Healthcare-Associated Infections in Solid Organ Transplant Recipients



Healthcare-Associated Infections in Solid Organ Transplant Recipients


Ryosuke Osawa

Nina Singh



Infections remain a significant complication and a leading cause of mortality, particularly within the first year after transplantation. Most infections in transplant recipients are healthcare-associated and represent either opportunistic infections resulting from iatrogenic immunosuppression or infections resulting from conventional healthcare-associated pathogens. The incidence of several opportunistic infections (e.g., cytomegalovirus [CMV] and Pneumocystis jirovecii pneumonia [PJP]) has declined dramatically, largely because of the advent of effective prophylaxis. On the other hand, healthcare-associated infections (primarily due to bacteria) transmitted from environmental reservoirs or harbored as a result of endogenous colonization in healthcare-associated settings have emerged as leading infections in organ transplant recipients. In liver transplant recipients, 82% of the episodes of fever documented in consecutive patients over a 2-year period were healthcare associated, of which 62% were bacterial in origin (1). Fifty-three percent of all infections in heart transplant recipients in another study were healthcare-associated, and of these, 63% were bacterial (2).

Paralleling the trends in healthcare-associated infections, antimicrobial resistance is increasingly recognized as a problem in the transplant setting. It is noteworthy, however, that the emergence of several of the antibioticresistant pathogens was first documented in transplant recipients (3). For example, vancomycin-resistant enterococci (VRE) were initially discovered in liver transplant recipients at several institutions where they eventually became a more widespread problem.

Transplant recipients are uniquely vulnerable to colonization and infection resulting from healthcare-associated pathogens. Within the same institution, transplant recipients have been shown to have a significantly higher incidence of healthcare-associated infections than nontransplant patients (4). The predilection of immunocompromised patients to Legionella infection is well recognized. However, it is notable that within this subgroup, transplant recipients have the highest risk (5). Among patients undergoing surgical procedures at one institution where legionellosis was documented, renal transplant recipients had an attack rate of 50%, whereas the general hospital population experienced an attack rate of only 0.4% (6). Transplant recipients exposed to tuberculosis during an institutional outbreak were more likely to contract Mycobacterium tuberculosis as compared with nontransplant contacts of the source case (7). During a healthcare-associated outbreak of extended-spectrum β-lactamase-producing Escherichia coli, 67% of patients on the liver transplant service, but no other surgical patients on the same floor, were shown to be colonized or infected with the outbreak isolate (8).

This chapter discusses the potential sources of infections, unique risk factors according to the type of organ transplanted, and the treatment and prevention of infections in solid organ transplant recipients that may be acquired during or after transplantation.


SOURCES OF INFECTIONS IN RECIPIENTS


Donor-Derived Infections

Latent Infections in the Donor Viral infections latent in the donor have by far the greatest potential for transmission by the transplanted organ and exert a more profound clinical impact in the allograft recipient compared with many other donor-transmitted infections. Thus, serologic screening of the donor for hepatitis B virus (HBV), hepatitis C virus (HCV), CMV, EBV, and human immunodeficiency virus (HIV) is routinely recommended (9). Nonviral infections (e.g., toxoplasmosis) are also discussed here.

Hepatitis B Virus The risk of transmission of HBV varies according to the HBV serologic profile of the donor and the recipient and the type of organ transplanted (liver vs. nonliver). Transplantation of allografts from hepatitis B surface antigen (HBsAg)-positive donors carries the highest risk of HBV transmission and is recommended only in life-threatening situations. IgM antibody to hepatitis B core antigen (anti-HBc IgM) positivity indicates either recent or current infection; it should be managed as in HBsAgpositive donors. Anti-HBc IgG positivity in the absence of HBsAg poses a low likelihood of transmission of HBV. The liver may continue to harbor the replicative form of HBV in such donors with the potential of HBV transmission even in the presence of anti-HBs (10). Donors with isolated anti-HBc positivity should be considered infectious, especially for the hepatic allograft. Indeed, 78% (18/23) of the liver transplant recipients from donors with isolated
anti-HBc experienced HBV transmission (11). Transplantation of an anti-HBc-positive liver into a nonimmune recipient should be performed only if deemed medically urgent and under a prophylactic regimen of lamivudine with or without hepatitis B immune globulin (HBIG) (12,13). However, the risk of HBV transmission for recipients of nonhepatic organs is low. None of the seven heart transplant recipients and 2.3% (1/42) of the renal transplant recipients who received organs from isolated anti-HBc-positive donors became infected (14). General consensus is that the organs from anti-HBc positive donors should be used for recipients who are HBsAg positive or who have evidence of HBV immunity. The risk of HBV transmission from anti-HBc-positive donors to nonhepatic organ recipients can be further stratified based on the presence of HBV DNA in the serum at the time of transplantation (15) as the risk is considered negligible if serum HBV DNA is negative. The use of anti-HBc-positive nonhepatic allografts has not been associated with poor outcomes (16,17). Anti-HBs-positive liver donors who are negative for both HBsAg and anti-HBc are generally considered unlikely to transmit HBV. Anti-HBs positivity is usually explained by HBV vaccination or administration of hepatitis B immunoglobulin. However, the potential for HBV transmission can still exist for donors with isolated anti-HBs positivity since HBV DNA may be detectable in the hepatic allografts (18).

The most important measure to prevent HBV transmission is the administration of HBV vaccine to nonimmune transplant candidates. However, HBV transmission may occur even if recipients are immune to HBV (positive anti-HBs status). Transplantation of any organs from HBsAgpositive donors should be ideally avoided. If a recipient emergently needs an organ from HBsAg-positive donors due to life-threatening situations, the recipient should receive HBIG and prophylactic antiviral therapy with lamivudine for a minimum of 1 year with close monitoring of liver enzymes, HBsAg, anti-HBs, and HBV DNA. Liver transplant from an IgG anti-HBc-positive donor should be managed in a similar manner. HBV-immune candidates can receive extrahepatic organs from an IgG anti-HBc-positive donor without any prophylaxis; however, posttransplant surveillance for liver enzymes, HBsAg, anti-HBs, and HBV DNA are recommended. If potential candidates are not immune to HBV, HBIG, and/or lamivudine are typically administered. The duration of prophylaxis depends on the presence of the donor HBV DNA. If the donor HBV DNA at the time of transplant is negative, prophylaxis may be discontinued. If the donor HBV DNA is positive or unknown, HBIG for >3 to 6 months or lamivudine for >12 months should be continued (13,15).

