INFECTIOUS COMPLICATIONS FOLLOWING RENAL TRANSPLANTATION

RENAL TRANSPLANTATION 0039-6109/98 $8.00 + .OO

INFECTIOUS COMPLICATIONS FOLLOWING RENAL TRANSPLANTATION

Irene G. Sia, MD, and Carlos V. Paya, MD, PhD

Since the inception of renal transplantation in the early 1960s, infectious diseases have been a constant yet evolving problem. The changing patterns of infectious disease complications in renal transplant recipients, primarily toward a reduction in the incidence and severity, can be attributed to multiple factors: improved surgical techniques, alterations and improvement in immunosuppressive regimens, institution of prophylactic antimicrobial agents, better diagnostic armamentarium, and the availability of more effective means of preventing and treating certain types of infection. This is reflected by the fact that during the first decades of the renal transplantation era, a serious infectious complication developed in up to 70% of patients following transplant, resulting in fatal outcomes in as many as 11% to 40% of cases.', 11, 22, 26, 35, 36, 38, 43, 49

Recent studies have described an incidence of 15% to 44%, with mortality rate due to infections of less than 5?'03, 4, 14, 17, 18, 34, 39, 43, 45 (Table 1). Nevertheless, the challenge remains because infections continue to be an extremely important cause of post-transplant morbidity and a leading cause of death of renal allograft recipients at all points in the post- surgical course.22, %, 38, 42 Moreover, the introduction of more potent immunosuppressive agents may result in the resurgence of certain infectious complications. Hence, the prevention and effective treatment of infectious complications remain major concerns of the transplant clinicians.

The risk of infection in the renal transplant recipient is determined primarily by two factors: epidemiologic exposures to the infective agents and the net state of immunosuppression prior to transplantation (Table

From the Division of Infectious Diseases, Mayo Clinic, Rochester, Minnesota

SURGICAL CLINICS OF NORTH AMERICA

VOLUME 78 * NUMBER 1 - FEBRUARY 1998 95

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Table 1. INCIDENCE OF INFECTIOUS COMPLICATIONS IN RENAL TRANSPLANTATION

Incidence References

Bacterial Urinary tract infections Listeriosis Nocardiosis Salmonellosis Tuberculosis

Aspergillosis Candidiasis Cryptococcosis Coccidioidomycosis Histoplasmosis Mucormycosis Pneurnocystosis

Strongyloidiasis

Cytomegalovirus Epstein-Barr virus Hepatitis B virus Herpes simplex virus Varicella-zoster virus

Fungal

Parasitic

Viral

53.00/0-69.2% 1.9%6.9% 1.1 %-3.2%

3.4% 3.5%-5.4%

<1% 2.2%

1.8%-3% 7.8% <1% <1% 10%

<1%

18.2%-67% 2% 3% 50%

4.3%-10%

15,23 44,46 9, 35, 50 5 15, 35, 37

3, 4, 26 3, 4 3, 4, 16, 26, 35 4 29 3, 4 38,39

24,26

23, 40, 41, 51 19 13,23 39 23, 42

2). Past or recent exposures to infectious agents in the community may lead to infections by systemic mycoses, Mycobucteriurn tuberculosis, Strongyloides stercorulis, and influenza. Opportunistic infections due to Aspergillus species, Legionella species, and gram-negative bacteria have been associated with nosocomial outbreaks. Immunosuppression secondary to transplantation-related treatments is a main risk factor. How-

Table 2. INFECTIOUS DISEASE EVALUATION FOR ADULT RENAL TRANSPLANTATION

Pretransplant evaluation Serology-hepatitis B virus, hepatitis C virus, rapid plasma reagin,

anti-human immunodeficiency virus, anti-human T-cell lymphotropic virus, cytornegalovirus, Epstein-Barr virus, herpes simplex virus, varicella-zoster virus, Toxoplasma, endemic fungi

Urine analysis and bacterial culture Tuberculin skin test and anergy panel Chest radiograph Stool examination for ova and parasites

Vaccinations Pneurnovax Tetanus-diphtheria Influenza Hepatitis B Varicella

INFECTIOUS COMPLICATIONS FOLLOWING RENAL TRANSPLANTATION 97

ever, leukopenia, metabolic abnormalities present in patients with end- stage renal disease, and infection with one of the immunomodulating viruses, notably cytomegalovirus (CMV), Epstein-Barr virus (EBV), and hepatitis B and C, need to be considered as additional immunosuppressive circumstances.

