Infections in solid-organ transplant recipients

Infections in solid-organ transplant recipients

STATE OF THE SCIENCE Infections in solid-organ transplant recipients Nina Singh, MD Pittsburgh, Pennsylvania Despite remarkable progress and dramatic...

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STATE OF THE SCIENCE Infections in solid-organ transplant recipients Nina Singh, MD Pittsburgh, Pennsylvania

Despite remarkable progress and dramatic improvement in surgical techniques, immunosuppressive therapy, and postoperative management, infections remain a significant complication and a major cause of death after transplantation. The spectrum of infectious complications in organ transplant recipients, however, has continued to evolve. For example, a decrease in cytomegalovirus (CMV)-associated deaths (attributable largely to effective therapy and improved prophylaxis) and a marked decline in the incidence of Pneumocystis carinii p n e u m o n i a (as a result of routine use of prophylaxis) have been docum e n t e d in recent years. In contrast, the incidence of infections caused by gram-positive cocci (vancomycin-resistant enterococci and methicillinresistant Staphylococcus aureus) has increased, and opportunistic mycoses (e.g., invasive aspergillosis) continue to be associated with very high mortality rates. New (or previously unrecognized) pathogens have also been reported in transplant recipients. This report is an overview of the current knowledge of infections in organ transplant recipients with emphasis on advances in diagnosis and prevention. HERPESVIRUS INFECTIONS

Herpesviruses (CMV, herpes simplex viruses 1 and 2, Epstein-Barr virus [EBV], varicella-zoster virus, and h u m a n herpesvirus-6 [HHV-6]) are some of the most significant pathogens after transplantation. A characteristic virologic feature of all herpesviruses is latency (i.e., once infected, the viral genome remains in the infected cells of the host for life). Seropositivity, or the detection of antibodies to the virus, is reflective of latency. Immunosuppression can trigger the latent virus to actively multiply or replicate. Differentiation of From the Veterans Affairs Medical Center. Reprint requests: Nina Singh, MD, Infectious Disease Section, VA Medical Center, University Drive C, Pittsburgh, PA 15240. AJIC Am J Infect Control 1997;25:409-17.

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the terms infection and disease is also important. Infection with herpesviruses implies cultural or serologic evidence of viral replication, whereas the term disease indicates the presence of specific symptoms attributable to herpesviruses in patients with infection caused by these viruses.1 CMV

CMV is the foremost opportunistic pathogen in organ transplant recipients. In addition to its direct pathogenic effect, CMV is an i m m u n o m o d u latory virus, which can facilitate superinfection with other pathogens and m a y play a role in silograft rejection. CMV infection occurs in 30% to 70% of organ transplant recipients; nearly half of these infections are associated with symptomatic disease. 1,2 Epidemiologically, three patterns of CMV infection are recognized. Primary infection occurs when a seronegative recipient acquires CMV, usually from a latently infected donor allograft. Reactivation infection implies endogenous reactivation of the recipient's latent CMV, and superinfection is reinfection with an exogenous strain of CMV in a seropositive recipient. 1 Primary CMV infections are associated with a higher incidence of CMV disease, earlier onset after transplantation, recurrent episodes of CMV, higher rate of dissemination, and a higher mortality rate. Intensity and type of immunosuppression are also important determinants of the severity of CMV infection in transplant recipients. Anti-lymphocyte preparations (e.g., OKT3) are associated with an increased risk of CMV disease. CMV-specific class 1 restricted cytotoxic T cells and natural killer cells are the main host defenses against CMV after transplantation. An increase in the activity of these cells is associated with spontaneous recovery from CMV, whereas progressive infection is associated with impaired cellular responses. Humoral i m m u n i t y is relatively ineffective as a host defense against CMV. CMV itself is associated with a direct cell-mediated immunosuppressive effect that facilitates superinfections 409

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Table 1. Incidence of CMV infection and disease in solid organ transplant recipients Type of transplant

Incidence of CMV infection* (%)

Incidence of CMV diseaset (%)

Kidney Liver Heart Heart-lung or lung Small bowel

40-50 50-60 45-67 60-98 60-70

8-15 20-35 27-30 55-60 35-40

*CMV qfection implies cultural or serologic evidence of viral replication. tCMV disease indicates the presence of specific symptoms attributable to CMV in patients with CMV infection.