Hepatitis C Virus Approximately 5% of all cadaveric organ donors are positive for antibody to HCV (anti-HCV), and 50% of these have detectable HCV viremia by PCR (19). Nearly all the recipients from anti-HCV-positive donors become infected with HCV (20). Donor-derived HCV infection is associated with rapid progression of fibrosis and high mortality (21). Transplantation of livers from HCV-positive donors into HCV-positive recipients has not been associated with a decrease in graft or patient survival up to 8 years (22, 23 and 24). Most transplant centers use HCV-positive extrahepatic organs only for HCV-positive recipients, because there are data suggesting that donor HCV-positive status is independently associated with decreased survival regardless of recipient HCV status (25,26). The use of anti-HCV-positive organs in anti-HCV-negative recipients should be avoided; however, it may be considered in lifethreatening situations. Unlike HBV, no effective measures to prevent HCV transmission are currently available.

Herpesviruses The donor allograft is a significant and an efficient source of transmission of CMV (27,28). The morbidity from infection is greatest in CMV-seronegative recipients of CMV-positive allografts. Superinfection (i.e., infection with an exogenous strain of CMV in patients with prior evidence of CMV infection) has also been documented. Symptomatic CMV disease occurred more frequently in patients infected with the new CMV strain compared with those with reactivation of the latent virus (29). Donor transmission (documented by molecular typing) has also been demonstrated with other herpesviruses, including herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), and human herpesvirus-6 (HHV-6) (30, 31, 32, 33 and 34). EBV-seronegative recipients of EBV-positive allografts are at highest risk of developing EBV-associated posttransplant lymphoproliferative disorder, especially among intestinal transplant recipients (35,36). Transmission of herpesviruses from donors to recipients is not preventable; however, identification of recipients is at high risk (i.e., seronegative recipients) followed by use of antiviral prophylaxis (CMV, HSV) with or without monitoring of viral replication and close clinical follow-up with symptoms is crucial. Management issues of herpesviruses infection are discussed later in this chapter.

Human Immunodeficiency Virus Donor positivity for HIV by enzyme-linked immunosorbent assay (ELISA) is considered an absolute contraindication to organ donation. There is a remote possibility that HIV can be transmitted from donors who test negative for HIV antibody if the time of transplantation is during the window period or if the test is falsenegative due to resuscitation-associated hemodilution.

Recently, transmission of HIV was reported in three organ recipients from a donor who had sex with men who tested negative for HIV antibody (37,38,39). Scrutinizing the donor’s behavioral and medical risks of HIV in a limited time frame followed by weighing these risks against the benefits of transplantation are critically important (40). Use of special consent forms for transplantation of organs from high-risk donors has been utilized in many transplant centers. Although more sensitive nucleic acid amplification assays are available, the cost and delayed turnover time may prohibit their routine use.

Human T-Cell Lymphotrophic Virus Type 1/2 Human T-cell Lymphotrophic Virus Type 1/2 (HTLV-1/2) is a retrovirus with marked geographically variant prevalence from 0.035% to 0.046% in the United States blood donors to 30% in Southern Japan (41,42). UNOS data revealed that the prevalence of HTLV-1 and HTLV-2 among the US organ donors is 0.027% and 0.046%, respectively (43). Although HTLV-1 is associated with the development of acute T-cell lymphoma and HTLV-1-associated myelopathy, the majority of these patients remain asymptomatic. Only a few cases of documented transmission and development of HTLV-1-associated disease in solid organ transplant
recipients have been reported (44,45). HTLV-2 does not appear to be associated with the clinical syndrome. The OPTN/UNOS Ad Hoc Disease Transmission Advisory Committee recently recommended against routine screening for HTLV-1/2 given the lack of routine availability of some commercial assays, a high false-positive rate leading to the waste of organs, favorable short-term follow-up of recipients of HTLV-1/2 screen positive organs, and low prevalence of the disease in the United States (46).

Mycobacterium tuberculosis Transmission of M. tuberculosis to recipients receiving allografts from donors with active tuberculosis has been documented. Transmission of M. tuberculosis to two renal transplant recipients from a donor with unrecognized tuberculous meningitis at the time of organ retrieval has been reported (47). Tuberculin-positive donors without clinically overt tuberculosis may also transmit tuberculosis. Tuberculin-positive living donors should receive chemoprophylaxis after appropriate workup to rule out active tuberculosis if delay of transplant is acceptable. It is recommended that the recipients of allografts from donors with latent tuberculosis or a history of tuberculosis should receive chemoprophylaxis for tuberculosis after transplantation (47).

Toxoplasma gondii Toxoplasma gondii, because of its predilection for latency in muscle tissue, poses a substantial risk for transmission of toxoplasmosis in heart transplant recipients. In the absence of prophylaxis, 50% to 70% of the seronegative recipients of T. gondii antibody-positive allografts have developed toxoplasmosis (48). Heart transplant donors and recipients should be serotested to determine the risk for toxoplasmosis. Because of the paucity of Toxoplasma cysts in noncardiac tissue, toxoplasmosis is rarely transmitted by the nonheart organs and pretransplant screening is controversial in this population (49). Prophylactic use of trimethoprim-sulfamethoxazole significantly decreases the risk of developing toxoplasmosis posttransplant in heart transplant recipients (50,51). Some experts administer a higher dose of trimethoprimsulfamethoxazole or a combination of pyrimethamine and sulfadiazine to high-risk patients (seronegative recipients of a seropositive heart).