A well-defined temporal sequence of infections is present in the post-transplant period. The typical timetable is divided into three parts: the first month post-transplant; 1 to 6 months post-transplant; and the late period, which covers beyond 6 months of transplantation. Diagnos- tic evaluation is guided by the timing of infectious manifestations after transplantation, epidemiologic factors, and evidence of specific organ system involvement. Moreover, noninfectious causes of fever that develop in the post-transplant patient need to be considered and include allograft rejection, secondary effects of antilymphocyte therapy, pulmonary embolism, drug reactions, and malignancy.

In the first month after transplant, the major infectious complications include post-surgical bacterial and candidal wound infections, postoperative pneumonia, and intravenous- and urinary bladder catheter-related infections, complications that are similarly present in the nonimmunosuppressed pop~lation.~~, 38 Wound hematoma and urinary fistula or leaks increase the risk of infection. Deep perinephric infections can lead to the need for transplant nephrectomy, systemic sepsis, or the development of mycotic aneurysms. The declining frequency and severity of these infections, which used to occur in over half of patients during the early transplantation era, are largely attributed to improvement in surgical techniques, more effective immunosuppression, use of prophylactic antibiotics, and better methods of managing urinary catheters and intravenous indwelling catheters.l4. 17, 22, 23, 25, 30, 38 These infectious complications are later followed by others considered more unique to the immunosuppressed treatment regimen. These include infections caused by viruses of the herpes family and other opportunistic bacterial and fungal infections.

The late post-transplant period is characterized by a significant decrease in the level of maintenance immunosuppressive therapy. Most commonly, these patients develop infections similar to those present in the general community, such as influenza and pneumococcal pneumonia. In addition, subgroups of patients develop chronic viral infections that were acquired in an earlier period, namely, chronic hepatitis, CMV chorioretinitis, and EBV-associated lymphoproliferative disease. Finally, occasional opportunistic infections occur in those with relatively poor allograft function who are kept on an excessive amount of immunosuppressive drugs. Such subgroups of patients are at the highest risk for infections due to C yptococcus neoformans, Pneumocystis carinii, Listeria rnonocytogenes, and Nocardia asteroides.

BACTERIAL INFECTIONS

Bacterial infections are prevalent in renal transplant recipients, most of which originate from the urinary tract. Without antibiotic prophylaxis

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(Tables 3 and 4), the incidence of urinary tract infection varies from 35% to 79%.', lo, 15, 18, 22, 26, 347 35, 39 Predisposition to infections of the urinary tract is attributed to well-established risk factors.lO, 11, 14, 15, 18, 27, 31, 39

Causative agents are similar to those occurring in the general population: enteric gram-negative bacteria including Pseudomonas aeruginosa, entero- cocci, and staphylococci. Infections may be asymptomatic and follow a benign clinical course or may present as overt pyelonephritis with high fever, bacteremia, and a high relapse rate. The microbiology is mandated by the type of bacterial infection. Whereas gram-positive cocci are likely to cause catheter-related sepsis, gram-negative microorganisms may be involved in urinary tract and related infections. Most infectious episodes can be managed with a conventional 10- to 14-day course of antibiotic therapy. Prophylaxis with a regimen of low-dose trimethoprim-sulfamethoxazole or ciprofloxacin reduces the incidence of bacterial urinary tract infection.27 Recurrent infections should be investigated further by ultrasonography, CT scan, and/or nuclear imaging studies.

Of interest to renal transplantations, an increased risk of infection with nontyphoidal Salmonella, which commonly presents as a febrile illness with bacteremia, has been reported:, 15, 27 Recurrences are common, and seeding of the cardiovascular system is a major concern. Early institution of antimicrobial therapy is effective, but an extended course of treatment may be necessary. Nontyphoidal Salmonella infection can also present as an acute gastroenteritis, similar to that caused by Campy- lobacter jejuni or L. monocytogenes. Another form of bacterial gastrointestinal infection affecting the renal transplant patient is diverticulitis, which is accompanied by a high rate of perforation with peritonitis. A high index of suspicion despite the absence of typical clinical features, early surgical intervention, and treatment with broad-spectrum antimicrobial coverage are mandatory measures imperative for a good outcome.

LegioneIla infection can be community acquired or present as a nosocomial infection. Legionella pneumophila causes most of these infections, although L. micdadei, L. bozemanii, and L. dumofii have all been reported to cause disease. Typically, Legionella infection presents as a pneumonia with fever, chills, headache, diarrhea, chest pain, dyspnea, cough, and pulmonary infiltrates, and even perit~nitis .~~ Corticosteroid dosage and duration of hemodialysis are risk factors for legionellosis.2 Diagnosis is made by a positive direct fluorescent antibody test and/or

Table 3. ANTIBIOTIC PROPHYLAXIS FOR RENAL TRANSPLANT RECIPIENTS

Pretransplant

Posttransplant Cefazolin IV or vancomycin IV immediately preoperatively

Trimethoprim-sulfamethoxazole orally daily for 6 months Nystatin suspension or clotrimazole troches orally for 2 weeks, during rejection

