Robin Patel MD
Essentials of Diagnosis
General Considerations
Solid-organ, PBSC and bone marrow transplantation have become therapeutic options for many human diseases. PBSC, bone marrow, liver, kidney, heart, and lung transplantation have become standard therapy for selected end-stage diseases. Pancreas (including islet cell) and small bowel transplantation are also being evaluated in this regard. PBSC involves using stem cells mobilized by the administration of recombinant human granulocyte macrophage colony-stimulating factor. There are several types of PBSC or bone marrow transplants:
Infection remains a major complication of all types of transplantation. The optimal approach to infection in transplant recipients is prevention; failing this, its prompt and aggressive diagnosis and therapy are essential. The sources of infectious agents post-transplantation include endogenous organisms, the transplant allograft itself, and the environment. An important principle to consider when evaluating transplant recipients for infection is that the usual inflammatory response to an infectious organism may be attenuated as a result of immunosuppressive therapy and therefore that the signs and symptoms of infections may be blunted and diagnostic techniques may be compromised. Because of this, aggressive and often invasive investigations of seemingly minor findings may be warranted.
Pretransplantation Infectious Diseases Evaluation
Before transplantation, all potential candidates should be evaluated for active infection that may require therapy or preclude transplantation, risk factors for infection, including latent infections that might be reactivated post-transplantation, and the use of immunosuppressive agents. A complete history should be obtained, focusing on any history of infection and any unusual exposures (Table 24-1). A complete physical examination should also be performed. Table 24-1 outlines infectious disease tests that should be performed pretransplantation.
Further investigations are pursued depending on elicited risks. For example, serologic testing for Coccidioides immitis may be performed on a patient with a history of travel to or residence in the southwestern United States or Mexico. Patients who have traveled to or resided in an area where Strongyloides stercoralis is endemic should be examined for evidence of infection with this parasite. Lung transplant candidates should be evaluated for colonization of the respiratory tract with such agents as Aspergillus spp.
Timing of Post-Transplantation Infection
Table 24-1. Clues to the diagnosis of infections in transplant recipients. |
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Most infections during the first month post-transplantation are related to surgical complications and are similar to infections occurring in general surgical patients. These include bacterial and candidal wound infections, pneumonia, urinary tract infections, line sepsis, and infections of biliary, chest, and other drainage catheters. In general, any episode of unexplained fever or bacteremia occurring in the early post-transplantation period should be suspected as being caused by technical or anatomical problems related to the allograft. In the first month post-transplantation, renal and pancreas transplant recipients are at risk for perigraft abscesses, infected or uninfected hematomas, lymphoceles, and urinary leaks. Liver transplant recipients are at risk for portal vein thrombosis, hepatic vein occlusion, hepatic artery thrombosis, biliary stricture formation and leaks, infected and uninfected hematomas and hepatic and perihepatic abscesses. Heart transplant recipients are at risk for mediastinitis and infection at the aortic suture line, with resultant mycotic aneurysm, and lung transplant recipients at risk for disruption of the bronchial anastomosis and pneumonia. The only common viral infection seen during the first month post-transplantation is reactivated herpes simplex virus (HSV) infection in individuals seropositive for this virus pretransplantation. The prophylactic use of acyclovir during this period, however, has significantly reduced the incidence of reactivated HSV infection.
The period from the second to sixth month postsolid-organ transplantation is the time during which infections “classically” associated with solid-organ transplantation manifest. Opportunistic pathogens such as CMV, Pneumocystis carinii, Aspergillus spp., Nocardia spp., Toxoplasma gondii, and Listeria monocytogenes manifest during this period. In addition, during the early and middle periods, reactivation disease syndromes are occasionally encountered because of organisms present in the recipient pretransplantation. The introduction of high-dose immunosuppression may result in clinical illness owing to reactivation of Mycobacterium tuberculosis, an occult focus of bacterial infection, viral hepatitis, Histoplasma capsulatum, or C immitis. Chronic or latent infection of the donor that involves the allograft, such as HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), or fungal or mycobacterial infection, may be transmitted to the immunosuppressed recipient and become clinically apparent during the early and middle periods.
From 6 months post-transplant onward, most solid-organ transplant recipients do relatively well, suffering from the same infections seen in the general community. These include influenza virus infection, urinary tract infection, and pneumococcal pneumonia.
The only opportunistic viral infection commonly seen during this period is reactivated varicella zoster virus (VZV) infection manifesting as shingles. Rarely, CMV retinitis occurs.
