Opportunistic Infections—Coming to the Limits of Immunosuppression?

Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Jay A. Fishman

Transplant Infectious Disease and Compromised Host Program, Infectious Disease Division, MGH Transplantation Center, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114 Correspondence: jﬁ[email protected]

Possible etiologies of infection in the solid organ recipient are diverse, ranging from common bacterial and viral pathogens to opportunistic pathogens that cause invasive disease only in immunocompromised hosts. The recognition of infectious syndromes in this population is limited by alterations in the clinical manifestations by immunosuppression. The risk of serious infections in the organ transplant patient is determined by the interaction between the patients’ recent and distant epidemiological exposures and all factors that contribute to the patient’s net state of immune suppression. This risk is altered byantimicrobial prophylaxis and changes in immunosuppressive therapies. In addition to the direct effects of infection, opportunistic infections, and the microbiome mayadversely shape the host immune responses with diminished graft and patient survivals. Antimicrobial therapies are more complex than in the normal host with a signiﬁcant incidence of drug toxicity and a propensity for drug interactions with the immunosuppressive agents used to maintain graft function. Rapid and speciﬁc microbiologic diagnosis is essential. Newer microbiologic assays have improved the diagnosis and management of opportunistic infections. These tools coupled with assays that assess immune responses to infection and to graft antigens may allow optimization of management for graft recipients in the future.

f one were to design an experiment to study servations regarding infection in transplanta- Ithe effects of infection following organ trans- tion include: www.perspectivesinmedicine.org plantation, it is unlikely that one would use as subjects an outbred population with multiple, 1. The risk for infection is related to the nature severe comorbidities, uncontrolled infectious and intensity of immunosuppression and exposures, and a wide variety of regimens for the infectious exposures of the organ recip- immunosuppression undergoing major surgery ient and donor (Fishman and Rubin 1998; with implantation of organs from an equally Fishman et al. 2007). An understanding of diverse donor pool. Nonetheless, as regimens the relationship between the intensity of for immunosuppression have “stabilized,” some immunosuppression and infectious risk al- general observations can be made based on this lows the development of effective prophy- ongoing “experiment.” Important clinical ob- lactic strategies.

Editors: Laurence A. Turka and Kathryn J. Wood Additional Perspectives on Transplantation available at www.perspectivesinmedicine.org Copyright # 2013 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a015669 Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669

1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

J.A. Fishman

2. Recognition of infection is more difficult 1. The epidemiologic exposures of both the pain transplant recipients than in individuals tient and the organ donor including those with normal immune function given dimin- unrecognized by the patient or distant in ished signs and symptoms of infection and time (Rubin et al. 1981; Fishman and Rubin the array of noninfectious etiologies of fever 1998). (e.g., graft rejection, drug toxicity) (Fishman 2. The patient’s “net state of immunosuppres- and Rubin 1998; Fishman 2007). Nonspecif- sion” including all factors contributing to ic signs and symptoms must be appreciated. the risk for infection (Table 1) (Fishman and 3. Infection progresses rapidly in the immuno- Rubin 1998). compromised host. Thus, the prevention of These factors are conceptual assessments infection is essential. Confronted with infec- similar to measuring the area under the curve tion, early and effective therapy is required. of a formula relating epidemiology and im- 4. The spectrum of potential pathogens is mune function. At higher levels of immuno- broad; multiple pathogens may be present suppression, infection occurs at lower levels at the same time (e.g., virus and molds). of infectious “exposure” or with organisms of Rapid and specific diagnoses are needed to lower levels of native virulence. With lower guide antimicrobial therapies and to limit levels of immunosuppression, infection is less avoidable drug interactions and toxicities. common, drug toxicities are less frequent, but Rapid and improved microbiologic assays graft rejection more prevalent. Specific immune have greatly improved care. Surgical debride- deficits (genetic or acquired) and specific im- ment and invasive diagnostic procedures are munosuppressive regimens predispose to infec- often required. tion with specific classes of organisms (e.g., T-lymphocyte depletion activates latent cyto- 5. There are no currently available assays that megalovirus [CMV] and allows viral replica- can determine an optimal immunosuppres- tion to occur while corticosteroids predispose sive regimen while avoiding infection. to Pneumocystis and other fungal infections) The nature of the clinical transplantation (Table 2) (Issa and Fishman 2009). Successful experiment has tended to obscure the impact prophylaxis reduces the burden of organisms of diverse infections on immune functions in- or protects against invasive infection (e.g., bac- cluding tolerance induction and graft rejection. teremia) and allows more intensive immuno- Recent studies in animal models have empha- suppression. As a result, preventative strat- sized the importance of the microbiome, infec- egies must be adapted to immunosuppression www.perspectivesinmedicine.org tious exposures, and the innate immune system and to the individual’s risk factors for infec- in determining aspects of immune function in- tion. cluding the development of T-cell specificity and function, the risk for subsequent infections, EPIDEMIOLOGY and, to a degree, graft and patient survival (Fig. 1) (Selin et al. 1994; Yewdell and Bennink Epidemiologic exposures can be divided in- 1999; Adams et al. 2003a; Chong and Alegre to four categories: donor-derived (often un- 2012). This review focuses on more recent con- known exposures), recipient-derived infec- cepts in the impact of infection in solid organ tions and colonization, endemic community- transplantation. derived infections, and healthcare institu- tion-derived pathogens. The importance of an otherwise unimportant organism on the RISK FOR INFECTION AND THE TIMELINE skin of a transplant recipient is magnified in OF INFECTION the face of surgery, devitalized tissues, hema- The risk for infection in an individual trans- toma or fluid collections, and immunosup- plant recipient is determined by two factors: pression.

2 Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Infections in Organ Tranplantation

Timeline of posttransplant infections

Time of transplantation <4 Weeks 1–12 Months >12 Months

Common infections in solid organ transplant recipients

Infections of complex surgical patients Opportunistic Community-acquired • Line infection infections pneumonia • Wound infection • Pneumocystis jirovecii * • Aspiration • Cytomegalovirus* Urinary tract • Anastamotic leaks • Epstein–Barr virus* infections • Graft ischemia • Other Herpesviruses* • Clostridium difficile colitis • Nocardia species* Late opportunistic • Listeria monocytogenes* infections Antimicrobial-resistant species • Hepatitis B virus* • Molds and Cryptococcus • Methicillin-resistant Staphylococcus aureus (MRSA) • Hepatitis C virus • Nocardia species • Extended-spectrum β-lactamase (ESβL) Gram-negative bacilli • Toxoplasma gondii * • Rhodococcus species • Vancomycin-resistant Enterococcus (VRE) • Strongyloides stercoralis * • Candida species (non-albicans) • Leishmania species Late viral • Trypanosoma cruzi * • CMV (colitis/retinitis) Donor-derived (known and unknown pathogens) • Mycobacterium tuberculosis • Hepatitis (HBV, HCV) • Herpes simplex virus (HSV) • Community-acquired • HSV encephalitis

