Infection In Kidney Transplant


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  • Risk for infection is determined by epidemiologic exposures and the intensity of immune defects. Significant exposures may be derived from the organ itself, preexisting in the recipient, from the hospital environment, or due to exposures in the community. The timing of specific infections is dependent on the specific immunosuppressive regimen for each individual and other factors (“the net state of immune suppression”). The timeline of infections is an idealized view of the changing risk factors (eg, surgery/hospitalization, immune suppression, acute and chronic rejection, emergence of latent infections, exposures to novel community infections over time). The pattern of infections is changed with alterations in the immunosuppressive regimen (pulse-dose corticosteroids or intensification for graft rejection), intercurrent viral infection, neutropenia (drug toxicity), graft dysfunction, or significant epidemiologic exposures (travel or food).   The timeline reflects three overlapping periods of risk for infection: (1) the perioperative period to approximately 4 weeks after transplantation, (2) the period 1 to 6 months after transplantation (depending on the rapidity of taper of immune suppression and the type and dosing of antilymphocyte “induction,” which may persist) and (3) the period beyond the first year after transplantation.
  • The timeline of posttransplant infections may be used in a variety of ways: (1) to establish a differential diagnosis for the transplant recipient suspected of having infection, (2) as a clue to the presence of an excessive environmental hazard for the individual, either within the hospital or in the community, and (3) as a guide to the design of preventative antimicrobial strategies. Infections occurring outside the usual period or of unusual severity suggest either excessive epidemiologic hazard or excessive immunosuppression. The prevention of infection must be linked to the risk for infection at various times after transplantation.
  • In the first month after transplantation, a common type of infection that was present in the recipient prior to transplantation and/or was inadequately treated, now has emerged in the setting of surgery, anesthesia, and immunosuppression. Pretransplantation pneumonia and vascular access infections are common examples of this type of infection. Colonization of the recipient with resistant organisms is also common (eg, MRSA). The first rule of successful transplant infectious disease is the eradication of all infection possible prior to transplantation.   The second type of early infection is present in the donor before transplantation. This is often a nosocomially derived organism (eg, resistant gram‑negative bacilli, Staphylococcus aureus, Candida species) due to: (1) systemic infection in the donor (eg, line infection) or (2) contamination during the organ procurement process. The greatest risk is for infection of vascular suture lines with resultant mycotic aneurysm. Uncommonly, infections have been transmitted from donor to recipient, including tuberculosis or fungal (eg, histoplasmosis) infections that emerge earlier in the timeline than would be predicted. A common type of infection in the immediate posttransplant period is due to the complex surgical procedure of transplantation. These include surgical wound infections, pneumonia (aspiration), bacteremia due to vascular access or surgical drainage catheters, urinary tract infections, or infections of fluid collections—leaks of vascular or urinary anastomoses or of lymphoceles. These are nosocomial infections and, as such, are due to the same bacteria and Candida infections observed in nonimmunosuppressed patients undergoing comparable surgery. The signs of infection are often subtle and the severity often greater. The technical skill of the surgeons and meticulous postoperative care (ie, wound care, endotracheal tubes, vascular access devices, drainage catheters) are the determinants of risk for these infections. Clostridium difficile colitis is also common in this period. Limited perioperative antibiotic prophylaxis (ie, from a single dose to 24 hours of an antibiotic such as cefazolin) is usually adequate with additional coverage only for known risk factors (eg, prior colonization with MRSA). For pancreas transplantation, perioperative prophylaxis against yeasts with fluconazole is generally used, bearing in mind the interactions between azole antifungal agents and calcineurin inhibitors or rapamycin (levels may be increased significantly). Notable by their absence in the first month after transplantation are opportunistic infections, even though the daily doses of immunosuppressive drugs are at their highest during this time.
