunity is only marginally affected in patients with poorly controlled diabetes. [17] In a retrospective study evaluating the risk of infectious diseases in diabetic patients, Shah et al showed that many infections are more common in diabetic patients, especially serious bacterial infections. [18] It is not clear whether the risk of viral infections is increased in diabetics. In addition, DM can indirectly increase the risk of infections. For instance, neurogenic bladder can increase the risk of urinary tract infections (UTI), and of coloni­zation with Candida species which, in an immuosuppressed kidney transplant patient, may lead to ascending infections of the urinary tract.


   Sources of Infection Top


The source of infection can be divided into three groups: de novo infections which may arise from organisms colonizing the recipient or from a nosocomial origin, reactivation of latent infections present in the recipient or transmitted with the donor allograft, or contami­nation of the allograft during the procurement or preservation process.

De novo infections occur mostly in the first month and these include UTI, line sepsis, wound infections, and pneumonia. These can be caused by organisms colonizing the recipient's skin and/or mucous membranes or by organisms acquired from the hospital environment and which are often resistant to antimicrobial agents.

Reactivation of latent infections in the recipient accounts for a number of infections. This includes CMV, tuberculosis, and histo­plasmosis. Transmission of infectious agents from the donor occurs, and these may be latent chronic infections or active asymptomatic infe­ctions that are transmitted with the allograft. True donor transmitted infections are uncommon and sometimes difficult to prove. Plausible reports of organ transmission through kidney transplants of infectious organisms have been described for a number of agents listed in [Table - 1]. These include human immunodeficiency virus (HIV), CMV, herpes simplex virus (HSV), rabies virus, hepatitis B virus (HBV), the delta agent (HDV), hepatitis C virus (HCV), adenovirus, West Nile virus (WNV), polyoma viruses BK and JC, bacteria, fungi (histo­plasma, cryptococcus, candida), monosporium, mycobacteria (TB and atypical mycobacteria), malaria, toxoplasma, trypanosoma, and strongy loides. [19],[20],[21] In the setting of immunosuppression these infections tend to become disseminated and carry a high mortality rate. There are no reported cases of organ transmission of syphilis. In fact, a positive serum RPR in a donor is not a contraindication to organ procurement. [21] The risk of transmission of syphilis by organ transplantation is lowered by the frequent use of penicillin in perfusion solutions and by low temperatures at which organs are stored, thereby causing inactivation of Treponema pallidum [ . [22] There are three reported cases of transplantation of kidneys from donors with serological evidence of syphilis without transmission to the recipients. Standard courses of penicillin were successfully used to prevent infection in the recipients. [23],[24] Most cases of reported organ transmission have involved latent viruses such as CMV, HBV, HCV, and HIV.

Another cause of infection is contamination of the allograft during procurement or preser­vation. The incidence of bacterial contamination of donor kidneys varies widely, ranging from 2.1% to 23.4%. The majority of cultures indicate that the organisms are skin contaminants or organisms of low virulence. [21],[25]  Staphylococcus epidermidis Scientific Name Search is the most commonly grown bacterium from allograft perfusates. However, virulent organisms causing contamination of the allograft have been described as well. Of the patients receiving an organ infected by Pseudomonas species, over 10% died and almost 50% lost their grafts or had serious sequelae. Gottesdiener et al reviewed several cases of bacterial graft infections and noted that anastomotic rupture is a common compli­cation of infection with Staphylococcus aureus, Gram-negative rods and Bacteroides species. 21 Fungi have also been implicated in organ contamination. In one series, fungal contami­nation occurred in 0.2% to 2.5% of cultures taken from flushing or perfusion solutions used for allograft preservation. Fungal contamination of the allograft can be associated with anasto­motic complications and serious morbidity in transplant recipients. [21]

In view of the above mentioned data, it is essential to screen donors carefully for any infections with particular emphasis on endemic pathogens, which may be latent. This may not be feasible for all cases, as some infections have a prolonged incubation period and may not be suspected in donors. In the US, approxi­mately half of the kidneys are now procured from deceased donors, and a full history is not always available on the donor. Hence, the need for routine bacterial and fungal culturing of the allograft tissue at harvest and at transplant­ation, and routine blood cultures from deceased donors to minimize transmission of infections. [26] In general, donor seropositivity for HSV, VZV, EBV, human herpes virus 8 (HHV-8) or CMV is not a contraindication to donation even when the recipient is seronegative, as infection with these agents could be prevented or treated in the recipient with appropriate antimicrobials; moreover, this kind of donors represent a majority of the population inter­nationally and excluding them from the donor pool would exacerbate the extreme shortage in organs available for transplantation.


   Special Considerations Top


Dialysis Modality

Passalacqua et al demonstrated by a large retrospective analysis that there were more infectious complications within 30 days after transplantation in patients on peritoneal dialysis (PD) just prior to transplantation than in hemo­dialysis (HD) patients. 27 Patients on PD were found to have a greater incidence of infections with microorganisms that colonize the human skin, and were more likely to have an episode of acute rejection than HD patients and to have a longer hospital stay. The increased risk of infections with PD seems reversible once PD is discontinued. Nevertheless, it seems reasonable to be particularly vigilant for infectious complications in the PD population in the immediate period preceding the trans­plantation. The reason for the increased risk of infection with PD could be related to the glucose load provided by the PD fluid or by inadequate dialysis. In contrast, a large study demonstrated a modest increase in delayed graft function (DGF) in deceased donor RTR who were receiving HD pre-transplantation compared to PD, and DGF is a risk factor for infectious complications after transplantation. [28],[29]

Another potentially unrecognized source of infection in RTR is the arteriovenous graft. Nassar et al presented a series of five RTR who developed acute life-threatening infections related to occult infections of old nonfunctioning arteriovenous grafts. Screening for occult infect­ions of the vascular grafts may be important before transplantation especially in patients who have previously documented episodes of bacteremia or unexplained febrile illnesses. [30] An infected vascular graft may be appreciated on careful physical examination or white blood cell scan. [31]

Immunosuppressive Agents

A higher incidence of CMV and more severe bacterial and systemic fungal infections have been described in patients receiving cytolytic, lymphocyte-depleting therapy for acute rejection. [32] The risk of infection increases three-fold in patients treated with steroids and OKT3, a monoclonal CD3 antibody preparation. In contradistinction, interleukin-2 (IL-2) receptor antagonists such as basiliximab and daclizumab have been shown to reduce the incidence of acute rejection without increasing the incidence of opportunistic infections or malignancy in low risk renal transplant recipients. [33] Infectious risk varies with the immunosuppressive agent used. Patients receiving azathioprine (AZA) have more overall infections than patients receiving cyclosporine A (CsA), and this finding is most pronounced in the first three months after transplantation. [34] This increased risk of infection with AZA compared with CsA is probably related to the increased use of AZA in anti-rejection treatment. In one series, patients receiving mycophenolate mofetil (MMF) were found to have a higher incidence of CMV disease mainly affecting the upper gastrointestinal tract compared with patients on azathioprine. [35] Nonviral infection rates in patients receiving tacrolimus have been lower than those in patients receiving CsA-based immunosuppression, probably as a result of lower steroid requirements and less use of antilymphocyte treatment (ALT) preparations. [8] Comparing different antilympho­cyte preparations used for induction and for treatment of acute rejection, an increased risk of infection was observed with the monoclonal CD3 antibody preparation OKT3 compared to nonspecific antilymphocyte globulins. [36] In addition to their immunosuppressive role in preventing and treating rejection, some immunosuppressive agents may have anti­proliferative and anti-infective properties that may be beneficial in specific settings. Sirolimus may be beneficial in preventing or managing post-transplant malignancy because of its anti-proliferative properties, and MMF may act in synergy with ganciclovir to alter the long-term effects of CMV on graft function. [37] Also, CsA may reduce the cumulative incidence of acquired immunodeficiency syndrome (AIDS) by its inhibitory effect on the IL-2 dependent T-lymphocyte proliferation and differentiation. [38]


   Categories of infections Top


During a one-year follow-up of RTR in the Netherlands, 71% of patients had at least one episode of infection, most commonly urinary tract infections (UTI) (61%) followed by respiratory tract infections, intra-abdominal infections and CMV. [4]

Urinary Tract Infections

The incidence of UTI in patients who are not receiving antimicrobial prophylaxis has been reported to vary from 5%-36%. [39] Beyond three months after transplantation, the incidence of UTI decreases progressively. [40] Risk factors include pre-transplantation UTI, prolonged period of HD, polycystic kidney disease, DM, prolonged postoperative bladder catheterization, immunosuppression, allograft trauma, and technical complications associated with ureteral anastomosis. [41] Takai et al found that female recipients had significantly more UTI than males, and that the majority of the organisms were Gram-negative bacilli with  Escherichia More Details coli being the most common. [42] Most UTI are asymptomatic.

The long-term effect of UTI on graft and patient survival is debatable. While some studies demonstrated an increased risk of chronic rejection with urinary tract infections, [43] others failed to show that effect. [40],[44] Although the incidence of UTI is increased in patients with urologic complications, no differences in long-term graft or patient survival were seen in multiple studies addressing this problem. [42],[45],[46]

In view of the high incidence of UTI and the potential morbidity associated with it, prophy­lactic antimicrobial therapy is now universally used and is maintained for a minimum of 6-12 months following kidney transplantation. [41] Two antibiotics have proven beneficial in prophylaxis against UTI, ciprofloxacin and trimethoprim-sulfamethoxazole. [47],[48] Trime­thoprim-sulfamethoxazole (TMP-SMX) offers the additional advantage of preventing Pneumocystis carinii pneumonia (PCP). Earlier bladder catheter removal also helps reduce the incidence of UTI. [49]

Wound Infections

Early reports of surgical wound infections (SWI) described a rate of 14-34% with a sub­sequent decline to 3-4%. [50] The declining incidence of postoperative wound infections over the years is likely multifactorial. Intra­operative antibiotic bladder irrigation, peri­operative antibiotics, and meticulous surgical techniques avoiding hematoma, seroma and urinoma are important preventative measures.

The most significant risk factors for wound infections are obesity, urine leak, reoperation through the transplant incision, DM and use of MMF as opposed to AZA. Wound infe­ction may be associated with lower graft survival. [52]

Administration of intravenous perioperative antibiotics is now commonly used to prevent wound infections. [53] However, local wound irrigation with antibiotics, meticulous hemostasis and improved surgical technique, improved organ procurement and preservation techniques may reduce the risk of surgical wound infection without using systemic antibiotics.