• Lymphocytic choriomeningitis virus (LCMV) respiratory viruses • Community acquired • Rabies • BK polyomavirus • JC polyomavirus leading • West Nile virus • Clostridium difficile to progressive multifocal • Cryptococcus neoformans leukoencephalopathy (PML) Recipient-derived (latent or colonized) • Skin cancer • Aspergillus Anastamotic • Posttransplant lymphoproliferative disorder • Pseudomonas complications (PTLD) • Strongyloides • Trypanosoma cruzi *Many infections prevented by appropriate prophylaxis

Sources of infection www.perspectivesinmedicine.org

Donor or recipient Nosocomial, technical, Activation of latent Community acquired derived donor/recipient infections, relapsed, residual, opportunistic infections

Figure 1. The timeline of infections following organ transplantation. The risk for infection following organ transplantation follows a standard pattern with routine immunosuppression and infectious exposures. The potential pathogens for which the risk is modified by prophylaxis, including vaccinations and antimicrobial agents, are indicated (). Individual risk is modified by events such as surgery, treatment of graft rejection, or malignancy. Note that graft rejection and drug reactions may be among noninfectious causes of fever in transplant recipients. (From Fishman 2007; modified, with permission, from the author.)

Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 3 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

J.A. Fishman

Table 1. Factors contributing to the “net state of im- The interpretation of serologic tests from donors munosuppression” must include consideration of the potential for Immunosuppressive therapy: Type, temporal false-positive assays after blood transfusion or sequence, intensity false-negativeassaysafterhemodilutionofblood Prior therapies (chemotherapy or antimicrobials) samples following infusion of colloids and Mucocutaneous barrier integrity (intravenous access crystalloids (Eastlund 2000). Similarly, testing and urinary catheters, surgical drains) for viral antibodies from newborns less than Neutropenia, lymphopenia (often drug-induced) 1 mo of age is unreliable given exposure to Underlying immune deficiency (e.g., adrenal insufficiency, systemic lupus, complement maternal antibodies and the inconsistent anti- deficiencies) body responses of the immature immune sys- Metabolic conditions: Uremia, malnutrition, tem. diabetes, alcoholism/cirrhosis Known, asymptomatic infections of donors Viral infection (CMV, hepatitis B and C, RSV) are commonly transmitted including cytomegalovirus (CMV), Epstein–Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster Donor-Derived Infections virus (VZV). Donor screening is then useful to develop posttransplant preventative or moni- Infection is transmitted efficiently with the toring strategies for recipients. These same path- transplantation of viable tissues; transmission ogens may cause significant disease if infec- is likelyenhanced by immunosuppression (Fish- tion is active (i.e., viremia) at the time of pro- man 2007). Data on allograft-associated disease curement. Some donor-derived pathogens may transmissions are limited by difficulties in dis- require posttransplant therapy: Treponema pal- tinguishing allograft-derived infections from lidum, M. tuberculosis, nontuberculous myco- recipient-derived infections (e.g., because of bacteria, Histoplasma capsulatum, Coccidioides latent infections or nosocomial infections) and immitis, Paracoccidioides spp., Blastomyces. Do- by the failure to recognize or to report these nors from endemic regions merit screening for events (Fishman 2007, 2008; Fishman et al. 2009; Grossi and Strong 2009; Grossi et al. 2009). In immunosuppressed hosts, the inci- Table 2. Immunosuppression and infection: Com- dence of donor-derived infection may be under- mon associations estimated owing to the absence of leukocytosis, Antilymphocyte globulins (lytic depletion) and pain (in a denervated graft), or erythema. alloimmune response Some infections generally preclude organ T lymphocytes: Activation of latent (herpes)viruses, fever, cytokines www.perspectivesinmedicine.org donation (e.g., uncontrolled sepsis, HIV or HTLV infection, West Nile virus, Rabies virus, B lymphocytes: Encapsulated bacteria LCMV). Guidelines precluding the use of organs Plasmapheresis: Encapsulated bacteria from HIVor HTLV-infected individuals are be- Costimulatory blockade: Unknown so far; possible / ing reconsidered in some countries (Huang and increased risk for EBV PTLD Corticosteroids: Bacteria, PCP, hepatitis B, possibly Fishman 2011). The potential donor with mi- hepatitis C crobiologically undiagnosed and untreated in- Azathioprine: Neutropenia, possibly papillomavirus fection (e.g., sepsis, meningitis, or encephalitis) Mycophenolate mofetil (MMF): Early bacterial and/or for whom resolution has not been doc- infection, B cells, late CMV umented may represent a significant risk to Calcineurin inhibitors: Enhanced viral replication the recipient (Satoi et al. 2001). Some common (absence of immunity), gingival infection, pathogens may limit the use of donor organs intracellular pathogens (to infected or immune recipients) and are in- mTOR inhibitors: cludedindonor(andrecipient)screening panels Poor wound healing (Table 3). These include serologic and other as- Excess infections in combination with other agents says for hepatitis B and C viruses (HBV, HCV). Idiosyncratic interstitial pneumonitis

4 Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Infections in Organ Tranplantation