Ganciclovir IV during antilymphocyte globulin therapy Acyclovir IV or PO for 4 weeks for herpes simplex virus-seropositive recipients

or additional antibiotic treatment


Table 4. PROPOSED PREVENTIVE AND THERAPEUTIC APPROACHES TO THE FEBRILE RENAL TRANSPLANT RECIPIENT

Type of Infection Time of Onset Preventive Measures Treatment

Bacterial Urinary tract infections

Wound infections 1 4 weeks

Listeriosis 1 4 months

Legionellosis 1-8 weeks Nocardiosis 1 4 months Pneumococcal

infection Mycobacterial

Fungal Tuberculosis 3 months-years

Candidiasis 1 month-years

Histoplasmosis 2 months-years Aspergillosis 1-5 months Pneumocytosis 1-5 months

Cytomegalovirus 1-4 months Viral

TMP-SMX, ciprofloxacin;

Perioperative antibiotic; e.g., catheter removal

cephalosporin; expert surgery

TMP-SMX

Decontaminate water supply

Vaccination, PCN, TMP- TMP-SMX

SMX

lsoniazid

Nystatin, clotrimazole

HEPA filtration Prevent CMV; TMP-SMX

Donodblood product selection; IVlg; ?CMV vaccine; ?ganciclovir, acyclovir

Epstein-Barr virus 2-6 months

Hepatitis B virus Vaccination; donor

Herpes simplex virus 1-8 months Acyclovir

Varicella zoster virus 1 - 6 months Vaccination; zoster immune

Influenza Vaccination

Strongyloidiasis Years Pretransplant screening Toxoplasmosis 1-5 months

screening

g I o b u I i n

Parasite

Depends on etiologic bacteria

Cephalosporin or alternative agents; debridement

Ampicillin ? gentamicin;

Erythromycin Sulfonamide PCN

TMP-SMX

Multidrug regimen

Topical agents; fluconazole, amphotericin 2 flucytosine

Amphotericin; azole Amphotericin TMP-SMX; pentamidine

Ganciclovir, foscarnet

Decreased immunosuppression; chemotherapy, radiotherapy; ?acyclovir, ganciclovir

?Interferon

Acyclovir, ganciclovir, famciclovir, valacyclovir

Acyclovir, famciclovir, valacyclovir

Amantadine, rimantadine

Thiabendazole Pyrimethamine + sulfadiazine

or clindamycin

Abbreviations: TMP-SMX, trimethoprim-sulfamethoxazole; PCN, penicillin; CMV, cytomegalovirus; IVlg, intravenous immune globulin.

culture of sputum or bronchoalveolar lavage specimen, or a positive urinary antigen test. Erythromycin administered intravenously at high doses is the initial treatment of choice. In suspected cases of nosocomi- ally acquired infections, an environmental search for the appropriate sources should be made, especially in the hospital’s hot water supply and ventilation systems.30, 43

An important cause of opportunistic bacterial infection in renal transplant patients is L. monocytogenes. The portal of entry of the organ- ism is the gastrointestinal tract via ingestion of contaminated food. Abdominal cramps and diarrhea may be the initial manifestations. Bac-

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teremia, pneumonia, and endophthalmitis are frequently reported. How- ever, the major impact of listerial infection is on the central nervous system, presenting as an acute or subacute meningitis, meningoencephalitis, or cerebritis. Listerial infection in renal transplant recipients is associated with significant 46 Intravenous ampicillin or penicillin and gentamicin are the antibiotics prescribed routinely. Trimetho- prim-sulfamethoxazole is an effective alternative agent.

Nocardial infections, namely those caused by N. asteroides, need to be considered in renal transplant patient^.^, 36, 50 Typically, patients com- plain of fever and cough, and pulmonary infiltrates are seen on chest radiographs. Bloodstream invasion occurs frequently, with potential involvement of the skin and central nervous system. An aggressive approach to obtaining tissue for diagnosis is vital. Microorganisms are seen as gram positive and partially acid-fast staining granular branching filaments. Sulfonamides, alone or in combination with trimethoprim, are considered the therapy of choice. An extended course of treatment is necessary, as relapse is the rule with suboptimal therapy.50

MYCOBACTERIAL INFECTIONS

Solid organ transplant recipients, including those with renal allografts, are at an increased risk for both primary infection and reactivation of quiescent lesions of M . tuberculosis. Although it afflicts only a minority of these patients (<lo%), half of them have disseminated infection.20, 33,

