Infectious Complications in Renal Transplant Recipients

Infectious Complications in Renal Transplant Recipients

Infectious Complications in Renal Transplant Recipients N. Tom Tanphaichitr and Daniel C. Brennan Infectious complications present major challenges to...

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Infectious Complications in Renal Transplant Recipients N. Tom Tanphaichitr and Daniel C. Brennan Infectious complications present major challenges to physicians caring for renal transplant recipients. The high rate of infection reflects the net state of immunosuppression associated with end-stage renal disease, transplantation, donor and environmental exposure. An understanding of the factors that affect the patients' overall state of immunosuppression is essential to prevent and treat infectious complications, which may lead to significant morbidity, graft dysfunction, or mortality. Familiarity with the various pathogens, clinical presentation, diagnostic options, treatment, and prophylaxis is important to care for renal transplant patients. The authors present their approach, based on review of current literature, to these issues. © 2000 by the National Kidney Foundation, Inc. Index Words: Infection; transplant; kidney; immunosuppression; cytomegalovirus.

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nfectious complications present some of the major challenges to physicians caring for renal transplant recipients. In the first year after transplantation, approximately two thirds of the patients will experience infectionrelated complications leading to significant morbidity, graft failure, and even mortality. The high rate of infection reflects the overall state of immunosuppression associated with end-stage renal disease (ESRD), transplantation, donor, and environmental exposure.! The effectiveness of an individual's immune system depends on several factors including age, nutrition, and comorbid conditions. Therefore, immunosuppression begins even before transplantation. Malnutrition associated with chronic renal failure and ESRD, uremia, and dialysis procedures are immunosuppressive. Many renal diseases also are treated with immunosuppressants before transplantation. Prior infections of donors with viruses such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), or hepatitis C virus (HCV) may be transmitted, which may lead to primary infectious disease in the recipients. Moreover, these infections may exert an immunomodulatory effect that contributes to the net immunosuppression leading to other opportunistic infections, allograft rejections, or posttransplant lymphoproliferative disease (PTLD). Immunosuppressive agents used to prevent allograft rejection will, of course, contribute to the patient's net state of immunosuppression. Finally, all patients are exposed to infectious agents in the community and environment. Whether an individual has complications related to infections depends on the net state of immunosuppression and the

appropriate use of preemptive, prophylactic, and treatment strategies. 2

Pretransplant Evaluation The pretransplant infectious disease evaluation begins with a complete history and physical examination. Special attention is given to eliciting past history of exposure including childhood illnesses, travel history, and exposure to endemic diseases such as coccidiomycosis and histoplasmosis. An extensive review of systems is done to determine the presence of any active infections or predisposing risk factors. The type of dialysis therapy and its complications are reviewed. Those with recurrent infections may require antistaphylococcal prophylaxis or removal of the peritoneal dialysis (PD) catheter at the time of transplant surgery. An immunization history should be obtained, and vaccinations for tetanus, diphtheria, influenza, pneumococcus, hepatitis B, and Hemophilus influenza type b (in pediatric patients) are administered before transplantation. Live vaccines for measles and varicella should be given several months before transplantation if not current or previously administered.

From the Renal Division, Department of Medicine at Washington University School of Medicine, St Louis, MO. Address correspondence to Daniel C. Brennan, MD, FACp, Associate Professor of Medicine, Director, Transplant Nephrology, 6107 Queeny Tower, One Barnes-Jewish Hospital Plaza, St Louis, MO 63110; e-mail: [email protected] © 2000 by the National Kidney Foundation, Inc. 1073-4449/00/0702-0003$3.00/0 doi:10.1053/rr.2000.5270

Advances in Renal Replacement Therapy, Vall, No 2 (April), 2000: pp 131-146

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Donors are screened for human immunodeficiency virus (HIV) 1 and 2; human T cell leukemia virus-1 (HTLV-1); hepatitis A, B, and C; CMV; EBV; herpes simplex virus (HSV); varicella zoster virus (VZV); syphilis; and Toxoplasmosis gondii. Currently, infection with HIV precludes donation or reception of kidneys. Also, donor seropositivity for HBV as evidenced by hepatitis B surface antigen (HBsAg) is a contraindication to organ donation. However, evidence of a donor's immunity to HBV with core and surface antibody (HBcAb, HbsAb) seropositivity and negative HBsAg is considered a relative contraindication to kidney donation because risk of HBV transmission is low. 3 Serological evidence of other viral infection must be considered on a case-by-case basis. In general, donor seropositivity for HSV, VZV, EBV, or CMV is not considered a contraindication to organ donation even when the recipient is seronegative. Transplantation of HCV donor seropositive (D+) kidneys into recipients who are HCV seropositive (R +) is associated with similar short and medium graft and patient survival as donor seronegative (D-) into recipient seronegative (R_).4 Kidneys from donors with serological evidence of infection with syphilis, positive rapid plasma reagin (RPR), or Venereal Disease Research Laboratories (VDRL), may be used. However, appropriate therapy for syphilis and chlamydia should be given to the recipient because patients with syphilis often are coinfected with chlamydia. Donors also should have screening urinalysis and urine cultures. Cadaveric donors should have screening blood cultures especially if there has been a prolonged (>72 hours) hospitalization before donation. Bacterial contamination of cadaveric kidneys may be as high as 25% but in general is not a contraindication to transplantation. s Cadaveric donors usually receive cefazolin during organ procurement, and recipients also should receive perioperative antibiotic prophylaxis.