Table 3. Common screening tests for organ donorsa cleic acid tests or NAT) for donors (Table 3). Human immunodeficiency virus antibody This is a reflection of at least three areas of un- Hepatitis B (HBV) serologies including HBV surface certainty. First, the degree to which it is possible antigen, core antibody, surface antibody, and to reduce infection. Second, the advantages and hepatitis d antigen and/or antibody in HBsAg- disadvantages of NATassays compared with se- positive donors rologic (antibody-based) tests. Third, the actu- Hepatitis C antibody al risk of transmission posed by individuals Nontreponemal and treponemal testing (rapid plasma with possibly increased risk of disease transmis- reagin [RPR] TPHA or TPPA or FTA-Abs) þ sion, notably for HCV, HBV,or HIV, is unclear. Human T-cell lymphotrophic virus (HTLV-I/II) antibody (less common currently given assay HIV infectious risk is inferred from the donor’s performance) medical and social history, in addition to data Toxoplasma antibody (notably in cardiac donors) from screening assays. The U.S. Public Health Cytomegalovirus antibody Service (PHS) published guidelines in 1994 de- Epstein–Barr virus (EBV) antibody panel (EBV viral scribing the epidemiological risk factors identi- capsid antigen, ± early antigen, and nuclear antigen fied for HIV transmission; those guidelines have antibody levels) also been applied widely for HCV and HBV Herpes simplex virus antibody prevention (USPH Service 1994). Given the Varicella-zoster virus antibody low incidence of reported viral transmission Blood and urine cultures associated with organ transplantation, these aMany procurement organizations supplement these tests guidelines appear to have been effective, notably withadditionalassaysbasedonlocalepidemiologyand/oruse for HCV. Updated draft guidelines reflect the nucleic acid-based assays (NAT)(see also Grossi et al. 2009). availability of, and controversy over, highly sensitive NAT and protein-based assays for HIV, parasites (Trypanosoma cruzi, Plasmodium spp., HCV, and HBV (USPH Service 2011). Strongyloides stercoralis, Schistosoma spp., Leish- A limitation to serologic assays is the time mania spp.) as well as epidemic or endemic vi- required to develop positive assays compared ruses (Chikungunya virus, West Nile virus, and with nucleic acid or protein detection assays. human T-cell lymphotropic virus, HTLV-I/II). Transmission of infection may occur in this Donors also may be screened for infectious “window period” between donor infection and agents of importance in the transplantation of seroconversion (Schreiber et al. 1996; Pillonel specific organs (e.g., Toxoplasma gondii in cardi- et al. 1998; Kolk et al. 2002; Biswas et al. 2003; ac recipients). Fiebig et al. 2003; Kleinman et al. 2003; Busch Unintentional transmission of infection oc- et al. 2005; Kleinman and Busch 2006; Yao et al. www.perspectivesinmedicine.org curs in at least 1%–2% of recipients (Len et al. 2007, 2008). HIV antibody assays can show se- 2008; Ison et al. 2011). Clusters of infection in roconversion within approximately 22 d of in- recipients of allografts from a single donor have fection (but can be as long as 6 mo), with NAT included Mycobacterium tuberculosis, Candida, detection reducing the window period for de- and Aspergillus (and other fungal) species, her- tection from 5.6 to 10.2 d (i.e., 4–15 d in which pes simplex virus (HSV) and human herpes infection is detected by NAT but not ELISA). virus 8, lymphocytic choriomeningitis virus HBV surface antigen (HBsAg) ELISA assays (LCMV), rabies virus, Trypanosoma cruzi, HIV, have a window period of 38.3 to 49.7 d, with and hepatitis C virus. Detection of transmission NAT in the range of 20.4 to 25.7 d (Busch et al. requires clinical suspicion, access to advanced 1995, 2005; Schreiber et al. 1996; Pillonel et al. microbiologic testing including nucleic acid 1998; Kolk et al. 2002; Biswas et al. 2003; Fiebig amplification technologies (NAT), recognition et al. 2003; Kleinman et al. 2003; Kleinman and of epidemiologic exposures, and, where appro- Busch 2006; Yao et al. 2007, 2008). The use of priate, assistance by public health authorities. HBV NAT testing may detect HBV infection in Significant controversy exists over the opti- donors who are HBSAg negative. The HCV mal screening panel and specific tests (e.g., nu- ELISA assays have window periods of 38 to

Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 5 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

J.A. Fishman

94 d, which is reduced to 6.1 to 8.7 d using NAT Community Exposures assays. A careful epidemiologic history may provide Decisions regarding the use of organs from microbiologic clues to possible infectious pre- donors with active or suspected infection take sentations. Outbreaks of viral respiratory illness into account the urgency of transplantation for (e.g., influenza, respiratory syncytial virus) oc- the recipient, microbiological data and treat- cur earlier in the season in immunocom- ment options for the donor or recipient, and promised individuals than in normal hosts. the availability of alternatives. The key concept Travel, hobbies (gardening, hiking), or work underlying donor screening is to provide data (teachers) exposures may suggest exposures to for clinicians and potential recipients that allow contaminated food or water (Listeria, Crypto- informed decisions balancing the risk of in- spoduals ridium), soil (Aspergillus or Nocardia), fection against the benefits of organ replace- birds (Cryptococcus), or geographically restrict- ment. ed mycoses (Blastomyces dermatitidis, Cocci- dioides immitis, Paracoccidioides sp., and Histo- Pretransplant Infections in Organ Recipients plasma capsulatum). Before donation, potential recipients (or donors) may become colonized by nosocomially Nosocomial Exposures acquired organisms carrying resistance to mul- Nosocomial infections are of increasing im- tiple antimicrobial agents (e.g., vancomycin-re- portance in transplant donors and recipients. sistant Enterococcus [VRE], multidrug-resistant As patients wait for organs and may have un- Klebsiella pneumoniae, azole-resistant Candida dergone multiple procedures and antimicrobial species). As a result, routine surgical prophylaxis exposures, colonization may occur with hospi- may be inadequate to prevent transmission. tal-acquired antimicrobial-resistant pathogens. The presence of, and microbiological suscepti- Among the common pathogens are vanco- bility patterns for, such colonizing organisms mycin-resistant enterococci (VRE), methicillin- should be discerned before transplantation resistant staphylococci (MRSA), fluconazole- when possible (notably in lung transplant can- resistant Candida species, Aspergillus species, didates). and highly resistant Gram-negative bacteria Any active infections in the recipient should (van Delden et al. 2009). Respiratory viral in- be treated and, ideally, resolved before procure- fections may be acquired from visitors and hos- ment or transplantation (Delmonico and Snyd- pital staff. man 1998; Freeman et al. 1999; Lumbreras et al. www.perspectivesinmedicine.org 2001; Satoi et al. 2001; Singh 2002; D’Albuquer- THE NET STATE OF IMMUNOSUPPRESSION que et al. 2007; Fishman 2007; Nanni Costa et al. 2008). There are no data on which to base a The net state of immunosuppression is a con- recommendation for the optimal duration of ceptual measure of factors contributing to a pa- therapy or the interval between resolution of tient’s risk for infection (Table 1) (Fishman infection and procurement. Clearance or con- 2007). Among these are: trol of infection should be documented and 1. The specific immunosuppressive therapy, consideration given to surgical or posttrans- including dose, duration, and sequence of plant prophylaxis. The inflammation associated agents. with bacterial peritonitis is a common source of diffuse intraoperative bleeding or of subse- 2. Surgical issues resulting from the transplant quent fibrosis in liver transplantation—increas- procedure, resulting in leaks (blood, lymph, ing the surgical technical difficulty and the risk urine) and fluid collections, devitalized tis- for infection. Spillage from infected renal or sue, poor wound healing, and surgical drain- hepatic cysts may also contaminate a surgical age catheters. field. 3. Prolonged ventilatory support.