Trypanosoma cruzi Trypanosoma cruzi is an endemic parasitic disease in Latin America (American trypanosomiasis). It is transmitted by the triatomine insect, but blood transfusion, maternal-fetal transmission, and organ transplant are also the major routes of transmission in a nonendemic area (52,53). Donor screening should be performed for those who lived or traveled in an endemic area. Organs from donors positive for T. cruzi should not be utilized especially for heart transplant given its fatal outcomes (54). If nonheart organs are utilized in emergent situations, aggressive monitoring with direct parasitological tests and/or PCR-based assays (51).

Other Pathogens Transmission of endemic fungi including Histoplasma capsulatum and Coccidioides immitus via donor allograft has been reported (55,56). Although active fungal infections should be excluded prior to procurement, no consensus exists with regard to donor screening for latent fungal infection. West Nile virus (WNV), rabies, and lymphocytic choriomeningitis virus (LCMV) are the examples of emerging pathogens that have been reported to be donor derived (57, 58 and 59).

Acquired Infections in the Donor Life-sustaining measures in critically ill donors may render them susceptible to healthcare-associated infections with the potential for transmission to allograft recipients. Two recent studies comprising a large number of patients have shown that donor bacteremia did not portend a higher risk of infectious complications or compromise graft or patient survival (60,61). The most frequent cause of the donor bacteremias in these studies was gram-positive bacteria, of which Staphylococcus aureus was the predominant pathogen. Most recipients of organs retrieved from bacteremic donors in the aforementioned studies received antimicrobial therapy. In the study by Lumbreras et al. (60), specific antibiotics were administered to the recipients for 7 to 10 days on receipt of donor blood culture results. In the report by Freeman et al. (61), 91% of the recipients received antibiotics for a mean of 3.8 days. These data suggest that with appropriately administered antibiotic therapy, organs from bacteremic donors can be successfully transplanted without incurring an additional risk for infection or allograft dysfunction in the recipient.

A similar dilemma exists regarding the feasibility of using organs from donors with bacterial meningitis (62). Lopez-Navidad et al. (62) described the outcome in 16 recipients who had received organs from five patients with bacterial meningitis. The pathogens included Neisseria meningitidis, Streptococcus pneumoniae, and E. coli. With antibiotic administration ranging from 5 to 10 days, infection caused by the aforementioned bacteria was not documented in any of the recipients. Thus, patients with brain death attributable to bacterial meningitis caused by these bacteria can also be suitable organ donors, if the donor and the recipient receive appropriate antibiotic therapy. An exception, however, is donors with a less commonly encountered bacterial infection, that is, M. tuberculosis. Unrecognized active M. tuberculosis infection in the donor can be efficiently transmitted to the recipient with deleterious sequelae. Moreover, caution must be exercised when transplantation from donors with a presumptive diagnosis of bacterial meningitis is considered.

Donor organs colonized with Candida or Aspergillus may transmit the fungi to lung and heart-lung transplant recipients. Karyotypic analysis of the Candida albicans isolates demonstrated identical strains from the donor lung and C. albicans isolates causing disseminated infection in a lung transplant recipient (63). Donor organs have also been documented to transmit other fungal infections (e.g., Cryptococcus neoformans and Histoplasma capsulatum) (64).


Contamination during Organ Procurement

Contamination during harvesting and preservation of the allograft has been reported to occur in 2% to 23% of the kidney allografts. Although some bacteria (e.g., Staphylococcus epidermidis, diphtheroid species, and Propionibacterium acnes) present little risk of infection to the allograft recipient, more virulent pathogens (e.g., gram-negative rods, particularly Pseudomonas aeruginosa; S. aureus; and
fungi) cultured from the donor or the preservation fluid can lead to serious infections (e.g., mycotic aneurysm and anastomotic rupture) in kidney transplant recipients (64, 65 and 66).


Blood Products

Although CMV infection has been shown to be transmitted by blood products in organ transplant recipients, the risk is small and has not been shown to correlate with the number of blood products transfused (33). Over a 13-year period, only 2.6% (3/112) of CMV-seronegative recipients who received CMV negative renal, heart, lung, or liver allografts were documented to develop transfusion-associated CMV infection (67). Furthermore, transfusion, compared with donor-transmitted CMV infection, has been associated with a lower frequency of symptomatic disease and, therefore, has a less profound clinical impact (68). Nevertheless, the use of CMV seronegative blood products or leukoreduced blood product for recipients who are seronegative for CMV should be considered. Finally, the use of leukoreduced blood product further reduced the risk of CMV transmission.

Since 1990, all blood products in the United States have been routinely screened for HCV. Consequently, the risk of posttransfusion HCV has declined from 8% to 10% to <1% currently.


Environmental Reservoirs and Sources

Environmental sources are significant sites for acquisition of a number of infectious agents, particularly healthcareassociated pathogens in transplant recipients (Table 58-1). Most cases of Legionella in solid organ transplant recipients are healthcare-associated (69). The source of posttransplant legionellosis in all studies where an environmental link was sought was the hospital’s potable water distribution system (5). Restriction fragment length polymorphism patterns documented that the hospital’s central hot water supply was the source of legionellosis in a hospital where 14 cases were documented in transplant recipients over an 8-year period (70). Healthcare-associated legionellosis in heart-lung transplant recipients at one institution was linked to a contaminated ice machine (71).

Outbreaks of invasive aspergillosis in transplant recipients have been linked to construction or demolition activity within or near a hospital; contaminated or poorly maintained ventilation ducts, grids, or air filters; and other dust-generating activities that may aerosolize Aspergillus spores. Accommodation of marrow transplant recipients outside of rooms with laminar air flow and high-efficiency particulate air (HEPA) filters during periods of neutropenia have been shown to be a risk factor for invasive aspergillosis (72). A seasonal variation in the incidence of invasive aspergillosis, coinciding with a high outdoor concentration of airborne spores in late summer or fall and a lower concentration in the winter months, has also been observed. The prevailing belief that Aspergillus is predominantly an airborne pathogen acquired via inhalation has recently been challenged. It has been proposed that Fusarium and Aspergillus can be detected in hospital water systems, and aspiration, as opposed to inhalation of Aspergillus, may be the mode of acquisition of healthcare-associated invasive aspergillosis in susceptible hosts (73).