with fungi, bacteria, and Pneumocystis species. 1 CMV-induced production of suppressive cytokines that impair lymphocyte/macrophage function is believed to be the likely m e c h a n i s m for this phenomenon. The incidence of symptomatic disease caused by CMV varies with the type of solid organ transplanted (Table 1) and is likely related to varying intensity of overall immunosuppression in these patients. Most CMV infections occur between 1 and 4 months after transplantation (usually between 4 and 6 weeks). A febrile mononucleosis syndrome characterized by fever, arthralgias, leukopenia, and atypical lymphocytosis is the most c o m m o n symptomatic disease caused by CMV, although localized or disseminated tissue-invasive disease m a y also occur. A peculiar feature of CMV is its predilection to involve the transplanted allograft (e.g., CMV hepatitis occurs most frequently in liver transplant recipients). Likewise, CMV pneumonitis occurs most frequently in heart-lung and lung transplant recipients, and CMV enteritis occurs most frequently in bowel transplant recipients. Unlike AIDS, retinitis is an u n c o m m o n manifestation of CMV after transplantation. The diagnosis of CMV infection has traditionally been m a d e by viral isolation, which can take up to 4 weeks. The currently available tests allow rapid and reliable diagnosis of established CMV infection and m a y also be used to detect viral shedding at an early stage. The shell vial assay for viral cultures uses a monoclonal antibody to detect a 72 kd immediate early CMV antigen and allows detection of CMV within 16 to 24 hours. More recently, a CMV antigenemia assay with monoclonal antibodies directed against the 65 kd structural late viral protein has been developed. 3 The CMV antigenemia assay is more sensitive and allows earlier detection of CMV than viral cultures. Furthermore, results of the antigenemia assay can be

quantitated; the n u m b e r of antigen-positive cells has been shown to correlate with the likelihood of CMV disease and can also be used to monitor response to antiviral therapy. 3 Detection of viral DNA by polymerase chain reaction (PCR) is also available. Because PCR can detect even minute amounts of viral DNA, it m a y not differentiate between replicating and latent virus. The precise role of quantitative PCR or reverse-transcriptase PCR (which selectively detects replicating virus) for the diagnosis of CMV remains to be established. Ganciclovir is the drug of choice for the treatm e n t of CMV disease. 4 Ganciclovir-resistant CMV has not been problematic in organ transplant recipients thus farS; foscarnet is reserved for patients with CMV who are intolerant of ganciclovir. For the treatment of severe CMV disease (e.g., CMV pneumonia), CMV immunoglobulin can be used in conjunction with ganciclovir¢ EBV

Primary EBV infection occurs in 70% to 80% of EBV-seronegative recipients, and reactivation EBV infection occurs in 30% to 40% of seropositive transplant patients. 6 Posttransplant lymphoproliferative disorder (PTLD) is the most serious complication of EBV after transplantation. Defective cytotoxic cell immunity in transplant recipients results in uncontrolled proliferation of transformed EBV-infected B cells. The incidence of PTLD was 1% in kidney transplant recipients, 2.7% in liver transplant recipients, and 3.3% to 3.8% in heart and heart-lung transplant recipients¢ Primary EBV infection and OKT3 use are risk factors for PTLD. Clinical presentation ranges from a self-limited infectious mononucleosis-like syndrome to nodal or extranodal disease (involving central nervous system, gastrointestinal tract, lungs, or bone marrow). Reduction of immunosuppression is the mainstay of therapy. The efficacy of acyclovir, ganciclovir, interferon-a, or antiB-cell antibodies for the treatment of PTLD is uncertain. Older age, monoclonality of tumor, and longer interval after transplantation are associated with a poor outcome in PTLD. Herpes simplex virus

Herpes simplex virus (HSV) infections occur in 25% to 40% of transplant recipients, usually between 2 and 4 weeks after transplantation. Oral or genital mucocutaneous infections are the usual clinical manifestations. Most infections represent reactivation infections in seropositive patients, although donor transmission has been demon-

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T a b l e 2. Major pathogens, mode of acquisition, and usual timing of onset after transplantation Pathogen

Mode of acquisition

Usual timing of onset

Endogenous reactivation, donor transmission, transfusions Endogenous reactivation (rarely donor transmission) Endogenous reactivation, donor transmission Endogenous reactivation (rarely donor transmission) Endogenous reactivation, donor transmission Endogenous reactivation, donor transmission Endogenous reactivation

6-12 wk 0-4 wk 0-4 mo 3 too-3 yr 0-4 wk 4 too-1 yr 3-8 mo

Endogenous infection or environmental acquisition Environmental acquisition Environmental acquisition Environmental acquisition Environmental acquisition

0-3 0-3 0-3 0-3 0-3

Endogenous infection Environmental acquisition Unknown Endogenous reactivation

0-4 wk 0-2 mo >6 me 3-6 mo

Donor transmission, endogenous reactivation

1-3 mo

Viruses Herpesviruses CMV Herpes simplex virus EBV Varicella-zoster virus HHV-6 HCV Hepatitis B virus