Timing of Posttransplantation Infections Traditionally, posttransplant infections are considered in 3 time frames: the initial hospitaliza-

tion and the first month, the second through sixth month, and after 6 months. 6,7 Initial Posttransplantation and the First Month Infections occurring during the initial hospitalization primarily are nosocomial and related to the surgical procedure, indwelling lines, drainage tubes, and catheters. Most transplant programs administer perioperative cefazolin to the recipient during the first 24 hours to prevent these infections. Postoperatively, patients are at risk for bacterial pneumonia from atelectasis. Good pulmonary toilet and early ambulation reduce the risk of pneumonia. Bacterial and fungal wound infections are common especially in association with the presence of fat necrosis, hematoma, seroma, urinoma, or lymphoceles. Urinary tract infections also occur frequently postoperatively, particularly with the use of an indwelling urinary bladder catheter. The prophylactic use of double-strength trimethoprim-sulfamethoxazole (TMP-SMX 320 mg/1,600 mg) orally regardless of serum creatinine while the bladder catheter remains in place has reduced the risk of bacterial urinary tract infection (UTI) to less than 10% and the risk of bacteremia by 10-fold.8 The optimal duration of this prophylactic therapy is unknown, although we continue it for life in nonallergic patients because of its protection against opportunistic infections. Prior viral infections, particularly with HSV1 and 2 and human herpes virus 6 and 7, may become reactivated during the first month. Reactivation of VZV, CMV, or EBV is less common during the first month. Similarly, primary viral infection from the donor generally does not become symptomatic until after the first month. Oral acyclovir given at 200 to 400 mg twice daily is an effective prophylaxis against reactivation of HSV 1 and 2. For patients at high risk for CMV, we have found oral ganciclovir, 1,000 mg 3 times per day to be an effective prophylaxis against CMV as well as most human herpes viral infections including HSV 1 and 2, VZV, and EBV. 9,10 The Second to the Sixth Month

The second through the sixth month is the time when reactivation of donor and recipient

Infections in Renal Transplantation

as well as primary infection with viruses including CMV, EBV, VZV, HHV-6, and HHV-7 is most likely to occur. These viral infections can be immunomodulatory leading to further immunosuppression and opportunistic infections. Pneumocystis carin ii, Aspergillus species, Norcardia species, Toxplasmosis gondii, Listeria monocytogenes, and Legionella pneumophila are examples of opportunistic infections that commonly make their appearance during this time period. Primary infection or reactivation of organisms such as mycobacteria, histoplasma, blastomycoses, and coccidiomycoses also can occur. Other viruses such as HBV and HCV may be reactivated causing low-grade fever. Common respiratory viruses such as adenovirus and respiratory syncytial virus can infect the recipients more easily and tend to present with more severe symptoms than in normal hosts. After the Sixth Month By 6 months, most transplant programs have tapered their immunosuppression to a relatively low basal state. Consequently, after the sixth month, most patients are affected by the same infections as the general population. Community-acquired infections including pneumococcal pneumonia, UTIs, and influenza become more common during this time period. This is not true, however, for patients with a failing transplant and associated renal insufficiency because of their intrinsic immunosuppression. Furthermore, the use of augmented or "rescue" immunosuppressant therapy predisposes the patients to increased risk of opportunistic infections beyond the usual time frame. CMV retinitis also is a late-appearing complication, usually occurring with reactivation of other herpes viruses.lO,ll The appearance of herpes or zosteriform lesions, therefore, may be the sentinel signs of CMV.12 Posttransplant-acquired immunoglobulin deficiencies can occur caused by immunosuppression, CMV infection, and vitamin B12 deficiency. These patients are especially prone to infections with encapsulated organisms. 13 Although it is helpful to use the above time frame in the workup of differential diagnoses for etiologies of infectious complications, the time course described reflects the state of

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transplantation from approximately 1985 to 1995. Use of tacrolimus (FK506) in combination with mycophenolate mofetil (MMF) may produce a continuous and prolonged increased state of immunosuppression that puts the patient at risk for opportunistic infections beyond the traditional second to sixth month. Evaluation of Fever in the Renal Transplant Patient The lack of signs and symptoms of infections caused by immunosuppression can complicate the evaluation of fever in transplant patients. In addition, not all fever can be attributed to an infectious etiology. Our approaches to the workup of the febrile patients are represented by Figures 1,2, and 3. An empiric antimicrobial treatment often is started while awaiting the results of the investigation. For outpatient therapy, ciprofloxacin, 500 mg/ d orally is initiated. This dose is used because the glomerular filtration rate for most transplant patients rarely exceeds 50 mL/min. Alternatively, oral azithromycin, 500 mg on day 1 followed by 250 mg daily for 5 days is started. Ciprofloxacin has mild effects on cyclosporine and FK506 metabolism that can usually be monitored. Unlike other macrolides such as erythromycin and clarithromycin, azithromycin does not inhibit the cytochrome CYP3A4 system and does not increase the cyclosporine or tacrolimus leveP4 For patients who require hospitalization, we use vancomycin and cefepime or ceftazidime for the first 48 to 72 hours while awaiting definitive identification of a specific infectious agent. Once the responsible organism has been identified, the antimicrobial agents should be reevaluated and tailored accordingly. More aggressive evaluation is needed when there is inadequate response to treatment or failure to identify an etiologic agent.

Bacterial Infections Bacterial infections account for over 50% of all infectious complications in renal transplant patients. Of these, UTIs are the most common. Typical pathogens include Escherichi Coli, Klebsiella, Proteus, Enterococci, Enterobacter, Staphylococci, Psuedomonas, and rarely, Corynebacterium bacterium. UTIs most commonly occur during

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Fever and non-localizing symptoms

1

Chest radiograph, PCR for CMY Cultures (urine, blood, sputum) for bacteria, virus, and fungus

positive -------~~

Treat infection based on results of studies and sensitivities

negative

Sinusitis

Diarrhea

Rejection

~

~

Stool Culture C. difficile toxin

Biopsy

~

Limited CT of Sinus

OKT3 or ATGAM Drug reaction (after 1st and 2nd dose)

Phlebitis or central line sepsis

1 Remove IV, Lines

DVT

1

Doppler Ultrasound

If fever persists, Repeat cultures, CMV PCR q 2-3 days Viral titer g week

Figure 1. Fever workup without localizing symptoms. CT, computed tomography; DVT, deep vein thrombosis.

