SEARCH

SEARCH BY CITATION

Keywords:

  • Donor-derived infection;
  • fungus;
  • immunosuppression;
  • opportunistic infection;
  • prophylaxis;
  • timeline;
  • transplant infectious disease;
  • virus

Introduction

  1. Top of page
  2. Introduction
  3. General Principles: Risk of Infection after Transplantation
  4. Prevention of Infection
  5. The Timeline of Infection
  6. Future Directions
  7. Definitions
  8. Disclosure
  9. References

Infectious disease after transplantation remains a field in evolution. Improved immunosuppressive therapies for organ transplantation have reduced the incidence of allograft rejection while increasing susceptibility to opportunistic infections and virally mediated malignancies. Traditional patterns of opportunistic infection after transplantation have also been altered by the emergence of organisms with antimicrobial resistance and by antifungal (including Pneumocystis) and antiviral prophylaxis (i.e. for cytomegalovirus [CMV] and other herpesviruses) (1). Improved microbiologic diagnostic tools (e.g. nucleic acid testing) are used in the routine management of common infections (e.g. CMV, Epstein-Barr virus [EBV]) and have allowed the definition of new clinical syndromes (e.g. BK polyomavirus nephropathy) and of donor-derived infections (e.g. due to lymphocytic choriomeningitis virus [LCMV]). At the same time, a variety of newer techniques are available, largely on a research basis (e.g. HLA-linked tetramer binding, intracellular cytokine staining) to assess pathogen-specific immunity. These may be used to investigate the recipient's susceptibility to specific infections and are increasingly entering clinical practice. In the past decade, Transplant infectious disease has emerged as an integral subspecialty component of most successful transplant programs.

General Principles: Risk of Infection after Transplantation

  1. Top of page
  2. Introduction
  3. General Principles: Risk of Infection after Transplantation
  4. Prevention of Infection
  5. The Timeline of Infection
  6. Future Directions
  7. Definitions
  8. Disclosure
  9. References

Recognition of infection is more difficult in transplant recipients than in individuals with normal innate and acquired immune functions. Presentations are often complicated by noninfectious causes of fever (e.g. graft rejection). Drug interactions (e.g. azole antifungal agents with calcineurin inhibitors) and toxicities are common. Early and specific microbiological diagnosis is essential to guide treatment and minimize exposures to nonessential antimicrobial agents. Invasive diagnostic procedures are often required for accurate and timely diagnosis.

In the absence of assays that allow individualization of immunosuppression after transplantation or that measure an individual's risk for infection, prophylactic strategies are based on an assessment of the anticipated risk for infection based on experience (i.e. universal prophylaxis with trimethoprim–sulfamethoxazole [TMP–SMX] for Pneumocystis pneumonia [PCP]) or on known or likely infectious exposures based on serologic and microbiologic testing, epidemiologic history and the perceived intensity of immunosuppression. The risk for infection is a continuous function of the interplay between these factors.

Epidemiologic exposures

Epidemiologic exposures can be divided into four overlapping categories: donor- and recipient-derived infections, and community or nosocomial exposures. Transplanted organs facilitate transmission of microbes from organ donors. Unexpected clusters of donor-derived infections in transplant recipients have occurred including those due to West Nile virus, LCMV, rabies, HIV, hepatitis B and hepatitis C viruses, herpes simplex virus and Chagas’ disease (4–7). Infected organ donors may also transmit organisms resistant to routine surgical antimicrobial prophylaxis. Mandatory reporting of transplant-associated infections has increased awareness of this problem. Use of organs from deceased donors with ‘fever’, ‘viral syndromes’ or other unexplained illness is controversial and illustrates the need for improved microbiologic screening tools and therapies. Active infection in transplant recipients should be eradicated or controlled prior to transplantation to the degree possible as these may be reactivated with immunosuppression (8). Common recipient-derived pathogens include Mycobacterium tuberculosis, some parasites (Strongyloides stercoralis, Trypanosoma cruzi), viral infections (herpes simplex virus or varicella zoster virus [VZV, shingles]), endemic fungi (Histoplasma capsulatum, Coccidioidioides immitis, Paracoccidioides braziliensis), hepatitis B or C or, more recently, HIV. Although previously contraindicated, successful kidney and liver transplantation have been achieved in HIV-infected patients treated with highly active antiretroviral therapy (9,10). Activities and hobbies including travel, pets or marijuana use (Aspergillus species) may provide clinically important exposures.

Net state of immunosuppression

The concept of ‘net state of immunosuppression’ comprises all factors that contribute to risk for infection (Table 1).The main determinants of risk are the dose, duration and sequence of immunosuppressive therapies. The effects of some of these therapies such as the T-lymphocyte depleting antibodies persist well after the period of T-cell depletion. Breeches in mucocutaneous integrity (e.g. vascular and urinary catheters), fluid collections (hematoma, ascites, effusions) are major targets for microbial seeding.