Two situations, however, predispose patients to other infections in this late post-transplant period. First, patients who have had frequent episodes of acute rejection requiring augmented immunosuppressive therapy or those with chronic rejection who are maintained at a high baseline level of immunosuppression remain at increased risk for the opportunistic agents more classically seen in the second to the sixth months post-transplant (CMV, P carinii, L monocytogenes, T gondii, Aspergillus spp., and Nocardia spp.). Second, patients with chronic infections such as HIV, HBV, and HCV infections, may suffer from morbidity associated with these agents.
During the second to third month after PBSC and bone marrow transplant when engraftment has occurred, patients have profound impairment of both cellular and humoral immunity. These abnormalities are more severe and persist longer in patients with acute graft-versus-host disease (which is the major risk factor for infection during the second to third month after transplantation). Autologous and syngeneic transplant recipients who are not usually at risk for graft-versus-host disease experience significantly fewer and less severe infections after engraftment than allogeneic transplant recipients. Interstitial pneumonia related to CMV and pulmonary aspergillosis are the major infectious complications seen in patients with graft-versus-host disease, especially when high doses of immunosuppressive therapy are given for treatment. Gram-positive bacterial infections related to indwelling intravenous catheters, gram-negative bacteremia in patients with graft-versus-host disease of the gastrointestinal tract, pulmonary infection caused by adenovirus, respiratory syncytial virus, or parainfluenza virus, hemorrhagic cystitis caused by BK virus or adenovirus, as well as viral gastroenteritis, may be seen during this time period.
The period from 3 months onward after PBSC and bone marrow transplantation is characterized by gradual recovery over several months of both cellular and humoral immunity. The process of donor-derived immune reconstitution is generally complete by 1–2 years after transplantation. Except for reactivation of VZV infections (shingles) and infections of the respiratory tract caused by Streptococcus pneumoniae and Haemophilus influenzae or common respiratory viruses, PBSC and bone marrow transplant recipients without graft-versus-host disease experience relatively few late infections. Immune recovery, however, is seriously delayed by chronic graft-versus-host disease, which causes persistent and profound defects in both cellular and humoral immune responses. Decreased secretory IgG production, impaired splenic function, inadequate opsonizing antibody, and the bronchopulmonary sicca syndrome characteristic of chronic graft-versus-host disease contribute to respiratory tract infections. Late onset interstitial pneumonia that is caused by CMV or P carinii may occur in patients with ongoing graft-versus-host disease. The destructive effects of chronic graft-versus-host disease on mucocutaneous surfaces also provide a source for infection by staphylococci and other bacteria.
BOX 24-1 Microbiology of Infection in Solid-Organ Transplant Recipients |
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BACTERIAL INFECTIONS
COMMON BACTERIAL INFECTIONS
Clinical findings and treatment of common bacterial infections in transplant recipients are discussed in the relevant syndrome and organism chapters (see chapter cross references below).
Prevention
Selective bowel decontamination reduces gram-negative infections in liver transplant recipients.
Prevention
The incidence of bacterial pneumonia in lung transplant recipients may be dramatically reduced by the use of antimicrobial agents tailored to the results of cultures and stains for bacteria and fungi from the airways of the donor and recipient at the time of transplantation.
Prevention
Prophylaxis with trimethoprim-sulfamethoxazole reduces the incidence of bacterial infection of the urinary tract and bacteremia after renal transplantation. However, controversy exists regarding the exact dosing, timing, and duration of trimethoprim-sulfamethoxazole for urinary tract infection prophylaxis in renal transplant recipients.
An increased risk of both colonization and bacteremia caused by viridans streptococci has been associated with quinolone prophylaxis in PBSC and bone marrow transplant recipients. Septic shock and the adult respiratory distress syndrome are occasionally seen in association with viridans streptococcal bacteremia. Despite the apparent decline in gram-negative bacterial infections, the possibility of infection caused by Escherichia coli and other Enterobacteriaceae, as well as P aeruginosa and other nonfermenting gram-negative bacilli, must still be considered when decisions about empiric antibiotic therapy are being made.
Bacteremia and soft tissue infections are the most common presentations of bacterial infections during the initial months after PBSC and bone marrow transplant (see Chapter 13). Exit site infections of intravenous catheters, infections involving the perirectal area, and oral mucositis are common local types of bacterial infection. Bacterial infections of the respiratory tract may occur at anytime, including 4 or more months after transplantation. At this later time period, encapsulated bacteria (eg, S pneumoniae and H influenzae) are frequent pathogens that may cause pneumonia, bronchitis, sinusitis, and, less commonly, meningitis.