Bacteria Enteric gram-negative

Pseudomonas aeruginosa Legionella S. aureus VREF

Fungi Candida Aspergillus Cryptococcus Pneumocystis carinii Protozoa 7[ gondii

strated after kidney and liver transplantation. Visceral HSV infection is rare; fulminant hepatitis with fever, hypotension, and disseminated intravascular coagulation are the initial features. 7 Varicella-zoster

virus

Varicella-zoster virus infections occur in 3% to 7% of transplant recipients, most often more than 3 m o n t h s after transplantation. D e r m a t o m a l zoster is the usual initial symptom; however, prim a r y infection in pediatric transplant recipients can result in disseminated disease with hepatitis, pneumonitis, hemorrhagic rash, and rapid death. Intravenously administered acyclovir (10 mg/kg every 8 hours) is the drug of choice for serious disease; localized zoster can be treated with highdose oral acyclovir. HHV-6

The newest herpesvirus to be recognized as a pathogen in transplant recipients is HHV-6. 8 HHV-6 is a large, double-stranded DNA virus that bears 66% DNA sequence homology with CMV. Transmission from donors has been reported; however, most HHV-6 acquisition in transplant recipients results from endogenous reactivation of the recipient's latent virus. 8 Although its pathogenesis in solid-organ transplant recipients remains to be fully elucidated, HHV-6 infection has been reported in 31% to 55% of kidney and liver

me mo mo mo mo

transplant recipients. HHV-6 infections characteristically occur earlier than CMV infection in transplant recipients; the usual timing of onset is between 2 and 4 weeks after transplantation. Bone m a r r o w suppression, encephalitis, and interstitial pneumonitis are the most commonly reported types of clinical disease caused by HHV-6. The primary target cell for HHV-6 is CD4 ÷ lymphocytes. HHV-6 itself is associated with depression of cell-mediated immunity, which m a y facilitate CMV and EBV infections after transplantation. 8 The antiviral susceptibilities of HHV-6 resemble those of CMV. HHV-6 is sensitive to both ganciclovir and foscarnet. Treatment is indicated if active HHV-6 infection, along with clinical disease caused by HHV-6 (e.g., bone m a r r o w suppression, encephalitis, or pneumonitis), is documented. 8 OTHER VIRAL INFECTIONS Hepatitis C virus

Hepatitis C virus (HCV) has emerged as a leading cause of hepatitis after transplantation; its clinical impact is greatest in the context of liver transplantation. 9 Virtually all liver transplant recipients with pretransplant HCV infection remain viremic after liver transplantation. Recurrent HCV hepatitis occurs in 30% to 70% of the patients between 1 and 12 months (usually 6 months) after transplantation (Table 2). Progression to cirrhosis occurs in 10% to 20% of the patients with HCV, al-

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though graft and overall patient survival at 5 years have not been different in patients with and without HCV infection. 9 A high level of pretransplant viremia, HCV genotype lb, and intensity of posttransplantation immunosuppression have been shown to be associated with a higher incidence and severity of recurrent HCV hepatitis after liver transplantation. After kidney transplantation, chronic liver disease has been reported in 10% to 60% of the patients and is more frequent in patients with HCV than in those without Hev. Therapeutic options for HCV hepatitis after transplantation remain unsatisfactory. After a 6m o n t h course of interferon-a, response has been documented in up to 28% of liver transplant recipients, l°,H although relapse after cessation of treatment with interferon is frequent. Likewise, ribavirin has not been very effective22 The efficacy of ribavirin combined with interferon is unproven yet. H e p a t i t i s B virus

Recurrent hepatitis B virus (HBV) hepatitis has been d o c u m e n t e d in 78% to 90% of liver transplant recipients undergoing liver transplantation because of end-stage liver disease caused by HBV. HBV adversely affects patient and graft survival; at 3 years, 54% of the patients with HBV recurrence versus 83% of those who remained hepatitis B surface antigen (HBsAg) negative after transplantation survived. 13 Anti-HBsAg immunoprophylaxis significantly reduces the rate and time to recurrence after transplantation. The risk of recurrence is greater in patients with markers for active replication of HBV before transplantation, that is, those seropositive for hepatitis B surface antigen and HBV DNA. 13 Fulminant HBV hepatitis and coinfection with hepatitis delta virus decreases the risk of HBV recurrence after liver transplantation. Interferon is not effective for the treatment of HBV. Ganciclovir, with or without foscarnet, has been associated with an unsustained decrease in HBV replication in liver transplant recipients. 14 Trials are underway to assess lamivudine (3TC) or famciclovir Is for the treatment of HBV in the posttransplantation setting. NIV

A vast majority of HIV infections reported in organ transplant recipients were acquired before the routine screening of HIV in 1985. An acute febrile syndrome attributable to primary HIV infection was observed in 17% of HIV-seronegative transplant recipients, 1 to 7 weeks after transplantation. ~ Progression to AIDS occurred in 28%, and