6 Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Infections in Organ Tranplantation

4. Broad-spectrum antibiotics. Among underappreciated “immune de- 5. Posttransplant renal, hepatic, pulmonary or fects” are breaches in cutaneous barriers. As cardiac dysfunction, or diabetes. was noted, the combination of “sticky” organisms such as VRE, Candida spp., or Staphylococ- 6. Prolonged use of urinary, vascular access, or cus aureus from colonized skin often associ- dialysis catheters, surgical drains, or other ated with biofilms on in-dwelling catheters or breaks in skin or mucosal defenses. surgical drains leads to increased risk for bacter- 7. Viral infection with resulting local or system- emia. These effects are amplified by neutropenia ic immunosuppression and increased risk caused by drug effects (e.g., ganciclovir, myco- for superinfection. Of special importance in phenolate mofetil, allopurinol, trimethoprim- transplantation are the herpesviruses (CMV, sulfamethoxazole) and nutritional deficits. Sur- EBV,HSV, VZV), HBVor HCV, or HIV. gical, invasive radiologic, or gastrointestinal 8. Malnutrition. procedures used to repair technical complications such as bile leaks or biliaryor ureteric stric- 9. Neutropenia, which may be related to med- tures, risk dissemination of organisms from ications such as mycophenolate mofetil, aza- those sites with distant seeding and abscess for- thioprine, ganciclovir, valganciclovir (rarely mation in joints or ischemic regions of grafts. to trimethoprim-sulfamethoxazole). Over- estimates of renal function based on serum creatinine levels are often associated with TIMELINE OF INFECTION drug toxicity. With more standardized immunosuppressive regimens, common infections are observed in a Individual drugs are associated with in- relatively consistent pattern based on the time creased risk for certain infections (Table 2), al- elapsed since transplantation (Fig. 2). This is a though the degree of immunosuppression asso- reflection of changing risk factors over time: ciated with a specific regimen varies between surgery/hospitalization, immune suppression, individuals relative to the risks of both graft re- acute and chronic rejection, emergence of latent jection and for infection. Assays that measure infections, and exposures in the community the level of “immunity” against specific patho- (Fishman 2007). A key concept is that predict- gens (e.g., cellular immune function orantibody able changes in the risk for infection occur with levels against specific organisms) are not yet pre- unique epidemiologic exposures (e.g., returning dictive of infectious risk. Serologic assays deter- to work) and with alterations in the drug regi- mine past exposures and latent infections (her- men (interactions, treatment of graft rejection, www.perspectivesinmedicine.org pesviruses) but are poorly predictive of the neutropenia). Infections appear later than usual efficacyof the immune response to specific path- when delayed by effective prophylaxis and as al- ogens in immunosuppressed hosts. Measures lograft function improves. of “global” immune function remain relatively The timeline reflects three overlapping pe- crude (Husain et al. 2009). Few data exist on the riods of risk for infection: (1) the perioperative integrity of immune reconstitution against in- period to approximately 30 d after transplanta- fection after T- or B-lymphocyte depletion or tion, (2) the period 1–6 mo after transplanta- treatment with other antibody preparations tion (depending on the use of antilymphocyte (e.g., antibodies to tumor necrosis factor, co- “induction” therapy and the level of immuno- stimulatory blockade). Immune deficits associ- suppression), and (3) the period beyond the 6– ated with biologic agents are generally more se- 12 mo after transplantation. The timeline may vere and persist longer (months to years) than is be used in a variety of ways: (1) to establish a generally appreciated. Similarly, the effects of differential diagnosis for the transplant patient organdysfunction (e.g.,cirrhosis,renaldysfunc- suspected of having an infection, (2) as a clue to tion) onsystemicimmune functionresistprecise the presence of an excessive environmental haz- quantification. ard for the individual, either within the hospital

Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 7 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

J.A. Fishman

Infection, inflammation, and transplantation

Pretransplantation Transplant surgery Posttransplantation • Organ dysfunction • Infection • Depletion and immune

• Microbiome • Technical reconstitution • Immunosuppression • Colonization • Nosocomial • Community exposures • Infections • Tissue injury • Opportunistic infection • Antimicrobials • Organ dysfunction • Vaccination

Inflammation and injury • Ligands for pattern- recognition receptors → Heterologous and cross- Immune memory cytokines, chemokines reactive memory • Vaccine-derived • Pathogen- and allograft- • → Rejection infections derived antigens • Failure of tolerance induction • Latent or persistent • Damage-associated • Narrowed cellular immune infections molecular patterns responses • Developmental • Alloimmune stimulation → • Stimulation by new or “persistent decreased tolerance infections” (graft injury) → • Enhanced antigen nonspecific cytokines, chemokines

presentation • Increased effector over Treg cells

Figure 2. The impact of infectious exposures, inflammation, the microbiome, heterologous immunity, and innate immune stimulation on transplantation. The microbiome is the sum of colonizing organisms, acute and chronic infections, and reflects alterations in this flora by the immune system, vaccination, or antimicrobial agents. Antigens and activating molecular patterns from microbes or damaged tissues are released during all phases of transplantation and are present during graft rejection, immunosuppression, and/or immune reconstitution following lymphocyte depletion. These antigenic exposures and inflammatory mediators shape immune function via both the innate and adaptive immune systems and impact the outcome of transplantation (see also Chong and Alegre 2012).

or in the community, and (3) as a guide to the Phase 1: 1 Month Posttransplantation www.perspectivesinmedicine.org design of prophylactic antimicrobial strategies. Infections occurring outside the usual period or During the first month after transplantation, the with unusual severity suggest the presence of an types of infection are generally related to com- excessive epidemiologic hazard or of excessive plications of the transplant surgery (fluid collec- immunosuppression (Fishman 2007). Routine tions, sepsis), infections present in the donor or preventative strategies from the Massachusetts recipient before transplantation, or nosocomial General Hospital are outlined in Tables 4 and 5. infections. Graft rejection may occur but is It should be noted that such strategies serve uncommon. Early removal of lines and drains, only to delay the onset of infection in the face appropriate prophylaxis for surgery based on of epidemiologic pressure. The use of antibiot- knowledge of the patient’s colonization status, ic prophylaxis, vaccines, and behavioral modi- discontinuation of unneeded medications in- fications (e.g., routine hand washing or advice cluding antimicrobial agents, drainage of he- against buying new kittens) may only result in matomas and other collections, and meticulous a “shift to the right” of the timing of infection wound care are essential. Opportunistic in- unless the intensity of immune suppression is fections are uncommon in this period despite reduced or immunity develops. intensive immunosuppression; sustained ad-

8 Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Infections in Organ Tranplantation