Septicemia

The urinary tract is the most common source of septicemia, followed by the lungs, the wound site and the abdomen. [54],[55] Most cases occur within the first 6 months after transplantation. In an early series studying septicemia following kidney transplantation, UTI and wound infect­ions accounted for about half of the episodes of septicemia with Gram-negative bacilli implicated in more than 70% of the episodes. Poor prognostic factors in septicemia include persistent septicemia beyond 7 days, pulmonary portal of entry, leucopenia (WBC< 3000), metastatic abscesses, acute respiratory failure and shock. [54] Abbott et al reported an increased incidence of hospitalizations for septicemia in patients with DM, urologic disease, female gender, delayed graft function, rejection and pre-transplantation dialysis. Those recipients hospitalized for septicemia had a decreased survival rate. [29],[56]

Pneumonia

Pneumonia is the most common infection after transplantation of any organ and is the infection with the highest mortality. Survival is the highest in kidney transplants, with only 5%-8% one-year mortality. [57] The incidence of pneumonia in kidney transplants is the lowest of all solid organ transplants (8%­16%). [58] Bacterial pneumonia usually occurs late in the first year, and the risk is higher in patients receiving antilymphocyte preparations and having CMV infection. It appears that pneumonia within the first six months has a higher mortality than late pneumonia. Pneumo­nia due to certain etiologic agents could be prevented through vaccination such as pneu­mococcus, influenza or prophylaxis such as PCP, and nocardia. Specific organisms causing pneumonia in RTR will be discussed indi­vidually in later sections.


   Viral Infections Top


Infections with the herpes virus group namely CMV and the viral hepatitides are the most common and problematic of all viral infections post transplantation. Less common viruses yet important pathogens will also be covered in this section.


   CMV Top


Incidence

Cytomegalovirus, a member of the herpesvirus family, is a widely distributed human pathogen and has the capacity to remain latent in a variety of nucleated cells. Immunosuppression given following transplantation can reactivate or enhance viral replication causing CMV infection. Primary infection refers to reactivation of donor virus in a CMV-seronegative recipient.

Secondary infection occurs when an endogenous latent virus is reactivated in a seropositive recipient, and reinfection refers to reactivation of the virus of donor origin in a seropositive recipient. It is estimated that 60-90% of all renal transplant candidates have latent CMV infections, but symptomatic CMV infection occurs in only 20-60% of all renal transplant recipients. [59] The incidence varies according to the CMV serostatus of the donor and recipient. Without prophylaxis, CMV infection has been reported to occur in 65.9-88% of seronegative recipients of seropositive donor kidneys, 48.8-60% of which develop CMV disease. 60 In the donor (D)+/ recipient ( R )+ category, 50­80% of the recipients develop CMV infection. Despite prophylaxis, CMV disease occurs in 15% of D+/R- patients at 6 months and in 20% by one year post-transplantation. [61]

Risk Factors for CMV

The predictors of CMV disease after solid organ transplantation (SOT) have been well defined and include CMV mismatch, use of lymphocyte-depleting therapy, and the use of high doses of methylprednisolone. [62],[63] Risk factors for late-onset CMV disease that occurs after completing three months of prophylaxis include CMV D+/R- status and allograft rejection. [64]

Clinical Manifestations

Clinical manifestations of CMV range from asymptomatic infection characterized by CMV DNAemia to symptomatic infection often referred to as CMV disease and presenting as a flu-like illness or invasive CMV disease with target-organ damage such as necrotizing laryngitis, hepatitis, esophagitis, colitis, pan­creatitis, retinitis, myocarditis, pneumonitis, epididymitis, cholangitis and encephalitis.

CMV Relapse

Relapsing CMV disease occurs in 15-35% of SOT patients. Risk factors for relapse include D+/R- serostatus, disseminated CMV disease, and repeated courses of antirejection therapy. [64],[65]

When using a quantitative CMV DNA assay, predictors of CMV relapse were higher median pretreatment viral loads and persistent detectable viral DNA after treatment with intravenous ganciclovir. [66]

Late-onset CMV usually occurs between 3 and 6 months after SOT and appears to be of a less severe nature. Conditions associated with immune dysfunction and CMV reacti­vation such as allograft rejection and treatment with high dose methylprednisolone have been identified as important predisposing factors for late-onset CMV disease in high-risk SOT patients who received antiviral prophylaxis. [64]

Effects on Graft Survival, Patient Survival and Rejection

The mortality of CMV infection has been reported to be as high as 90% if left untreated. [67] Studies of the effects of CMV disease or asymptomatic infection on graft function and the risk of acute rejection have had conflicting results. Some studies have shown an association of CMV disease with an increased graft loss, [68] while others failed to show this effect. [69],[70] While some investigators revealed that CMV infection is a risk factor for development of graft failure and death, [71],[72] and associated it with acute rejection, [72],[73],[74] others have failed to show this correlation. [69],[75] In a recent prospective study, Sagedal et al showed that both CMV disease and surprisingly, even asymptomatic CMV infection, both detected by the CMV pp65 antigenemia test were independent risk factors for overall mortality beyond 100 days post transplantation and reduced graft survival. [76]

On a pathologic level, CMV can replicate in the kidney tissues and cause acute allograft dysfunction which usually improves with ganciclovir treatment and reduction of immunosuppression. [77] Infection with CMV has also been implicated in chronic allograft nephropathy which is the major reason for the loss of renal allografts after the first year post­transplantation. [78] Helantera demonstrated that patients with a history of acute rejection and findings of CMV on kidney biopsy had arteriosclerotic changes in small arterioles. [75]

Immunomodulating Effects

Cytomegalovirus-associated mononucleosis in humans is associated with decreased lymphocyte proliferation responses to mitogens and herpes­virus antigens, decreased interferon (IFN) production and reversal of the T-helper to suppressor cell ratio. [79] Due to its immunomodu­lating effects, CMV has been implicated in the increased risk of fungal infections in renal transplant recipients.

Diagnosis

Several diagnostic tests have been used to detect acute CMV infection. These include serology, viral culture, shell vial culture, pp65 antigenemia test, qualitative and quantitative nucleic acid detection assays. A clinically useful test should ideally have good sensitivity and specificity, be able to detect asymptomatic CMV infection and predict CMV disease thus helping in treatment decisions, and be technically easy to perform. Different studies report different sensitivities and specificities for the same test because these studies vary by design, the blood component studied and the choice of the gold standard test.

The pp65 antigenemia assay has a sensitivity of 75%-87.5% and a positive predictive value (PPV) of 57% for CMV disease compared with 64% and 79% sensitivity and 49% and 46% PPV for CMV rapid nested DNA polymerase chain reaction (PCR) and virus isolation from leukocytes by culture respectively. [80] When compared to serology, positive antigenemia results were obtained a median of 19 days before the serological response and a median of 9 days before the onset of CMV syndrome. [81] In addition, there is an association between higher quantitative antigenemia test results and clinical symptoms. [82] The use of the pp65 antigenemia test may be hampered because pp65Ag seems to be rapidly degraded in antigen-bearing cells. [82],[83],[84] Another disadvantage of this assay is that the sensitivity could markedly decrease in the presence of a delay in processing exceeding 6 hours. [84] This is also true of CMV culture specimens as demonstrated by Brennan et al. [85]

Another test is the hybrid capture CMV DNA assay which is more sensitive than the shell vial assay but less sensitive than plasma PCR. [86] Brennan et al demonstrated that buffy coat qualitative DNA PCR had a sensitivity of 91%. [85]

The quantitative plasma CMV DNA-PCR was shown to have a sensitivity of 95.9% versus 88.9% and 76.9% for the pp65 antigen assay and the qualitative plasma CMV DNA PCR respectively. [87] In addition, the amount of CMV DNA in the plasma was a good predictor of CMV disease. [87],[88] In another study with contrasting results, plasma quantitative DNA PCR used to detect CMV during and after prophylaxis for 100 days had a poor sensitivity of 38% and a PPV of 17% for CMV disease. [89] Although this may be due to a problem inherent to the test itself, it may be explained by the fact that the majority of patients with CMV viremia in this study did not develop disease.

The analysis of late viral transcripts by use of the pp67 mRNA CMV assay should be more relevant for detection of active CMV replication, because transcription of the viral genome is repressed during latency. Pellegrin et al found a poor sensitivity for this test, in contrast to the findings by Meyer et al and Gaeta et al. [90],[91],[92] Pellegrin et al compared different assays to detect CMV and the positive and negative predictive values for symptomatic CMV. [90] The results are illustrated in [Table - 2]. After establishing that quantitative CMV DNA PCR assays have good sensitivities and clinical usefulness, it is important to identify the best blood component for this test to be performed. It is suggested that whole blood (WB) is better than peripheral blood which is better than plasma for detection of CMV by PCR. [66],[90],[93] The WB assay is laborious, and there are concerns for possible unnecessary treatment as a result of its superior sensitivity. However, this is offset by the quantitative ability of the PCR, in that higher levels are predictive of the risk of disease. During anti­viral treatment, plasma DNA levels are often low and disappear early, whereas peripheral blood lymphocytes (PBL) DNA levels may be much higher and persist much longer. [94] Therefore, CMV DNA levels in PBL could be particularly helpful in monitoring the response to treatment and in individualizing the length of therapy. However, analysis of plasma offers the advantage of easier specimen processing and handling. Comparing quanti­tative DNA assays on different blood com­partments of SOT recipients, Razonable et al demonstrated a higher sensitivity of WB DNA determination and a yield of higher CMV DNA levels compared to plasma. [93] He also showed that PBL and peripheral blood mononuclear cells (PBMC) were comparable throughout the course of CMV disease and treatment and that the time to PCR negativity was directly related to the level of CMV DNA at baseline.

Taken together, we recommend that in RTR, quantitative CMV of WB be used for diagnosis and treatment. Currently, we are treating asymptomatic CMV with quantitative WB levels above 2,000 copies per ml.

Treatment Agents

A number of antiviral agents are available for use in prophylaxis or treatment of CMV. These include intravenous CMV hyperimmune globulins, acyclovir, valacyclovir, ganciclovir which is available in oral and intravenous preparations, valganciclovir, foscarnet and cidofovir.

Hyperimmune CMV immunoglobulin treat­ment reduces CMV disease from 55% to 25% in organ transplant recipients. [95] When given as prophylaxis, it does not affect the incidence of CMV infection but reduces the severity of the disease, and its role may be reduced in patients who are seropositive for CMV pre-transplantation. [96] Disadvantages of using immunoglobulin therapy are the cost of such a treatment and the heterogeneity of the prepa­ration from one country to another. [97] These agents are still used as adjunct therapy to IV ganciclovir in severe CMV infections.

