Clinical Description and Epidemiology
The course of solid organ transplant recipients is often complicated by infectious processes, owing to defects in both cellular and humoral immunity. However in the past several decades, improvements in graft and patient survival and a decline in infection-related mortality have been observed, probably related to better regulation of chronic immunosuppressive therapy, better selection of transplant candidates, improved antimicrobial prophylaxis, and advances in surgical techniques.
Cell-mediated immune defects predominate in the solid organ transplant recipient. Chronic immunosuppressive administered following transplantation to maintain the recipient organ results in additional immunosuppression. Corticosteroids, although now used in lower dosages than in the past, result in defects in both cell-mediated and humoral immunity, with resultant decreases in both CD4 and CD8 T-lymphocytes and monocytes, and impaired macrophage function. Other immunosuppressive agents employed such as azathioprine, cyclosporine, and tacrolimus also result in significant prolonged defects in cell-mediated immunity. Additional factors that contribute to the type and severity and related mortality of infection in the solid organ transplant recipient include the presence of underlying medical conditions such as diabetes or hepatitis, the specific organ transplanted, and the duration of the surgical transplant procedure. It is recognized that the incidence of infection and subsequent mortality are lowest in renal transplant recipients, and highest in the heart-lung recipients. Liver transplant surgery has its own attendant complications related to the length and technical difficulty of the procedure, and anastomotic connections to nonsterile sites including the biliary tree and intestine.
The majority of infections following solid organ transplantation occur within four months of transplant. However, a temporal sequence of infections in the post-transplant period has been recognized (21). Most infections that occur within the first month following transplant are either preexistent preoperative infections (such as hepatitis), routine postoperative infections (pneumonia, wound, or line related infections), or reactivated HSV infections. In the following interval of 2-6 mo after transplant, various etiologies of infection are seen. Bacterial infections may involve sites such as the bladder and sinuses; in addition, opportunistic organisms including mycobacteria, Nocardia, and Listeria may cause infection. Fungal isolates in this period include Aspergillus and Cryptococcus. Other causative agents include viruses (predominantly cytomegalovirus [CMV], Toxoplasma, and Pneumocystis.
In the period of > 6 mo following transplant, three clinical groups with characteristic infectious complications are seen. Approximately 60-75% of patients require minimal immunosuppression and have good graft function by this time. In these patients, common infections such as respiratory tract infections, diverticulitis, and cholecystitis may occur. However, these infections may present in an atypical manner or have more serious sequelae due to the chronic immunosuppression. From 10% to 15% of patients will have chronic recrudescent viral infections, which may lead to end-organ damage. Etiologies include papovavirus (BK, JC), which may cause urethral stricture and hemorrhagic cystitis; hepatitis B or C, which may result in subacute or chronic hepatitis; Epstein-Barr virus, a causative agent of post-transplant lymphoproliferative disorders; CMV, which most commonly manifests as retinitis at this time; adenovirus; and VZV. The remaining 10-20% of patients have poor allograft function and are receiving excessive amounts of immunosuppressive therapy due to episodes of acute/chronic allograft rejection. This subset of patients is at greatest risk of life-threatening opportunistic infections; immunomod-ulatory viruses such as CMV are common causative agents.
The etiologic organisms are often dictated by the site of infection in the solid organ transplant recipient (22-25). Skin infections are very common, although rarely life threatening. The most common causative agents are viral, such as herpes simplex virus (HSV) and varicella zoster virus (VZV), with other agents such as Papillomavirus and various dermatophytes being less common. The skin may also represent a target organ for disseminated infection, with a variety of bacterial (including atypical mycobacte-ria), fungal, and viral etiologies. The incidence of wound infections varies with the type of transplant, being most common in liver transplant recipients. Although S. aureus is the most common wound isolate, Gram-negative enteric organisms, coagu-lase-negative staphylococci, and rarely Mucor may also be etiologic.
In the era before routine prophylaxis, the incidence of urinary tract infection following renal transplantation ranged from 35% to 80%. However, with the institution of trimethoprim-sulfamethoxazole prophylaxis, this incidence has now dropped to <10%. Common isolates include enteric Gram-negative organisms, Enterococcus, and Candida species (26). Less frequently isolated are Mycoplasma, Mycobacterium spp., papovavirus (BK, JC), and CMV.