Prevention
Bacterial infections in PBSC and bone marrow transplant patients with graft-versus-host disease after engraftment may be prevented by prophylaxis with trimethoprim-sulfamethoxazole. Oral chemophylaxis with quinolones in granulocytic patients is widely used. Oral quinolones are well tolerated and eliminate most gram-negative bacterial infections. The use of quinolones for prophylaxis is, however, controversial.
LEGIONELLA SPECIES
General Considerations
Legionella infection can occur in any type of transplant recipient, can be nosocomial or community acquired, and can be seen at any time post-transplant. Legionella pneumophila is the most common species involved but Legionella micdadei, Legionella bozemanii, Legionella dumoffii, and other Legionella spp., may be pathogens in transplant recipients. More details are found in Chapter 58.
Clinical Findings
Treatment
Treatment is classically with a quinolone or macrolide with or without rifampin (Box 24-2). If legionellal pneumonia is nosocomial, a search should be made for sources of legionella in the environment, especially in the hot water supply and ventilation systems.
NOCARDIA SPECIES
General Considerations
Nocardial infections have been reported to occur in all types of transplant recipients. Nocardial infection is most commonly caused by Nocardia asteroides, but other species of Nocardia may also cause infections in transplant recipients. More details are found in Chapter 63.
Clinical Findings
Treatment
Sulfonamides, either alone or in combination with trimethoprim, are the treatment of choice for nocardiosis (Box 24-2). Alternatives include minocycline, chloramphenicol, erythromycin, amikacin, ampicillin, amoxicillin-clavulanate, ciprofloxacin, imipenem, meropenem, ceftriaxone, cefuroxime, and cefotaxime, but antibiotic susceptibility testing should be performed because resistance may be present. Antimicrobial therapy should be continued for a prolonged period after cure because of the tendency for relapse, although the optimal duration of therapy is unknown.
Prevention
Trimethoprim-sulfamethoxazole used for P carinii prophylaxis may prevent nocardiosis (Box 24-3).
SALMONELLA SPP.
There is an increased incidence of salmonellal infection in renal transplant recipients. The most common presentation is a febrile illness with bacteremia. Salmonella infections are discussed further in Chapter 53.
LISTERIA MONOCYTOGENES
General Considerations
Transplant recipients are at greatest risk for infection caused by L monocytogenes during the first 2–3 mo after transplant, but listerial infection may occur at any time after transplant. Listeriosis occurs in all types of transplant patients and may be transmitted via contaminated food. It is most commonly seen from the months of July through October. More details are found in Chapter 51.
BOX 24-2 Empiric Therapy of Infections in Transplant Recipients |
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Clinical Findings
BOX 24-3 Control of Infections in Transplant Recipients |
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Treatment
Intravenous ampicillin and gentamicin are recommended for treatment (Box 24-2). Trimethoprim-sulfamethoxazole is also effective.
Prevention
Trimethoprim-sulfamethoxazole, used for P carinii prophylaxis, may additionally prevent listeriosis (Box 24-3).
VIRAL INFECTIONS
CYTOMEGALOVIRUS
General Considerations
CMV is extensively discussed in Chapter 33. CMV infection occurs in the majority of solid-organ and allogeneic PBSC and bone marrow transplant recipients, primarily in the first 3 mo post-transplant. CMV infection also occurs in 40–45% of recipients of syngeneic or autologous PBSC and bone marrow transplant recipients, but symptomatic infections are infrequent in these groups. CMV may be transmitted to transplant recipients via infected donor material or transfused cellular products.
Three major patterns of CMV transmission are observed in transplant recipients. Primary infection develops when a CMV seronegative individual receives cells latently infected with the virus from a seropositive donor followed by viral reactivation. Secondary infection or reactivation infection develops when endogenous latent virus is reactivated in a CMV seropositive individual post-transplantation. Superinfection or reinfection occurs when a seropositive recipient receives latently infected cells from a seropositive donor and the virus that reactivates post-transplantation is of donor origin.
After primary infection with CMV, long-term cellular and humoral immunity usually develop, but CMV remains latent or persistent within the host. Viral persistence is controlled in the immunocompetent host by an intact cellular immune system. Immunosuppression administered after transplantation may lead to uncontrolled viral replication and consequently symptomatic CMV infection. A solid-organ transplant recipient without prior immunity to CMV pretransplantation who receives an organ containing latent or persistent virus (primary infection) is at higher risk of uncontrolled viral replication than a patient who has prior immunity to CMV pretransplantation (secondary infection or reinfection). In PBSC and bone marrow transplant recipients the CMV seropositive recipient with a CMV seronegative donor is at higher risk of uncontrolled viral replication than patients in other serologic groups. Likewise, the higher the degree of immunosuppression, the higher the risk of uncontrolled viral replication. In solid-organ transplant recipients, the use of antilymphocyte preparations (eg. OKT3 monoclonal antibodies) and fulminant hepatitis at the time of transplantation (in liver transplant recipients) are risk factors for symptomatic CMV infection. Graft-versus-host disease is a risk factor for CMV infection in PBSC and bone marrow transplant recipients.