Table 4. Prophylaxis for Pneumocystis jiroveci pneu- Phase 2: 1 to 6 Months Posttransplant monia (PCP) The opportunistic infections emerge in the Background: Low dose trimethoprim- first 6 mo posttransplant coupled with tech- sulfamethoxazole prophylaxis (in adults: 1 single strength per day orally) is well tolerated and nical issues remaining from the transplant essentially eradicates Pneumocystis infection from admission. Use of anti-CMV therapy with broad this patient population. Lower doses (3 days per antiherpes efficacyand trimethoprim–sulfame- week) prevent PCP but may not prevent other thoxazole (TMP-SMX) prophylaxis has altered infections such as urinary tract infection, the pattern of posttransplant infections. TMP- including those attributable to susceptible SMX eliminates P. jiroveci pneumonia (PCP) Nocardia and Listeria, toxoplasmosis, and a and, given daily, reducesthe incidence of urinary variety of gastrointestinal and pulmonary tract infection and urosepsis, some respiratory infections. and GI infections, L. monocytogenes meningitis, Regimen: One single strength trimethoprim- many Nocardia species infections, and Toxoplas- sulfamethoxazole tablet (containing 80 mg ma gondii. TMP-SMX also have activity against trimethoprim, 400 mg sulfamethoxazole) po qhs many strains of community-acquired MRSA. for a minimum of 4–6 mo posttransplant. Patients Other agents substituted for TMP-SMX in the infected with CMV, with chronic rejection, sulfa-allergic or neutropenic patient do not pro- recurrent infections, and most lung, liver, and heart recipients may benefit from lifelong vide the same spectrum of benefits. In practice, prophylaxis. most “allergies” to TMP-SMX merit reconsider- ation unless well documented. Effective anti- Alternative regimen: For patients proven not to CMV prophylaxis should prevent most CMV tolerate trimethoprim-sulfamethoxazole, alternative regimens include: (1) a combination of infections (and those caused by most herpesvi- atovaquone 1500 mg po with meals once daily plus ruses) for the duration of therapy. Thus, the dif- levofloxacin (or equivalent fluoroquinolone ferential diagnosis of infectious syndromes in without antianaerobic spectrum) 250 mg once this period includes: daily, (2) pentamidine (300 mg iv or inhaled q 3–4 weeks), and (3) dapsone (100 mg po qd to biw) ± † Graft rejection. pyrimethamine. Each of these agents has toxicities † that must be considered including hemolysis in Persistent infection from the perisurgical pe- G6PD-deficient hosts with dapsone. None of these riod including relapsed C. difficile colitis, in- alternative programs offer the same broad adequately treated pneumonia, or infection protection of TMP-SMX. related to graft-specific technical problems (e.g., pleural effusion, urine leak, cholangitis,

www.perspectivesinmedicine.org lymphocele, infected hematoma, airway ne- ministration of immunosuppressive agents is crosis). generally required to allow organisms of low † Viral infections including CMV, herpes sim- native virulence to establish invasive disease. plex virus (HSV), shingles (localized or dis- When these occur, they reflect prior immune seminated zoster attributable to varicella zos- defects (pretransplant therapies) or environ- ter virus, VZV), human herpesvirus 6 or 7, mental exposures. BK polyomavirus, EBV, relapsed hepatitis In this period, the stage is also set for the (HBV, HCV), and the community-acquired emergence of a subgroup of patients—the respiratory viruses (adenovirus, influenza, “chronic ne’er do well”—individuals with early parainfluenza, respiratory syncytial virus, infectious complications and/or graft dys- metapneumovirus). Secondary postviral in- function and who may require sustained higher fections (bacterial or fungal) are common. levels of immunosuppression. Such individuals show lifelong susceptibility to infection and † Opportunistic infection as a result of Pneumo- merit prolonged (lifelong) prophylaxis (Tables cystis jiroveci,Listeriamonocytogenes,Toxoplas- 4 and 5). ma gondii, Nocardia species (in the absence

Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 9 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

J.A. Fishman

Table 5. Prophylaxis for herpes group virusesa CMV universal antiviral prophylaxisa CMV serologic status ± antilymphocyte-globulin- induction therapy (ALG) Prophylaxis Monitoring (antigenemia) Dþ/R2 no ALG Intravenous ganciclovir 5 mg/kg iv (loading Monthly for 6 mo after dose) then po valganciclovir (900 mg/d discontinuation of therapyb corrected for renal function) or po ganciclovir (3 gm/d)c 3mo Dþ or Rþ with ALG Intravenous ganciclovir 5 mg/kg iv for first Monthly for 6 mo after dose then either per renal function to discontinuation of therapyb discharge or switch to po valganciclovir (900 mg/d corrected for renal function) or po ganciclovir (3 gm/d)c 6mo D2/Rþ no ALG Oral valganciclovir (900 mg/d corrected for Symptoms only renal function) 3mo D2/R2 Oral famciclovir 500 mg po qd 3–4 mo Symptoms, fever/neutropenia (or valacyclovir 500 bid or acyclovir 400 tid). Use of CMV-negative or leukocyte- filtered blood Status unknown with ALG Intravenous ganciclovir 5 mg/kg iv for first As above dose and QD (corrected for renal function) until sero-status determined. The human herpes viruses are among the most important causes of infectious disease morbidity and mortality in the transplant recipient. Preventative regimens are determined by the clinical risk, the major determinants of which are the past experience of donor and recipient with the virus (as defined by the presence or absence of circulating antibody before transplant) and the nature of the immunosuppressive therapy. The dose of antiviral therapies are not, in general, reduced for neutropenia. aPreemptive therapy: Preemptive therapy requires a carefully organized monitoring program and patient compliance. Either a molecular CMV viral load test or a pp65 antigenemia assay may be used for monitoring. Monitoring should be performed once weekly after transplantation for 12–24 wk. Infections indicated by positive assays are treated with either oral valganciclovir (900 mg 2 times a day) or intravenous ganciclovir (5 mg/kg 2 times a day). Full doses are used for loading after which dosing is corrected for renal function. Therapy is continued until viremia is undetectable. Mixed prophylaxis: Many centers prefer universal prophylaxis for highest risk recipients (Dþ/R2 or Rþ with lymphocyte depletion) and preemptive therapy for other groups. bALG: Antilymphocyte antibodies include any of the lytic, lymphocyte-depleting antibody preparations. www.perspectivesinmedicine.org cValacyclovir (8 gm/d) has been used as an alternative agent in renal transplant recipients.

of TMP-SMX), Aspergillus species, and other or for primary CMV infection (socially ac- agents. The specific opportunistic infections quired) but have community-acquired expo- thatoccurreflectthespecificimmunosuppres- sures as their main risk, which may predispose sive regimen used and the presence or absence to more serious opportunistic superinfections. of immunomodulating viral infection. Respiratory viruses or infections related to underlying diseases (e.g., skin infections in diabetes) are common. The major challenges include Phase 3: More than 6 to 12 Months EBV and posttransplant lymphoproliferative Posttransplant disorders, persistent BK polyomavirus infec- After the first 6–12 mo, transplant recipients tion, hepatitis C virus in liver recipients, and with good graft function and reduced mainte- papillomavirus (warts, anogenital, and skin can- nance immunosuppression remain at some risk cers). Advanced therapies for HIV and HCV for reactivation of latent infections (e.g., VZV) have dramatically altered the impact of these in-