The prevailing assumption has been that P. jirovecii infection arises from reactivation of endogenous infections
acquired in childhood. However, healthcare-associated patient-to-patient transmission and environmental contamination of P. jirovecii has also been documented (74,75). A cluster of renal transplant recipients who developed PJP shared the same strain confirmed by multilocus DNA sequence typing (76,77). P. jirovecii DNA has been demonstrated in more than 50% of the air samples from the hospital rooms of P. jirovecii-infected patients (78). It remains to be determined whether isolation of patients with PJP decreases the incidence of PJP, though such trials would be difficult in the current era of routine anti-PJP prophylaxis.








TABLE 58-1 Mode of Acquisition of Major Pathogens in Transplant Recipients
















































































Pathogen


Mode of Acquisition


Viruses


Cytomegalovirus



Seronegative recipient


Donor transmission, rarely transfusions



Seropositive recipient


Reactivation and donor transmission


Herpes simplex virus


Reactivation, rarely donor transmission


Varicella zoster virus


Reactivation, rarely donor transmission


Human herpesvirus-6


Reactivation and donor transmission


Hepatitis C virus


Reactivation, unless donor anti-HCV positive


Hepatitis B virusa


Rarely donor transmission


Adenovirus


Donor and healthcare-associated transmission


Respiratory viral infections


Healthcare-associated and community acquisition


Bacteria


Staphylococcus aureus


Endogenous colonization, healthcare-associated transmission


Vancomycin resistant enterococci


Healthcare-associated transmission, endogenous gastrointestinal colonization


Pseudomonas aeruginosa


Healthcare-associated environmental acquisition


Enterobacteriaceae


Endogenous colonization, healthcare-associated transmission


Legionella


Environmental acquisition


Mycobacterium tuberculosis


Reactivation, donor transmission, healthcare-associated transmission


Fungi


Candida


Endogenous infection (liver transplants), donor transmission (lung transplants)


Aspergillus


Environmental acquisition


Pneumocystis jirovecii


Reactivation, possibly healthcare-associated transmission


Cryptococcus neoformans


Primarily reactivation


Protozoa


Toxoplasma gondii


Donor transmission, rarely reactivation


a HBsAg-positive donors can transmit hepatitis B virus (HBV) but are not considered acceptable organ donors. Rarely anti-HBs-positive donors (particularly of hepatic allografts) can transmit HBV.


VRE and methicillin-resistant S. aureus (MRSA) have become established as endemic pathogens in many institutions and are increasingly recognized as significant microorganisms in transplant recipients. At many centers, VRE, MRSA, or Clostridium difficile are currently the most frequent etiologic agents of infections in transplant recipients. Although patient-specific variables (e.g., severity of illness, intensity of antimicrobial use, and length of hospital stay) are risk factors for acquisition, environmental contamination and, more importantly, person-to-person transmission are also considered significant factors in the healthcare-associated spread of these bacteria. Equipment and surfaces in the vicinity of patients colonized and infected with VRE have been shown to become contaminated with VRE; VRE could be recovered for at least 7 days from the surfaces of countertops and after 30 minutes from the stethoscopes (79). Furthermore, epidemiologic studies have documented healthcare-associated VRE transmission by molecular typing techniques (80). Likewise, pulse-field gel electrophoresis demonstrated that 43% of the MRSA isolates causing invasive infections at a transplant unit shared the same pattern, suggesting healthcare-associated transmission (80).

C. difficile is currently the most common cause of infectious diarrhea in transplant recipients. Liver transplantation was identified as the most significant independent risk factor for C. difficile acquisition in one report (81). Although the precise mode of transmission of C. difficile has not been determined, environmental contamination and healthcareassociated transmission are the likely mode of transmission of C. difficile; however, airborne dispersal of spores could be another important source (82,83). C. difficile was recovered from 9% to 51% of the environmental cultures; objects contaminated with feces (e.g., bed pan, toilet seats, sinks, and scales were most likely to yield C. difficile) (84). Positive hand cultures were documented in 59% of the hospital personnel caring for the patients with C. difficile, implicating hands of hospital personnel as a likely mode of transmission (85). Prudent use of antimicrobial agents and measures to curtail healthcare-associated transmission are key toward effective prevention of infections caused by these pathogens.


RISK FACTORS FOR INFECTIONS

Surgical factors, intensity of immunosuppression, and variations in local and systemic host response are among the variables that determine not only the type but also the site and the severity of infections in different types of organ transplant recipients (Table 58-2).








TABLE 58-2 Risk Factors for Infection with Major Healthcare-Associated Pathogens in Transplant Recipients



























































Pathogen


Risk factors


Fungi Aspergillus


Lung transplantation


Single-lung transplant, CMV infection, airway ischemia, hypogammaglobulinemia, pretransplant and posttransplant Aspergillus colonization, bronchial stent


Liver transplantation


Poor allograft function, renal failure (particularly a requirement for dialysis), retransplantation


Heart transplantation


Isolation of Aspergillus species in respiratory tract cultures, reoperation, CMV disease, posttransplant dialysis


Renal transplantation


Augmented immunosuppression, graft failure requiring hemodialysis


Candida


Liver transplantation


Prolonged operation time, high transfusion requirement, renal failure, repeat operation, retransplantation, choledochojejunostomy


Pancreatic transplantation


Diabetes, exocrine enteric drainage


Pneumocystis jirovecii


Augmented immunosuppression, allograft rejection, CMV infection, low CD4 count


Viruses


Cytomegalovirus


Donor CMV seropositivity, Augmented immunosuppression (particularly, antilymphocyte agents), allograft rejection, HHV-6 infection


Bacteria


Vancomycin-resistant enterococcus


Rectal colonization prior to transplant, previous antibiotic use, biliary complications, prolonged hospitalization, surgical reexploration, allograft nonfunction


Methicillin-resistant


Nasal S. aureus carriage, prolonged hospitalization, ICU stay


Staphylococcus aureus


Legionella


Contaminated hospital potable water system, humidifiers, and ice machines


Mycobacterium tuberculosisa (risk factors for early-onset tuberculosis)


Nonrenal transplantation, history of prior M. tuberculosis (positive tuberculin test or old active tuberculosis on chest radiographs), OKT3 use


Pseudomonas aeruginosa


Donor colonization (lung transplants), cystic fibrosis


a Early-onset tuberculosis implies infection occurring within 12 months of transplantation.