37, 39, 40 The clinical presentations of disease in the renal transplant recipient are often ill defined and highly variable: typical cavitary pulmonary lesion, miliary disease, or multi-organ system involvement. Pulmonary tuberculosis should be considered in any transplant recipient with pulmonary infiltrates or culture-negative exudative pleural effusions. Risk factors for the development of active tuberculous disease include previous residence in an endemic area, malnutrition, a history of inadequately treated infection, and close contact with an untreated patient with active tuberculosis. The tuberculin skin test is positive in only a minority of renal transplant recipients with active disease and is of limited value as a diagnostic 33, 39 Smears for acid-fast bacilli and cultures for mycobacteria should be performed on appropriate specimens. Early invasive interventions such as bronchoscopy with bronchoalveolar lavage, transbronchial biopsy, and/or open lung biopsy should be considered in transplant recipients with undefined lung infiltrates. Moreover, other diagnostic procedures like gastric washings and biopsies of the liver, lymph node, and bone marrow should be performed when disseminated infection is suspected. In those patients with active tuberculosis, treatment with a minimum of three bactericidal agents-that is, isoniazid, rifampin, and pyrazinamide-should be given for at least 12 months. It should be remembered that antimycobacterial therapy in transplant patients is significantly complicated by hepatic dysfunction, hyperuricemia, and potential drug interactions (i.e., with cyclosporine),


which may lead to nephrotoxicity. Thus, dose adjustments of cyclosporine guided by monitoring of drug levels and adequate hydration are almost always necessary. The importance of tuberculosis prevention cannot be overemphasized. However, controversy regarding the recom- mendations for isoniazid prophylaxis exists because a large number of patients who are tuberculin positive prior to transplantation do not develop disease. Some transplant centers reserve isoniazid treatment only for those individuals with additional risk factors for active disease or recent skin test conversion and recipients of organs from skin test- positive 38, 39 In our opinion, isoniazid prophylaxis should be administered prior to transplantation when any of the mentioned risk factors are identified.

Although uncommon, nontuberculous or atypical mycobacterial or- ganisms can cause disseminated disease in renal transplant recipients.20, 33

Infections with M . hnsasii, M . rnarinum, M . haemophilum, and M . chelonei result in chronic cutaneous lesions, tenosynovitis, and/or joint infections, usually following local skin injury. Cutaneous lesions appear as painful erythematous or violaceous subcutaneous nodules that may progress to form abscesses with or without ulcerations. The most frequently involved joints are the digits, wrists, ankles, and knees. The diagnosis of atypical mycobacteriosis is made by identifying acid-fast bacilli from smears or cultures and by the typical histopathology of specimens ob- tained by aspiration or biopsy of lesions. Treatment is not well established and is based largely on the results of in vitro susceptibility testing. Different drug combinations may include isoniazid, rifampin, rifabutin, ethambutol, streptomycin, and clarithromycin. Moreover, surgical d6- bridement may be necessary, and reduction of immunosuppression im- proves the chance for cure.

FUNGAL INFECTIONS

Since the beginning of renal transplantation, fungal infections have played a major role in causing morbidity and mortality. The incidence of systemic fungal infection in these patients varies from 2% to 14Yi3, 4,

12, 18, 30, 36 Risk factors for fungal infections include large doses of cor- ticosteroids, multiple episodes of allograft rejection, hyperglycemia, poor allograft function, prolonged antibiotic use, leukopenia, and older age.4r 12, 27

Candidiasis

The interplay between the type of immunosuppressive regimen used, the suppression of endogenous gut bacterial flora by antibacterial therapy, confounding metabolic derangements that support fungal growth such as diabetes and corticosteroid use, and the use of indwelling urinary and intravenous catheters are important factors in the develop-

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ment of candidal infections. Candida albicans is the most frequently encountered pathogen, and C. krusei, C. glabrata, and C. tropicalis are all potentially pathogenic.

The most common manifestation of candidal infection in the transplant recipient is mucocutaneous disease, presenting as oropharyngeal thrush, esophagitis, vaginitis, intertrigo, and digital inflammation. Fur- thermore, fungal infections of the urinary tract are common, which may present as a relatively benign asymptomatic candiduria or cystitis. Serious disease is caused by obstructing fungal balls that result in ascending infection, overt candidal pyelonephritis, and bloodstream invasion. Disseminated infection markedly increases the risk of visceral seeding with endocarditis, aortitis, invasive cutaneous lesions, ocular involvement, osteomyelitis, meningitis, and brain abscess.

Candidal infections can be diagnosed by obtaining fungal stains and culture of the urine or blood specimen. Fine-needle aspiration may be necessary when fungal pyelonephritis is suspected. Treatment of these infections should be pursued aggressively. Topical therapy with nystatin, clotrimazole, or oral fluconazole is usually effective for mucocutaneous disease. C. krusei and C. glabrata should be considered fluconazole resistant and treated with amphotericin (Table 4). This drug is, to date, the one of choice for disseminated infection. The liposomal formulation of intravenous fluconazole is an alternative in the face of nephrotoxicity.