10 Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Infections in Organ Tranplantation

fections. Viral infections are often the major fac- activities in both the graft and host. These re- tor in risk for infections or graft rejection. main an important area for investigation. The patients with less satisfactory allograft Infection and the microbiome control many function or with renal dysfunction or diabetes aspects of alloimmunity in transplantation as a result of calcineurin inhibitor toxicity (Chong and Alegre 2012). Thus, consistent tend to be relatively over-immunosuppressed. with experience, “dirty” transplantation (e.g., This group includes those identified early in lung or intestine) would be expected to have the posttransplant course caused by delayed lower graft survival than cleaner (e.g., kidney, or poor initial graft function or complications heart) procedures without exposure to organ- and is at persistent risk for opportunistic in- isms and the environment. This may also be a fections such as Pneumocystis, Zygomycetes,or reflection of technical difficulty and differing Cryptococcus (Fishman 2007). Lesions identified immunologic challenges. in this group such as of skin or lungs should Heterologous immunity is the concept used be biopsied to exclude fungal infection or ma- to describe immune memory responses to pre- lignancy. viously encountered pathogens that alter subsequent immune responses to unrelated pathogens or to grafts. Some of these effects are “INDIRECT EFFECTS,” THE MICROBIOME, attributed to the generation of immunological AND IMMUNE FUNCTION cross reactivity between viral epitopes and graft Latent or acute infections are associated with and other antigens. Virally induced alloreactive adverse outcomes in the transplant recipient in- memory may create a barrier to transplantation cluding an increased risk for opportunistic in- toleranceorinducegraftrejectionorautoimmu- fection and graft rejection. The existence of these nity (Braciale et al. 1981; Adams et al. 2003a,b). “indirect effects” has been implied based on The observed effects may be mediated via mem- clinical observations and the effects of effective ory CD8þ cells following viral infection or more prophylaxis. For CMV, in addition to an in- broadly by inflammatory mediators such as creased rate of opportunistic infections (fungal TNF-a and IFN-g. Such virally induced allor- including aspergillosis, accelerated HCV infec- eactive memory may create a barrier to trans- tion), effects include coronary vaculopathy in plantation tolerance or induce graft rejection heart recipients, bronchiolitis obliterans syn- or autoimmunity. Such effects have been shown drome in lung recipients, and an increased rate for both CMV and EBV. Viral reactivation may of EBV-associated posttransplant lymphopro- also compress the T-cell repertoire and diminish liferative disorders (PTLD) and increased mor- responses to new antigens with an increased risk www.perspectivesinmedicine.org tality in the absence of prophylaxis. In liver for opportunistic infections (Yewdell and Ben- transplant recipients with recurrent HCV hepa- nink 1999; Brehm et al. 2002). All limbs of the titis, there is an increased rate of infections, post- host immune response may be altered by infec- transplant diabetes, and mortality (Hodson et tion, including adaptive as well as NK cell, neu- al. 2005; Kalil et al. 2005; Bloom and Lake 2006; trophil, and macrophage responses, and may Small et al. 2006). HCV infection may also en- contribute to the risk for graft injury and oppor- rich the hepatic regulatory T cell population, tunistic infections. which may persist after liver transplantation (Spangenberg et al. 2005; Nellore and Fishman GENERAL APPROACHES TO INFECTION 2011). IN TRANSPLANT RECIPIENTS These effects may be mediated by innate or adaptive immune mechanisms and should not The spectrum of infection in the immunocom- be confused with “chronic allograft rejection” promised host is broad. Given the potential tox- but are rather viral effects on cellular prolifera- icity of antimicrobial agents and the need for tion, functions of immune cells and inflamma- rapid interruption of infection, early and specif- tory networks, and modulation of cellular gene ic diagnosis is essential in this population. Ad-

Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 11 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

J.A. Fishman

vances in diagnostic modalities, including ad- CMV, other herpesviruses, and Pneumocystis vanced imaging and molecular microbiologic have been important advances in transplanta- techniques, greatly assist in this process. Howev- tion. Infection is often preventable with correc- er, the need for invasive diagnostic approaches tion of technical problems (e.g., drainage of cannot be overemphasized. Whereas these ap- fluid collections before infection). Patients with proaches carry some risk, the failure to achieve viremia are over immunosuppressed relative to a specificdiagnosis often necessitates broad, em- their immune systems. In the absence of assays piric therapy without clear endpoints for thera- useful for the individualization of global immu- py. Initial, often empiric, therapy will target a nosuppression, sensitive molecular tests, and broad range of potential pathogens with rapid assays for pathogen-specific immune function narrowing of the antimicrobial spectrum as data may guide the modulation of the intensity of become available. the individual’s regimen. In the future, host A central consideration for the patient with risk factors will be amenable to investigation in- an “infectious syndrome” is whether to reduce cluding genetic polymorphisms (e.g., toll-like the intensity of immunosuppression as a part of receptors) and immunoregulatory elements to therapy, risking graft rejection or an immune allow the individualization of transplant immu- reconstitution syndrome (IRIS). Given that in- nosuppression. fection and rejection are often linked, clear dis- tinctions between these processes may be diffi- REFERENCES cult. For example, recurrent HCV infection may increase the risk for liver graft rejection. Pneu- Adams AB, Pearson TC, Larsen CP. 2003a. Heterologous monia, including aspiration, community-ac- immunity: An overlooked barrier to tolerance. Immunol Rev 196: 147–160. quired respiratory viruses, CMV, and bacterial Adams AB, Williams MA, Jones TR, Shirasugi N, Durham infections, will increase the rate of obliterative MM, Kaech SM, Wherry EJ, Onami T, Lanier JG, Kokko bronchiolitis in lung recipients (Bando et al. KE, et al. 2003b. Heterologous immunity provides a po- tent barrier to transplantation tolerance. J Clin Invest 111: 1995; Kroshus et al. 1997; Avery 2006). CMV 1887–1895. also contributes to cardiac and renal allograft Avery RK. 2006. Infections after lung transplantation. Semin rejection (Lowance et al. 1999; Potena and Val- Respir Crit Care Med 27: 544–551. antine 2007). In practice, it is often possible to Bando K, Paradis IL, Komatsu K, Konishi H, Matsushima M, Keena RJ, Hardesty RL, Armitage JM, Griffith BP. decrease the intensity of immune suppression 1995. Analysis of time-dependent risks for infection, re- in the face of significant infection; however, as jection, and death after pulmonary transplantation. J the patient improves, rejection may occur. The Thorac Cardiovasc Surg 109: 49–57; discussion 57-49. selection of the specific agents to be reduced Biswas R, Tabor E, Hsia CC, Wright DJ, Laycock ME, Fiebig EW, Peddada L, Smith R, Schreiber GB, Epstein JS, et al. www.perspectivesinmedicine.org should depend on the organisms isolated— 2003. Comparative sensitivity of HBV NATs and HBsAg and often is not the calcineurin inhibitor. No assays for detection of acute HBV infection. Transfusion prospective studies of the efficacy of reduced 43: 788–798. immunosuppression have been performed. Re- Bloom RD, Lake JR. 2006. Emerging issues in hepatitis C virus-positive liver and kidney transplant recipients. Am J versal of immune deficits (neutropenia, hypo- Transplant 6: 2232–2237. gammaglobulinemia) may be possible with ad- Braciale TJ, Andrew ME, Braciale VL. 1981. Simultaneous junctive therapies (colony stimulating factors or expression of H-2-restricted and alloreactive recognition by a cloned line of influenza virus-specific cytotoxic T antibody). Coinfection with virus (CMV) is a lymphocytes. J Exp Med 153: 1371–1376. universal concern and merits therapy. Brehm MA, Pinto AK, Daniels KA, Schneck JP, Welsh RM, Selin LK. 2002. T cell immunodominance and maintenance of memory regulated by unexpectedly CONCLUSION cross-reactive pathogens. Nat Immunol 3: 627–634. Busch MP, Lee LL, Satten GA, Henrard DR, Farzadegan H, Transplant infectious disease has increasingly Nelson KE, Read S, Dodd RY, Petersen LR. 1995. Time become a field characterized by preventative ap- course of detection of viral and serologic markers pre- ceding human immunodeficiency virus type 1 serocon- proaches and early therapies based on sensitive version: Implications for screening of blood and tissue molecular diagnostic tests. The prevention of donors. Transfusion 35: 91–97.