In the immunosuppressed transplant recipient, CMV has four major effects:
CMV infection therefore has a potential impact on both patient and graft outcome.
Clinical Findings
Organ involvement by CMV correlates with the organ transplanted as follows: Hepatitis occurs most frequently in liver transplant recipients; pancreatitis occurs most frequently in pancreas transplant recipients; and pneumonitis occurs most frequently in lung, heart and lung, and PBSC and bone marrow transplant recipients. Gastroenteritis is also frequently seen in PBSC and bone marrow transplant recipients. In addition, myocarditis, although rare, typically presents in heart transplant recipients. Other sites of involvement of CMV include the gallbladder, pancreas, epididymis, biliary tract, retina, skin, endometrium, and central nervous system. CMV retinitis is distinctive in that it usually presents > 6 mo post–solid-organ transplantation.
Molecular techniques can detect CMV DNA in peripheral blood leukocytes, whole blood, serum, plasma, and other clinical specimens and can detect CMV RNA in peripheral blood leukocytes and whole blood.
The serologic diagnosis of CMV infection is suboptimal compared to the above techniques; many patients with positive CMV cultures do not show concomitant evidence of seroconversion. Serologic testing, however, is recommended for the pretransplantation evaluation of the CMV serostatus of transplant donors and recipients.
Treatment
Effective currently available antiviral agents for the treatment of CMV include ganciclovir, foscarnet, cidofovir, and intravenous immune globulin (Box 24-2). In solid-organ transplant recipients, intravenous ganciclovir is the mainstay of therapy. Ganciclovir alone is generally of little benefit for treatment of either CMV pneumonia or gastroenteritis in PBSC and bone marrow transplant recipients, although the combination of intravenous ganciclovir plus intravenous immune globulin appears to have some efficacy. The absorption of ganciclovir after oral administration is low, and its use cannot be recommended for the treatment of CMV infection and disease after transplantation.
Side effects of ganciclovir include leukopenia, thrombocytopenia, anemia, nausea, infusion site reactions, diarrhea, renal toxicity, seizures, mental status changes, fever, rash, and abnormal liver function tests. Hematologic and renal function should be monitored while patients are receiving ganciclovir. Renal toxicity may occur when ganciclovir is used in conjunction with other nephrotoxic agents such as amphotericin B, azathioprine, aminoglycosides, and cyclosporine.
The possibility of viral resistance should be considered in patients with poor clinical response or persistent viral excretion during ganciclovir therapy. Mutations in viral thymidine kinase and/or DNA polymerase genes mediate resistance.
Prevention
On the basis of published randomized trials, a 2-week course of intravenous ganciclovir may be considered for CMV prophylaxis in certain solid-organ transplant recipients; a 4-week course is recommended for CMV seropositive recipients of heart allografts. Intravenous ganciclovir alone is not effective, however, in solid-organ transplant populations at highest risk for CMV disease, including lung transplant recipients and donor CMV seropositive recipients CMV seronegative individuals, unless it is administered for a prolonged period (90 days). The studies to date have used intravenous ganciclovir, which is not ideal because of the ongoing need for intravenous access and the costs engendered. In this regard, oral ganciclovir has been shown as effective in preventing CMV infection and disease in liver and kidney transplant recipients and has been widely adapted for CMV prophylas, replacing intravenous ganciclovir in most instances.
Limitations associated with oral ganciclovir use include the need to take multiple tablets each day, cost, potential emergence of ganciclovir-resistant CMV stains, and the emergence of late onset CMV disease (following discontinuation of prophylacis). New agents, such as valganciclovir as well as other promising compounds that are being developed, may provide improved CMV prophylacis for solid-organ and PBSC and bone marrow transplant recipients.
Candidate laboratory tests for this therapeutic mode include molecular and antigenemia tests. Many transplantation programs are using molecular or antigenemia tests to monitor their transplant recipients after transplantation and intervening with preemptive therapy based on a positive result.