Cryptococcosis

Cryptococcal infection occurs in 2.5% to 3.6% of renal transplant The lung is the portal of entry, and a flu-like syndrome

may be the initial presentation of this infection. Asymptomatic pulmonary nodules are seen on chest radiographs. Dissemination occurs frequently, with a predilection to involve the central nervous system. It presents typically as a subacute to chronic type of meningitis with headache, fever, and mental status changes, and neurologic deficits and seizures can occur. Other major sites of infection include the skin and the urinary tract. In men, the prostate gland may be a source of hematog- enous dissemination. Diagnosis is made rapidly by testing the serum or cerebrospinal fluid for cryptococcal antigen. In critically ill patients, amphotericin alone or combined with flucytosine remains the regimen of choice for initial treatment, followed thereafter by prolonged therapy with oral fluconazole (see Table 4).

Aspergillosis

Aspergillus furnigatus and A. j7avus infection cause life-threatening invasive infections in renal transplant recipients. Excessive immunosuppression, elevated creatinine level, CMV infection, and neutropenia have


all been implicated as risk factors for invasive infections. These fungi are commonly acquired in the community, although they can be trans- mitted from exposures to constructions within the hospital environ- ment.43, 48 Lungs, nasal sinuses, and skin are portals of entry. The usual clinical presentation is that of a febrile illness with pulmonary symptoms, with or without evidence of metastatic infection. Cutaneous and central nervous system involvement is frequent. Early and aggressive diagnosis and therapy are the keys to a successful outcome but are seldom adhered to. Isolation of the fungus from multiple sputum specimens is highly suggestive of disease. In some cases, bronchoalveolar lavage with transbronchial biopsy or open lung biopsy is warranted to establish the diagnosis. Amphotericin is the mainstay of treatment for this potentially fatal infection. Surgical resection of single, localized, and limited pulmonary focus needs to be considered (see Table 4).

Endemic Mycoses

Infection with the geographically restricted systemic mycoses (His- toplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis) should be suspected in the transplant recipient with a history of travel to endemic areas. Disease dissemination with metastatic foci of infection is common with histoplasmosis and coccidioidomycosis, and thus the diagnosis of localized disease should trigger a search for sites of metastatic spread. The central United States is endemic for H. capsulatum. Histoplasmosis in transplant patients usually occurs as a primary infection in the context of community epidemics. Occasionally, reactivation of chronic foci of infection can present acutely. Disease usually presents with a variety of nonspecific signs and symptoms, with fever being the most frequent complaint. Mucocutaneous lesions such as papules, plaques, ulcers, and abscesses may predominate. Hepatosplenomegaly, pulmonary abnormalities, meningitis, or focal brain disease can occur.

Infection with C. immitis occurs in the immunosuppressed renal transplant patient who has been exposed to the endemic areas of the southwestern United States, Northern Mexico, and Latin America. Both primary and reactivation infections occur, and in the majority of cases the infection is disseminated. Fever and pneumonia are typical, whereas distant sites of involvement including skin, joints, central nervous system, liver, and spleen are less frequent. Blastomycosis occurs uncom- monly in the transplant population and is limited to residents in the southern United States along the Mississippi and Ohio River Valleys and the Upper Midwest. Like most endemic mycoses, the lung and the skin are predominant sites of disease. Patients present either with an acute disease resembling bacterial pneumonia or with a subacute illness.

The diagnosis of these endemic mycoses can be made by fungal smears and cultures of the appropriate specimens as well as by histopathologic examination of tissues taken from biopsies. Serologic testing, which is of value in immunocompetent individuals, may be suboptimal

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in the work-up of immunocompromised transplant recipients. Systemic amphotericin remains the cornerstone of therapy for these fungal infections, whereas azole antifungal agents such as fluconazole and itracona- zole are of value for maintenance therapy (see Table 4).

Mucormycosis

An uncommon but dreaded complication of renal transplantation is infection with the ubiquitous fungi, Rhizopus species, Absidiu species, and Mucor species. Corticosteroid use, underlying diabetes mellitus, metabolic disturbances that result in an acidotic state, and deferoxamine therapy are all known risk factor^.^, 6, 39, 48 The infection can lead to an invasive rhinocerebral disease or a form of hemorrhagic pneumonia. Cutaneous and soft tissue infections are also encountered clinically. Early biopsy and histopathologic examination showing broad nonseptate branching hyphae are crucial for diagnosis. Despite aggressive surgery and administration of amphotericin, mortality remains high.l 8, 23 Reduc- tion or termination of immunosuppression may be necessary for a successful outcome.