Despite promising results from earlier investi­gations, [98],[99],[100] oral acyclovir and valacyclovir have not proven to have a beneficial effect on CMV infection and disease. [101],[102] In contrast, ganciclovir has been shown to be effective for prophylaxis and treatment of CMV infection in multiple studies. [103],[104] Valganciclovir is currently FDA approved for CMV retinitis and for prevention of CMV disease in kidney, heart, and kidney-heart transplants at high risk (D+/R-). It has a ten-fold better bioavailability than oral ganciclovir. Valganciclovir given at a dose of 900 mg orally results in a similar systemic exposure to ganciclovir administered at 5mg/kg IV. [105] Based on many comparative studies, valganciclovir and oral ganciclovir were found to be similar in efficacy, tolerability and cost of prophylaxis for CMV disease in solid organ transplant recipients at high risk for CMV disease. [61],[106] The advantages of valganci­ clovir over ganciclovir are the oral bioavail­ability, the once-daily dosing which promotes patient adherence and the reduced risk of development of resistance. [107] There is, however, a higher incidence of neutropenia with val­ganciclovir compared to oral ganciclovir. [61]

Cidofovir is a nucleotide that acts directly on viral DNA polymerase and does not require viral enzymes for activation; its activity is independent of the UL97-encoded viral protein and may be used as an alternative to foscarnet in the case of ganciclovir resistance. Its use is limited by nephrotoxicity. [108]

Treatment Approaches

The primary goal in dealing with CMV in SOT recipients is prevention. Review of studies of vaccination revealed no effect on the rates of CMV infection or disease but a reduction in disease severity. [96] Therefore the CMV vaccine is not being used, but there are several approaches for prevention and/or treatment of CMV infection. Universal pro­phylaxis refers to giving prophylactic therapy to all renal transplant patients regardless of their CMV serostatus. Selected prophylaxis refers to giving prophylaxis to patients at high risk for CMV namely the D+/R- category. The preemptive approach treats asymptomatic CMV infection in an effort to prevent CMV disease, and the deferred approach treats active CMV disease. Each approach has its advantages and disadvantages and there is no consensus on the best approach to use.

Prophylactic therapy is very effective in reducing CMV disease in high risk patients such as D+/R- patients receiving antilymphocyte therapy. [109],[110] Brennan et al showed that the incidence of CMV is lower in patients who had been on prophylaxis even in those who subsequently received antilymphocyte therapy. [111] The evidence for benefit in low risk patients and in patients not receiving antilymphocyte therapy is established but not as strong. [109],[111] Since CMV infection occurs in 65.9-88% of D+/R- patients, critics of the prophylactic approach claim that it exposes a significant proportion of patients who would never have developed disease to a prolonged course of antiviral therapy that may have side effects, encourage viral resistance, is costly, and may be only delaying the disease. [60],[111],[112],[113]

The beneficial effects of preemptive therapy on graft and patient survival have been described in a large retrospective study. [114] Preemptive and deferred therapies were found to be equivalent in reducing CMV disease in high risk patients who received anti-thymocyte induction therapy, with a higher CMV-related cost but equivalent overall costs for the preempt­ive approach. [85] Allograft function and survival were similar with the two approaches.

Brennan et al compared prophylactic and deferred therapy in RTR and found that 61% of patients in the deferred group developed CMV disease, but none in the ganciclovir prophylaxis group during prophylaxis. [111] However, 21% developed symptomatic CMV after 3 months of prophylaxis. Studies com­paring prophylactic and preemptive approaches are under way.

Disadvantages of deferred therapy are higher rates of CMV infection, recurrence, and mortality compared with the prophylactic and preemptive approaches, therefore, it is rarely applied. Preemptive therapy may be less costly in theory as you are treating a smaller number of patients, but this may be outweighed by the need for frequent monitoring. However, a lower cost for deferred and preemptive therapies compared to prophylactic therapy was demonstrated if these could be admini­stered in the outpatient setting. [60] The preemptive approach is limited by the fact that CMV disease has been reported to develop in 60% of transplant patients without previous viral shedding, [115] in addition, this approach might not avoid the risk of rejection, allograft dysfunction, and mortality that may be trig­gered by CMV replication even in asymptomatic patients. [60],[72],[76],[97]

Ganciclovir Resistance

Ganciclovir resistance has been demonstrated in multiple studies. [111],[116] It is postulated that persistent high subclinical CMV levels in the presence of relatively low serum concentrations of oral ganciclovir for a long period of time may lead to the emergence of resistance. [112] Viral resistance to ganciclovir may be due to a mutation in the UL97 gene encoding the viral protein kinase or the UL54 gene that encodes the DNA polymerase. [105] In a large study of SOT, Limaye et al demonstrated the development of ganciclovir-resistant CMV disease in 7% of patients in the D+/R- category compared with none in the seropositive recipients. [112] Resistance develops more in patients receiving the most potent immuno­suppression such as kidney-pancreas or pancreas alone transplantation. It tends to occur after prolonged exposure to ganciclovir, and may lead to serious complications such as allograft loss, progressive allograft dysfunction, rejection or CMV retinitis. Importantly, four of the five resistant strains isolated in Limaye's study showed cross-resistance to cidofovir.

CMV and Pregnancy

Several cases of congenital CMV in infants born to renal transplant mothers are reported in the literature. [117],[118],[119] The most severely affected symptomatic infants are almost always those born to mothers who have a primary CMV infection. Blau et al described an infant severely affected with congenital CMV who was born of a mother with renal transplantation who had a distant CMV infection and probable reactivation of CMV during her pregnancy. [120] Miller et al reported on a RTR who developed CMV during pregnancy and was successfully treated with ganciclovir, with mother and child in good health at 18 months of follow-up. [121]


   HSV Top


Herpes simplex virus (HSV) is of two types: 1 and 2. Type 1 is commonly associated with oral herpes, and type 2 is more frequently a cause of genital herpes. The virus remains latent in the sensory ganglia after the initial infection. After institution if immunosuppression, HSV reactivates mostly in the form of mucocutaneous ulcerations. Less commonly, HSV can cause severe infections such as esophagitis, pneumo­nitis, hepatitis, encephalitis, nephritis, and rarely disseminated disease. [122],[123],[124],[125] Reports of organ transmission of HSV with severe manifestations in the recipients exist in the literature. [126],[127] Diagnosis is mostly clinical and also relies on identification of cytotoxic changes by Tzanck smear, culture, PCR, or direct fluorescent antibody testing. Treatment is effective with acyclovir, valacyclovir, famciclovir, ganciclovir, and valganciclovir. Immunosuppressed patients are about ten times more likely to have resistant HSV that requires treatment with foscarnet or cidofovir. [128],[129] RTR not receiving ganciclovir or vanganciclovir for CMV prophylaxis usually receive acyclovir prophylaxis to prevent reactivation of HSV which happens most commonly in the first month after transplantation. [130] Once prophylaxis is discontinued, patients may develop HSV infections again.


   HHV-8 Top


HHV-8 has been implicated in the develop­ment of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. The incidence of Kaposi's sarcoma (KS) shows a marked geographic variation with a considerably high seroprevalence in Saudi Arabia (5.3%) and Italy. [131] African or Middle Eastern origins and the use of anti­lymphocyte therapy are risk factors for develop­ment of KS in kidney transplant recipients. [132] About 68% of RTR with HHV-8 antibodies before or after transplantation develop KS, therefore seropositivity confers a 28-fold increased risk of KS. [132] The degree of HHV-8 viremia detected by quantitative DNA PCR correlates with disease progression in organ transplant recipients. [133] It may also be useful to predict the onset of post-transplantation KS in HHV-8 seropositive patients and to monitor the follow-up of RTR with KS. [132] Patients may be infected with HHV-8 before transplantation in endemic areas or become infected after transplantation through the allo­ graft in non-endemic areas. [134],[135] In addition to its potential for oncogenic transformation, HHV-8 may have other clinical manifestations. Luppi et al reported a RTR who developed a fatal primary HHV-8 infection that manifested with fever, splenomegaly and bone marrow suppression. [135] The same authors described a RTR who developed visceral KS that was associated with severe pancytopenia, hemo­phagocytosis, and a high-level HHV-8 viremia. The patient responded to treatment with foscarnet, reduction of immunosuppression and microsomal daunorubicin with complete resolution of symptoms and no recurrence for two years. 136 KS may regress after the cessation of immunosuppression in RTR. [137],[138] Newer agents have shown promising results in the treatment of KS including thalidomide, inter­feron and anti-angiogenesis agents. [139],[140]


   EBV Top


Post-transplantation lymphoproliferative dis­orders (PTLD) represent a heterogeneous group of abnormal lymphoid proliferations that occur in the setting of ineffective T-cell function because of pharmacologic immunosuppression after organ transplantation. The majority of PTLD are of B-cell origin and are associated with EBV infection. T-cell PTLD are com­paratively rare and less frequently associated with EBV. [141] Increasing immunosuppression augments the rate of EBV reactivation. [142] Levels of EBV by semiquantitative DNA PCR in blood showed that levels higher than 500 EBV DNA copies/75,000 peripheral blood mononuclear cells were found in all patients with PTLD but in only 7.5% of RTR with­out that complication. [143] PTLD can be potentially fatal. Immune-based therapies such as monoclonal anti-B-cell antibodies, interferon­alpha, and EBV-specific donor T cells represent promising approaches for treatment of PTLD or prophylaxis in high-risk patients. [144]


   HHV-6, HHV-7 Top


Epidemiology/Introduction

HHV-6 and HHV-7 infect the CD-4 lympho­cyte. Antibodies to both viruses can be detected in approximately 90-95% of the adult popu­lation, and 7% and 9% of healthy individuals are positive for HHV-6 and HHV-7 DNAemia respectively. Much of the infection caused by these viruses is manifested as exanthema subitum which occurs in early childhood. [145],[146] Antirejection therapy has been associated with an increase in the frequency of HHV-6 and HHV-7. [147] HHV-6 affects 24-82% of SOT recipients. [148],[149] DesJardin et al showed that HHV-6 reactivation occurred in 66% of RTR, and was associated with primary CMV infection and CMV syndrome in patients at risk for primary CMV. [150] A study comparing CMV, HHV-6, and HHV-7 levels of viremia found that CMV DNAemia peaks at 7-9 weeks post transplantation whereas HHV-7 DNAemia peaks earlier at 4-6 weeks. With HHV-6 DNAemia, there was no obvious pattern in relation to the time post-transplantation; however, isolation of HHV-6 after SOT usually occurs within the first 4 weeks. [147],[148] HHV-6 has been isolated from donor kidneys at the time of transplantation and could potentially be transmitted by this route. [149]

Clinical effects/Association with CMV

A number of studies revealed that HHV-7 DNAemia is a risk factor for progression to CMV disease. [147],[151] Osman et al showed that the risk of progression to CMV disease was increased 3.7 fold in patients with concurrent DNAemia to CMV, HHV-6, and HHV-7. [147] It is possible that HHV-7 may potentiate CMV disease either by direct interaction with CMV or by immunomodulatory effects on the host immune system. [151] Similarly, HHV-6 can have immunomodulatory effects, such as inducing production of interleukin-1beta and TNF­alpha, suppressing T-lymphocyte function and suppressing bone marrow function, and may potentially increase the risk of infection with other pathogens. [152],[153],[154]

Diagnosis

Diagnosis of reactivated infection with HHV-6 or HHV-7 relies on serology or DNA qualitative or quantitative assays. It has been shown that the median time to detection of HHV-6 IgM was 47 days after transplantation. [150] There is a cross reaction in serological responses between HHV-6 and HHV-7 which are anti­genically related, thus making serology a poor differentiating test. Detection of HHV-6 or HHV-7 viral DNA in PBL specimens by qualitative DNA PCR is not an evidence of active viral replication and may reflect latent virus. [147] A quantitative assay may be a better reflection of active viral replication.