CMV, cytomegalovirus; HHV-6, human herpesvirus-6; ICU, intensive care unit.




Liver Transplantation

Liver transplant recipients, by virtue of having hepatic failure and malnutrition before transplantation, represent severely compromised hosts. Many of these patients have concomitant renal failure as a result of hepatorenal syndrome. Renal failure, particularly the requirement for dialysis, was an important predictor of early infections and adversely affected survival after liver transplantation (86,87).

Liver transplant recipients are uniquely susceptible to invasive candidiasis. Most cases originate from endogenous sources; deficient reticuloendothelial function and translocation across the gut mucosa are considered important pathogenetic factors predisposing to invasive candidiasis (88). Vascular and anastomotic complications are also significant risk factors for infectious morbidity in liver transplant recipients. Duct-to-duct biliary anastomosis compared with Roux-en-Y choledochojejunostomy is associated with a lower incidence of infections, because the latter involves the breach of the bowel integrity and sacrificing the sphincter of Oddi, which may promote reflux of bowel contents into the biliary tree (89). Hepatic artery thrombosis may lead to the development of hepatic infarcts with subsequent gangrene and abscess formation. The clinical presentation is usually acute or fulminant, although hepatic artery occlusion may occasionally be occult and present with a clinical picture of unexplained fever and relapsing subacute bacteremia. Hepatic artery thrombosis may also lead to liver abscesses by compromising the biliary vascular supply. Impaired arterial flow to the hepatic allograft preferentially affects the biliary tree because of the biliary tract’s almost total reliance on the hepatic arterial blood supply. Hepatic artery thrombosis may thus lead to biliary tract ischemia and biliary leaks, eventually resulting in intrahepatic abscess formation.

The biliary tract may be a source of infection even with an intact vascular supply. Biliary composition is altered during liver transplantation, leading to supersaturation with cholesterol and sludge and stone formation that may predispose to infections (e.g., cholangitis). T tubes, commonly used to protect duct-to-duct biliary anastomoses, are prone to microbial colonization and form a nidus for the deposition of biliary sludge.

Portal vein thrombosis was shown to be the most significant independent predictor of early bacterial infections after liver transplantation (90). Recurrent viral HCV hepatitis has been documented in nearly 50% of the patients undergoing liver transplantation for end-stage liver disease resulting from HCV. HCV is considered an immunosuppressive and an immunomodulatory virus. Patients with HCV recurrence were significantly more likely to develop late-occurring infections, particularly fungal infections after liver transplantation (91).


Renal Transplantation

Urinary tract and postoperative surgical site infections are two of the most frequent and serious healthcare-associated infections in renal transplant recipients. Urinary tract infections occur in more than 50% of patients during the first 3 months after transplantation and are the most frequent source of bacteremia during this time. In the absence of antimicrobial prophylaxis, surgical site infections have been reported in up to 20% of patients. Organ/space surgical site infections after renal transplantation have been shown to adversely affect graft survival.

Surgical site infections in renal transplant recipients are usually due to staphylococci or gram-negative bacilli (92,93). Staphylococcal infections were associated with incisional surgical site infections and occurred earlier, whereas those due to gram-negative bacilli occurred later; were organ/space surgical site infections; and often led to bacteremia, graft loss, or death. Prolonged urinary catheterization, a surgical site hematoma, a reopened surgical site, and a cadaveric donor graft are risk factors for healthcare-associated urinary or surgical site infections in renal transplant recipients (94,95). Renal trauma with nephrectomy and graft contamination during transportation may likely account for a higher risk of infection in cadaveric compared with living allograft recipients. Bacteriuria occurring in the late posttransplant period is usually benign and rarely symptomatic; however, late-onset (>6 months) urinary tract infections were significantly associated with an increased risk of graft loss (96, 97 and 98). Antimicrobial prophylaxis has proven highly effective in reducing the rate of urinary tract and surgical site infections in renal transplant recipients. A single perioperative dose of antibiotics led to a reduction in the incidence of surgical site infections from 25% to 2% (99). Prophylaxis with trimethoprim-sulfamethoxazole has been shown to significantly lower the incidence of urinary tract infections, bacteremias, and infections caused by gram-negative bacilli and S. aureus when compared with placebo (100). Currently, no recommendations are made for screening and treatment of asymptomatic bacteriuria in renal transplant recipients (101).


Heart and Lung Transplantation

Heart and lung transplant recipients are uniquely susceptible to healthcare-associated bacterial pulmonary infections, particularly in the first month after transplantation. Bacterial pneumonia has been reported in 35% to 48% of the lung and heart-lung transplant recipients (102,103). Impaired mucociliary clearance, loss of cough reflex, postoperative pain with splinting, and donor tracheal colonization are some factors contributing to a high risk of postoperative pneumonia in lung transplant recipients.

Multiple drug-resistant strains of P. aeruginosa and Burkholderia cepacia complex are of particular concern in patients undergoing lung transplantation for cystic fibrosis. Although panresistant P. aerguinosa colonization was associated with worse survival (88.6% vs. 96.6% at 1 year) than sensitive P. aeruginosa colonization, their survival is comparable to CF patients in the UNOS registry (86% at 1 year) (104). Thus, panresistant P. aeruginosa colonization should not be considered as a contraindication to lung transplant. Among B. cepacia complex, most transplant centers consider B. cenocepacia (B. cepacia complex genovar III) colonization or infection to be a contraindication for lung transplant given its worse outcomes compared with nongenovar III B. cepacia complex (105,106,107). In a retrospective study of 75 cystic fibrosis lung transplant recipients, 1-year survival rates are 92%, 89%, and 29% in noninfected patients, those with B. cepacia complex species other than B. cenocepacia, and those with B. cenocepacia, respectively (107). Although the infected lung is removed during transplantation, residual colonization of the airway, nasopharynx, and sinuses remains a potential
nidus for subsequent infection. Typically, a course of antimicrobial prophylaxis is given to prevent development of posttransplant lung infections based on the result of bacterial cultures from donor-and recipient-bronchus at the time of procurement.