Identifying patient characteristics that place the transplant recipient at risk for CMV infection is another facet of preemptive therapy. Such risk factors include the use of OKT3 monoclonal antibodies in solid-organ transplant recipients and the presence of fulminant hepatitis at the time of transplantation in liver transplant recipients. Many transplantation programs are intervening with preemptive ganciclovir when antilymphocyte therapy is used in solid-organ transplant recipients. A similar approach based on other risk factors requires further study but may also be beneficial.
HERPES SIMPLEX VIRUS
General Considerations
Herpes simplex virus most commonly causes reactivation infection but may cause primary infection transmitted by person to person contact or via the transplant donor. Herpes simplex virus antibodies are found in three-quarters of adult transplant recipients. After primary infection, the virus remains latent in sensory nerve ganglia. Herpes simplex virus infection occurs in all types of transplant recipients. More information is found in Chapter 33.
Clinical Findings
Most orolabial infections are mild, although severe ulceration and discomfort, which may be complicated by bacterial superinfection or esophageal involvement, are noted in some patients. Anogenital infection usually presents as large areas of ulceration and may or may not have the typical vesicular appearance of HSV infection in the nonimmunocompromised host.
Herpes simplex virus can cause pneumonia and may be associated with a high mortality rate. This usually occurs as a secondary pneumonia in intubated patients with severe pneumonia caused by other agents. The virus is reactivated in the oropharynx. The mucosa is traumatized by the endotracheal tube, and the virus is presumably spread via the endotracheal tube to the lower respiratory tract. Certain caveats must be noted. Herpes simplex virus isolated from sputum or other respiratory secretions does not definitively imply HSV pneumonitis. Also, even if HSV is believed to be causing pneumonitis, another pathogen should be sought as HSV is often a secondary pathogen.
Herpes simplex virus esophagitis causes dysphagia and mimics candidal esophagitis. Esophagitis may complicate orolabial infection, particularly if the mucosa has been traumatized by endotracheal intubation or nasogastric tubes. Herpes simplex virus is also a cause of diffuse or focal hepatitis in solid-organ transplant recipients, usually during the first 2 months after transplantation. Diffuse or focal hepatitis secondary to herpes simplex virus is characterized by a rapidly progressive course accompanied by hypotension, disseminated intravascular coagulation, metabolic acidosis, gastrointestinal bleeding, and associated bacteremia. Disseminated HSV disease may rarely occur. Uncommonly, disseminated cutaneous infection with HSV may occur at sites of previous skin injury such as burns or eczema (eczema herpeticum).
Treatment
Treatment of HSV infection is with acyclovir (Box 24-2). Side effects of acyclovir include local inflammation or phlebitis after intravenous infusion, renal toxicity caused by precipitation and crystallization of the drug in the renal tubules, confusion, delirium, lethargy, tremors, seizures, nausea, light-headedness, diaphoresis, and rash. Mucocutaneous infection in transplant recipients should be treated with oral acyclovir if the infection has a benign course or with intravenous acyclovir in more serious cases. Disseminated or deep HSV infection should always be treated with intravenous acyclovir.
Newer agents, such as famciclovir and valacyclovir, may be used instead of acyclovir. Although more toxic than acyclovir, ganciclovir and foscarnet are also effective against HSV. A concern with respect to chronic acyclovir use is the development of acyclovir resistant mutants of HSV. Acyclovir resistance may arise from mutations in the genes for thymidine kinase or DNA polymerase. Acyclovir resistance has been associated with progressive and severe disease in immunocompromised patients, particularly in those with HIV, and it is possible that resistance will become a problem for transplant recipients in years ahead.
Prevention
Low-dose acyclovir prevents HSV stomatitis in transplant recipients (Box 24-3).
VARICELLA ZOSTER VIRUS
General Considerations
Varicella zoster virus causes two distinct clinical diseases after transplant. Ninety percent of adult transplant recipients are VZV seropositive pretransplant; VZV reactivation in this group will cause herpes zoster (shingles). The remaining 10% are VZV seronegative and thus are at risk for primary infection. More information is found in Chapter 33.
Clinical Findings
Treatment
For localized dermatomal zoster, the recommended treatment is intravenous acyclovir (Box 24-2). Oral famciclovir, valacyclovir, or acyclovir may be used as an alternative. For primary VZV infection, treatment consists of intravenous acyclovir in addition to varicella zoster immune globulin.