Pneumocystosis

Pneumonia caused by P. curinii occurs in 5% to 10% of renal transplant patients who are not receiving prophylactic therapyz7, 39, 48 It is closely associated with CMV infection and recurrent allograft rejection, which requires extensive additional immunosuppression. Presentation is typically subacute with fever, nonproductive cough, dyspnea, hypox- emia, and lung infiltrates. The diagnosis is made by the demonstration of cysts or vegetative forms of P. curinii in a bronchoalveolar lavage fluid or lung biopsy specimen. Treatment is high-dose trimethoprim- sulfamethoxazole or intravenous pentamidine. A major advance in recent years has been the prevention of this potentially fatal infection with the institution of low-dose trimethoprim-sulfamethoxazole. This practice provides excellent prophylaxis against pneumocystosis, listeriosis, and nocardiosis as well as against the usual bacterial urinary tract pathogens.

VIRAL INFECTIONS

Viral infections are the most important causes of infectious disease morbidity and mortality in the transplant population.', 23, 31, 39 The herpes group of virusesXMV, EBV, varicella-zoster virus (VZV), herpes simplex viruses 1 and 2 (HSV-1 and 2), and human herpes virus 6 (HHV-6)-have the greatest impact. Once infected with these viruses, an individual harbors the virus in a latent and persistent state. Decreased immune surveillance secondary to exogenous immunosuppression or


direct reactivation by agents such as antilymphocyte antibodies influ- ences the incidence rate and severity of the clinical presentation. In addition, this group of viruses has immunosuppressive, immunomodu- latory, and oncogenic properties. Transplant patients are also more sus- ceptible to more severe manifestations of common viral infections such as influenza, adenovirus, and other viral infections affecting the normal hosts, such as human papillomavirus and an array of hepatitis viruses.

Cytomegalovirus

Cytomegalovirus is the most important microbial pathogen encountered by renal transplant patients, occurring at an incidence of 34% to 55% of renal allograft recipient^.'^, 22, 23, 30, 31, 40, 41, 45, 47, 51 Transmission of the virus occurs with the transplantation of an infected donor organ or transfusion of cellular blood products from a seropositive donor. Among transplant recipients, three categories of infection are observed. Primary infection develops when latently or persistently infected cells from a seropositive donor are transplanted to a seronegative recipient. Reactiva- tion disease happens when seropositive individuals reactivate endoge- nously latent virus. Finally, CMV superinfection occurs as a result of reactivating latent virus of donor origin when transplanted to a seropositive patient. In all instances, the immunosuppression used and the rejection episodes that follow transplant surgery can lead to viral replication that is not controlled by the established CMV-specific immune surveillance. Primary infection, excessive immunosuppression, and the use of antilymphocyte antibody preparation all increase the risk of CMV disease.22, 30, 38, 42, 47, 51 Furthermore, the cyclosporine-based regimens have been linked to a higher incidence of symptomatic disease than tacrolimus-based regimens.47 The role of new immunosuppressive agents in influencing CMV infection needs to be thoroughly evaluated in ongoing and upcoming clinical trials.

The effects of CMV infection in the renal transplant recipient can be divided into direct and indirect. Direct morbidity caused by CMV in- cludes an acute illness with an onset in the first 1 to 4 months after transplant, manifesting as a febrile illness, leukopenia, thrombocyto- penia, pneumonitis, hepatitis, and gastrointestinal ulcerations; or a progressive chorioretinitis that presents later in the post-transplant period with blurring of vision, scotomata, or decreased visual acuity. The disease may also present as an asymptomatic infection, which is detected by surveillance cultures.38 An important indirect effect of CMV infection is an augmented immunosuppression of host defenses, which leads to the predisposition to superinfection with other opportunistic pathogens. Frequent co-infection is observed between CMV and l? carinii, Aspergil- lus, and L i s t e r i ~ . ~ ~ , 4M2 Some evidence suggests that infection with CMV may play a role in early-onset allograft rejection after renal transplanta- ti01-1.~~

The identification of cytomegalic inclusion bodies by immunohisto-

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chemistry or DNA hybridization techniques in tissue specimens establishes the diagnosis of invasive CMV disease. Conventional tube cell culture and shell vial culture techniques using peripheral blood samples are alternative means of making the diagnosis. Markers of infection that are currently being evaluated include the detection of CMV antigenemia and polymerase chain reaction-based detection of CMV DNA. Intrave- nous ganciclovir and foscarnet are both effective agents in treating systemic disease. Extensive efforts have been directed toward the prevention of CMV infection, and numerous strategies have been investigated. High-risk transplant recipients, that is, D + /R - , have benefited from the administration of intravenous immunoglobulin preparations, with reductions in the incidence and severity of CMV disease.41, 51 Trials on the efficacy of acyclovir in CMV prophylaxis have shown contradic- tory results. Oral ganciclovir prophylaxis in D + /R - patients is under study. The non-D + /R - group should not receive antiviral prophylaxis unless additional risk factors are present, such as administration of antilymphocyte immunoglobulin. Several additional compounds are currently under investigation as possible agents against CMV (see Table 4).30.39.51