Treatment

Brennan et al showed that ganciclovir treat­ment had no effect on the prevalence of HHV­7 viremia. [155] HHV-6 is two types: A and B. HHV-6 A is the most common and is relatively insensitive to ganciclovir. HHV-6 B is less common and is sensitive to ganciclovir in vitro and to foscarnet. Antiviral therapy with these agents appears to be clinically efficacious but has not been studied in great detail. [156] Like CMV, HHV-6 lacks a thymidine kinase and is therefore not susceptible to acyclovir.


   Hepatitis viruses Top


Introduction

Chronic liver disease affects about 15% of the renal allograft recipients. [157] Renal transplant recipients with chronic viral hepatitis have a significant increase in mortality from hepatic failure and concomitant sepsis. [158] There is an increased risk of infection attributed to infection with HCV namely an increased risk of bloodstream, pulmonary and CNS infections and Gram-negative bacterial infections. [157] This may be explained by the immunomodu­latory effects of the hepatitis viruses. In addition to infecting hepatocytes, the hepatitis viruses infect the peripheral blood mononuclear cells, [159],[160] and cause decreased cellular immunity and a reduction in CD4 T-cells and T4/T8 ratio. [157],[161],[162] Through their suppressive effect on the host immune response, the hepatitis viruses may contribute to improved survival by reducing the incidence of allograft rejection, but at the same time, they increase the overall risk of infection. [157]


   Hepatitis C virus Top


Epidemiology

The prevalence of HCV antibody positivity in RTR is about 10.3%. [163] Risk factors for developing HCV infection are time on dialysis, the number of blood transfusions before transplantation and the number of previous arteriovenous grafts. [164] Mycophenolate mofetil therapy is associated with a significant increase in HCV viremia but without a significant change in liver enzymes. [165] HCV infection remains the main cause of chronic liver disease after renal transplantation, and studies of its effect on allograft and patient survival have had conflicting conclusions. Pereira et al showed that post-transplantation prevalence of anti­HCV and HCV RNA was 67% and 96% among recipients from anti-HCV positive donors, and 20% and 18% among recipients from anti­HCV negative donors, [166] suggesting potential transmission of HCV with the allograft at the time of transplantation.

Clinical Effects

Patients infected with HCV who undergo renal transplantation may have a better chance of survival than those who remain treated with dialysis despite data demonstrating acceleration of liver disease in kidney recipients. [167] Also, there was no increase in post-transplantation prevalence of liver disease or graft or patient survival between anti-HCV-positive recipients who received kidneys from anti-HCV-positive donors compared with anti-HCV-positive recipients of kidneys from anti-HCV-negative donors, suggesting that transplantation of organs from anti-HCV-positive donors into recipients with preexisting HCV infection may be safe at least in the short term. [168] Membranoproliferative glomerulonephropathy (MPGN) or membranous glomerulonephropathy (MGN) in HCV-positive patients has been well documented after kidney transplantation.

Recurrence of these diseases may be a cause of proteinuria and chronic allograft nephropathy in this population. [169]

While the clinical effects on liver function and kidney function are well described, the long-term effects of HCV infection on patient and graft survival are not entirely elucidated. Depending on the donor/recipient serostatus and the criterion used for diagnosis of HCV, such as HCV antibody positivity, liver enzyme elevation, or HCV viremia, different studies have shown variable results. A large number of studies, some with a long follow-up showed no adverse effects of HCV infection on graft or patient survival; [166],[174] some even showed a long-term survival benefit in patients with positive HCV antibodies especially if no clinical chronic hepatitis developed. [170]

Mahmoud et al showed that HCV-viremic RTR did not have an increased risk for death or graft failure unless there was chronic alanine aminotransferase elevation. [169]

In contrast, a number of studies suggested an increased risk of death, and graft failure in RTR infected with HCV. It is postulated that the increased risk of death and possibly graft failure is related to liver disease and the risk of sepsis. [164]

Treatment of HCV

The mainstay of treatment of HCV is a combination of interferon-alpha (IFN) and ribavirin with variable duration depending on genotype and response to therapy. Treatment of HCV-positive RTR with IFN increases the risk of acute rejection. However, HCV­infected patients treated with IFN-alpha prior to transplantation and who had clearance of HCV viremia, sustained this clearance at a median of 22.5 months of follow-up after transplantation despite chronic immunosuppre­ssion, [172] hence, the recommendation to consider therapy for hepatitis C in appropriate candidates before transplantation. Rostaing et al showed that treatment of chronic HCV infection in RTR with recombinant interferon-alpha was beneficial while IFN was given, but there was a high rate of relapse after discontinuation of therapy and a concern with increased creatinine level, probably from rejection. [173] In a small study on 4 pts in China, Tang et al reported a successful treatment of HCV post-transplant­ation with combined IFN-alpha and ribavirin without development of allograft dysfunction. [174] In contrast, Abdalla et al reported a case of gradual progression of HCV to cirrhosis and hepatocellular carcinoma (HCC) after 10 years following transplantation. [175] The patient had developed steroid-resistant acute rejection after IFN-alpha therapy and required antilymphocyte therapy. Ribavirin monotherapy and amantidine monotherapy in RTR are able to improve liver enzymes but have no impact upon HCV viremia or liver histology. [176],[177]

Hepatitis B Virus

Hepatitis B virus infection can occur in transplant patients as a result of primary infection, reactivation, or donor transmission. The impact of HBV infection on the clinical outcome of renal transplantation has been controversial. Rao et al showed that renal transplant patients with a positive hepatitis B surface antigen (HBsAg) had more severe histological forms of disease and a higher incidence of cirrhosis and mortality from liver failure compared with HBsAg-negative patients. [158] The use of Hepatitis B core antibody positive donor kidneys is considered safe in vaccinated patients and those with evidence of prior HBV infection. [178] Lamivudine has been used as prophylaxis and treatment; [179],.[180] however, there are reports of lamivudine­resistant HBV in kidney transplant patients and HD patients. [181]

Other Hepatotropic Viruses

Newly recognized hepatotropic viruses such as GB virus C or HGV and TT virus were studied in India in RTR. [182] Exposure rates for HGV, TTV, HBV, HCV and HDV were 58.6%, 32.9%, 52.9%, 54.3%, and 2.9% respectively. The majority of HGV and TT infections were seen as co-infection with other hepatitis viruses. HGV RNA is significantly associated with the number of hemodialysis (HD) sessions. The long-term effects of these viruses on liver function are unknown. [182]


   BK Virus Top


Epidemiology

BK virus (BKV), a member of the polyoma­virus family remains dormant in the urinary tract and circulating leukocytes after the primary childhood infection and becomes reactivated during immunosuppression. Analysis of risk factors has underscored the central role played by serologic status of the donor, immuno­suppressive regimens, and acute rejection. [183] A higher number of human leukocyte antigen (HLA) mismatches and anti-rejection therapy especially with corticosteroids were associated with BKV replication and nephropathy. BKV nephropathy develops in 1 to 5 percent of RTR, with loss of allograft function occurring in about half the cases. [184] Distinction of BKV infection from allograft rejection is of parti­cular importance, although these processes may coexist in some cases. [185]

Clinical effects

BKV has been reported to cause ureteral stenosis, [186] interstitial nephritis and allograft nephropathy. [187] Among RTR who are receiving immunosuppressive therapy, 10-60% have reactivation of polyomavirus accompanied by shedding of urothelial cells, and this shedding is inconsistently associated with allograft dysfunction. [188] The patients usually present between 2 and 60 months after trans­plantation and have a high serum creatinine concentration that mimics either acute tubular necrosis or rejection. Persistent active replication of BKV in kidney-allograft recipients had been identified as an important cause of interstitial nephritis, which may lead to graft failure in as many as 45% to 67% of the affected patients. [185],[188],[189],[190],[191],[192] In contrast, the largest documented series of BKV infection in kidney transplant recipients based on 496 patients found no detrimental effect on graft survival in BKV and JCV infected patients, when compared to non-infected controls. [193] Tacrolimus or MMF therapy and recurrent rejection episodes have been reported to increase the risk of persistent BKV replication in patients with renal allografts. [190],[192] In a large randomized prospective trial, Brennan et al showed that tacrolimus or MMF were not independently associated with BK viruria, viremia or sustained viremia, a predictor of BK nephropathy. [194] However, the combination of tacrolimus and MMF maintenance therapy was associated with sustained viremia com­pared to the combination of CsA and MMF. On a pathologic basis, tubular necrosis is the chief cause of graft dysfunction and is a direct consequence of extensive replication of the virus.

Diagnosis

In a study from 1978, routine screening of Papanicoulau (PAP) smear of urinary sediments from RTR revealed changes consistent with BKV in 14% of the cases. [195] The cytologic detection of virally infected transitional urotehlial cells referred to as decoy cells in the urine has limited capacity to predict clinical disease, since it is associated with BKV nephropathy in only 28% of the cases, but it serves as a screening test because it is 100% sensitive in diagnosing BKV infection. [192] Howell et al showed that electron microscopy is a sensitive method to diagnose BKV infection. [191] It has been recently demonstrated that PCR testing of BKV in plasma is a sensitive and specific method for identifying viral nephropathy and DNA can be detected 16 to 33 weeks before nephropathy becomes clinically evident and confirmed by biopsy. [185],[189] Higher viral load in plasma is associated with biopsy­proven BKV nephropathy. [185] There is no quantitative relationship between BK viremia and viruria, possibly reflecting independent BKV reactivation in different tissues during immunosupression. [187] The presence of viruria does not reliably indicate the presence of viremia, a predictor of BK nephropathy.

Treatment

Currently no established antiviral treatment is available, and control of viral infection is tentatively obtained by means of reduction of immunosuppression. [188],[189],[190] Treatment attempts have included immunoglobulins without proof of efficacy. Immunoglobulins can have a dual effect, treating polyoma infection and allograft rejection. Retinoic acid, 5-bromo-2-deoxy­uridine, cidofovir, leflunomide, quinolones, and gyrase inhibitors have antiviral activity in vitro but have not been tested in patients in a systematic fashion. [196],[197],[198],[199] Cidofovir use is limited by its nephrotoxicity. There also exists a report of success with vidarabine in treating BKV-associated hemorrhagic cystitis occurring after bone marrow transplantation. [200] Retransplantation remains an option if other therapies fail.