Prevention
Because of the high mortality rate associated with primary VZV infection in transplant recipients, all candidates should be screened for antibody to VZV pretransplantation (see Box 24-3). Seronegative individuals should be urged to report promptly all exposures to VZV and varicella zoster immune globulin should be administered within 96 hours of exposure. Intravenous acyclovir should be administered within 24 hours of eruption of a skin rash if one occurs. Unfortunately, progression to severe disease and death can still occur. The use of low-dose acyclovir as HSV prophylaxis probably prevents VZV reactivation and possibly primary infection, although this has not been formally studied. Despite concerns regarding the use of live vaccines in transplant recipients, a recent study has demonstrated the safety of the VZV vaccine in pediatric renal transplant recipients. This vaccine should preferably be administered several months prior to solid-organ transplant, should reduce morbidity in seronegative solid-organ transplant recipients, and should provide considerable cost savings.
Table 24-2. Treatment of EBV-related conditions in the solid-organ recipient.1 |
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It is important to keep in mind that although most infections in transplant recipients are not communicable to health care workers, contact with a patient who has VZV infection, be it shingles or chickenpox, is a risk for all seronegative contacts including healthy staff working in transplant centers.
EPSTEIN BARR VIRUS
General Considerations
Epstein Barr virus (EBV) infection in transplant recipients may be associated with post-transplantation lymphoproliferative disease (PTLD), which is a significant cause of morbidity and mortality (Table 24-2). Post-transplantation lymphoproliferative disease occurs in solid-organ transplant recipients as well as in PBSC and bone marrow transplant recipients. The term PTLD acknowledges the fact that these lesions are heterogeneous and may not meet the diagnostic criteria for lymphoma. The spectrum of PTLD ranges from polyclonal to monoclonal. Monoclonal lesions may or may not contain detectable chromosomal abnormalities. PTLD is often multicentric and may involve the central nervous system, eyes, gastrointestinal tract, liver, spleen, lymph nodes, lungs, allograft, oropharynx, and other organs.
The pathogenesis of PTLD involves EBV replication often stimulated by antilymphocyte therapy, followed by cyclosporin-induced inhibition of virus specific cytotoxic T lymphocytes that normally control the expression of EBV infected, transformed B cells.
Risk factors for PTLD include EBV seronegativity pretransplantation, antilymphocyte therapy for rejection or graft-versus-host disease, and CMV seromismatch. Increased levels of circulating EBV-infected lymphocytes and decreased EBV nuclear antigen antibody responses have been associated with the development of PTLD in solid-organ transplant recipients in some, but not all, studies. More information is provided in Chapter 33.
Clinical Findings
Epstein Barr virus infection (without PTLD) may manifest as malaise, fever, headache, and sore throat. Clinical presentations of PTLD are varied and include a mononucleosis-like syndrome with fever, adenopathy, tonsillitis, and sore throat, fever, abdominal pain, anorexia, jaundice, bowel perforation, gastrointestinal bleeding, renal dysfunction, hepatic allograft dysfunction, pneumothorax, pulmonary infiltrates, and weight loss.
Treatment
Treatment of EBV-related PTLD is outlined in Table 24-2. High-level EBV oropharyngeal shedding found in primary infection is inhibited by acyclovir and ganciclovir, suggesting that antiviral therapy may be useful early when levels of viral replication are low. Unfortunately, once PTLD is established, treatment has been disappointing with the exception of drastically reducing the level of immunosuppression, which appears to have a beneficial effect in localized or polyclonal as well as multifocal or monoclonal PTLD. Disease localized to the transplanted organ or lymph nodes can be reversed with reduced immunosuppression and antiviral therapy; extranodal, multifocal, and brain disease typically require chemotherapy, radiation therapy, or both and are associated with a high mortality rate.
OTHER VIRUSES
General Considerations
Other viruses occasionally cause infection in transplant recipients. Adenovirus (Chapter 32), parainfluenza virus (Chapter 30), respiratory syncytial virus (Chapter 31), and influenza virus (Chapter 29) may cause upper respiratory tract infections and pneumonia (see also Chapter 9). Sporadic outbreaks of gastroenteritis caused by coxsackievirus (Chapter 27) or rotavirus occur (Chapter 37). BK virus (Chapter 45) and adenovirus viruria (Chapter 32) have been associated with hemorrhagic cystitis. BK virus has been associated with allograft nephropathy in renal transplant recipients. Both HBV and HCV may cause liver dysfunction after transplantation (Chapter 39). Transplant recipients are also at risk for human papilloma virus-associated malignancies (Chapter 45).
FUNGAL INFECTIONS
PNEUMOCYSTIS CARINII
General Considerations
P carinii pneumonia has been virtually eliminated in transplant recipients by the use of prophylactic trimethoprim-sulfamethoxazole. Clusters of cases of P carinii pneumonia have been reported, and a question of person-to-person transmission has been raised. More details are found in Chapter 79.