Circulatory support devices (e.g., intraaortic balloon pump and left ventricular assist devices) are required in many potential heart transplant recipients, and their prolonged placement is a major risk factor for bacterial colonization and subsequent healthcare-associated infections after transplantation. Sternal surgical site infections occur in 5% to 20% of heart and heart-lung transplant recipients; staphylococci, Enterobacteriaceae, and P. aeruginosa are the most common causative microorganisms. Sternal surgical site infections may directly extend into the mediastinum and predispose to mediastinitis or mycotic aneurysms at the suture sites. Mediastinitis occurs in 2% to 9% of the heart and heart-lung transplant recipients; S. aureus, P. aeruginosa, and C. albicans have been the most commonly reported microorganisms (108, 109, 110 and 111). An unusual cause of mediastinitis in transplant recipients is Mycoplasma hominis (112).


Pancreatic Transplantation

Surgical site infections, abscesses, or urinary tract infections occur in 7% to 50% of the pancreatic transplant recipients (113, 114, 115 and 116). Organ/space surgical site infections are a significant cause of graft loss and mortality in these patients. The postoperative infection rates and the causative pathogens depend primarily on the technique used for the drainage of exocrine secretions of the pancreas. Enteric drainage (diversion into the small bowel) and bladder drainage are the main approaches used for drainage of exocrine secretions. Infection rates are generally higher with enteric drainage (which facilitates contamination with gastrointestinal bacteria); however, in a recent retrospective review of pancreatic transplant recipients, bladder drainage was associated with higher risk of bacterial infections (117).

Whereas aerobic and anaerobic enteric flora predominates in abscesses associated with enteric drainage, microorganisms in infections in which the viscus has not been opened are usually from the skin flora. Candida, however, is a common pathogen in all types of surgical site infections, including those using bladder drainage. A high incidence of Candida urinary colonization, because of diabetes in these patients, along with the nonacidic environment in the bladder created by the exocrine pancreatic secretions facilitate Candida colonization.


Small-Bowel Transplantation

Unique features predisposing to infections in small-bowel transplant recipients are the fact that the contents of the transplanted organ are nonsterile and that these patients require a higher intensity of immunosuppressive therapy to prevent graft rejection (118, 119, 120, 121 and 122). Virtually all smallbowel transplant recipients experience at least one episode of infection; the number of infectious episodes per patient may range from 1 to 11 (median, 5) (119). Multivisceral transplant recipients and those undergoing colonic segment transplantation with small-bowel transplantation are more likely to develop infections (119). It is noteworthy that small-bowel transplant recipients remain susceptible to infections, even in the late posttransplant period (i.e., more than 6 months after transplantation) (119,123).

Small-bowel transplant recipients, particularly CMV-seronegative recipients of seropositive grafts, are uniquely vulnerable to CMV infection and to recurrent episodes of CMV disease (118). CMV disease in recipient-negative donor-positive patients has been shown to adversely affect outcome in these patients. Consequently, some transplant centers do not use CMVseropositive small-bowel grafts for CMV-seronegative recipients (122). Notably, a small-bowel graft is involved in 81% to 90% of the patients with CMV disease (118,122).

Bacterial translocation in small-bowel transplant recipients predisposes these patients to intra-abdominal infections (peritonitis and abscesses). Selective decontamination of the gut after transplantation has been proposed to reduce early postoperative infections in small-bowel transplant recipients (120).


TIME TO ONSET

The relative frequency, types of infection, and the specific pathogens encountered after transplantation generally have a predictable time of onset. Thus, infections in transplant recipients must be evaluated in the context of time elapsed since transplantation. These data also have implications relevant for the institution of prophylaxis and the duration of prophylaxis.


Infections During the First 30 Days

Most infections occurring within 30 days of transplantation are a consequence primarily of surgical or technical complications related to transplantation, healthcare-associated acquisition, and rarely reactivation of latent infections (e.g., herpesviruses) in the recipient. Bacterial infections are by far the most frequently occurring infections during this period; vascular catheter-related infections, healthcare-associated pneumonia, C. difficile infection, and surgical site infections are the most common types. Fungal infections likely to be encountered in the first month after transplantation include candidiasis and aspergillosis. Nearly 75% of the cases of invasive candidiasis and aspergillosis in liver transplant recipients occur within the first month and virtually all within 2 months of transplantation (88,124). More recently, however, delayed occurrence of Aspergillus infections has been noted; 55% of the cases of invasive aspergillosis in liver transplant recipients occurred after 90 days of transplantation (125). Liver transplant recipients are uniquely susceptible to invasive candidiasis; disruption of the integrity of the bowel and gastrointestinal translocation are the proposed mechanisms. The only significant viral infection occurring within the first 30 days of transplantation is that due to the HSV. However, there is accumulating evidence to suggest that HHV-6 may also be a pathogen in the early posttransplant period (126). HHV-6 infection characteristically occurs earlier than CMV and may cause fever of unknown origin and idiopathic cytopenia during this period.



Infections Occurring between 30 and 180 Days

Although healthcare-associated infections may continue to pose a threat in patients requiring prolonged hospitalization, most infections occurring between 30 and 180 days after transplantation are opportunistic infections related to the effects of immunosuppression. The foremost pathogen in transplant recipients during this time period is CMV; however, infections resulting from M. tuberculosis, P. jirovecii, T. gondii, and Nocardia are also likely to be encountered during this interval. Clinically and histopathologically manifest recurrences of HCV hepatitis usually occur within 6 months of transplantation. In the absence of immunoprophylaxis for HBV, recurrence of HBV infections in the recipient occur a median of 3 months after transplantation.


Infections Occurring 6 Months or Later

Infectious diseases in the last posttransplant period are typically community-acquired infections similar to those occurring in the general population. However, patients requiring aggressive immunosuppression for recurrent or chronic rejection and those with poorly functioning allografts (e.g., liver transplant recipients with recurrent viral HBV or HCV) continue to be at risk for opportunistic infections. Posttransplant lymphoproliferative disorder, varicella-zoster virus (VZV) infections, cryptococcosis, and infections resulting from dematiaceous fungi typically occur 6 or more months after transplantation.