12 Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Infections in Organ Tranplantation

Busch MP, Glynn SA, Stramer SL, Strong DM, Caglioti S, lung transplant recipients: Correlation of low immune Wright DJ, Pappalardo B, Kleinman SH. 2005. A new function with infection. Transplantation 87: 1852–1857. strategy for estimating risks of transfusion-transmitted Ison MG, Llata E, Conover CS, Friedewald JJ, Gerber SI, viral infections based on rates of detection of recently Grigoryan A, Heneine W, Millis JM, Simon DM, Teo infected donors. Transfusion 45: 254–264. CG, et al. 2011. Transmission of human immunodefi- Chong AS, Alegre ML. 2012. The impact of infection and ciency virus and hepatitis C virus from an organ donor tissue damage in solid-organ transplantation. Nat Rev to four transplant recipients. Am J Transplant 11: 1218– Immunol 12: 459–471. 1225. D’Albuquerque LA, Gonzalez AM, Filho HL, Copstein JL, Issa NC, Fishman JA. 2009. Infectious complications of Larrea FI, Mansero JM, Peron G Jr, Ribeiro MA Jr, Oli- antilymphocyte therapies in solid organ transplantation. veira e Silva A. 2007. Liver transplantation from deceased Clin Infect Dis 48: 772–786. donors serologically positive for Chagas disease. Am J Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld AG. 2005. Transplant 7: 680–684. Meta-analysis: The efficacy of strategies to prevent organ Delmonico FL, Snydman DR. 1998. Organ donor screening disease by cytomegalovirus in solid organ transplant re- for infectious diseases: Review of practice and implica- cipients. Ann Intern Med 143: 870–880. tions for transplantation. Transplantation 65: 603–610. Kleinman SH, Busch MP. 2006. Assessing the impact of Eastlund T.2000. Hemodilution due to blood loss and trans- HBV NAT on window period reduction and residual fusion and reliability of cadaver tissue donor infectious risk. J Clin Virol 36: S23–S29. disease testing. Cell Tissue Bank 1: 121–127. Kleinman SH, Kuhns MC, Todd DS, Glynn SA, McNamara Fiebig EW, Wright DJ, Rawal BD, Garrett PE, Schumacher A, DiMarco A, Busch MP.2003. Frequency of HBV DNA RT, Peddada L, Heldebrant C, Smith R, Conrad A, Klein- detection in US blood donors testing positive for the man SH, et al. 2003. Dynamics of HIV viremia and an- presence of anti-HBc: Implications for transfusion trans- tibody seroconversion in plasma donors: Implications for mission and donor screening. Transfusion 43: 696–704. diagnosis and staging of primary HIV infection. AIDS 17: Kolk DP,Dockter J, Linnen J, Ho-Sing-Loy M, Gillotte-Tay- 1871–1879. lor K, McDonough SH, Mimms L, Giachetti C. 2002. Fishman JA. 2007. Infection in solid-organ transplant recip- Significant closure of the human immunodeficiency vi- ients. N Engl J Med 357: 2601–2614. rus type 1 and hepatitis C virus preseroconversion detec- Fishman JA. 2008. Rapporto dell’OMS sulla valutazione del tion windows with a transcription-mediated-amplifica- programma nazionale trapianti in Italia. Trapianti 12: tion-driven assay. J Clin Microbiol 40: 1761–1766. 37–53. Kroshus TJ, Kshettry VR, Savik K, John R, Hertz MI, Bol- Fishman JA, Rubin RH. 1998. Infection in organ-transplant man RM 3rd. 1997. Risk factors for the development of recipients. N Engl J Med 338: 1741–1751. bronchiolitis obliterans syndrome after lung transplanta- Fishman JA, Greenwald MA, Kuehnert MJ. 2007. Enhancing tion. J Thorac Cardiovasc Surg 114: 195–202. transplant safety: A new era in the microbiologic evalu- Len O, Gavalda J, Blanes M, Montejo M, San Juan R, Mo- ation of organ donors? Am J Transplant 7: 2652–2654. reno A, Carratala J, de la Torre-Cisneros J, Bou G, Cor- Fishman JA, Strong DM, Kuehnert MJ. 2009. Organ and dero E, et al. 2008. Donor infection and transmission to tissue safety workshop 2007: Advances and challenges. the recipient of a solid allograft. Am J Transplant 8: 2420– Cell Tissue Bank 10: 271–280. 2425. Freeman RB, Giatras I, Falagas ME, Supran S, O’Connor K, Lowance D, Neumayer HH, Legendre CM, Squifflet JP, Ko- Bradley J, Snydman DR, Delmonico FL. 1999. Outcome varik J, Brennan PJ, Norman D, Mendez R, Keating MR,