Clinical Findings
Treatment
P carinii pneumonia is treated with high doses of trimethoprim-sulfamethoxazole or intravenous pentamidine (Box 24-2). The former regimen is preferable.
Prevention
Trimethoprim-sulfamethoxazole provides excellent prophylaxis for P carinii pneumonia and should be given to all transplant recipients following transplantation (Box 24-3). Prolonged prophylaxis is indicated for heart-lung and lung transplant recipients and for patients with ongoing risk factors for P carinii pneumonia such as multiple episodes of rejection, ongoing graft-versus-host disease, treatment with antilymphocyte therapy, or persistent allograft dysfunction. Importantly, prophylaxis should be reinstituted if it has been discontinued, in patients receiving augmented immunosuppression. Alternatives to trimethoprim-sulfamethoxazole for prophylaxis include intravenous or aerosolized pentamidine, dapsone, and atovaquone. For single lung allograft recipients who cannot tolerate trimethoprim-sulfamethoxazole, there is some controversy about the use of aerosolized pentamidine that may be inadequately delivered to the remaining diseased and therefore poorly ventilated lung.
CANDIDA SPECIES
General Considerations
Among the Candida species, C albicans is most frequently implicated in causing infections in transplant recipients, however, C krusei, C glabrata, C zeylanoides, and C tropicalis have also been reported as pathogens and may infect any type of transplant recipient. More details are found in Chapter 73.
Clinical Findings
Treatment
Agents used for the treatment of serious candidal infections in transplant recipients include amphotericin B, fluconazole, ketoconazole, itraconazole and caspofungin (Box 24-2). The choice of the agent depends on the clinical presentation and typical fungal susceptibility pattern of the organism. Importantly, azole antifungal drugs may increase blood levels of cyclosporin.
Prevention
The use of a selective bowel decontamination regimen may reduce the incidence of candidal infections in liver transplant recipients. Fluconazole has been shown to prevent both deep and superficial candidal infections, excluding those caused by C krusei, in liver and PBSC and bone marrow transplant recipients (Box 24-3).
CRYPTOCOCCUS NEOFORMANS
General Considerations
Infections caused by C neoformans can occur at any time after transplantation in any type of transplant recipient. More details are found in Chapter 74.
Clinical Findings
MYCELIAL FUNGI
General Considerations
The Aspergillus spp. most frequently implicated in causing disease in transplant recipients include A fumigatus, A flavus, A niger, and A terreus. In addition, an expanding list of unusual organisms including Pseudalleschia boydii, Scopulariopsis brumptii, Trichosporon beigelii, Fusarium spp., zygomycetes, and others, have been reported as causes of serious fungal infections in transplant recipients. Most fungal infections caused by Aspergillus spp. occur in the first 3 months after solid-organ transplantation and are associated with a high mortality rate. In PBSC and bone marrow transplant recipients, the onset of aspergillal infections is bimodal, peaking 16 and 96 days after transplant. The portal of entry of Aspergillus spp. is usually the respiratory tract (lungs and sinuses). Rarely, dissemination from a primary skin lesion or contiguous spread from a previously sustained skin lesion to bone may occur. Aspergillus spp. may also invade the gastrointestinal tract or rarely gain entry through an intravenous catheter. More details are found in Chapters 75 and 77.
Zygomycetes, including Rhizopus spp., Mucor spp., Absidia spp., and Cunninghamella bertholletiae have been reported as pathogens in transplant recipients. Underlying metabolic disturbances resulting in an acidotic state such as that associated with diabetic ketoacidosis or that found in pancreatic transplant recipients with a bicarbonate leak and deferoxamine therapy are risk factors for zygomycosis. Zygomycetes are associated with rhinocerebral, pulmonary, gastrointestinal, cutaneous, and disseminated infections.
Endemic dimorphic fungal infections with geographically restricted endemic mycoses (H capsulatum, C immitis, B dermatitidis, and Paracoccidioides brasiliensis) can occur at any time after transplantation. In many cases, and especially with histoplasmosis, disseminated infection is seen. For more details, see Chapter 70.