Physical exam, CXR, ABG Cultures, serology, crvrv PCR

Atelectasis

1

Incentive Spirometry, Ambulation, Deep breathing

Segmental/lobar Infiltrates

~ Antibiotics based on cultures

Hypoxemia rio PE

~ V/Q Scan

Hypoxemia with interstitial infiltrates (CMY, PCP, fungus, legionella, etc)

1

Broncoscopy

1

Open lung Bx if no response to treatment or no diagnosis

Figure 2. Fever and pulmonary symptoms. CXR, chest x-ray; ABC, arterial blood gas; FE, pulmonary embolism; V IQ, ventilation-perfusion scan; Bx, biopsy.

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Injections in Renal Transplantation

Physical Exam, CT scan Lumbar Puncture* Cultures, serology CMVPCR

Skin Lesions: Consider Herpes simplex, Varicella-zoster, Histoplasma, Nocardiosis

Symptoms developed after 1st and 2nd doses ofOKT3

Neutrophilic pleocytosis inCSF

~

Empiric treatment with vancomycin + ceftriaxone + rifampin + ampicillin

1

Consider aseptic meningitis

* Send CSF for gram stain, ME smear, India ink stain, cell count, glucose, protein, cryptococcal Ag, and cytology; culture for bacteria, fungi, virus, and protazoa. Figure 3. Fever and CNS signs and symptoms. CT, computed tomography; AFB, acid-fast bacillus; Ag, antigen. . the immediate postoperative period particularly when associated with indwelling catheter or stent, prostatic obstruction, or neurogenic bladder. Routine use of prophylactic antibiotic (TMP-SMX) has reduced the incidence of UTIs to less than 10% and has made complications like urosepsis or perinephric abscess rare. Therefore, occurrence of these complications or recurrences of UTIs should prompt further investigation with ultrasonography or computed tomography to rule out abscesses, obstruction, or other nidi of infections. Therapy should be directed according to culture result and sensitivity. Legionellosis

Legionella pneumophilia is the most common cause of infection in renal transplant patients among the legion ella species usually presenting with pneumonia with pulmonary infiltrate on chest radiograph. It is associated frequently with epidemics and has been linked to drinking water, contaminated respiratory equipment, and heating and air conditioning systems. Diagnosis is made by direct fluorescent antibody (DFA) testing of sputum or bronchoalveolar lavage specimens. Acute and convalescent sera also may be obtained, although

empiric therapy has long been started before the diagnosis can be made with these tests. Furthermore, appropriate antibody responses to Legionella as well as other pathogens may be absent in transplant recipients even in the presence of positive cultures.15 Erythromycin (500 to 1,000 mg intravenously every 6 hours) is the classic treatment for Legionella. However, the cyclosporine or tacrolimus level must be monitored closely because erythromycin inhibits the cytochrome CYP3A4 system. Azithromycin, also a macrolide, is a reasonable alternate, and it does not inhibit the cytochrome CYP3A4 system. Rifampin frequently is added for severe disease, but it can increase the cytochrome CYP3A4 system and drastically reduces cyclosporine and tacrolimus levels. Another alternative is a fluoroquinolone such as ciprofloxacin, which usually has minimal effect on the cyclosporine or the tacrolimus level. TMP-SMX, used as Pneumocystis carinii pneumonia (PCP) prophylaxis, also may be an effective prophylaxis against Legionella. 16 Nocardiosis

Nocardia asteroides is the usual cause of Nocardia infection in renal transplant patients. The

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most common presentation is pulmonary with nodules or cavitary lesions on chest radiograph. Patients often present with fever, productive cough, hemoptysis, dyspnea, and weight loss. Less commonly, Nocardia infections can disseminate to involve other organ systems. Skin involvement with sulfur granules and central nervous system (CNS) involvement with headache, focal neurological defects and seizures are common extrapulmonary manifestations. Because CNS involvement is fairly common and can be clinically silent, all patients with diagnosis of Nocardia infections should be evaluated to exclude CNS lesions. 17 Diagnosis of Nocardia is made by the growth on culture and identification of branching weakly Gram-positive rods on Gram stain. Treatment with TMP-SMX is the treatment of choice, although other agents including minocycline, ampicillin, ciprofloxacin, and ceftriaxone may be effective. Therapy should be continued for at least 4 to 8 weeks because relapse is common. Treatment of disseminated infections or CNS disease may require prolonged therapy of up to 1 year. TMP-SMX used for PCP prophylaxis also may be effective as prophylaxis for Nocardia. Listeriosis Listeria monocytogenes infections historically have been most common during the first 2 months posttransplant usually during the months of July to October.1 8 However, the routine use of TMP-SMX prophylaxis has made this infection relatively uncommon. Listeria may be transmitted by contaminated food or via endogenous infection of the gut of asymptomatic carriers. 19 The most common initial manifestations are abdominal cramping, fever, and diarrhea. Two-thirds of infected patients will have CNS involvement. Patients may not have symptoms such as headache or meningismus, but they still require lumbar puncture with examination of cerebrospinal fluid (CSF). Examination of CSF may find a predominance of polymorphonuclear monocytes with relatively low glucose content and negative Gram stain. Intravenous ampicillin is the treatment of choice. Alternatively, TMP-SMX is also effective and may provide an effective prophylaxis against Lis teria. 20,21

Salmonellosis Nontyphoid Salmonella infection in the renal transplant patient is 20 times more common than in the nonimmunocompromised adult population. 22 The most common presentation is bacteremia and fever. 23 However, Salmonella infection may occur at multiple sites including the gallbladder, native kidneys, or dialysis graft. Persistent or recurrent infections, therefore, should prompt an investigation for an occult focus of infection that may require surgical intervention. TMP-SMX used for PCP prophylaxis also may be effective as prophylaxis for Salmonella.