Frequent sources of septicemia in transplant recipients are the lung, abdomen, biliary tract, urinary tract, skin/soft tissues, and intravascular catheters. Polymicrobial bacteremia is not uncommon, especially in the setting of liver and small intestine transplants. Common isolates are enteric Gram-negative organisms, Enterococcus, S. aureus, Candida spp., and CMV (27). Nontyphoidal Salmonella bacteremia has also been reported in renal transplant recipients.
A variety of pulmonary infections may occur after solid organ transplantation (28). Community-acquired pneumonia is frequently seen in these patients, and may be caused by traditional organisms such as S. pneumoniae, or other isolates such as respiratory syncitial virus. Although primary pulmonary tuberculous disease may occur in these patients, in one recent large series, 33% of Mycobacterium tuberculosis infections were disseminated (29). Histoplasma, Blastomyces, and Coccidioidomyces may cause pulmonary infections in patients from areas endemic for these fungi. In patients with a prolonged duration of symptoms, diffuse or nodular infiltrates, or nonproductive cough, atypical or opportunistic pathogens need to be considered. Opportunistic organisms such as CMV, Legionella, Pneumocystis, and Aspergillus may be etiologic agents of pulmonary processes in this population in up to 60% of cases (30,31).
Intraabdominal infections may be problematic, especially in patients who have undergone transplant procedures involving the abdomen. Candida spp. may cause ulcerative lesions throughout the gastrointestinal tract, as may CMV and HSV. Hepatitis may be viral in etiology (CMV, hepatitis C, VZV, HSV, adenovirus type 5), or be a presentation of disseminated fungal infection with organisms such as Candida, Aspergillus, or Histoplasma. Liver abscesses and cholangitis may occur in the setting of biliary tract obstruction after liver transplant, and can be caused by various Gramnegative enteric organisms, Enterococcus, or anaerobes.
The greatest risk for CNS infections is in the first 4 mo following solid organ transplantation, although these may also occur later in patients whose course is complicated by chronic rejection and intensified immunosuppressive therapy. The presentation of these processes is often subtle, with focal necrologic signs infrequently present. Pyo-genic bacteria are uncommonly isolated, while opportunistic organisms such as Liste-
ria, Nocardia, Mycobacterium spp., Aspergillus, Cryptococcus, Toxoplasma, and Poly-omavirus are more frequent.
Infections may be transmitted from the donor to the recipient by the allograft. Agents transmitted in this manner include CMV, HSV, hepatitis B and C, human immunodeficiency virus (HIV), and Toxoplasma gondii. In addition, outbreaks of infection may occur, either related to the nosocomial flora at the transplant center (which may include drug-resistant isolates), or the water supply (as in Legionella outbreaks).
The use of various prophylactic antimicrobial agents has resulted in an improved outcome in solid organ transplant recipients owing to the decreased frequency of and mortality from infectious complications. Trimethoprim-sulfamethoxazole prophylaxis has been advocated for a minimum period of 6 mo following transplantation. Not only does this provide prophylaxis against many urinary tract pathogens, it also is protective against organisms such as Toxoplasma, Pneumocystis, Nocardia, and Listeria. Ciprofloxacin may also be utilized for prophylaxis of urinary tract infections, although its spectrum of coverage is more limited than that of trimethoprim-sulfamethoxazole. Aerosolized pentamidine is an alternative agent for Pneumocystis prophylaxis in patients who are intolerant to trimethoprim-sulfamethoxazole (32). Although the use of isoniazid prophylaxis is controversial, it may be considered for patients who have additional risk factors for active tuberculous disease or recent skin test conversion, and for recipients of organs from skin test positive donors. Nystatin suspension or clotrima-zole troches are used to reduce the risk of candidal infections, especially when patients are receiving broad-spectrum antimicrobials or heightened immunosuppressive therapy, as during episodes of rejection. Prophylactic acyclovir, administered for a month post-transplant in HSV-seropositive recipients, has markedly reduced the incidence of HSV infections. In settings in which immunosuppressive therapy is intensified, such as acute rejection, ganciclovir prophylaxis may be utilized to prevent CMV infection (33,34). With any of these prophylactic measures, the potential for development of drug-resistant isolates must be recognized (35). Lastly, pretransplant vaccination may be considered to help prevent pneumococcal infection, influenza, hepatitis B, and VZV, although data on the latter are limited.
Treatment of established infection depends on the etiologic agent. The antimicrobial sensitivity pattern of nosocomial isolates should be kept in mind, as these patients may be colonized, and subsequently infected with these isolates. A reduction in immuno-suppressive therapy may be indicated in the management of certain viral processes, such as post-transplant lymphoproliferative disorders caused by Epstein-Barr virus.
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