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80% of those in w h o m AIDS developed died a m e a n of 37 months after transplantation. 16 It has been proposed that cyclosporine m a y favorably affect the course of HIV in organ transplant recipients17; cyclosporine pretreatment prevented subsequent viral binding of T lymphocytes in vitro. Use of OKT3, on the other hand, adversely affected the o u t c o m e in HIV-infected transplant recipients. BACTERIAL INFECTIONS

The incidence and type of bacterial infections vary with the type of organ transplantation. P n e u m o n i a is the predominant type of infection in heart-lung and lung transplant recipients, intraabdominal and biliary infections are the predominant types in liver transplant recipients, and urinary tract infections are the predominant type in kidney transplant recipients.18 Urinary tract infections are also a frequent complication of pancreas transplantation in which bladder drainage of exocrine pancreatic secretions is used. I9 Bacteria account for 40% to 80% of the cases of p n e u m o n i a after organ transplantation. A vast majority of these occur within 4 months of transplantation. 2° Requirement of mechanical ventilation and intensive care unit monitoring during this period m a y predispose the patient to oropharyngeal colonization and subsequent pneumonia. 2° Gram-negative bacteria (e.g., Pseudomonas aeruginosa and Enterobacteriaceae) are the pred o m i n a n t pathogens in nosocomial p n e u m o nias21; however, S. aureus is being increasingly recognized as a significant pathogen in early posttransplantation nosocomial pneumonitis. Legionella p n e u m o n i a has been reported in 2% to 9% of solid-organ transplant recipients22; Legionella pneumophila and L. micdadei are the most c o m m o n species implicated. Legionella organisms are fastidious bacteria that do not grow on standard bacteriology media; selective dyecontaining media are needed for optimal detection. Legionella urinary antigen is a sensitive and specific test for the diagnosis of legionellosis and can also be performed in body fluids (e.g., pleural fluid). 22 Therapy for legionellosis in transplant recipients can be problematic because erythromycin can increase cyclosporine and tacrolimus levels and rifampin can lower these. Ciprofloxacin is the therapy of choice for Legionella infection in transplant recipients. = The a b d o m e n is the most c o m m o n site of bacterial infections after liver transplantation. The type of biliary duct anastomosis influences the

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rate of intraabdominal infections. Choledochocholedochostomy (duct-to-duct) biliary anastomosis, as opposed to choledochojejunostomy with Roux-en-Y anastomosis, is associated with a lower incidence of infections because the Oddi's sphincter is preserved in the former procedure. 21 Hepatic artery thrombosis may predispose patients to intrahepatic abscess, whereas biliary tract strictures may lead to cholangitis. Bacteremia has been reported in 6% of kidney transplant recipients, 11% of heart transplant recipients, and 25% of liver transplant recipients. TM Fifty to eighty percent of the bacteremias in heart and liver transplant recipients occur within 90 days of transplantation, whereas nearly 50% of bacteremias in kidney transplant recipients occur more than 1 year after transplantation. Gram-negative bacteria comprised 48% of the blood isolates in kidney transplant recipients, 49% in liver transplant recipients, and 39% in heart transplant recipients in the 1980s. TM Staphylococci, however, are being increasingly recognized as a significant cause of nosocomial bloodstream infections, with intravascular catheters being the predominant source.

23,24

Of great concern, particularly in liver transplant recipients, are vancomycin-resistant Enterococcus faeciurn (VREF). VREF colonization before transplantation increased the rates of serious intraabdominal and bloodstream infections after transplantation and was significantly associated with death. 2s Hospital and intensive care unit stays were significantly longer for patients with VREF than for patients with vancomycin-sensitive Enterococcus faecium infections. Antimicrobial therapy for VREF infections remains largely ineffective; adequate drainage of an infected focus is the major determinant of outcome. FUNGAL INFECTIONS

Fungal infections have been reported in 5% to 40% of organ transplant recipients. 26 Liver transplant recipients have a higher incidence of invasive fungal infections (particularly caused by Candida species) than do recipients of other solid-organ transplants. Liver transplant surgery, by disrupting the integrity of the gut and biliary tree, may promote dissemination of gastrointestinal candidiasis. More than 80% of the fungal infections occur within 2 months of transplantation. Fungal colonization, prolonged operation time, retransplantation, increased blood loss, and CMV infection have been recognized as risk factors for invasive fungal infections in transplant recipients. 26