Viral Infection Herpes Virus Infections Eight human herpes viruses (HHV) have been identified. HHVs are characterized by their ability to establish a latent state after a primary infection that may be reactivated with immunosuppression. Herpes Simplex Virus There are 2 types of herpes simplex virus (HSV), type 1 and 2. HSV-l usually is associated with herpes labialis, whereas HSV-2 is more often associated with herpes genitalis. However, both types may be cultured from either location. About two thirds of adults have evidence of prior infection with HSV. The virus remains latent in the sensory nerve ganglia after primary infection. Reactivation commonly occurs within the first 2 weeks posttransplant. The most common manifestations are mild ulcerlike mucocutaneous lesions but also may present with other skin lesions. HSV also may cause esophagitis with dysphagia and odynophagia similar to candidal esophagitis. Less commonly, HSV can cause pneumonitis, hepatitis, encephalopathy, and disseminated disease. Demonstration of multinucleated giant cells on Tzanck test, culture of virus, or DFA confirms diagnosis. An increase in IgG or IgM serology also may be helpful. HSV contains a thymidine kinase that phosphorylates acyclovir making this virus the most sensitive of all HHV to acyclovir. 24 Mucocutaneous lesions are treated with oral acyclo-

Infections in Renal Transplantation

vir, 200 mg, 4 to 5 times per day for 5 days. Systemic or disseminated infections are treated with intravenous acyclovir, 5 mg/kg every 8 hours. Patients also should be evaluated for CMV and EBV infections because they often coinfect patients with HSV.11,13 Low-dose acyclovir, 200 to 400 mg, orally twice daily is an effective prophylaxis for HSV However, patients at high risks for CMV diseases should be placed on ganciclovir prophylaxis, which also is effective against HSV and EBVlO Varicella-Zoster Virus Approximately 90% of adults have been infected with VZV before transplantation. Diagnosis of reactivation usually is made clinically by observation of shingles or zoster lesions in a dermatomal distribution. However, dermatomal pain without cutaneous lesions also may occur.25 Primary infection may present as skin lesions, pneumonitis, encephalitis, pancreatitis or hepatitis, or disseminated intravascular coagulation. Suspected cases of primary infections should be confirmed with viral cell cultures, Tzanck test, or direct immunofluorescence. Treatment for zoster reactivation is a 7-day course of acyclovir, 800 mg orally 5 times per day; famciciovir, 500 mg 3 times daily; or valacyclovir, 1,000 mg 3 times daily. Primary infection is treated with intravenous acyclovir, 500 mg/kg every 8 hours for 7 days along with varicella-zoster immune globulin (VZIG). Seronegative patients who have been exposed to chicken pox or VZV should receive VZIG within 72 hours and be placed on acyclovir, 200 mg orally 5 times a day. Administration of VZV vaccine should also be considered at the time of exposure. This vaccine recently has been shown to be safe in pediatric renal transplant patients. 26 Low-dose acyclovir or ganciclovir used for prophylaxis of HSV or CMV probably is also effective for VZV Epstein-Barr Virus Serological evidence of prior EBV infection can be seen in 95% of the adult population. EBV may cause mononucleosislike syndrome, chronic fatigue, or fever of unknown origin (FUO). It also has been associated with Burkitt's lymphoma and nasopharyngeal carcinoma. EBV has an innate ability to transform

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and immortalize B cells. In immunocompetent individuals, a latent carrier state exists because proliferation of immortalized B cells is contained by cell-mediated immunity. In immunosuppressed individuals, however, this containment is impaired making patients prone to uncontrolled proliferation resulting in PTLD. Risk factors for PTLD include EBV seronegativity, the use of OKT3 or FK506, and CMV seromismatching. Some PTLD also has been shown to be donor derived. 27 Both acyclovir and ganciclovir are effective against EBV However, because CMV and EBV are reactivated contemporaneously, and acyclovir is ineffective against CMV; ganciclovir is the drug of choice for treatment of EBV infection in patients at high risk for CMV.1°,14 Prophylaxis for CMV with ganciclovir also may reduce the risk of PTLD. Although PTLD is not an infectious disease, acyclovir and ganciclovir have been used along with reduction in immunosuppressive therapy and standard radiotherapy and chemotherapy for treatment. 28 Cytomegalovirus Symptomatic cytomegalovirus (CMV) infection occurs in 20% to 60% of all renal transplant recipients and is a significant cause of morbidity and mortality.29 The most common presentation is fever associated with leukopenia. CMV also can cause pneumonitis, colitis, esophagitis, hepatitis, pancreatitis, retinitis, and encephalopathy. Concern has been focused mainly on avoiding CMV infection in the CMV D+ /R - group. Recent analyses of data from the United States Renal Data System and United Network of Organ Sharing has shown that by 3 years, it is the D+ /R + group that has the worst graft and patient survival rate.30 The reason for this is unclear. CMV infection may mimic or predispose to late acute rejection and graft loss.31 CMV also has been implicated as an important contributor to chronic rejection, atherosclerosis, and restenosis of coronary arteries after angioplasty.32-34 The diagnosis of CMV is made by demonstration of CMV antigens or CMV deoxyribonucleic acid (DNA) via polymerase chain reaction (PCR). Serological confirmation of active CMV infection with detection of IgM, IgG and rise of the titer between acute and convales-