VIRAL INFECTIONS


Herpesviruses

Cytomegalovirus CMV has been recognized as one of the most significant pathogens in organ transplant recipients (127,128,129,130). Depending on the pretransplant CMV serostatus of the recipient, three distinct epidemiologic patterns of CMV infection exist. Primary infection occurs when a seronegative recipient acquires CMV, either from the transplanted allograft or less commonly from blood products. Reactivation infection results from endogenous reactivation of the latent virus. Superinfection implies acquisition of a new strain of CMV in a patient seropositive for CMV before transplantation. Because 50% to 70% of the general population is seropositive for CMV, most infections in transplant recipients represent reactivation infections. However, the clinical impact of CMV is by far greatest in the context of newly acquired or primary infection. Primary CMV acquisition is associated with a higher rate of CMV infection and symptomatic disease, earlier onset of CMV infection posttransplantation, higher incidence of recurrence, greater risk of dissemination, and higher mortality (131,132). Symptomatic disease, CMV hepatitis, invasive fungal infections, and death in liver transplantation were more likely to occur when primary infection in the recipient was acquired from the donor organ compared with acquisition from transfusions (68). The time to onset of CMV infection after transplantation is also shorter with donor versus transfusion-associated CMV infection (68). Superinfection, as compared with reactivation infection, is also associated with a higher incidence and severity of symptomatic CMV disease (133).

Risk Factors CMV serologic status of the recipient and donor is the most significant factor influencing the rate and severity of CMV infection. Eighty percent to 100% of the seronegative recipients of a seropositive donor allograft (D+/R−) acquire CMV infection after transplantation. The risk of CMV infection is lowest (<10%) in seronegative recipients of seronegative organ donors. CMV-seropositive recipients have an intermediate risk (40% to 60%) for developing CMV infection. The intensity and type of immunosuppression are also important determinants of the risk of CMV infection (134). Antilymphocyte preparations (e.g., OKT3, thymoglobulin) are extremely potent reactivators of CMV. Primary immunosuppressive agents (e.g., cyclosporine and tacrolimus), on the other hand, are not efficient reactivators, but, when CMV reactivation occurs, they interfere with the host’s ability to limit viral replication (134).

Primary infection with HHV-6, which is considered an immunomodulatory virus, has been proposed to be a risk factor for subsequent CMV invasive disease (135,136). Intraoperative hypothermia is a common complication of liver transplant surgery. In a study in liver transplant recipients, intraoperative hypothermia was an independently significant risk factor for early CMV infection and active warming using a convective heating device appeared to curtail this risk (137). Human leukocyte antigen matching and retransplantation have also been shown to be risk factors for CMV infection (131,138).

Pathogenesis CMV-specific major histocompatibility complex (MHC)-restricted cytotoxic T cells are pivotal in host defense against CMV; clinically significant CMV occurs predominantly among patients without an adequate T-lymphocyte response. Humoral immunity, on the other hand, is an ineffective host defense against CMV, although it may modify (or temper) the severity of infection. Tumor necrosis factor-alpha has been shown to be a powerful promoter of CMV (134,139,140). Any physiologic stimulus for tumor necrosis factor-alpha release (e.g., OKT3, sepsis, and rejection), therefore, has the potential to activate CMV.

CMV is considered an immunosuppressive virus that may facilitate superinfection with opportunistic pathogens (e.g., fungi, gram-negative bacteria, and P. jirovecii) (131,141). Other indirect sequelae of CMV infection include acute and chronic allograft rejection, bronchiolitis obliterans in lung transplant recipients, atherogenesis in heart transplant recipients, and glomerulopathy in renal transplant recipients.

Epidemiology and Clinical Features The overall incidence of CMV infection ranges between 40% and 90% in organ transplant recipients. Without prophylaxis, the highest incidence of CMV infection has been documented in lung or heart-lung transplant recipients (60-98%) and the lowest (40-50%) in renal transplant recipients. Liver and heart transplant recipients have an intermediate risk of CMV infection (50-67%). The frequency of symptomatic disease resulting from CMV ranges from 8% to 15% in renal, 20% to 35% in liver, 27% to 30% in heart, and 55% to 60% in lung transplant recipients. The incidence of CMV infection in small-bowel transplant recipients approaches that in lung transplant recipients (118). Small-bowel transplant patients also appear to be uniquely susceptible to recurrent episodes of CMV infection (118).


Traditionally, most CMV infections have occurred between 4 and 6 weeks. In patients receiving prolonged antiviral prophylaxis, onset of CMV infection has been noted to be delayed (142, 143, 144 and 145) as antiviral prophylaxis only inhibits viral replication and does not eradicate latent infection. A febrile mononucleosis syndrome characterized by fever, arthralgias, myalgias, leukopenia, and atypical lymphocytosis is the most common symptomatic disease caused by CMV, although localized or disseminated tissue invasive disease may also occur. Predilection to involve the transplanted allograft is a peculiar characteristic of CMV. CMV hepatitis occurs most commonly in liver transplant recipients, CMV pneumonitis occurs most commonly in lung transplant recipients, and CMV enteritis occurs most commonly in small-bowel transplant recipients. It is proposed that the transplanted allograft may provide a sequestered site for latently infected cells, because MHC mismatches at these sites may prevent the generation of virus-specific cytotoxic T-cell responses (146).

Diagnosis The diagnosis of CMV infection has traditionally been made by viral isolation. These culture-based assays are considered obsolete because of their low sensitivity and time-consuming nature. Conventional cultures take up to 4 weeks. The shell vial assay uses a monoclonal antibody to detect a 72-kDa immediate early CMV antigen and allows detection of CMV within 16 to 24 hours (147). The currently available tests not only allow rapid and reliable diagnosis of CMV infection but also may detect viral shedding at an earlier stage. The pp65 antigenemia assay detects CMV-infected leukocytes with monoclonal antibodies directed against the 65-kDa lower matrix phosphoprotein (148,149). The CMV antigenemia assay is more sensitive and allows earlier detection of CMV than shell vial culture does. Furthermore, results of the antigenemia assay can be quantitated; the number 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. The major drawback of the antigenemia assay is the need for immediate processing of blood samples. Detection of viral DNA by PCR in the plasma or whole blood is also very sensitive for the diagnosis of CMV, and it has been considered the gold standard given its high sensitivity and rapid turnover time. Although the PCR assays are not fully standardized, they have emerged as the preferred diagnostic tests for CMV.