Clinical Findings
Treatment
Treatment of deep fungal infections in transplant recipients does not differ significantly from that in other types of immunocompromised hosts (Box 24-2). Immunosuppression should be reduced as tolerated. Surgical extirpation or debridement should be performed for diagnostic and therapeutic purposes, if appropriate. Intravenous amphotericin B has been the mainstay of treatment for deep fungal infections in transplant recipients. The combination of cyclosporin and amphotericin B has been associated with renal failure. Some organisms (eg P boydii) are resistant to amphotericin B, emphasizing the need for identification of all fungal isolates in transplant recipients. Lipid formulations of amphotericin B have fewer side effects, especially including nephrotoxicity, than the standard preparation, but are more costly. Because of the high frequency of toxicity seen with amphotericin B, the use of azole antifungal agents for treating select fungal infections in transplant recipients is attractive. This is discussed further in chapters dealing with specific fungal organisms.
Prevention
Laminar air flow isolation in PBSC and bone marrow transplant units prevents aspergillal infections. Intravenous amphotericin B should be given to PBSC and bone marrow transplant recipients with a well-documented history of invasive aspergillosis pretransplant.
MYCOBACTERIAL INFECTIONS
MYCOBACTERIUM TUBERCULOSIS
General Considerations
All types of transplant recipients are at increased risk for both primary and reactivation M tuberculosis infection and disseminated disease is more commonly seen in transplant recipients than in nonimmunocompromised populations. For more information, see Chapter 61.
Clinical Findings
Treatment
See Chapter 61.
Prevention
A detailed history of tuberculosis exposure should be obtained on all transplant candidates and a tuberculin test should be performed on all solid-organ transplant candidates and on PBSC and bone marrow transplant candidates with a history of tuberculosis exposure. Isoniazid prophylaxis is recommended for patients with positive tuberculin tests or other risk factors for tuberculosis. If possible isoniazid prophylaxis should be administered for nine months pretransplantation. If this is not feasible, isoniazid can be given following transplantation. In addition, tuberculin test positive transplant recipients who have not previously received treatment or prophylaxis might benefit from isoniazid prophylaxis when they receive antilymphocyte preparations.
NONTUBERCULOUS MYCOBACTERIA
General Considerations
Nontuberculous mycobacteria reported as pathogens in transplant recipients include M kansasii, M avium-intracellulare, M fortuitum, M xenopi, M haemophilum, M marinum, M chelonai, M abscessus, M gastri, M scrofulaceum, M szulgai, and M thermoresistibile, among others. These infections are rare, generally occur late in the post-transplant period and are most commonly chronic, manifesting as cutaneous lesions of the extremities, tenosynovitis, and/or joint infection. Less frequently, allograft, pulmonary, or intestinal involvement may occur. For more details, see Chapter 62.
PARASITIC INFECTIONS
Parasitic infections in transplant recipients are generally not associated with distinctive presentations with the exception of Trypanosoma cruzi, Toxoplasma gondii, and S stercoralis.
TRYPANOSOMA CRUZI
General Considerations
In patients with T cruzi-associated cardiomyopathy undergoing heart transplantation, a new acute phase of Chagas' disease may develop. This is characterized by fever, cutaneous lesions (with or without parasites), and myocarditis (with or without parasites) and is responsive to specific drug therapy. Parasites have been demonstrated in the transplanted hearts of such patients, (see also Chapter 85).
TOXOPLASMA GONDII
General Considerations
Toxoplasmosis after transplantation is usually the result of reactivation of latent donor-derived disease in T gondii seronegative heart transplant recipients. This typically occurs in the seropositive donor heart because of a predilection of the parasite to invade muscle tissues. Rarely, T gondii infection may be seen in other types of transplant recipients. Most cases occur within 2 months post-transplantation although cases have been reported between 1 day and 7 years after transplantation. For more details, see Chapter 81.
Clinical Findings
Treatment
Toxoplasmosis is treated with pyrimethamine with folinic acid and either sulfadiazine or clindamycin (Box 24-2).
Prevention
Toxoplasmosis is generally prevented by the same doses of trimethoprim-sulfamethoxazole used for P carinii prophylaxis (Box 24-3). An alternative is pyrimethamine.
STRONGYLOIDES STERCORALIS
General Considerations
S stercoralis is the one helminth that deserves special mention as concerns transplant recipients (see also Chapter 86).
Clinical Findings
Treatment
Thiabendazole or ivermectin is used to treat strongyloidiasis (Box 24-2).
Prevention
As noted in the discussion on the pretransplantation evaluation, patients who have traveled to or resided in an area of endemic infection should be examined for evidence of infection with this parasite pretransplantation.
Differential Diagnosis in Transplant Recipients
The main differential diagnosis of infections in transplant recipients is rejection. Drug toxicity must also be considered.
Prevention of Infections in Transplant Recipients
For PBSC and bone marrow transplant recipients, vaccinations are administered following transplantation (Box 24-3).
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