   HIV Top


Several important issues arise in the discussion of HIV and renal transplantation such as long-term outcomes after transplantation, the interaction between immunosuppressive drugs, HIV and antiretroviral agents, the transmission of HIV with the allograft and possible ways to increase the donor pool for HIV-infected patients. HIV-infected patients have historically been excluded from consideration for trans­plantation out of concern for the effects of immunosuppression on the progression of HIV disease. [201] Before the HAART era, some transplant centers reported good outcomes for SOT in HIV-infected patients [201],[202], other reports have been less favorable with docu­mented increased risk of death and graft loss. [203] Encouraging preliminary data are increasingly available in the HAART era. [204] Among all solid organ transplants, the renal transplant experience with HIV-infected patients is the most promising with the largest retrospective review demonstrating 6 of 11 renal allografts functioning at a mean follow-up of 31 months. [202],[204] In a follow-up of SOT in HIV­ infected patients for a mean of 480 days, all of the kidney transplant recipients remained alive with functioning grafts. [201]

The interaction between immunosuppression and HIV is complex and not very well under­stood. It is increasingly appreciated that immune activation is a prominent feature of HIV pathogenesis, thus immunosuppression may have beneficial effects in people with HIV infection through moderation of immune activation or reduction of HIV reservoirs. In contrast, HIV-infected transplant patients maintained on immunosuppression may be at increased risk of accelerated CD4-infected T-cell depletion or increased CD4 T-cell dys­function and the development of opportunistic infections, or difficulty in controlling HIV replication. [204]

Antiretroviral drugs interact with many immunosuppressive agents and careful moni­toring and dose adjustment is needed. For example, patients receiving protease inhibitors require 25% of the dose of CsA compared with patients receiving NNRTI drugs. [201] Recommendations for use of HAART in trans­plant recipients are done on an individual basis pending recommendations. Specific immuno­suppressant drugs also have antiviral properties and may interact synergistically with certain antiretroviral agents. [204] Sirolimus, MMF, and CsA have been reported to have anti-HIV effects. [205] Cyclosporine A may indirectly suppress viral replication by inhibiting IL­2-dependent proliferation of T-cells and MMF may work synergistically with the antiretro­viral agents abacavir, ddI and tenofovir. [205]

There are several reports of HIV transmission with the renal allograft where the recipients later died of opportunistic infections. [206] To expand the pool of donors, some have advocated for the use of organs from HIV-infected donors to transplant into HIV-infected recipients, but the phenomenon of superinfection with a new strain of HIV has recently been documented. [207] If superinfection occurred soon after transplantation, transmission of more virulent or resistant HIV strains would be of more serious concern for patients with well-controlled HIV infection.


   Adenovirus Top


Adenovirus is a common cause of pharyngitis, conjunctivitis and respiratory infection in the pediatric age group. Infection is limited, but may be life-threatening in immunocompromised hosts. It has been associated with hemorrhagic pyelonephritis, allograft dysfunction, liver necrosis, and fatal dissemination in kidney transplant recipients. [208],[209],[210] No specific anti­ viral therapy exists but reduction in baseline immunosuppression may lead to viral clearance.


   West Nile Virus Top


West Nile virus (WNV) is a flavivirus and is endemic in Africa, the Middle East and southwestern Asia. [211] The virus is maintained in a bird-mosquito-bird cycle, and human infection results from mosquito bites. Other rare modalities have been reported such as transplacental, breast feeding, blood transfusion, organ transplantation and percutaneous inoculation. Only 1 in 150 patients develop a serious illness such as neurological compli­cations including meningitis, encephalitis, and acute flaccid paralysis. [212] Advanced age (>70 years) is a risk factor, and immuno­suppressed patients have been noted to have poor outcomes, with a mortality rate of 17% among reported cases. [213] Limited data also suggests that immunocompromised patients may have prolonged viremia, delayed develop­ment of antibody and increased likelihood of severe disease. [24] Ravindra et al reported three patients with kidney or pancreas transplants who got infected with WNV after transplantation presumably through mosquito bites and survived encephalitis with reduction of immunosupp­ression and supportive care. [211] The first cases of organ transmission of WNV to four recipients: 2 kidneys, 1 heart and 1 liver were reported by Iwamoto et al. [213] Prevention of transmission requires exclusion of viremia in donors by screening appropriate patients, however it is not clear whether donor organs remain infected after the apparent resolution of viremia and may possibly still cause a symptomatic infection in the recipients. [215]


   Rabies Top


In June 2004, the center for disease control (CDC) confirmed the diagnosis of rabies encephalitis in three recipients of organ trans­plants (2 kidneys and one liver) from an infected donor. All recipients subsequently died. [216] Diagnosis was made on autopsy by histologic examination and immunohistochemical staining. Rabies is an acute fatal encephalitis caused by bites by rabid animals. The incubation period ranges from weeks to months. Rabies can be prevented by administration of post-exposure prophylaxis (PEP) which is highly effective when administered before the onset of clinical signs. Rabies has also been documented to be transmitted via infected corneal transplants. [217] Routes of possible exposure include percu­taneous and mucocutaneous entry through an open wound, nonintact skin or mucous membrane, but this is rare. Hematogenous spread does not happen. [216] No specific therapy is available for an established infection which is usually fatal. Therefore, suspicion for this infection should remain high in potential donors with symptoms of encephalitis.


   Parvovirus Top


Parvovirus B19 causes erythema infectiosum in children, transient aplastic crisis in patients with underlying hemolytic anemia or AIDS, and hydrops fetalis during pregnancy. In immunocompromised patients, it can cause persistent infection leading to chronic anemia and myelosuppression. [218],[219],[220] Parvovirus trans­mission is thought to occur via respiratory secretions primarily during the week before the development of the rash. [218] B19 IgM remains a useful diagnostic investigation even in the immunocompromised patient. The only treat­ment with documented efficacy is IVIG which contains high titers of B19-specific neutralizing IgG antibodies. [218]


   Bacterial Infections Top


Over 50% of renal transplant recipients will experience a bacterial infection within the first year. [4] As discussed in previous sections, urinary tract infections are the most common bacterial infections in renal transplant patients. Wound infections, line sepsis and pneumonia occur most frequently in the first month after transplantation. Antimicrobial prophylaxis with TMP-SMX or ciprofloxacin has been shown to reduce the incidence of urinary tract infections and wound infections. The following discussion will focus on selected bacterial infections with peculiar presentations.


   Nocardia Top


Nocardia is a soil-borne aerobic actinomycete that can cause infection in humans by inhalation of the organism. Renal transplant recipients have been identified in many series as especially susceptible to nocardia infection and account for 2-13% of all cases. Risk factors include the number of rejection episodes, high dose steroids, deceased donor kidney, and granulo­ cytopenia. [221],[222],[223],[224] The onset of nocardial infection after transplantation ranges from one week to 338 weeks with an average of 30 weeks, and an average of 16 weeks after a rejection episode. [225]

Depending on the transplant center, the estimated incidence of nocardiosis among RTR varies from 0-20%. Prior to TMP/SMX pro­phylaxis, mortality was 80-85% and this was reduced to 3% in mild infections and 44% with CNS involvement after institution of prophylaxis. [226] Outbreaks in renal transplant units have been reported and have been attributed to patient-to-patient transmission, with cultures from air and dust being positive for nocardia, suggesting a possible role for respiratory isolation of patients with nocardia in reducing spread within a hospital. [227],[228] Overall, pulmonary involvement (88%) is the most frequent finding followed by cutaneous (20%) and CNS infections (17%). [229] The nocardia species involved are N. asteroides (90% of the cases), then N. brasiliensis, N. caviae and others. [225] Other reported clinical manifestations of nocardia in RTR are bacteremia, and thyroiditis/thyroid abscess. Disseminated disease results from hemato­genous or lymphatic spread and is almost always due to Nocardia asteroides. Secondary CNS infection accounts for about 20-38% of cases of disseminated disease. The skin is the second most common site of dissemination after CNS. Diagnosis may be difficult because of the nonspecific clinical presentation complicated by nonspecific radiologic findings. Nocardial infections are treated with TMP-SMX. Anti­microbials showing activity in combination with sulfonamides and TMP/SMX include imipenem, amikacin, cycloserine, and ampi­cillin. [230],[231] Successful treatment of nocardia infection with minocycline has been reported. [232] Therapy for 2-3 months with minor infections and up to a year with more severe infections and lifelong suppression for chronically immunosuppressed individuals is recommended. Late recurrence of nocardiosis can occur in RTR after discontinuation of chronic suppressive therapy. [233]


   Listeria Top


 Listeria monocytogenes Scientific Name Search nes is found naturally in soil and water and may contaminate raw foods including dairy products, vegetables, and meats. Transmission to humans occurs via the gastrointestinal tract, commonly during late summer and early fall. Possible nosocomial transmission through contaminated food has been reported but could not be proven. [234] Listeria infections in RTR commonly involve the CNS causing meningitis in 50% of the reported cases, parenchymal disease of the CNS in 10%, both meningitis and parenchymal disease of the CNS in 9%, and primary bacte­remia in 30%. The overall mortality approaches 26%, and is high in patients with pneumo­nia. [235] Other clinical manifestations of listeria in RTR have been described and include endophthalmitis, and septic arthritis. TMP-SMX is an effective treatment and offers protection when used as a prophylactic agent.


   Legionella Top


Legionella organisms are Gram-negative rods that are ubiquitous in nature. Most human infections are caused by Legionella pneumophila, serogroup one. Other species reported to cause infections in RTR are  Legionella cincinnatiensis Scientific Name Search sis and Legionella micdadei. Infections are usually community-acquired but nosocomial trans­mission and outbreaks of legionella pneumonia have been described in renal transplant recipients. [236],[237] Water lines, drinking water, contaminated respiratory equipment, heating and air conditioning ventilation systems have been implicated as possible sources of noso­ comial spread. [236],[237] Corticosteroid dosage and number of days of hemodialysis are risk factors for infection with legionella. Most infections with legionella are pneumonia, but lung abscess and cavitary lung disease have been described as well, and cavitary disease appears to carry a high mortality of 24-58% even with effective therapy. 238 Diagnosis by culture may be difficult because of the slow growth of the organism and the need to use selective media. Identification of Legionella pneumophila Scientific Name Search  serogroup 1 can be easily achieved by testing the urine for legionella antigen. Effective antimicrobial therapy includes macro­lides, quinolones and possibly rifampin. [237],[238] TMP/SMX seems to be an effective prophylaxis.