Prevention

Matching Donors and Recipients by Serologic Status Attempts to decrease the morbidity associated with primary donoracquired CMV infection have included the use of CMV-seropositive donor organs only for seropositive recipients. Although a decrease in graft loss and mortality attributable to CMV was noted in one report (150), others have not shown a significant impact with such an approach. Widespread adoption of this approach, however, is not feasible given the limited organ donor pool.

Prophylaxis Two approaches exist for CMV prophylaxis: universal prophylaxis and preemptive therapy (129). Universal prophylaxis requires administration of antiviral prophylaxis to all organ transplant recipients except for seronegative recipients from seronegative donors for typically 3 to 6 months. The advantage of this strategy includes relatively easy implementation and favorable effects on “indirect effects” such as rejection and opportunistic infections; however, drug costs, their adverse effects, late-onset disease, and emergence of drug-resistant CMV may be potential issues (3,142,151,152). Preemptive therapy requires periodic monitoring of CMV replication for early identification of CMV infection with prompt treatment to prevent asymptomatic infection from progressing to CMV disease. It decreases the cost and adverse effects; however, continuous CMV monitoring can be logistically difficult and viral load thresholds for initiating antiviral therapy have not been precisely defined. Preemptive therapy is typically administered until resolution of CMV viremia. Both strategies are efficacious to reduce the rate of CMV disease (153,154), although superiority of one approach over the other has not been incontrovertibly documented. Although not approved for use in liver transplant recipients, valganciclovir is the most commonly used antiviral agents for prophylaxis of CMV.

Herpes Simplex Virus HSV infections in transplant recipients present as mucocutaneous lesions resulting from reactivation of the latent virus. However, visceral or disseminated HSV infection can be donor-transmitted and may have a fulminant presentation with a grave outcome without antiviral therapy. HSV hepatitis is the most frequently documented site of disseminated HSV infection; its incidence (cases per thousand) is reported to be 2.11 in renal, 2.23 in heart, and 4.81 in liver transplant recipients. In a report comprising 12 cases of HSV hepatitis in solid organ transplant recipients, 33% were due to primary HSV infection believed to be acquired from the donor (155). The median time to onset of HSV hepatitis was 18 days, although it occurred as early as 5 days posttransplantation (155). This characteristic time of onset is in contrast with CMV hepatitis, which usually occurs 30 to 40 days after transplantation. Clinical manifestations of HSV hepatitis include fever, leukocytosis, thrombocytopenia, and marked elevation of hepatocellular enzymes. Mortality from primary visceral HSV infection in seronegative recipients was 75%; hypotension, disseminated intravascular coagulation, metabolic acidosis, low platelet count, and high creatinine were significant predictors of mortality (155).

HSV accounted for 41% of all non-CMV isolates from the respiratory tract in lung transplant recipients; 80% of the isolates were deemed clinically significant and were associated with pneumonitis (156). Another clinical presentation of HSV, predominantly reported in intubated lung and cardiac transplant recipients, is HSV tracheobronchitis that manifested as fever, bronchospasm, leukocytosis, and difficulty weaning. Paradoxically, HSV tracheobronchitis had a more severe presentation and worse outcome in immunocompetent compared with immunosuppressed patients (157). It was proposed that this may be due to a more exuberant local immune response in the immunocompetent patients (157).

Low-dose acyclovir (200-400 mg orally three times daily) generally used for a month posttransplant is highly effective as prophylaxis for HSV in transplant recipients (158). At one institution, HSV hepatitis was documented
in 12 of 3,536 solid organ transplant recipients before the routine use of acyclovir prophylaxis and in none of the 1,144 patients since the use of acyclovir prophylaxis (155). Longer duration of acyclovir can be considered for organ recipients who develop frequent recurrences of HSV lesions.

Varicella-Zoster Virus Up to 70% of the pediatric and 5% of the adult transplant recipients have been reported to be seronegative for VZV (159,160). Exposure to VZV infection may result in primary varicella in these susceptible patients. Donor-derived primary varicella infection was also reported in a cardiac transplant recipient whose donor suffered from varicella 2 weeks prior to transplant (34). Median time to onset of varicella was 2 years after transplantation in one report (160) and 2.4 years in another (161). Visceral dissemination, frequently documented in transplant recipients, is the primary cause of mortality in patients with VZV. Hepatitis, pneumonitis, pancreatitis, gastroenteritis, or meningoencephalitis are the most commonly documented sites of visceral dissemination. Varicella may initially present with acute abdominal pain, and in the absence of skin lesions can defy early recognition. It is notable that up to 16% to 18% of the pediatric transplant recipients may have recurrent varicella infections (161,162).

All transplant candidates susceptible to VZV should receive varicella vaccination prior to transplantation. Varicella-zoster immunoglobulin (VZIG) is recommended for susceptible transplant recipients exposed to varicella within 96 hours. VZIG, however, is not entirely protective; in up to one third of the patients with varicella, lesions have occurred despite VZIG prophylaxis. Since the production of VZIG was discontinued, VariZIG is the only immunoglobulin currently available in the United States under an investigational new drug application. Exposed susceptible organ recipients should be isolated in Airborne and Contact Precautions from day 10 to day 21 (day 28 if receiving VZIG or VariZIG) to decrease the risk of transmission to other susceptible patients. Some centers use high-dose oral acyclovir or valacyclovir for the duration of the incubation period of varicella (i.e., 2-3 weeks after exposure of susceptible patients to varicella). Use of varicella vaccine is not recommended in transplant recipients (163) (see also Chapter 43).

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Jun 22, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Healthcare-Associated Infections in Solid Organ Transplant Recipients
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