www.perspectivesinmedicine.org of transplantation of organs procured from bacteremic Coggon GL, et al. 1999. Valacyclovir for the prevention of donors. Transplantation 68: 1107–1111. cytomegalovirus disease after renal transplantation. In- Grossi P,Strong DM. 2009. The role of testing in determin- ternational Valacyclovir Cytomegalovirus Prophylaxis ing suitability of donors and tissues. In Tissue and cell Transplantation Study Group. N Engl J Med 340: 1462– donation: An essential guide (ed. Warwick DFRM, Bru- 1470. baker SA, Eastlund T). Blackwell, New York. Lumbreras C, Sanz F, Gonzalez A, Perez G, Ramos MJ, Grossi PA, Fishman JA, AST Infectious Disease Community Aguado JM, Lizasoain M, Andres A, Moreno E, Gomez of Practice. 2009. Donor-derived infections in solid or- MA, et al. 2001. Clinical signiﬁcance of donor-unrecog- gan transplant recipients. Am J Transplant 9: S19–S26. nized bacteremia in the outcome of solid-organ trans- Hodson EM, Jones CA, Webster AC, Strippoli GF, Barclay plant recipients. Clin Infect Dis 33: 722–726. PG, Kable K, Vimalachandra D, Craig JC. 2005. Antiviral Nanni Costa A, Grossi P, Gianelli Castiglione A, Grigioni medications to prevent cytomegalovirus disease and early WF. 2008. Quality and safety in the Italian donor evalu- death in recipients of solid-organ transplants: A system- ation process. Transplantation 85: S52–S56. atic review of randomised controlled trials. Lancet 365: Nellore A, Fishman JA. 2011. NK cells, innate immunity and 2105–2115. hepatitis C infection after liver transplantation. Clin In- Huang RC, Fishman JA. 2011. Screening of deceased organ fect Dis 52: 369–377. donors: No easy answers. Transplantation 91: 146–149. Pillonel J, Saura C, Courouce AM. 1998. Prevalence of HIV, Husain S, Raza K, Pilewski JM, Zaldonis D, Crespo M, HTLV, and hepatitis B and C viruses in blood donors in Toyoda Y, Shutt K, Spichty K, Bentlejewski C, Pakstis France, 1992–1996 (in French). Transfus Clin Biol 5: DL, et al. 2009. Experience with immune monitoring in 305–312.

Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 13 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

J.A. Fishman

Potena L, Valantine HA. 2007. Cytomegalovirus-associated during chronic hepatitis C virus infection. Hepatology 42: allograft rejection in heart transplant patients. Curr Opin 828–837. Infects Dis 20: 425–431. USPH Service. 1994. PHS guideline for preventing trans- Rubin RH, WolfsonJS, Cosimi AB, Tolkoff-Rubin NE. 1981. mission of HIV through transplantation of human tissue Infection in the renal transplant recipient. Am J Med 70: and organs. In Morbidity and mortality weekly report 405–411. (MMWR), pp. 1–17. Satoi S, Bramhall SR, Solomon M, Hastings M, Mayer AD, USPH Service. 2011. (Draft) Public Health Service guideline de Goyet JV,Buckels JA, McMaster P,Mirza DF.2001. The for reducing transmission of human immunodeﬁciency use of liver grafts from donors with bacterial meningitis. virus (HIV), hepatitis B virus (HBV), and hepatitis C Transplantation 72: 1108–1113. virus (HCV) through solid organ transplantation (ed. Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ. 1996. DoHaH Services), Docket No. CDC–2011–0011. CDC The risk of transfusion-transmitted viral infections. The Federal Register. Retrovirus Epidemiology Donor Study. N Engl J Med van Delden C, Blumberg EA, AST Infectious Diseases Com- 334: 1685–1690. munity of Practice. 2009. Multidrug resistant Gram-neg- Selin LK, Nahill SR, Welsh RM. 1994. Cross-reactivities in ative bacteria in solid organ transplant recipients. Am J memory cytotoxic T lymphocyte recognition of heterol- Transplant 9: S27–S34. ogous viruses. J Exp Med 179: 1933–1943. Yao F, Seed C, Farrugia A, Morgan D, Cordner S, Wood D, Singh N. 2002. Impact of donor bacteremia on outcome Zheng MH. 2007. The risk of HIV,HBV,HCVand HTLV in organ transplant recipients. Liver Transpl 8: 975– infection among musculoskeletal tissue donors in Aus- 976. tralia. Am J Transplant 7: 2723–2726. Small LN, Lau J, Snydman DR. 2006. Preventing post-organ Yao F, Seed C, Farrugia A, Morgan D, Wood D, Zheng MH. transplantation cytomegalovirus disease with ganciclo- 2008. Comparison of the risk of viral infection between vir: Meta-analysis comparing prophylactic and preemp- the living and nonliving musculoskeletal tissue donors in tive therapies. Clin Infect Dis 43: 869–880. Australia. Transpl Int 21: 936–941. Spangenberg HC, Viazov S, Kersting N, Neumann-Haefelin Yewdell JW,Bennink JR. 1999. Immunodominance in major C, McKinney D, Roggendorf M, von Weizsacker F, Blum histocompatibility complex class I-restricted T lympho- HE, Thimme R. 2005. Intrahepatic CD8þ T-cell failure cyte responses. Annu Rev Immunol 17: 51–88. www.perspectivesinmedicine.org

14 Cite this article as Cold Spring Harb Perspect Med 2013;3:a015669 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press

Opportunistic Infections−−Coming to the Limits of Immunosuppression?

Jay A. Fishman

Cold Spring Harb Perspect Med 2013; doi: 10.1101/cshperspect.a015669

Subject Collection Transplantation

Heart Transplantation: Challenges Facing the Overview of the Indications and Contraindications Field for Liver Transplantation Makoto Tonsho, Sebastian Michel, Zain Ahmed, et Stefan Farkas, Christina Hackl and Hans Jürgen al. Schlitt Bioethics of Organ Transplantation Facial and Hand Allotransplantation Arthur Caplan Bohdan Pomahac, Ryan M. Gobble and Stefan Schneeberger Overview of Clinical Lung Transplantation Induction of Tolerance through Mixed Chimerism Jonathan C. Yeung and Shaf Keshavjee David H. Sachs, Tatsuo Kawai and Megan Sykes Immunological Challenges and Therapies in Pancreas Transplantation: Solid Organ and Islet Xenotransplantation Shruti Mittal, Paul Johnson and Peter Friend Marta Vadori and Emanuele Cozzi Clinical Aspects: Focusing on Key Unique Tolerance−−Is It Worth It? Organ-Specific Issues of Renal Transplantation Erik B. Finger, Terry B. Strom and Arthur J. Matas Sindhu Chandran and Flavio Vincenti T-Cell Costimulatory Blockade in Organ Lessons and Limits of Mouse Models Transplantation Anita S. Chong, Maria-Luisa Alegre, Michelle L. Jonathan S. Maltzman and Laurence A. Turka Miller, et al. Regulatory T-Cell Therapy in Transplantation: Effector Mechanisms of Rejection Moving to the Clinic Aurélie Moreau, Emilie Varey, Ignacio Anegon, et Qizhi Tang and Jeffrey A. Bluestone al. Opportunistic Infections−−Coming to the Limits of The Innate Immune System and Transplantation Immunosuppression? Conrad A. Farrar, Jerzy W. Kupiec-Weglinski and Jay A. Fishman Steven H. Sacks

For additional articles in this collection, see http://perspectivesinmedicine.cshlp.org/cgi/collection/