Epstein-Barr Virus

Infection with EBV in the renal transplant patient may cause an uncomplicated mononucleosis syndrome characterized by fever, leukopenia, mild hepatitis, and atypical lymphocytosis with a negative hetero- phile test. At the other end of the spectrum is the role of EBV in the pathogenesis of post-transplantation lymphoproliferative disease (PTLD). With the immunosuppressive program these patients are subjected to, EBV replication in the oropharyngeal mucosa is stimulated. The use of antilymphocyte antibody therapy substantially potentiates viral proliferation, increasing the risk of triggering the oncogenetic process.l0 Additional risk factors that enhance the malignant process include EBV seronegativity prior to transplant, tacrolimus-based regimen, and CMV seromismat~h.~~

Clinically and histopathologically, EBV-associated lymphoprolifera- tion covers a wide spectrum, ranging from a polyclonal disease that runs a benign course to a monoclonal, rapidly progressive, malignant process that requires aggressive treatment and carries a poor prognosis. Disease presentation is likewise varied: Tonsillitis, fever of unknown origin, weight loss, hepatocellular dysfunction, pulmonary infiltrates, focal gastrointestinal disease with bleeding or bowel perforation, brain lesions, and invasion of the allograft have all been caused by EBV.

Pathologic diagnosis rests on histologic features and the cellular clonality of tissue samples, as well as detection of EBV in these lesions. Reduction of immunosuppression has a drastic effect on EBV-related lesions. Although high-dose acyclovir may be beneficial in those with monoclonally transformed lymphocytes and uncomplicated infectious


mononucleosis, treatment of the malignant form of PTLD has been di~appointing.'~ Despite the combination of reduced immunosuppression, high-dose antiviral therapy, chemotherapy, and/or radiation therapy, mortality from this illness remains substantial.

Herpes Simplex Virus

The vast majority of orofacial and anogenital herpes simplex infections seen in renal transplant recipients are due to reactivation of HSV. Significant and recurrent disease occurs frequently during the first month after transplant. Mucocutaneous ulcerations are prominent, causing severe discomfort, and can be complicated by bacterial superinfection. Less commonly, HSV infection can result in a zosteriform rash with a sacral dermatomal distribution or as disseminated cutaneous lesions that occur at sites of previous skin trauma. Primary and reactivation HSV infection can occasionally present as a pneumonitis, tracheobronchitis, esophagitis, hepatitis, or disseminated infection.

Identification of the presence of viral particles is made by per- forming a direct immunofluorescence test, Tzanck smear, or culture of body fluids, respiratory secretion, and/or tissue. Serology is helpful in establishing the diagnosis. Oral or intravenous acyclovir is effective treatment. Ganciclovir and foscarnet are also of proven efficacy. The generalized use of acyclovir prophylaxis has significantly reduced or eliminated the incidence of HSV infection following transplantation.

Varicella-Zoster Virus

Similar to most herpes viruses, VZV causes two distinct clinical entities in renal transplant patients. The vast majority of patients present with a reactivation-type infection with localized dermatomal involvement and occasional cutaneous dissemination. In contrast, primary VZV infection follows viral exposure in a seronegative transplant recipient. A chickenpox syndrome or a virulent life-threatening infection characterized by hemorrhagic pneumonia, encephalitis, pancreatitis, hepatitis, disseminated intravascular coagulation, and death follows the exposure.

The appearance of unilateral vesicular lesions in a dermatomal pattern is highly suggestive of herpes zoster. Infected cells appear as multinucleated giant cells on Tzanck smear; direct immunofluorescence and culture of body fluid or tissue confirm the diagnosis of VZV infection. Acyclovir or its ester formulation, valacyclovir, and famciclovir are the recommended drugs for the treatment of primary and reactivation infections. Varicella vaccination of seronegative patients should be considered prior to organ transplantation. Prompt postexposure administration of zoster immune globulin can prevent serious illness.

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Hepatitis Virus

The major causes of liver disease in renal transplant recipients are hepatitis B and hepatitis C infections; 10% to 15% of transplant recipients develop chronic liver disease from viral hepatitis.13, 38, 39, 47 Transplantation of an infected organ and transfusion of contaminated blood products, as well as intimate mucosal contact, are effective means of transmitting these viruses. Immunosuppressive therapy directly stimulates viral replication. Hepatitis B and C infections result in active hepatitis, cirrhosis, and hepatocellular carcinoma. Both viruses augment the suppressive effect on the host's immune system following transplantation that is most pronounced in the first 2 years after transplant.