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Invasive candidiasis accounts for nearly 80% of all fungal infections. Tracheobronchial colonization, including that of the donor trachea in heartlung transplant recipients, and gastrointestinal colonization in liver transplant recipients are the potential sources of invasive candidiasis. The unique susceptibility of pancreas transplant recipients to candidiasis results from a combination of factors including underlying diabetes, presence of indwelling bladder catheters, and drainage of exocrine secretions into the bladder (which create a nonacidic environment promoting Candida colonization). 19 Aspergillosis accounts for 15% to 20% of all fungal infections and is associated with a mortality rate of virtually 100% in transplant recipients. 26 Most Aspergillus infections occur between 2 and 6 weeks after transplantation. 26 The lungs are the predominant site of involvement. Central nervous system involvement occurs in 10% to 50% of patients with disseminated invasive aspergillosis. 27 Other potential extrapulmonary sites of involvement include heart, kidneys, thyroid, bone, and gastrointestinal tract. Surgical wound infections in liver transplant recipients and anastomotic tracheobronchial infections in heart-lung or lung transplant recipients are unique presentations of invasive aspergillosis after transplantation. Amphotericin B (1.0 to 1.5 mg/kg/day) is the mainstay of therapy for invasive aspergillosis. However, the mortality rate remains unacceptably high despite early diagnosis and institution of amphotericin B. Liposomal forms of amphotericin are associated with fewer side effects, including nephrotoxicity; their efficacy for the treatment of invasive aspergillosis in transplant recipients remains to be established. The role of itraconazole for the initial treatment of invasive aspergillosis is unproven; however, it may be used as follow-up therapy for patients who have been initially treated and experienced improvement with amphotericin B. The role of immunotherapy (e.g., colony-stimulating factors) in adjunct with antifungal agents merits further study. Cryptococcal infections have been reported in 1% to 4% of organ transplant recipients. 28The primary mode of acquisition is pulmonary with subsequent hematogenous dissemination, most frequently to the central nervous system. Cryptococcal infections are late infections and usually occur more than 6 months after transplantation. 28 Meningitis of subacute or insidious onset is the usual manifestation. Skin lesions caused by Cryptococcus species may occur in up to 10% to

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15% of patients with cryptococcosis./s Serum in cryptococcal antigen is positive in virtually all patients with cryptococcosis and may be helpful in the diagnosis of this infection. Amphotericin B, preferably with fiucytosine, is the treatment of choice. Experience with fluconazole as therapy in transplant recipients is limited. In the absence of routine prophylaxis, Pneumocystis carinii pneumonia has been observed in 3% to 15% of transplant recipients. 19Prophylaxis with trimethoprim-sulfamethoxazole is highly effective in the prevention of Pneumocystis pneumonia. 29 Most infections occur between 2 and 6 months after transplantation or after additional immunosuppression (e.g., with OKT3). Unlike HIV infection, extrapulmonary pneumocystosis is virtually nonexistent in transplant recipients. PROTOZOAL INFECTIONS Toxoplasmosis

Toxoplasmosis poses a notable risk for heart transplant recipients because of the predilection of the Toxoplasma gondii cysts for the muscle tissue. 3° Toxoplasmosis may develop in 50% to 75% of the seronegative recipients of seropositive cardiac allografts. Toxoplasmosis is rare in kidney and liver transplant recipients because of the paucity of toxoplasma cysts in these tissues. P R E V E N T I O N A N D C O N T R O L OF I N F E C T I O N S Pretransplant measures

Screening of the donors for infections that can be potentially transmitted to the recipient (e.g., CMV, EBV, HBV, HCV, and HIV) is routinely recommended. For heart transplant recipients, serostatus of the donor for T. gondii should also be determined. 31 Organs from donors testing positive for HBsAg and HIV are not acceptable for transplantation. Donor CMV seropositivity is not deemed a contraindication for transplantation, although knowledge of the donor CMV serostatus is important in the posttransplantation care of the recipient because the incidence of CMV infection and disease is higher in recipients of organs from CMV-positive donors. 1 Use of organs from HCV-positive donors is controversial. 32 It is suggested that these organs should be used only for patients in emergent need of lifesaving heart, liver, or lung transplantation. 32 Before transplantation, the recipient should be evaluated for previous exposure to infections likely to pose a risk after transplantation. Serologic tests for CMV, EBV, varicella-zoster virus, HBV, HCV,

and HIV should be routinely performed. Heart transplant recipients should also have serologic tests for T. gondii performed before transplantation. Answers to explicit questions about exposure to tuberculosis or evidence of past tuberculosis infection and a skin test for tuberculosis are required. Careful travel history, including exposure to geographically restricted endemic mycoses, should be specifically sought; and fungal serologic status (e.g., for coccidioidomycosis) should be determined in patients with such exposures. Coccidioidal skin test alone is a poor predictor of exposure in immunosuppressed patients. In patients with travel or residence outside the United States (e.g., to Southeast Asia or South America), stool ova and parasitic examination should be performed for Strongyloides stercoralis. Influenza and pneumococcal vaccine should be administered before the institution of immunosuppression. Posttransplantation measures