Table 1.  The ‘net state of immune deficiency’
Immunosuppressive therapies (current and past)
Prior therapies (chemotherapy, Antimicrobials)
Mucocutaneous barrier integrity (catheters, lines, drains)
Neutropenia, lymphopenia
Underlying immune deficiencies (e.g. hypogammaglobulinemia, SLE)
Metabolic conditions: uremia, malnutrition, diabetes, cirrhosis
Viral coinfection (e.g. CMV, HCV, HBV)
Risk assessment in transplantation
Greater infectious risk
Induction therapy–lymphocyte depletion
High-dose corticosteroids
Plasmapheresis
High rejection risk
Early graft rejection
Graft dysfunction
Active/latent donor/recipient infection
Technical complications
 Anastamotic leak
 Bleeding
 Wound infection/poor wound healing
 Prolonged intubation/intensive unit care
 Surgical, vascular or urinary catheters
Lower infectious risk
Immunologic tolerance
Good HLA match
Technically successful surgery
Good graft function
Appropriate surgical prophylaxis
Effective antiviral prophylaxis
PCP prophylaxis
Appropriate vaccination

Prevention of Infection

  1. Top of page
  2. Introduction
  3. General Principles: Risk of Infection after Transplantation
  4. Prevention of Infection
  5. The Timeline of Infection
  6. Future Directions
  7. Definitions
  8. Disclosure
  9. References

Antimicrobial prophylaxis has altered the incidence and severity of posttransplant infections. Three general preventive strategies are used: (1) vaccination, (2) universal prophylaxis including surgical prophylaxis and (3) preemptive or presymptomatic therapy. ‘Universal prophylaxis’ provides antimicrobial therapy to all ‘at-risk’ patients for a defined time period. ‘Preemptive therapy’ utilizes sensitive, quantitative assays (e.g. molecular, antigen detection) to monitor patients at predefined intervals to detect early infection prior to the emergence of invasive disease. Positive assays initiate therapy. Thus, the term ‘presymptomatic’ might be better employed for these interventions. Preemptive therapy incurs extra costs for monitoring and coordination of outpatient care while reducing drug costs and drug toxicities. These are discussed elsewhere in regard to anti-CMV therapies. Lifestyle changes may also limit exposure to potential pathogens. Routine surgical prophylaxis should be adjusted to the organ transplanted and individual exposures or colonization patterns and hospital epidemiology. Prophylaxis may be adjusted based on known colonization patterns with organisms such as Pseudomonas, MRSA, VRE or fungi.

Two advances in prophylaxis have significantly altered transplant medicine. First, TMP–SMZ is given for three months to lifetime to prevent PCP as well as Toxoplasma gondii, Isospora belli, Cyclospora cayetanensis, many Nocardia and Listeria species, and common urinary, respiratory and gastrointestinal pathogens. Low-dose TMP–SMZ is well tolerated and should be used in the absence of data demonstrating allergy or interstitial nephritis. Alternative anti-Pneumocystis prophylactic strategies lack this breadth of protection (11). The prevention of posttransplant CMV and other herpesvirus infections and the availability of oral antiviral agents have also revolutionized posttransplant care and is discussed in detail elsewhere (1).

The Timeline of Infection

  1. Top of page
  2. Introduction
  3. General Principles: Risk of Infection after Transplantation
  4. Prevention of Infection
  5. The Timeline of Infection
  6. Future Directions
  7. Definitions
  8. Disclosure
  9. References

The timeline of posttransplant infections reflects the posttransplantation relationship between the recipient's epidemiologic exposures and immunosuppressive strategy employed. Most centers use a variation of standard ‘triple immunosuppression’ (prednisone, calcineurin inhibitor, antimetabolite such as mycophenylate mofetil) (Figure 1) (1–3). Changes in immunosuppressive regimens, routine prophylaxis and improved graft survival have altered this timeline. Steroid-sparing regimens and anti-Pneumocystis prophylaxis have made PCP less common. Herpes virus infections are uncommon during antiviral prophylaxis. Lymphocyte depleting therapies produce prolonged T- and B-cell deficits and may alter T-regulatory subsets, antibody production and NK-cell function also. The long-term impacts of these agents and of the inhibitors of costimulatory T-cell pathways include a prolonged risk for (late) viral and fungal infections and increased risk for posttransplant lymphoproliferative disorders (PTLD) and other malignancies. Antibody depletion (plasmaphersis), bortezimib or splenectomy diminish opsonization and increase the risk for infection due to encapsulated bacteria. Sirolimus-based regimens have been associated with poor wound healing and with a form of noninfectious pneumonitis easily confused with PCP or viral pneumonia (12).

image

Figure 1. The timeline of posttransplant infections. Common patterns of opportunistic infection are observed following solid organ transplantation based on epidemiologic exposures and the ‘net state of immune suppression’. The timeline is altered based on the immunosuppressive regimen and prophylactic medications. The dynamic assessment of infectious risk represents assays that will measure an individual's risk for infection due to specific pathogens or in general.

Download figure to PowerPoint

The timeline is used to establish a differential diagnosis for infectious syndromes at various stages after transplantation. Infections occurring outside the usual period or of unusual severity suggest excessive immunosuppression or epidemiologic hazard. The timeline is ‘reset’ to the period of greatest risk for opportunistic infection with the treatment of graft rejection or intensification of immune suppression (e.g. bolus corticosteroids or T-cell depletion).