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cent sera can be made but can take up to 16 to 18 weeks for seroconversion. 35 Moreover, transplant patients may fail to produce an antibody response despite other evidence of viremia.1 5 Recent evidence indicates that PCR should be the test of choice for the diagnosis of CMV. PCR has a processing time of 6 to 8 hours and can be performed in batches. Because of the stability of DNA, it can also be performed on stored blood; formalin-fixed, Bouin-fixed, or paraffin-embedded tissues; plasma; or CSF. The CMV DNA is unaffected by delays in processing or storage temperatures. 9,36 This is in contrast to the effect of a delay in processing on both conventional and shell vial cultures and the antigenemia assay. For these assays a delay in processing the sample as brief as 6 hours may decrease the sensitivity of detection to 50%, and a delay of 24 hours decreases the sensitivity to almost zero. 9,36,37 Therapeutic treatment of established CMV disease is primarily with the antiviral agent, ganciclovir. Although CMV-infected cells lack a thymidine kinase necessary to phosphorylate acyclovir, they do contain a phosphokinase, which is a product of the CMV UL 97 that is capable of phosphorylating ganciclovir into an active moiety. Ganciclovir, 5 mg/kg intravenously every 12 hours for 21 days is effective for retinitis and sepsis, but it is less efficacious for more severe invasive CMV syndromes such as pneumonia or gastrointestinal involvement. For severe CMV disease, the addition of hyperimmune CMV immunoglobulin, 100 mg/kg intravenously every other day for 5 doses may be beneficial. Foscarnet also may be used, but is nephrotoxic and inconvenient to administer. Preemptive therapy of CMV infection has been advocated for solid organ transplant recipients. 38 We performed a study of preemptive therapy in which patients were intensively monitored, and intravenous ganciclovir was initiated based on a positive PCR result compared with deferred therapy in which patients were intensively monitored and treatment initiated only on development of symptomatic episodes. Deferred therapy was as effective in controlling CMV morbidity and mortality in renal transplant recipients but more cost effective. 9 Prophylactic therapy with antiviral agents

such as oral acyclovir, intravenous ganciclovir, or intravenous immunoglobulin preparations such as hyperimmune CMV immunoglobulin (Cytogam) or standard pooled immunoglobulin have been used to control CMV infection but are associated with variable efficacy and significant expense. High-dose oral acyclovir, 800 mg orally 5 times a day, was reported initially to prevent CMV disease in renal transplant patients. 39 Subsequent studies, however, have failed to confirm these findings. 40,41 Valacyclovir has been shown in a recent trial to be a possible prophylactic agent for CMV. 42 Its mechanism of action is not well understood. Additionally, an important side effect of valacyclovir is hallucination, which limits its use. We have shown that oral ganciclovir is highly effective for the prevention of CMV disease and infection in renal transplant patients.1° Ganciclovir, 1,000 mg orally 3 times daily was compared with deferred therapy in which recipients received acyclovir, 200 mg orally twice daily for 12 weeks for herpes simplex prophylaxis. PCR for CMV was performed on buffy-coat specimens weekly for 15 weeks and at 5 and 6 months. During prophylaxis no patients in the ganciclovir group had CMV disease versus 61% of patients in the deferred group. Only 2 patients in the ganciclovir group ever had a positive CMV PCR finding during prophylaxis. In contrast, 100% of patients were viremic in the first 12 weeks after transplant in the deferred group. After discontinuing oral gancidovir, 58% of additional patients in the ganciclovir group subsequently had PCR evidence for CMV viremia, but only 21 % had CMV disease. Human Herpes Virus 6, 7, and 8 HHV-6 and HHV-7 are 2 newly discovered and closely related beta herpes viruses. HHV-6 has been identified as the cause of roseola, and it has recently been associated with multiple sclerosis. 43 ,44 HHV-7 also is quite common and has been proposed as the etiology of both roseola and pityriasis rosea. 45,46 The specific route of transmission for these viruses is unknown. As with other herpes viruses, HHV-6 and HHV-7 remain in a latent state in immunocompetent individuals after the primary infection. Both viruses may be cofactors for CMV infections. 47

Infections in Renal Transplantation

It is believed, but not widely seen, that HHV-6 and perhaps HHV-7 are suppressed by intravenous ganciclovir. It is unknown whether oral ganciclovir can achieve adequate serum levels for all strains of HHV-6. Acyclovir has no in vivo activity against HHV-6. 43 HHV-8 recently has been identified as the etiologic agent of Kaposi's sarcoma and body cavity-based lymphoma in AIDS and transplant recipients. 48 It may be a cofactor for other herpes virus infections or HIY.

The Hepatitis Viruses Hepatitis B virus (HBV) is a DNA virus associated with an increased risk of mortality in renal transplant recipients.49 All nonimmune renal transplant recipients should receive the 40-J.lg series of HBV vaccination before transplantation. Organs from HBsAg+ individuals should not be transplanted. The use of organs from HBcAb+ donors is controversial, but it is generally safe in renal transplantation, although these organs should be reserved for patients who are HBV immune. 50 HBV also may be reactivated in patients who are HBcAb+, HBsAb+ . The safety and efficacy of transplantation in HBsAg+ patients is controversial. In HBsAb + patients, one approach is to quantitate anti-HBsAb levels and try to maintain them above 100 IU through the periodic infusion of HBV Ig analogous to the treatment used for hepatitis B liver transplant recipients. Treatment with interferon may be beneficial but predisposes to graft rejection. Lamivudine, ganciclovir, and foscarnet also may be helpful in treatment of recipients before transplantation. 49 HeV, a single-stranded RNA virus, is a major cause of chronic hepatitis after renal transplantation. The impact of Hev on transplant outcome is becoming clear. In a recent study, recipients without anti-Hey antibody before transplantation were compared with recipients with anti-Hey before transplantation.51 After extended follow-up of 6 to 7 years, there continued to be no significant difference between groups with respect to graft loss. However, mortality, especially from sepsis, was significantly higher among recipients with detectable anti-Hey antibody before transplantation. Paradoxically anti-HeY-positive recipients of HeV-positive kidneys had a higher