Several prophylactic approaches have been used for CMV. High-dose oral acyclovir (800 mg four times daily), administered to kidney transplant recipients for 12 weeks, decreased the rate of CMV disease. 33 A vast majority of subsequent studies in solid-organ transplants showed no significant benefit from acyclovir. Ganciclovir for 12 weeks after transplantation decreased the incidence of CMV disease in heart 34 transplant recipients with reactivation CMV infection, but this approach requires administration of ganciclovir to all patients, most of whom will not experience CMV disease. Ganciclovir for 100 days after transplantation was effective against CMV35; however, the feasibility and cost of intravenous administration of ganciclovir for 100 days to all patients can be prohibitive. Preemptive (as opposed to universal) prophylaxis involves administration of prophylaxis for brief periods only to patients at highest risk for serious disease caused by CMV. The criteria used to identify high-risk patients may either be a laboratory marker (viral shedding has been shown to precede symptomatic CMV disease) or a clinical event (e.g., institution of OKT3 therapy). A short course (7 days) of preemptive ganciclovir for CMV shedding significantly reduced CMV disease in liver transplant recipients. 36CMV antigenemia is a sensitive and reliable marker for the early diagnosis of CMV infection and initiation of preemptive therapy; the role of PCR in this setting remains to

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be defined. Recipients of OKT3 therapy should also receive preemptive ganciclovir. Low-dose acyclovir for 3 to 4 weeks after transplantation is effective prophylaxis against HSV infections. The most effective approach to prevent recurrent HBV after liver transplantation has been the use of high-dose anti-HBsAg immunoglobulin in the perioperative and postoperative periods. 37 Passive immunoprophylaxis neutralized circulating HBV. The standard protocol used in the European centers is anti-HBsAg immunoglobulin, 10,000 IU/L, during the anhepatic phase and then 10,000 IU/L daily for the first 6 postoperative days. 37 Dosing is repeated (usually monthly) whenever anti-HBsAg titers fall below 100 IU/L and is continued indefinitely. An intravenous preparation is currently not available in the United States. Consequently, anti-HBsAg immunoglobulins have been administered intramuscularly; however, the achievable anti-HBsAg titers have been variable. An effective prophylaxis is not yet available for HCV after transplantation. Nonabsorbable antibiotics for the selective decontamination of the gastrointestinal tract are often used for the prevention of postoperative infections after liver transplantation. Data from largely uncontrolled trials suggest that selective bowel decontamination decreased the rates of colonization and infection by gram-negative bacteria. A recent randomized controlled trial showed no difference in the overall rates of bacterial and/or yeast infections with selective bowel decontamination; however, a trend toward lower key site (abdomen, wound, lungs, and bloodstream) infections was observed in patients who received the regimen more than 3 days before liver transplantation. 38 Given the link of colonization of Legionella within the water distribution system to nosocomial Legionnaires' disease, hospitals where transplantation is performed should routinely culture the water supply for Legionella organisms. 39 The presence of Legionella organisms in the water distribution system should increase the index of physician suspicion of legionellosis in transplant recipients with pneumonia, intensify surveillance by infection control practitioners, and most importantly, stimulate the introduction of specialized Legionella testing into the hospital clinical microbiology laboratory. Should cases of nosocomial Legionnaires' disease be observed, the prime suspects should be the water taps or the showerheads in the patient rooms or the ice machines of the affected patients. Two disinfection methods

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for the water supply have emerged as cost-effective: superheating the water to 70 ° C and flushing the distal outlets or the installation of copper-silver ionization units. 4° Hyperchlorination is no longer recommended because of the expense, erratic efficacy, corrosive damage to the pipes, and carcinogenic potential of the ingested chlorine. VREF carriage before liver transplantation increased the risk of infections caused by VREF41; VREF colonization, once established, is usually a persistent event. Because colonization cannot be effectively eradicated, the control of such infections is centered on the judicious use of antibiotics and measures to limit nosocomial transmission. Transplant centers in Europe and the United States are reporting emergence of staphylococci as significant pathogens in transplant recipients. 23,24 Most such infections occur in the early posttransplantation period and are acquired in the intensive care u n i t y Rigorous infection control measures to curtail nosocomial acquisition, and the role of nasal carriage of staphylococci, as a risk factor for staphylococcal infections in transplant recipients need to be addressed. Oral nystatin or amphotericin B and low-dose intravenous amphotericin B (10 mg/kg/day) have been used as prophylaxis against invasive fungal infections; however, their efficacy has not been proven in controlled clinical trials. Liposomal amphotericin B (1 mg/kg/day) for 5 days significantly lowered the incidence of candidiasis in liver transplant recipients in a placebo-controlled European trial. 42 The n u m b e r of infections caused by Aspergillus species was too small to assess the efficacy against aspergillosis, and no difference in 30-day survival was observed. 42 Unless proven efficacious in larger studies, the reader is advised against the widespread use of low-dose amphotericin B as prophylaxis, because such an approach was shown to predispose liver transplant recipients to invasive aspergillosis in one report. 43 Trimethoprim-sulfamethoxazole is highly effective as prophylaxis against Pneumocystis carinii pneumonia in transplant recipients; prophylaxis is generally administered for 1 year after transplantation or at times of additional immunosuppression (e.g., OKT3 for graft injection). Seronegative recipients of cardiac allograft from a T. gondii-seropositive donor should receive prophylaxis with pyrimethamine and folinic acid. 31 In conclusion, implementation of effective prophylactic strategies, early detection, and better therapy have contributed to a decrease in infec-