   Salmonella Top


Most cases of Salmonella reported in RTR were caused by non-typhoid Salmonella species. The incidence is 3.4% in the transplant popu­lation and is higher in tropical than subtropical regions. The vast majority of the cases present within 6 months after transplantation. About 35% of patients have recurrence of infection after stopping antibiotics. [239] Outbreaks of non-typhoid  Salmonellosis More Details have been reported in patients on hemodialysis and may occur on renal transplantation units, hence the use of isolation techniques to reduce patient-to­patient spread. [240] Clinical manifestations of salmonellosis are variable and include bacte­remia, UTI (bacteriuria, pyelonephritis and perinephric abscess), gastroenteritis, and focal manifestations such as multiple abscesses, septic arthritis, pulmonary infection and vascular infections. Urinary salmonellosis occurs in patients with structural abnormalities of the urinary tract and bacteriuria has been associated with recurrent bacteremic episodes. Localization of non-typhoid salmonella to artificial structures or deep-seated locations such as vascular grafts, aneurysms, testis, prostate, and joints is parti­cularly difficult to eradicate and subject to recurrences. Salmonella infection may worsen graft function, and mortality as high as 5% has been reported. [239] Effective antibiotic therapy includes agents such as ampicillin, third­generation cephalosporins, TMP-SMX, and quinolones. Therapy should be prolonged in severe infections. Amoxicillin resistance has been described. [241]


   Tuberculosis Top


The incidence of tuberculosis varies by geography and endemicity. In RTR, it ranges from 0.5-1% in North America, 1-4% in Europe and the Middle East, and 10-13% in India. [242] Tuberculosis can occur any time after transplantation, but the majority of infections occur in the first 18 months. [243],[244] In endemic areas, the frequency of TB in solid organ trans­plants is 8.5 fold that of the general population. [243] In the USA, the minimal annual incidence of TB in RTR has been previously reported to be 37 times higher than in the general population. Immunosuppression results in a 100-fold increase in the risk of development of TB. [242] Uremia, with its immunosuppressive effects, and high dose steroids may promote reactivation of latent TB. Studies have generally shown a good response to treatment of TB in RTR without major reductions in immunosuppressive therapy. [245]

Isolated extrapulmonary disease is seen in 11-25% of the cases. [244] Clinical presentations of TB in RTR have included laryngeal infection, meningitis, monoarticular arthritis, military TB with involvement of the allograft, and choroiditis. Tuberculosis has been shown to be transmitted with the allograft, hence the importance of careful pre-transplantation screening. The tuberculin skin test (TST) may have poor sensitivity in transplant candidates with uremia, and identification of patients at risk should rely on careful history taking and radiological evaluation. [244] As high as 70% of renal transplant candidates may have anergy from impaired cell-mediated immunity, and negative TST results have been reported in up to 70% of patients with active TB because of the overwhelming nature of the infection. [246] Patients with a previous history of adequately treated TB do not run a high risk of relapse during immunosuppressive treatment, and therefore chemoprophylaxis is not indicated. [247] It is suggested that isoniazid prophylaxis be offered to patients with a history of inadequately treated TB, abnormal chest X-ray, a purified protein derivative (PPD) test >10 mm especially if recent conversion has occurred, contact with active TB and those with a negative PPD receiv­ing kidneys from PPD-positive donors. [244],[248]

When treating active tuberculosis in RTR, it is important to consider potential interactions between antituberculous drugs and immuno­suppressive medications, notably rifampin that alters cyclosporine pharmacokinetics. [244]




   Other Mycobacterial Infections Top


In a review of tuberculosis and other myco­bacterial infections in RTR in Saudi Arabia, Qunibi et al showed that disseminated disease occurred in 64.3% of the patients and carried a high mortality rate (37%). [244] Infections with mycobacterial organisms other than Mycobacterium tuberculosis mostly involve joints or subcutaneous tissues. Several reports of infections with Mycobacterium chelonae abscessus Scientific Name Search  in RTR exist in the literature and mostly describe cutaneous infections. There seems to be a predominance of infection with this organism in renal transplant patients. [249] Other mycobacterial infections reported in RTR include Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium gastri, and Mycobacterium haemophilum. These infections usually have a chronic course, may require prolonged treatment and surgical excision when feasible, with a possible risk for dissemination and recurrence. [244] Steroid use appears to be a risk factor for the development of infection with atypical mycobacteria. [250] Reduction of immunosuppression has been reported to be helpful. Atypical mycobacteria have also caused infection in RTR through contamination of the perfusate. [251] Macrolides are commonly used in the treatment of infections with atypical mycobacteria. Some macrolide antibiotics have been shown to produce significant drug-drug interactions through the inhibition of cytochrome P450 enzymes. In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A, a substrate of CYP3A4. Azithromycin does not alter the disposition kinetics of CSA in a clinically significant way, and CSA dosage adjustments are not warranted in renal transplant patients taking these two drugs together. [252]


   Ehrlichia Top


Ehrlichiosis is a tick-borne illness with two major clinical expressions in the US: human monocytic ehrlichiosis (HME) and human granulocytic ehrlichiosis (HGE). The geographic distribution of the two forms are different with HME seen predominantly in the south central and southwestern USA and HGE in the northeastern and midwestern USA. Five species have been reported to cause infection in humans worldwide: Ehrlichia chaffeensis, Anaplasma phagocytophilum, E. ewingii, Neorickettsia sennetsu, and E. canis. [253] In the USA, E. chaffeensis causes HME, while E. ewingii and A. phagocytophilum cause HGE. The clinical characteristics of HME and HGE are similar including fever, chills, myalgias, arthralgias, malaise, nausea, vomiting, and laboratory findings of leukopenia, anemia, thrombocytopenia with mild elevations of liver transaminases. Rash and CNS manifestations are more common with HME. Severe infection with multiorgan failure has been reported in the elderly and immunocompromised patients. [254] Mortality from HGE may reach 7-10%.The incidence of ehrlichiosis in the SOT population is similar to that in the US general population. [255] Both forms of disease have been reported in renal transplant patients. [255],[256] Diagnostic tests for human ehrlichiosis include the demonstration of morulae in leukocytes on the peripheral smear, serology, culture, and PCR which has emerged as a promising technique for rapid diagnosis with a sensitivity of 80-87% and a specificity of 100%. [257] Recommended treat­ment for ehrlichiosis is doxycycline for 14 days with patients responding promptly. Rifampin has been reported to be effective as well. [258]


   Fungal Infections Top


The incidence of fungal infections in solid organ transplant recipients ranges from 2­50%, with kidney recipients being the least affected. [259] Systemic fungal infections occur in 2%-14% of RTR and carry a high mortality rate. [260] Most fungal infections occur by six months post transplantation. [261] Risk factors for the development of fungal infections include environmental exposure and endemic burden and patient-related factors such as broad­spectrum antibiotics, corticosteroids, diabetes mellitus, chronic liver disease, duration of pre-transplantation dialysis, allograft rejection and CMV disease. [224],[260],[261] The clinical manifestations of systemic fungal infections in RTR are often non-specific and any delay in establishing a diagnosis can increase the risk of death, hence the need for a high index of suspicion, and an aggressive approach to diagnosis and treatment. Among systemic fungal infections affecting renal transplant patients, cryptococcal meningitis and pulmonary asper­gillosis are the most common. Zygomycosis and aspergillosis are associated with increased patient mortality and length of hospital stay. [261]


   Candida Top


Candidiasis is the most common fungal infection affecting renal transplant recipients. Several species are implicated, Candida albicans being the most common, in addition to C. tropicalis, C. krusei, and C. glabrata. Clinical manifestations include localized infections such as mucocutaneous involvement, UTI or disseminated disease such as candidal sepsis leading to metastatic foci of infection like intra­abdominal abscesses, meningitis, brain abscesses, endophthalmitis, endocarditis, arthritis, osteo­myelitis, and pyelonephritis. [262],[263] Diagnosis of candidal infections can be made clinically with the aid of culture. Some advocate for the treatment of asymptomatic candiduria in RTR to reduce the risk of an ascending infection and dissemination. [264] Treatment options depend on the type and location of the infection and the species of candida involved, as different species have differential susceptibilities to available antifungals. C. glabrata and C. krusei are relatively resistant to fluconazole. Ampho­tericin B is reserved for more severe infections. Two newer agents voriconazole, a triazole and caspofungin, an echinocandin have a broad anti-candidal activity and a less nephrotoxic profile than Amphotericin B. Careful monitoring of immunosuppressive drug levels of CsA, tacrolimus and sirolimus while on antifungal therapy is warranted as there is a significant interaction between the azoles and the cyto­chrome P450 system that increases the levels of these immunosuppressive agents.


   Aspergillus Top


Aspergillus species are ubiquitous in the environment and are readily aerosolized. Inhalation of the spores may result in infection of the respiratory tract and a means of systemic dissemination. Aspergillosis occurs in up to 3% of renal transplants, usually in the first three months after transplantation. [260],[265] Nosocomial outbreaks have been described and associated with hospital construction and the forced air exhaust system of the transplantation unit. Disseminated disease has been associated with the use of heavy immunosuppression and carries a high mortality rate nearing 100%. [266] Aspergillus has been reported to cause endoph­thalmitis and epidural abscesses secondary to dissemination. Aspergillosis can cause localized infections without evidence of dissemination, such as isolated CNS infection, osteomyelitis and septic arthritis. [267],[268] Organ transmission of aspergillus has also been described. [20] In May 2003, the FDA cleared the Platelia Aspergillus galactomannan antigen immunoassay for use to help diagnose invasive aspergillosis. This test has a sensitivity of 80.7% and a specificity of 89.2%. [269] Until recently, amphotericin had been the main effective therapy for invasive aspergillosis. However, over the last few years, evidence has emerged for the effectiveness and even superiority of voriconazole, a newer triazole in the initial treatment of invasive aspergillosis. [270],[271] A very recent study showed the effectiveness of combined therapy with voriconazole and caspofungin in the treat­ment of invasive aspergillosis in patients who have failed initial therapy with amphotericin preparations. Combination therapy reduced the mortality of invasive aspergillosis compared to monotherapy. [272]


   Mucormycosis Top


Infections with fungi of the class zygomycetes cause mucormycosis. This class includes Rhizopus, Mucor, Absidia, Rhizomucor and Cunninghamella species. These fungi are ubiquitous in nature. They are an uncommon cause of infection in renal transplants. [265] Common clinical presentations of mucor­mycosis include the rhinocerebral, pulmonary, and gastrointestinal forms. It has also been reported to involve the liver, the GU system, and the skin. [273] The rhinocerebral form of mucormycosis is most common in RTR and may be associated with a high mortality rate. [273],[274] The organisms have a propensity for vasotropic growth in invasive disease causing necrosis of blood vessels, tissue necrosis and hematogenous spread. Several risk factors for mucormycosis have been identified including metabolic acidosis, use of deferoxamine, both of which can cause a local abundance of iron and enhance the growth of the organism, and neutrophil or monocyte dysfunction from steroids or diabetes. [275] Most cases of mucormycosis infections in RTR have occurred within a month of treatment for a rejection episode or within two months after transplantation. [273],[276] Treatment usually involves aggressive surgical debridement in addition to systemic antifungal therapy. [277] Reduction of immunosuppression may prove helpful.