  • Information about possible donor-derived infections is critical to the management of the transplant recipient. The greatest risk is for nosocomial infection from the donor’s hospital or endemic infection from the donor’s past exposures, including travel and work. In the setting of “unusual” infectious syndromes, the local organ procurement organization may have additional information or tissues available for testing. Johnston L, Chui L, Chang N, et al. Cross-Canada spread of methicillin-resistant Staphylococcus aureus via transplant organs. Clin Infect Dis . 1999;29:819-823.
  • Vancomycin-resistant enterococcis (VRE) are an example of a common infectious agent seen early after transplantation. The incidence of VRE reflects excessive use of antimicrobial agents and attention to the avoidance of transmission of nosocomial infections. VRE are not especially virulent or invasive pathogens—colonization with VRE is common in patients undergoing organ transplantation. VRE emerge under antimicrobial pressure in “sick” patients—those with metabolic abnormalities, invasive monitoring, or drainage catheters.
  • Early infections are most common in those patients with poor initial graft function, surgical complications, or prolonged instrumentation, including intubation and vascular or drainage catheters. Infections early after transplantation should be anticipated in individuals with technical misadventures. Colonization with nosocomial organisms occurring during hospitalization may provide the source of future infections during periods of increased immune suppression, as with treatment of graft rejection.
  • The specific opportunistic infections that occur reflect the specific immunosuppressive regimen and the presence or absence of immunomodulating viral infection. Viral pathogens (and rejection) are responsible for many of the febrile episodes in this period. Anti‑CMV strategies and trimethoprim‑sulfamethoxazole prophylaxis are effective in decreasing the risk of infection.
  • Beyond 6 months after transplantation, recipients can be considered in three general groups in terms of infectious risk.  The majority of transplant recipients had a technically good procedure with good early allograft function, gradually reduced immunosuppression, and no early infections or chronic viral infections. These patients are at risk for infections similar to those of the general community (often of somewhat greater severity or duration), with community‑acquired respiratory viruses constituting the main risk. There is some risk for primary CMV infection (socially acquired) or infections related to underlying diseases (eg, skin infections in diabetes).
  • The second group of patients either had early infections or suffer from viral infections. Many of these, even in the presence of effective antimicrobial therapy, have persistently greater risk for other infections than does the general cohort. Viral infection may be confused with graft rejection (HCV in livers, CMV in lungs). Persistent viral infection (eg, HCV, CMV, EBV) may produce end-organ damage (eg, BK polyomavirus nephropathy, cryoglobulinemia or cirrhosis from HCV), recurrent bacterial or fungal infections, or malignancy (eg, PTLD due to EBV, skin or anogenital cancer due to papillomaviruses).
  • The third group of patients has less than satisfactory allograft function long-term. These recipients generally receive higher than usual amounts of immunosuppressive therapy, which may precipitate viral infections, and often suffer recurrent graft rejection. This group is often called chronic “ne'er‑do‑wells," who are at highest risk for opportunistic infection with such pathogens as Pneumocystis carinii/jiroveci , Listeria monocytogenes , Aspergillus species, Nocardia asteroides , and Cryptococcus neoformans . In these patients, minimal signs or symptoms of infection merit careful evaluation because of the extraordinary risk for infection and cancer. These patients tend to benefit from extended prophylaxis—lifelong attention to vaccines and bacterial or viral prophylaxis.
  • Infectious complications are the leading cause of morbidity and mortality in any transplant patient.