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tion-associated mortality rates in recent years. However, invasive aspergillosis, hepatitis B and C, CMV, and EBV are still serious pathogens after transplantation; and emergence of antimicrobialresistant nosocomial bacteria (e.g., VREF) poses new m a n a g e m e n t challenges. Continuing efforts toward control of these infections and effective therapeutic strategies are required to further reduce the infection-associated morbidity and mortality rates in organ transplant recipients. References 1. Kanj SS, Sharara AI, Clavien PA, Hamilton JD. Cytomegalovirus infection following liver transplantation: review of the literature. Clin Infect Dis 1996;22:537-49. 2. Wreghitt TG, Hakim M, Gray JS, Kucia S. Cytomegalovirus infections in heart and heart and lung transplant recipients. J Clin Pathol 1988;41:660-7. 3. The TH, van der Bij W, van der Berg AP, van der Giessen M, Weits J, Sprenger HG, et al. Cytomegalovirus antigenemia. Rev Infect Dis 1990;12(suppl):737-44. 4. Crumpacker CS. Ganciclovir. N Engl J Med 1996;335:721-9. 5. Sawyer M, Mayoral JL, Gillingham KJ, Kramer MA, Dunn DL. Treatment of recurrent cytomegalovirus disease in patients receiving solid organ transplants. Arch Surg 1993;128:165-70. 6. Nalesnik M, Starzl TE. Epstein-Barr virus, infectious mononucleosis, and posttransplant lymphoproliferative disorders. Transplant Sci 1994;4:61-79. 7. Kusne S, Schwartz M, Breinig MK, Dummer JS, Lee RE, Selby R, et al: Herpes simplex virus hepatitis after solid organ transplantation in adults. J Infect Dis 1991; 163:1001-7. 8. Singh N, Carrigan DR. Human herpesvirus-6 in transplantation: an emerging pathogen. Ann Intern Med 1996; 124:1065-71. 9. Gane E J, Portman BC, Naumov NV, Smith HM, Underhill JA, Donaldson PT, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med 1996;334:815-20. 10. Singh N, Gayowski T, Wannstedt C, Marino R, Wagener MM. Interferon-alpha therapy for hepatitis C virus recurrence after liver transplantation: long-term response with maintenance therapy. 1996; 10:348-51. 11. Wright TL, Combs C, Kim M, Ferrell L, Bacchetti P, Ascher N, et al. Interferon-alpha therapy for hepatitis C virus infection after liver transplantation. Hepatology 1994;20:773-9. 12. Gane EJ, Tibbs CJ, Ramage JK, Postmann BD, Williams R. Ribavirin therapy for hepatitis C infection following liver transplantation. Transplant Int 1995;8:61-4. 13. Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, et al. Liver transplantation in European patients with hepatitis B surface antigen. N Engl J Med 1993;329:1842-7. 14. Singh N, Gayowski T. Lack of sustained efficacy of combination ganciclovir and foscarnet for hepatitis B virus recurrence after liver transplantation. Transplantation 1995;59:1629-30. 15. Boker KHW, Ringe B, Druger M, Richlmayr R, Manns MR Prostaglandin plus famciclovir: a new concept for the