   Cryptococcus Top


Cryptococcus neoformans is the most common cause of CNS fungal infection in kidney transplant patients. The organism is present in soil contaminated with bird excreta. Infections are acquired by inhalation and occur in 0.3-4% of RTR. [278] Dissemination from the lungs is common, and may occur following urologic instrumentation. [279] The most common sites of isolated infection are the CNS (55%), skin (13%), and lungs (6%). [278] The majority of cases of cryptococcal meningitis occur after 6 months following transplantation. Cryptococcus can cause primary localized skin infections or secondary skin involvement from disseminated disease, in which case, it is a poor prognostic sign. With appropriate therapy, the survival rate of cryptococcal cellulitis is >80%. [280] Diagnosis relies on visualizing the organisms in the cerebrospinal fluid (CSF) using the India ink stain, identifying the crypto­coccal antigen in serum or CSF, or culturing the organism. Treatment with amphotericin B with or without 5-flucytosine is most effective for acutely ill patients. Less severe infections have been successfully managed with fluco­nazole. Treatment is usually prolonged and may need to be given for life to prevent recurrences. Tacrolimus has anti-cryptococcal activity and penetrates the CNS. Immunosuppressive regimens containing tacrolimus have been associated with less CNS infections compared to CsA-containing regimens. [278]


   Endemic Mycoses Top


These infections can occur at any time following transplantation. Histoplasmosis and coccidioidomycosis are more common in transplant patients. The clinical presentation is varied and dissemination is common.

Histoplasmosis

Histoplasma capsulatum
is endemic in the central US and is acquired by inhalation. Infection occurs in 0.4-2.1% of RTR. Cases of primary exogenous infection, reactivation of a latent infection, and transmission from the organ donor have been described. [281] Disseminated disease is common and clinical presentation may be nonspecific. Disseminated histoplasmosis has manifested as cellulitis, allograft involvement, necrotizing myofasciitis, and CNS disease.

In reported cases of disseminated histo­plasmosis in renal transplants, patients had received antilymphocyte therapy and intra­venous pulse steroids in the three months prior to the onset of infection. [282],[283] Diagnosis relies on serology, fungal stains, culturing the organism form specific foci or the bone marrow in cases of disseminated disease, or identification of the histoplasma antigen in the serum or urine. The antigen can be detected in the urine of 90% of patients with disseminated infection and 75% of patients with diffuse acute pulmonary histoplasmosis. [284] Treatment with amphotericin B and alternatively with itraconazole for milder cases is very effective.

Coccidioidomycosis

Coccidioides immitis is endemic in the south­western US, northern Mexico and regions of Latin America. Patients who have lived in or traveled to these areas are at increased risk of infection with C. immitis. The majority of cases are attributed to reactivation of old foci of infection and occur within the first year post-transplantation; however, coccidioido­mycosis can result from a primary infection and may occur at any time in an immuno­suppressed host. [285] Transplant recipients infected with C. immitis usually develop progressive disseminated disease associated with high mortality. Risk factors include male sex and blood group B. [286] Organ-systems most commonly involved are the lungs, CNS, skin, joints, and kidney. The radiographic mani­festations are highly variable and extrathoracic infection without evidence of pulmonary disease occurs not infrequently. Diagnosis of coccidioidomycosis is made by histologic examination of tissue specimens, culture, and serology. Treatment options include amphotericin B, fluconazole and itraconazole. A recent report described the successful use of caspo­fungin in the treatment of disseminated coccidioidomycosis in a renal transplant recipient. [287]

Reactivated paracoccidioidomycosis and disseminated blastomycosis have also been described in renal transplants. Treatment is usually prolonged and lifelong suppression may be necessary.

Pneumocystis

Pneumocystis jiroveci (previously known as Pneumocystis carinii) is an extracellular organism resembling both fungi and protozoan parasites. In solid organ transplants not receiving prophylaxis for pneumocystis (PCP), 6-20% develop PCP within the first year after trans­plantation. [288] The clinical presentation of PCP is usually subacute with symptoms of fever, non-productive cough, dyspnea and interstitial infiltrates with or without cysts, and variable degrees of hypoxemia. Pneumocystis infection is often associated with CMV infection, and may carry a high mortality rate. [289] The organism rarely disseminates. Outbreaks in renal transplantation units have been described. [289] Diagnosis relies on identification of the organisms using silver stains or immunofluorescent mono­clonal antibody on deep respiratory specimens. Pneumocystis infection can be prevented by using prophylaxis with TMP-SMX or alter­natively with dapsone or aerosolized penta­midine for 6-12 months post-transplantation. The treatment of choice is TMP-SMX in addition to steroids in severe cases. Alternative choices for treatment include a combination of prima­quine and clindamycin, dapsone or atovaquone.


   Parasitic Infections Top


Strongyloides

Strongyloides is a disease caused by an intestinal nematode Strongyloides stercoralis that is endemic in the Southern USA, South America, the Caribbean, Africa, Asia and the South Pacific. Its prevalence in the USA is 0.4­ 4%, and it is transmitted by fecal-oral spread and possibly with the renal allograft. [290],[291] Filariform larvae infect the host by skin penetration, migrate through the bloodstream to the lungs then are swallowed into the gastrointestinal (GI) tract. Infection is usually asymptomatic and can remain quiescent in the intestinal tract for more than 30 years, becoming apparent only after the initiation of immunosuppression. [290] Clinical presentations can be divided into intestinal strongyloidiasis, strongyloides hyperinfection referring to increased worm burden without accompanying spread of larvae outside the usual migration pattern of the GI tract and lungs, and strongy­loides dissemination which refers to systemic spread. Autoinfection refers to initiation of a new migratory cycle through penetration of filariform larvae from the small intestine through the intestinal mucosa or through the perianal skin causing prolonged infestation. Increased mortality is seen with disseminated strongyloidiasis (71%) and hyperinfection (50%). The clinical presentation of strongyloidiasis in RTR is variable and often atypical, with the majority of cases presenting during the initial 3-4 months of transplantation. Gastro­intestinal symptoms are observed in 78% of patients, and pulmonary symptoms in 68%. The crucial step in establishing the diagnosis is identification of the larvae from sites such as stool and pulmonary secretions. Systemic bacterial, fungal and viral infections are frequent complications of strongyloides hyperinfection and disseminated disease; with Gram-negative bacilli sepsis accounting for most of these coexisting infections. The treatment of choice is ivermectin. Thiabendazole is also effective and is given for two days for intestinal strongy­loidiasis, and 5-14 days for disseminated disease. Prophylactic monthly thiabendazole in patients who have survived strongyloides hyperinfection or dissemination until larvae have been absent from stool specimens for at least 6 months can prevent reinfection. [290] It is suggested that CsA has anti-strongy­loides activity. [292]

Leishmania

Leishmaniasis is a rare protozoal disease in the USA, but is endemic in Latin America, the Middle East, and North Africa. The organisms are transmitted to humans via sandflies and cause cutaneous, mucocutaneous and visceral forms of disease. Cutaneous leishmaniasis is the only form encountered in the USA and is most likely caused by L. braziliensis or L. mexicana. Visceral leishmaniasis occurs only rarely in recipients of solid organ grafts but is associated with an elevated mortality rate despite proper treatment. [293] It is caused by Leishmania donovani, Leishmania infantum and Leishmania chagas. Presentation of visceral leishmaniasis in RTR is often atypical and can manifest as fever of unknown origin. [293],[294]

Leishmaniasis is suggested by clinical features and supported by serologic or skin tests, but should be confirmed by finding or culturing the parasite. Diagnosis of visceral leishmaniasis is usually made by demonstrating amastigotes in bone marrow smears and positive serum antibodies. [293] First line agents used in treatment are pentavalent antimonials such as sodium stibogluconate and amphotericin B preparations.

Schistosomiasis

Schistosomiasis is the most significant helminthic infection in humans because of its global prevalence, the protean nature of its associated disease manifestations and the remarkable difficulties encountered in attempts to control its spread. Humans may be infected with one of five species, the most common three being S. haematobium, S. mansoni, and S. japonicum. Schistosomiasis is endemic in Africa and the Middle East.

There are conflicting reports regarding the risk of reinfection with post-transplant immuno­ suppression. [295] It seems that pre-transplantation treatment with adequate therapy is associated with little to absent risk of reinfection after transplantation. [296] Chronic shistosomiasis seems to increase the risk of urinary tract complications through anatomical abnormalities, and therefore increase the risk of UTI, but there is no long-term effect on the risk of rejection, patient survival or graft survival. [296],[298] Diagnosis relies on demonstration of the parasite egg and serology. Praziquantel is the drug of choice for treatment.


   Infection Control Considerations Top


Infection control in RTR combines different strategies such as screening patients for past and latent infections, treating active infections, and prevention of community-acquired and nosocomial infections with immunization, chemoprophylaxis, and appropriate infection control measures. Prevention and treatment of specific infections have been discussed in previous sections. This paragraph will focus on infection control measures applied in the hospital setting to prevent the nosocomial acquisition and spread of infections. Issues with immunization are detailed in the following section.

Careful attention should be given to good hand washing practices, central line care, and practices to decrease the risk of pneumonia. Specialized air filters and negative pressure rooms should prevent the infectious droplets of measles, varicella and tuberculosis from entering the general air supply and infecting others. Contact precautions must be applied to limit the spread of organisms such as methicillin-resistant staphylococcus aureus, vancomycin-resistant enterococci, clostridium difficile, respiratory syncytial virus, and other multi-drug resistant gram-negative bacilli. House staff and hospital employees should also receive adequate vaccination. CMV- negative blood products should be given to RTR at high risk for primary CMV infection. A special consi­deration should be given to reduce Aspergillus fungal spore count during construction or renovation in or around the hospital by providing laminar air flow and high-efficiency particulate air (HEPA) filtration to the rooms of patients on heavy immunosuppression. Also, regular monitoring of the water tubings and air con­ditioning units in the hospital for Legionella may help identify potential sources of infection in high-risk patient areas.