Phase 1: Early posttransplantation (1–4 weeks)

Opportunistic infections are generally absent in the first month after transplantation as the full impact of immunosuppression depends on prolonged exposure to suppressive therapies. Infections in this period are generally donor or recipient-derived (colonization, viremia, candidemia) or associated with technical complications of surgery (e.g. infected hematoma, peritonitis). Unexplained early infectious syndromes (hepatitis, pneumonitis, encephalitis, rashes, leucopenia) reflect donor-derived infection. Clostridium difficile colitis is common. Early graft injuries (e.g. ischemia to bile ducts or pulmonary reperfusion injury) may manifest later as foci for liver or lung abscesses (Figure 1).

Phase 2: One to 6 months posttransplantation

In this period, TMP–SMZ prophylaxis should prevent most urinary tract infections and opportunistic infections such as PCP, Listeria monocytogenes, T. gondii and sulfa-susceptible Nocardia species. Some infections (cholangitis, pneumonia, C. difficile colitis) persist from the perioperative period. Viral pathogens and graft rejection are responsible for the majority of febrile episodes in this period. Herpesvirus infections are uncommon in the face of antiviral prophylaxis but may emerge subsequently. Other viral pathogens including BK polyomavirus, adenovirus and recurrent HCV have emerged. Viral infections may cause immediate or ‘direct’ (tissue invasive) disease or may be reflected in an array of virus-associated phenomena loosely termed ‘indirect effects’. These include systemic (CMV) or local (influenza) immune suppression predisposing to or enhancing other opportunistic infections or PTLD and an increased risk for acute and chronic graft injury or rejection. Among infections reactivated during this period are the endemic fungi, Aspergillus species, Cryptococcus neoformans, T. gondii, T. cruzi and Strongyloides.

Phase 3: More than 6 months after transplantation

More than 6 months posttransplantation, infectious risk diminishes as immunosuppression is tapered in recipients with satisfactory allograft function. These patients tend to develop more severe manifestations of the common, community acquired infections but have limited risk for most opportunistic infections without other factors that contribute to the net state of immunosuppression. In some patients, chronic viral infections may produce graft injury (e.g. cirrhosis from HCV [livers], bronchiolitis obliterans [lungs] and accelerated vasculopathy [hearts] with CMV) or malignancy (PTLD, skin or anogenital cancers). A third, small group tends to have less adequate graft function, receive increased immune suppression and suffer recurrent infection despite attempts at minimization of immunosuppression. These ‘chronic ne’er-do-wells’ are at increased risk for opportunistic infection with Listeria or Nocardia species, invasive fungal pathogens (Zygomycetes, dematiacious moulds), and unusual organisms (e.g. Rhodococcus species). Minimal signs of infection merit careful evaluation in such ‘high risk’ individuals. They may benefit from lifetime TMP–SMZ or antifungal prophylaxis.

Future Directions

  1. Top of page
  2. Introduction
  3. General Principles: Risk of Infection after Transplantation
  4. Prevention of Infection
  5. The Timeline of Infection
  6. Future Directions
  7. Definitions
  8. Disclosure
  9. References

Given improved immunosuppression, the prevention of infection has become a major goal of transplantation. Advances in assay development, likely using some combination of pharmacogenomics, proteomics, nonspecific and pathogen-specific measures of cell-mediated ‘immune function’, will allow the individualization of immunosuppression. Newer immunosuppressive agents may provide more specific targeting of immune pathways, both intrinsic and acquired. In the meantime, investigations of vaccination strategies for pre- or posttransplant patients are needed. Improved microbiologic diagnostic tools (e.g. multiplexed assays using a variety of diagnostic modalities) will assist in the measurement of infectious risk and in the management of invasive infections in the transplant recipient. Investigation of the pathophysiologic mechanisms underlying the pleotropic effects of viral infection, particularly in predisposition to opportunistic infection and malignancy, are needed. Such advances may allow a reduction in the incidence or impact of graft dysfunction, cancers and infections after organ transplantation.

Definitions

  1. Top of page
  2. Introduction
  3. General Principles: Risk of Infection after Transplantation
  4. Prevention of Infection
  5. The Timeline of Infection
  6. Future Directions
  7. Definitions
  8. Disclosure
  9. References

Clinical practice guidelines are defined as ‘systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances’. This definition has been adapted to include only those statements and recommendations that are supported by a high level of scientific evidence. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. In an attempt to characterize the quality of evidence supporting recommendations, a category is assigned and reported with each recommendation (Table 2).

Table 2.  Quality of evidence on which a recommendation is based
GradeDefinition
IRandomized controlled trials
II-1Controlled trials without randomization
II-2Cohort or case-control analytic studies
II-3Multiple time series, dramatic uncontrolled experiments
IIIOpinions of respected authorities, descriptive epidemiology

References

  1. Top of page
  2. Introduction
  3. General Principles: Risk of Infection after Transplantation
  4. Prevention of Infection
  5. The Timeline of Infection
  6. Future Directions
  7. Definitions
  8. Disclosure
  9. References