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mortality rate than anti-HeY-negative recipients of HeV-positive kidneys. The increased mortality rate among recipients who acquired HeV infection before transplantation, but not among recipients who acquired HeV at the time of transplantation, could be explained by the longer duration of HeV infection in the former group. These findings were felt to be consistent with the known slowly progressive nature of HeV infection. Treatment of HeV with interferon is associated with allograft rejection. Ribavarin has shown some promise in an uncontrolled trial of HeV-infected renal transplant recipients. 52 One final question is whether it is better for an anti-Hey positive dialysis patient to remain on dialysis or undergo a transplant. In a preliminary report, anti-HeY-positive transplant patients had improved survival compared with matched-dialysis control patients. 53 Adenovirus Adenovirus is a common cause of pharyngitis, conjunctivitis, and respiratory infection from fall to spring. It has been associated with hemorrhagic cystitis in kidney transplant recipients. 54 Respiratory Syncytial Virus Respiratory syncytial virus (RSV) commonly occurs in children but is seen in adult renal transplant recipients as well. It is diagnosed by nasopharyngeal swab. When accompanied by pneumonitis and hypoxia, we administer ribavarin. Recently, Medimmune (Gaithersburg, VA) has developed a monoclonal antibody (Synergis) to RSV that may be considered for adjunctive therapy for this virus. Influenza Influenza A affects immunocompromised individuals more severely than immunocompetent individuals. It is recommended that all transplant recipients, their families, and transplant personnel receive yearly vaccination for influenza. When influenza develops we treat with amantadine, 100 to 200 mg/ d orally for 5 days. Alternatively, the recently available medications zanamivir (2 inhalations every 12 hours fo 5 days) or oseltamivir (75 mg orally twice per day for 5 days) can be initiated. These

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medications should be started within 48 hours of symptom onset. Polyoma Virus The polyoma viruses (BK, JC, and SV40), formally classified as "slow" viruses, are unenveloped 45-nm icosahedral agents in which genomic material is comprised of supercoiled, double-stranded DNA. The JC virus causes progressive multifocal leukoencephalopathy. Polyoma viruses are becoming increasingly implicated as causes of renal dysfunction with histological presentations of interstitial nephritis often mimicking acute rejection or even transitional cell carcinoma. 55-58 They also cause asymptomatic infection, ureteric stricture, and hemorrhagic cystitis. The diagnosis primarily is made by detection of viral particles of 40 to 50 nm in a characteristic paracrystalline array56 on electron microscopy.

Fungal Infections Systemic fungal infections occur in 2% to 14% of renal transplant recipients.7·59•60 The increased incidence of infection in this group of patients can be attributed to impaired phagocytosis and cellular immunity. Other predisposing factors include corticosteriod and antibiotic therapy, indwelling catheter, hyperglycemia, disruption of intestinal mucosa, and tissue ischemia. 61 A high index of suspicion as well as an aggressive approach to diagnosis is required because fungal infections lack specific signs and symptoms while maintaining a high associated mortality rate. Candidiasis Candida is the most common cause of fungal infection in renal transplant patients with Candida albicans being the usual pathogen. Other less common pathogenic species include Candida tropicalis, Candida krusei, and Candida glabrata. Clinically, candidal infection usually presents with mucocutaneous lesions such as thrush, intertrigo, onychomycosis, esophagitis, or vaginitis. These infections usually respond to topical therapy with nystatin or clotrimazole. Oral fluconazole usually is effective in cases resistant to topical therapy. More serious, invasive candidal infections occur when the surgical procedure, indwelling blad-

der, or intravenous catheters disrupt the mucocutaneous barrier. This may lead to an increased risk of hematogenous infection that is 10-fold higher in the immunosuppressed patients. Disseminated infections may present with skin lesions, intraabdominal abscesses, meningitis, brain abscesses, endophthalmitis, endocarditis, aortitis, arthritis, osteomyelitis, pneumonitis, pyelonephritis, and UTIs. Diagnosis is confirmed with fungal stain and culture of the appropriate site. Intravenous amphotericin B is used to treat severe candidiasis. Indwelling catheters should be removed. To minimize nephrotoxicity associated with amphotericin B, therapy can be switched to fluconazole once the infection is under control. Liposomal forms of amphotericin B have been reported to have less nephrotoxicity at equivalent dose, and it may proved useful in the transplant populations. C krusei and C glabrata usually are resistant to fluconazole and may require higher doses of amphotericin B. Cryptococcosis Cryptoccoccus neoformans is the most common cause of CNS infection in renal transplant recipients, occurring historically in 2% to 4% of the patients who undergo transplant. 62•63 The infection is acquired by inhalation of aerosolized fungal spores. C neoformans is widely distributed in the environment, being present in soil, vegetable matters, and bird dropping. Patients present with fever, headache, mental status change, and focal neurological deficits. The presentation often is subacute or chronic. One third of the patients also can present with pulmonary infiltrate with symptoms of cough, dyspnea, and chest pain. Cutaneous involvement may manifest as cellulitis, nodular skin lesion, acneiform eruption, ulcers, abscesses, ecchymoses, or palpable purpura. Diagnosis is made by detection of cryptococcus via India ink stain and culture of CSF. Cryptococcal antigen assay of the serum and CSF is both rapid and sensitive. Detection of cryptococcus in the urine generally indicates systemic infection, and appropriate therapy should be instituted. Acutely ill patients should be treated with amphotericin Band 5-flucyto-

Infections in Renal Transplantation sine. Less severe infections may be managed successfully with fluconazole. Cryptococcal antigen can be used to assess the effectiveness of treatment. 64 Aspergillosis The most common cause of aspergillosis is Aspergillus fumigatus. Other Aspergillus species that can cause infection include Aspergillus flavus and Aspergillus niger, and Aspergillus terreus. Like cryptococcus, aspergillus species are ubiquitous and are present in soil. Infections occur via inhalation of fungal spores often as a superinfection of a viral or bacterial pneumonia. Disease is rare in immunocompetent individuals, but occurs in 2% of renal transplant recipients usually within the first 3 months after transplantation. 65 Aspergillus species also has been isolated from air duct samples, dust, potted plants, and food in the hospital. Nosocomial outbreaks have been associated with hospital construction and renovation. Usual clinical manifestations include fever, cough, dyspnea, and pleuritic chest pain. The fungus causes necrotizing bronchopneumonia and invasion of pulmonary vessels. This can lead to hematogenous dissemination particularly to the CNS causing meningitis, encephalitis, brain abscesses, or granulomata. CNS symptoms are nonspecific and include headache, altered mental status, seizure, and evolving stroke. Other organs that can be involved include gastrointestinal tract, kidneys, liver, thyroid, heart, pericardium, spleen, bones, and joints. Risk factors for invasive aspergillosis include renal failure, immunosuppression with high-dose corticosteriod and antilymphocyte antibody, neutropenia, and CMV infection. 66,67 Diagnosis usually is confirmed by demonstration of Aspergillus in tissue biopsy specimens, body fluids, and nasopharyngeal swabs. Unfortunately, the fungal stain and culture of Aspergillus are not very sensitive. If invasive disease is suspected, tissue biopsy should be obtained for histological examination, fungal stain, and culture. Disseminated aspergillosis portends a poor prognosis with mortality approaching 100%. Amphotericin B is the treatment of choice. Prognosis is improved with early institution of therapy and high doses of intravenous ampho-