   Issues in immunization Top


Three vaccines: influenza, pneumococcus, and hepatitis B are usually given pre-transplant­ation. Although the response in hemodialysis patients is lower than in healthy individuals, it can be even lower in patients after solid organ transplantation. [299],[300]

Influenza

Influenza is a major cause of acute respiratory illness and may lead to pulmonary and extra­pulmonary complications such as secondary bacterial pneumonia, rhabdomyolysis, neurologic complications, hemolytic-uremic syndrome and allograft rejection. [301],[302],[303] The main strategy of influenza prevention has been immunization. Two forms of vaccine are available, an in­activated vaccine and a live attenuated one. The inactivated vaccine has been shown to be safe in RTR, but several studies have shown reduced antibody response to the vaccine that may be worsened by cyclosporine administration. [303],[304],[305] The live attenuated vaccine is currently not recommended for immunocom­promised patients as it may cause severe disease. Its safety and efficacy in this patient population need to be established. A number of agents are available for chemoprophylaxis and treatment of influenza. Examples include amantadine, rimantadine and the neuraminidase inhibitors zanamivir and oseltamivir which have a more tolerable profile. Care should be taken in patients with decreased renal function since all four drugs are cleared through the kidneys.

Hepatitis A

Renal transplant recipients with chronic hepatitis B or hepatitis C infection may be at increased risk of fulminant hepatitis A. Some centers in the USA recommend hepatitis A vaccination to this patient population. Hepa­titis A vaccine is safe and achieves good sero­conversion rates in renal transplant recipients albeit less effectively than in controls. [306] The seroconversion rate is inversely associated with the number of immunosuppressive drugs received by the patients. Moreover, a much more rapid antibody decline occurs in RTR than in controls. 307 The hepatitis A vaccine can be recommended to RTR patients, but the patients should receive a full course of 2 doses for a better protective effect. [306]

Pneumococcus

Streptococcus pneumoniae is a cause of morbidity and mortality in immunocompro­mised hosts and may cause invasive disease especially in asplenic individuals. Immunization is the best means of prevention. The most experience is reported with the pneumococcal polysaccharide vaccine. It was shown to be safe and effective in patients with well-functioning renal allografts, but protective antibody levels may decline faster than controls and RTR may need revaccination sooner than normal subjects. [309],[309] A recent comparison of the polysaccharide vaccine and the newer conjugated pneumococcal vaccine in RTR showed a trend towards enhanced immunogenicity for the conjugated vaccine but overall equivalent antibody responses. [310] The current practice is to revaccinate RTR with a pneumococcal vaccine every five years.

Varicella

In the few published reports, there is conflicting information on the morbidity and mortality of primary VZV in adult RTR. [311],[312] Primary infection in adults is usually associated with increased morbidity and mortality, and serious complications may occur including hepatitis, pneumonitis, encephalitis, pancreatitis, disse­minated intravascular coagulation and death. Disseminated cases of varicella infection in adult RTR may be due to primary infection or reactivation of old disease. [313],[314] High-dose acyclovir and reduction in immunosuppression may reduce mortality. The proper approach to adult RTR or transplant candidates who are susceptible to infection with VZV is not entirely known, as most data available on the subject comes from the pediatric literature. Vaccination and acyclovir prophylaxis are two possible strategies. Acyclovir given as prophylaxis against infection with HSV was shown to reduce the number of clinical and subclinical reactivations of VZV during treat­ment in adult BMT patients but not there­after. 315 End-stage renal disease may cause reduced response to the vaccine, but a higher dose, a two-dose immunization schedule and a booster dose were shown to improve results. [316] Several studies of varicella vaccination in children with ESRD before transplantation and post-transplantation showed vaccination to be safe and efficacious. [317]

Should susceptible household members of RTR be vaccinated with the live attenuated vaccine against varicella? Due to lack of data specifically addressing RTR, it is recommended to vaccinate susceptible household contacts because the benefits of vaccination outweigh the potential risk of transmission of vaccine­type virus to immunocompromised patients, and because the rate of transmission is low. [318] It is also recommended that vaccinees who develop a rash avoid contact with susceptible immunocompromised hosts for the duration of the rash. [319]

Diphtheria/Polio/Tetanus

Both diphtheria and tetanus booster vaccination can be performed effectively and safely in pediatric renal transplants. [320] Although an impaired immune response to primary vacci­nation with tetanus and diphtheria has been described in RTR and HD patients, it seems that the tetanus and inactivated polio vacci­nations are well tolerated and induce protective antibody levels, however diphtheria vaccination is less effective and protective antitoxin values decrease rapidly in these patients within one year after vaccination, hence the possible need for revaccination. [321],[322],[323]

Measles/Mumps/Rubella

Studies have shown an excellent response in children with ESRD to the measles/mumps/ rubella (MMR) vaccine. [324] Whether immuni­zation of adult susceptible RTR, transplant candidates or their susceptible household contacts with MMR vaccine is safe and effective has not been established, and guidelines for vaccination in this patient population are not available.

 
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284.Wheat LJ, Kohler RB, Tewari RP. Diagnosis of disseminated histoplasmosis by detection of Histoplasma capsulatum antigen in serum and urine specimens. N Engl J Med 1986;314:83-8.  Back to cited text no. 284    
285.Blair JE, Logan JL. Coccidioidomycosis in solid organ transplantation. Clin Infect Dis 2001;33(9):1536-44  Back to cited text no. 285    
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287.Antony, S. Use of the echinocandins (caspofungin) in the treatment of disseminated coccidioidomycosis in a renal transplant recipient. Clin Infect Dis 2004;39:879-80.  Back to cited text no. 287    
288.Spieker C, Barenbrock M, Tepel M, Buchholz B, Rahn KH, Zidek W. Penta­midine inhalation as a prophylaxis against Pneumocystis carinii pneumonia after therapy of acute renal allograft rejection with orthoclone (OKT3). Transplant Proc 1992;24:2602-3.  Back to cited text no. 288    
289.Hennequin C, Page B, Roux P, Legendre C, Kreis H. Outbreak of Pneumo­cystis carinii pneumonia in a renal transplant unit. Eur J Clin Microbiol Infect Dis 1995; 14(2):122-6.  Back to cited text no. 289    
290.DeVault GA Jr, King JW, Rohr MS, Landreneau MD, Brown ST 3 rd , McDonald JC. Opportunistic infections with Strongy­loides stercoralis in renal transplantation. Rev Infect Dis 1990;12(4):653-71.  Back to cited text no. 290    
291.Hoy WE, Roberts NJ Jr, Bryson MF, et al. Transmission f strongyloidiasis by kidney transplant? Disseminated strongy­loidiaisis in both recipients of kidney allografts from a single cadaver donor. JAMA 1981;246:1937-9.  Back to cited text no. 291    
292.Schad GA. Cyclosporine may eliminate the threat of overwhelming strongyloidiasis in immunosuppressed patients. J Infect Dis 1986;153:178.  Back to cited text no. 292    
293.Fernandez-Guerrero ML, Aguado JM, Buzon L, et al. Visceral leishmaniasis in immunocompromised hosts. Am J Med 1987;83(6):1098-102.  Back to cited text no. 293    
294.Berenguer J, Gomez-Campdera F, Padilla B, et al. Visceral leishmaniasis (Kala-Azar) in transplant recipients: case report and review. Transplantation 1998; 65(10):1401-04.  Back to cited text no. 294    
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296.Barrou B, Bitker MO, Boyer C, Sylla C, Chatelain C. Results of renal transplantation in patients with Schistosoma infection. J Urol 1997;157(4):1232-5.  Back to cited text no. 296    
297.Mahmoud KM, Sobh MA, el Agroudy AE, et al. Impact of schistosomiasis on patient and graft outcome after renal transplantation: 10 years' follow-up. Nephrol Dial Transplant 2001;16(11):2214-21.  Back to cited text no. 297    
298.Shokeir AA, Baker MA, el Diasty TA, et al. Urological complications following live donor kidney transplantation: effect of urinary schistosomiasis. Br J Urol 1992;70(3):247-51.  Back to cited text no. 298    
299.Crosnier J, Jungers P, Courouce AM, et al. Randomized placebo-controlled trial of hepatitis B surface antigen vaccine in French haemodialysis units. II. Haemo­dialysis patients. Lancet 1981;2:797-800.  Back to cited text no. 299    
300.Wagner D, Wagenbreth I, Stachan­Kunstyr R, Flik J. Failure of vaccination against hepatitis B with Gen H-B-Vax-D in immuosuppressed heart transplant patients. J Infect Dis 1992;166:1021-8.  Back to cited text no. 300    
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303.Grekas D, Alivanis P, Kiriazopoulou V, et al. Influenza vaccination on renal transplant patients is safe and serologically effective. Int J Clin Pharmacol Ther Toxicol 1993; 31(11):553-6.  Back to cited text no. 303    
304.Cavdar C, Sayan M, Sifil A, et al. The comparison of antibody response to influenza vaccination in continuous ambulatory peritoneal dialysis, hemodialysis and renal transplantation patients. Scand J Urol Nephrol 2003;37(1):71-6.  Back to cited text no. 304    
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311.Parnham AP, Flexman JP, Saker BM, Thatcher GN. Primary varicella in adult renal transplant recipients: a report of three cases plus a review of the literature. Clin Transplant 1995;9(2):115-8.  Back to cited text no. 311    
312.Bradley JR, Wreghitt TG, Evans DB. Chickenpox in adult renal transplant recipients. Nephrol Dial Transplant 1987;1(4):242-5.  Back to cited text no. 312    
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322.Kruger S, Mueller-Steinhardt M, Kirchner H, Kreft B. A 5-year follow-up on antibody response after diphtheria and tetanus vaccination in hemodialysis patients. Am J Kidney Dis 2001;38(6):1264-70.  Back to cited text no. 322    
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324.Flynn JT, Frisch K, Kershaw DB, Sedman AB, Bunchman TE. Response to early measles-mumps-rubella vaccination in infants with chronic renal failure and/or receiving peritoneal dialysis. Adv Perit Dial 1999;15:269-72.  Back to cited text no. 324    

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Daniel C Brennan
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    Abstract
    Introduction
    Timing of Infect...
    Infectious Consi...
    Sources of Infection
    Special Consider...
    Categories of in...
    Viral Infections
    Cmv
    Hsv
    HHV-8
    Ebv
    HHV-6, HHV-7
    Hepatitis viruses
    Hepatitis C virus
    BK virus
    Hiv
    Adenovirus
    West Nile Virus
    Rabies
    Parvovirus
    Bacterial Infections
    Nocardia
    Listeria
    Legionella
    Salmonella
    Tuberculosis
    Other Mycobacter...
    Ehrlichia
    Fungal Infections
    Candida
    Aspergillus
    Mucormycosis
    Cryptococcus
    Endemic Mycoses
    Parasitic Infections
    Infection Contro...
    Issues in immuni...
    References
    Article Tables
 

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