Acquisition of hepatitis B-virus (HBV) during or soon after transplantation carries a higher risk of fulminant hepatitis and death from liver fai1u1-e.~~. 27* 47 With the availability of sensitive serologic techniques for the determination of hepatitis B surface antigen (HBsAg), the primary acquisition of HBV infection at transplantation is now rare. Vaccination prior to transplantation is advocated for candidates without circulating antibodies to HBsAg. The use of 3TC (lamivudine) and drugs under development such as lobucavir may offer hope in decreasing the impact of this virus in renal transplantation.

Infection with the hepatitis C virus (HCV) accounts for the majority of hepatitis and chronic liver disease occurring in the renal transplant population.l0. 27, 39, 47 Acute symptomatic disease is rare, and progressive liver injury proceeds at a slow pace. Detection of the presence of HCV RNA is made by reverse transcriptase polymerase chain reaction. The formulation of an effective antiviral therapy is needed, as interferon confers only minimal benefit.

Human Immunodeficiency Virus (HIV)

The transplantation of an organ from an HIV-infected individual almost certainly transmits the virus (as shown in studies during 1980s). Available data indicate that HIV-infected individuals undergoing solid organ transplantation may do well and remain asymptomatic for years, whereas others develop full-blown AIDS and die of infections shortly after transplant surgery. Whether HIV-infected individuals should un- dergo renal transplantation in the face of more effective antiretroviral therapy needs to be addressed.

Papovavirus

In women with renal allografts, human papillomavirus infection is associated with an increased incidence of intraepithelial and invasive squamous cervical lesion^.^ Moreover, the virus has been implicated in the causation of urethral papillomatosis. The JC virus causes central


nervous system disease known as progressive multifocal leukoencepha- lopathy. Human polyoma (BK) virus infection in renal transplant patients results in ureteral strictures.”

PARASITIC INFECTIONS

Toxoplasmosis

With a greater propensity to cause disease in cardiac transplant recipients, primary Toxoplasrna gondii infection occurs rarely after renal transplantati~n.~~, 48 Infection causes meningoencephalitis, brain abscess, pneumonia, myocarditis, pericarditis, hepatitis, and chorioretinitis. Vari- ous serologic techniques can be used to document seroconversion but may not reflect clinical disease. Histologic demonstration of Toxoplasrna trophozoites in biopsy specimens establishes the diagnosis. Treatment is with pyrimethamine with folinic acid in combination with sulfadiazine or clindamycin.

Strongyloidiasis

Opportunistic infection with S. stercoralis is a potentially preventable cause of disease and death in the immunosuppressed renal transplant patient. Systemic strongyloidiasis causes a hyperinfection syndrome. Symptoms are predominantly gastrointestinal with severe ulcerating hemorrhagic enterocolitis, or respiratory with hemorrhagic pneumonia. The disseminated strongyloidiasis syndrome results from larval dissemination to extraintestinal sites, with gram-negative bacteremia, meningitis, and a high fatality. The parasite has a worldwide distribution. Initial infection may be asymptomatic or present with mild gastrointestinal symptoms. Chronic subclinical infection may persist for years, only to become life-threatening in the immunocompromised state. To make a diagnosis, larvae must be seen by direct microscopy of stool, body fluids, sputum, and tissue specimens. Peripheral eosinophilia provides an important clue to the diagnosis. Strongyloidiasis is treated with thiabendazole. Delay in making the diagnosis, failure to institute appropriate therapy, increased steroid use, persisting parasitemia, disseminated disease, bacteremia, and concurrent illnesses all contribute to increasing the risk of death.6, 24, 35, 48

CONCLUSION

Remarkable progress has been achieved in dealing with the infectious disease complications following renal transplantation. However, infection remains an important issue facing the transplant recipient. Advances in immunosuppressive regimen and more effective antimicro-

bial strategy will ensure the continued success of renal transplantation. The current thrust of infection management emphasizes preventive and pre-emptive therapy, as well as the aggressive pursuit of a diagnosis. Active infectious disease surveillance will continue to be an essential aspect in the management of the renal allograft recipient.

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Nephrol26587, 1994

Address reprint requests to Carlos V. Paya, MD, PhD

Mayo Clinic Division of Infectious Diseases

Guggenheim Building, Room 501 200 First Street SW

Rochester, MN 55905

INFECTIOUS COMPLICATIONS FOLLOWING RENAL TRANSPLANTATION

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