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tericin B (1.0 to 1.5 mg/kg/ d). Itraconazole (400 to 800 mg/ d intravenous) can be used in patients who did not respond to or tolerate amphotericin B. However, further study is needed, before itraconazole can be recommended as first-line therapy. Zygomycosis Infections with zygomycetes including Rizopus species or Mucor species occur in 1.2% of renal transplant patients. Inhalation, ingestion, or direct inoculation of spores may transmit infection. Nosocomial infection also can occur as a result of hospital construction or contaminated air-conditioning systems. Risk factors for infection include poorly controlled diabetes mellitus, prolonged metabolic acidosis, chelation therapy with deferoxamine, and corticosteroids. Infection leads to vascular invasion, infarction, and hemorrhage. Clinically, patients present with fever, headache, sinus swelling and pain, and coma as a result of rhinocerebral infection. The infection also can involve the lungs and skin and disseminate to liver, heart, and gastrointestinal tract. Diagnosis is made by tissue biopsy and histological examination of the involved tissue. The infection is treated with surgical debridement of the necrotic tissue and protracted course of intravenous amphotericin B. Endemic Mycoses Histoplasmosis and coccidiomycosis are the 2 common endemic mycoses infections seen in the renal transplant recipients caused by Histoplasma capsulatum and Coccidioides imitis, respectively. Clinical presentation is varied in these infections, and dissemination is common. Histoplasmosis is endemic in the central United States with an incidence of approximately 0.4% to 2.1 % in renal transplant recipients. 68,69 H capsulatum is present in soil and is acquired by inhalation. Primary infections occur in the lungs with symptoms of cough, fever, and myalgia. The infection then may disseminate in 77% of cases with nonspecific symptoms. These include fever, night sweats, fatigue, weight loss, and cough. Chest radiographs may show diffuse or miliary infiltrates, hilar adenopathy, or pleural effusion, but it can be normal in up to 50% of cases. Other manifes-

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tations include cutaneous lesions, hepatosplenomegaly, CNS disease, and adrenal and musculoskeletal lesions. A high index of suspicion and thorough travel history are important in the patient evaluation. Diagnosis can be made by methenamine-silver staining of blood, bone marrow, or other affected tissue. Serological antigen detection in blood as well as other body fluid also can be done for rapid diagnosis. Bone marrow culture is a high-yield test (positive in more than 90%), but it can take as long as 2 to 6 weeks. Amphotericin B is the treatment of choice. Alternatively, itraconazole can be used for patients who cannot tolerate amphotericin B. Histoplasma antigen level can be followed to assess the response of therapy and predict relapse. Coccidiomycoses are endemic in the southwestern United States and northern Mexico. Patients who have lived in or traveled to these areas are at an increased risk of infection with C immitis. Primary infection is acquired by inhalation, and many cases can be attributed to reactivation of foci of prior infections. Infection can occur at any time, but it is most likely to occur in the first year posttransplantation. Infection causes symptoms of fever, cough, chest pain, and malaise. Chest radiograph findings are diverse with hilar adenopathy, infiltrates, miliary, and, rarely, cavitary disease. Transplant recipients usually have progressive disseminated disease associated with a high mortality rate.7° Risk factors for dissemination include male sex and blood group B. Dissemination can involve the CNS, skin, liver, kidney, and skeletal system. Diagnosis of coccidiomycosis is made by serology or histological examination of biopsy tissue, culture of blood, bone marrow, or other body fluids. The infection can be treated with fluconazole. Severe or disseminated infection is treated with amphotericin B followed by long-term suppressive therapy with fluconazole or itraconazole. Pneumocytosis

Pneumocystis carinii is an extracellular organism resembling both fungi and protozoan parasites. Ten percent of renal transplant recipients not receiving prophylactic therapy have PCP, usually in the first 6 months posttrans-

plantation. P carinii has increased virulence in the immunocompromised host especially with coinfection with certain viruses such as HIV andCMy'71 PCP has a subacute presentation with symptoms of fever, nonproductive cough, and dyspnea. Interstitial infiltrates on chest radiograph and hypoxemia out of proportion to physical or radiographic finding also are common features. The diagnosis is made by identification of P carinii in induced sputum (30% to 55% yield), bronchoalveolar lavage fluid (>50% yield), or a lung biopsy specimen (>90% yield). More recently, monoclonal antibodies directed at the surface epitopes of P carinii have facilitated more rapid diagnosis with a higher yield than conventional stains.72 The drug of choice for initial treatment of PCP is TMP-SMX (15 mg/kg/ d of TMP and 75 mg/kg/ d of SMX) for 2 weeks. Second-line therapy for patients who did not tolerate TMP-SMX is intravenous pentamidine (4 mg/ kg/ d). Frequent side effects of pentamidine include renal dysfunction, hypotension, hypoglycemia, blood dyscrasias, and gastrointestinal disturbance.73 Other options for treatment of PCP are trimetrexate plus folinic acid, trimethoprim plus dapsone, atovaquone, or primaquine plus clindamycin. Concurrent bacterial or CMV infections also should be treated. Prophylactic therapy with low-dose TMPSMX (1 double strength tablet daily) is very effective at preventing P carinii infection in renal transplant recipients, and it should be continued for 6 to 12 months posttransplant.74,75 An alternative for those intolerant to TMP-SMX is aerosolized pentamidine (300 mg monthly) or oral dapsone (50 to 100 mg daily).