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treatment of severe hepatitis B after liver transplantation. Transplantation 1994;12:1706-8. 16. Erice A, Rhame FS, Heussner Re, Dunn DL, Balfour HH. Human immunodeficiency virus infection in patients with solid-organ transplants: report of five cases and review. Rev Infect Dis 1991;1:537-47. 17. Schwarz A, Offerman G, Keller F, Bennhold I, Uage-Stehr J, Krause PH, et al. The effect of cyclosporine on the progression of human immunodeficiency virus type 1 infection transmitted by transplantation: data on four cases and a review of the literature. Transplantation 1992;55:95-103. 18. Wagener MM, Yu VL. Bacteremia in transplant recipients: a prospective study of demographics, etiologic agents, risk factors, and outcomes. Am J Infect Control 1992;20:239-47. 19. Lumbreras C, Fernandez I, Velosa J, Munn S, Sterioff S, Paya CV. Infectious complications following pancreatic transplantation: incidence, microbiological, clinical characteristics and outcome. Clin Infect Dis 1995;20:514-20. 20. Lynch JP, Martinez FJ. Pulmonary infections to watch for in transplant recipients. J Respir Dis 1993;14:528-50. 21. Kusne S, Dummer JS, Singh N, Iwatsuki S, Makowka L, Esquivel C, et al. Infections after liver transplantation, an analysis of 101 consecutive cases. Medicine 1988;67:132-43. 22. Singh N, Muder RR, Yu VL. Legionella infection in liver transplant recipients: implications for management. Transplantation 1993;15:677-88. 23. Wade JJ, Rolando N, Hallar K, Philpott-Howard J, Casewell MW, Williams R. Bacterial and fungal infections after liver transplantation: an analysis of 284 patients. Hepatology 1995;21:1328-66. 24. Singh N, Gayowski 17,Wagener M, Marino IR. Bloodstream infections in liver transplant recipients: changing patterns of microbial origin [abstract]. Presented at 36th Interscience Conference on Antimicrobial Agents and Chemotherapy 1996; New Orleans, La. 25. Linden PK, Pasculle AW, Manez R, Kramer DE, Fung JJ, Pinna AD, et al. Differences in outcome for patients with bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin susceptible E. faecium. Clin Infect Dis 1996;22:663-70. 26. Paya CV. Fungal infections in solid-organ transplantation. Clin Infect Dis 1993;16:677-88. 27. Torre-Cisnero J, Lopez OL, Kusne S, Martinez AJ, Starzl TE. CNS aspergillosis in organ transplantation: a clinicopathologic study. J Neurol Neurosurg Psychiatry 1993; 56:188-93. 28. Singh N, Rihs JD, Gayowski T, Yu VL. Cutaneous cryptococcosis mimicking bacterial cellulitis in a liver transplant recipient: case report and review in solid organ transplant recipients. J Clin Transplantation 1994;8:365-8. 29. Dummer JS. Pneumocystis carinii infections in transplant recipients. Semin Respir Infections 1990;5:50-7. 30. Luft BJ, Naot Y, Araujo FG, Stinson EB, Remington JS. Primary and reactivated Toxoplasma infection in patients with cardiac transplants. Ann Intern Med 1983;99:27-31. 31. Petri WA. Infections in heart transplant recipients. Clin Infect Dis 1994;18:141-8. 32. Fishman JA, Rubin RH, Koziel MJ, Periera BJG. Hepatitis C virus and organ transplantation. Transplantation 1996;62:147-54. 33. Balfour HH, Chace BA, Stepleton JT, Simmons RR, Fryd DS. A randomized, placebo controlled trial of oral acy-

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clovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med 1989;320:1381-7. Merigan TC, Renlund DG, Keay S, Bristow MR, Starnes V, O'Connell JB, et al. A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation. N Engl J Med 1993;326:1182-6. Winston DJ, Wirin D, Shaked A, Busuttil RW. Randomized comparison of ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in liver transplant recipients. Lancet 1995;346:69-74. Singh N, Yu VL, Mieles L, Wagener MM, Miner RC, Gayowski T. High-dose acyclovir compared with shortcourse preemptive ganciclovir therapy to prevent cytomegalovirus disease in liver transplant recipients, a randomized trial. Ann Intern Med 1994;120:375-81. Samuel D, Bismuth H. Liver transplantation for hepatitis B. Gastroenterol Clin North Am 1993;22:271-83. Arnow PM, Carandang GC, Zabner R, Irwin ME. Randomized controlled trial of selective bowel decontamination for prevention of infections following liver transplantation. Clin Infect Dis 1996;22:997-1003. Allegheny County Health Department. Approaches to pre-

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vention and control of Legionella infection in Allegheny County health care facilities. Allegheny County Health Department 1993; April 1993. 40. Yu VL. Legionella pneumophila (Legionnaires' disease). In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious diseases. 4th ed. New York: Churchill Livingstone; 1995. p. 2087-97. 41. Linden P, Pinna AD, Mazareiogos G, Furkuwa H, Kramer DJ, Kusne S. Outcome of liver transplantation in patients colonized with vancomycin-resistant E. faecium (VREF). Presented at 35th Interscience Conference on Antimicrobial Agents and Chemotherapy 1995; [Abstract J 72]; San Francisco, Calif. 42. Tollemar J, Hockerstedt K, Ericzon BG, Jalanko H, Ringden O. Liposomal amphotericin B prevents invasive fungal infections in liver transplant recipients. Transplantation 1995;59:45-50. 43. Singh N, Mieles L, Yu VL, Gayowski T. Invasive aspergillosis in liver transplant recipients: association with candidemia, consumption coagulopathy, and failure of prophylaxis with low-dose amphotericin B. Ctin Infect Dis 1993;17:906-8.

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