Mycobacterial Infections Mycobacterium Tuberculosis

Mycobacterium tuberculosis infects approximately 1% to 4% of renal transplant recipients, and it can occur at any time after transplantation.76,77 Renal transplant patients are at increased risk for both primary infection and reactivation as well as disseminated diseases. Clinical manifestations include cavitary pulmonary disease, cutaneous lesions, and gastrointestinal and musculoskeletal involvement. In

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addition to the immunosuppressed state, risk factors for infection include nonwhite race, advanced age, malnutrition, diabetes mellitus, renal failure, upper gastrointestinal surgery, and history of inadequately treated mycobacterial disease. Patients suspected of having active tuberculosis should be isolated to prevent transmission of the disease. Unfortunately, the tuberculin (PPD) skin test is only positive in 25% to 30% of transplant recipients. Three induced sputum specimens should be obtained in the early morning and sent for aid-fast bacilli (AFB) stain and culture. Bronchoalveolar lavage fluid and postbronchoscopy sputum specimens also can be sent for acid-fast stain and culture. In the case of extrapulmonary disease, other body fluids (pleural, ascitic, cerebrospinal, synovial, or urine) should be concentrated before staining. Histopathologic examination of biopsy tissue for AFB and granulomata also may be diagnostic if tuberculosis is suspected and body fluid analysis is negative. Active M tuberculosis infection should be treated for at least 12 months with a minimum of 2 bactericidal drugs (isoniazid [INH), rifampin, or pyrazinamide) to which the organism is susceptible. Until drug sensitivities are known (usually the first 2 months), 4 antituberculous agents should be used (lNH, rifampin or pyrazinamide, and either ethambutol or streptomycin). The use of INH prophylaxis is controversial because of the risk of hepatotoxicity. However, most transplant centers agree that 6 to 12 months of prophylactic INH is indicated in transplant recipients with any of the following risk factors: recent PPD conversion; Asian, African, or Native American heritage; malnutrition; a history of partially treated tuberculosis; or abnormal chest radiograph. The adverse effects of antituberculous agents are well described. One effect of particular importance to the renal transplant patients is that INH and rifampin induce hepatic cytochrome CYP3A4 enzymes and increase the metabolism of glucocorticoids, cyclosporine, and tacrolimus. This can lead to underimmunosuppression and rejection if cyclosporine, and tacrolimus levels are not monitored closely.

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Atypical Mycobacteria Nontuberculous mycobacteria are ubiquitous in the environment and can infect renal transplant recipients, particularly late in the posttransplant period. Infections usually are chronic and involve the skin and musculoskeletal system. Occasionally, the pulmonary and gastrointestinal system can be involved. Dissemination of Mycobacterium kansasii can occur, but it is rare. Mycobacterium marinum, Mycobacterium hemophilum, and Mycobacterium chelone often cause cutaneous disease. Clinically, the cutaneous lesions are painful erythematous or violaceous subcutaneous nodules that may ulcerate or become superinfected. Successful diagnosis requires a high index of suspicion. Lesions should be aspirated or biopsied, and tissues should be sent for histopathology, acid-fast staining, and culture. Treatment includes surgical debridement and empiric antimycobacterial therapy. There are no uniformly accepted drug regiments because atypical mycobacteria have heterogeneous in vitro antimicrobial-susceptibility patterns. Empiric therapy should be modified when susceptibility testing results are available. The prognosis for nondisseminated disease is generally favorable.

Xenozoonoses Although much progress has been made in the field of transplantation, continuing shortage of human organs has limited access to this form of renal replacement therapy. Xenotransplantation offers a potential solution to this problem. In an early attempt of xenotransplantation, a chimpanzee was used as a donor. 78 Even though nonhuman primates are phylogenetically close to human, many species of primates are small in numbers, and there is also a fear of introducing simian viruses into the human population. 79 Recent efforts, therefore, have concentrated on using nonprimate donors, particularly the swine, as a source of kidneys. In addition to overcoming the immunologic barrier of transplanting an organ from a discordant species, another significant obstacle to the widespread use of xenotransplantation is xenozoonosis, transmission of pathogens from one species to another during trans-

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p1antation. 8o Bacterial, parasitic, and fungal infections transmitted to human from swine already have been described in immunocompetent hosts. Moreover, difficulties in preventing infections of herds, difficulties in establishing the diagnosis after contamination, and difficulties in handling persistent infections pose serious potential threats to success of xenotransp1antation. 81 Viruses such as porcine herpes viruses, porcine adenovirus, and porcine rotavirus have human viral counterparts, but they have not yet been shown to infect humans. In contrast, Japanese encephalitis virus, porcine rhabdoviruses, picornaviruses, and swine influenza have been known to infect humans as well as pigs. Although they have not been established firmly as pathogens, porcine retroviruses and swine prions represent serious potential risks to xenotransp1antation. 81 Retrovirus and prion infections have the potential to become widespread once the infections are established in humans. More research on better and reliable methods of detection of infections and strategies to minimize risks of infections must be done before xenotransp1antation can be considered a feasible alternative to allotransplantation.

Conclusion Infectious complications remain a significant challenge to physicians caring for renal transplant recipients. An understanding of factors that contribute to the patients' net state of immunosuppression before and after transplantation is essential. A familiarity with the usual timing of infections, the various pathogens, methods of detection, as well as therapeutic strategies also are important. Moreover, physicians must be aware of the potential effects that these infections and their treatment may have on the patients net state of immunosuppression, particularly the immunomodu1atory potential of viruses such as CMV causing further immunosuppression and interaction between the antimicrobial therapies and immunosuppressive medications. Finally, infectious complications are ever-changing problems. A better understanding of the pathogens and judicial use of prophylactic, preemptive, and treatment strategies have lessened the inci-

dence of certain infections such as UTIs, PCP, and nocardiosis. However, as newer and more powerful immunosuppressive agents or new practices such as xenotransp1antation are introduced, physicians will need to become aware of the changing face of infectious complications and their treatment strategies.

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