  • Figure 4. Changing Timeline of Infection after Organ Transplantation. Infections occur in a generally predictable pattern after solid-organ transplantation. The development of infection is delayed by prophylaxis and accelerated by intensified immunosuppression, drug toxic effects that may cause leukopenia, or immunomodulatory viral infections such as infection with cytomegalovirus (CMV), hepatitis C virus (HCV), or Epstein-Barr virus (EBV). At the time of transplantation, a patient's short-term and long-term risk of infection can be stratified according to donor and recipient screening, the technical outcome of surgery, and the intensity of immunosuppression required to prevent graft rejection. Subsequently, an ongoing assessment of the risk of infection is used to adjust both prophylaxis and immunosuppressive therapy. MRSA denotes methicillin-resistant Staphylococcus aureus, VRE vancomycin-resistant Enterococcus faecalis, HSV herpes simplex virus, LCMV lymphocytic choriomeningitis virus, HIV human immunodeficiency virus, PCP Pneumocystis carinii pneumonia, HBV hepatitis B virus, VZV varicella-zoster virus, SARS severe acute respiratory syndrome, PML progressive multifocal leukoencephalopathy, and PTLD post-transplantation lymphoproliferative disorder. Modified from Fishman and Rubin1 and Rubin et al.45
  • Cytomegalovirus (CMV) is a member of the Herpesvirus group and shares with this family the characteristic ability to remain latent in the body over long periods. CMV most often presents as an acute primary infection or as a latent infection that is reactivated to clinical disease only during immunosuppression. CMV infection is defined as viral replication in the presence or absence of symptoms, whereas CMV disease requires symptomatic viral reactivation with either a viral syndrome or tissue invasive disease. CMV is a common pathogen in solid organ transplant recipients. CMV is an established cause of morbidity and an occasional cause of mortality during the first year post transplant. Without prophylaxis, CMV infection can be detected in >75% of SOT recipients, with an overall mean incidence of symptomatic CMV disease in the transplant population of 30% (range 11-72%). CMV infection is most frequent and most severe in lung recipients. Like all herpes viruses, once CMV infection is established its replication is highly dynamic. This can lead to a rapid increase in viral load, which is a measure of the severity of a viral infection and represents the amount of virus in an involved body. Infection with increased viral load may then lead to tissue invasive disease. (1) Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med . 1998;338; 1741. (2) Hodson EM, Jones CA, Webster AC, et al. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: A systematic review of randomised controlled trials. Lancet . 2005;365:2105-2115.
  • Risk categories for CMV infection have been developed and can be used to target preventive measures / therapies. Those at highest risk of symptomatic CMV disease are CMV seronegative patients (R-) who receive organs from CMV seropositive donors (D+) (High Risk D+/R-), and CMV seropositive patients on heavily immunosuppressive regimens. Low risk D-/R- patients should receive CMV negative or leukodepleted blood products. Some may occasionally develop CMV disease due to exogenous exposure or inaccurate testing. Fishman JA, Emery V, Freeman R, et al. Cytomegalovirus in transplantation – challenging the status quo. Clinical Transplantation . 2007;21:149-158.
  • Like most viral infections, the development of CMV infection and its severity reflects the balance between the unique properties of the virus and factors related to the robustness of the host immune response. Viral factors contributing to the development of CMV infection include the amount of virus to which the individual is exposed as well as the replication dynamics of that virus. The ability of the virus to evade the host immune system and other factors unique to that viral species also determine its virulence. The presence of other viral and bacterial co-infections also increase susceptibility to infection by CMV. Host factors include the state of host immune defense mechanisms such as their ability to mount a full cell-mediated (T-cell) or humoral (B-cell) response. This is compromised through the use of therapeutic immunosuppressive agents in SOT. In addition, the immune status of the donor organ and recipient also determine the likelihood of CMV infection.
  • Reactivation of CMV in the context of SOT is a result of a combination of events. The use of immune suppressive therapies, especially those designed to suppress cell-mediated immune responses such as monoclonal anti-lymphocytic antibodies, co-infection with other herpes viruses, acute organ rejection, and the sepsis resulting from co-infection as well as prolonged and complex surgery increases the likelihood of reactivation of latent CMV.
  • Viral factors contributing to the development of CMV infection include the amount of virus to which the individual is exposed, the viral load, as well as the replication dynamics of that virus. The ability of the virus to evade the host immune system and other factors unique to that viral species also determine its virulence. Immunosuppressive therapy increases the ability of the virus to replicate as does the presence of other viral and bacterial co-infections. This combination increases the risk of developing CMV disease with tissue invasion of other organs such as liver, and lung.
  • CMV infections produce a number of ‘direct’ and ‘indirect’ effects. CMV has the propensity to establish lifelong 'latency' infection in the host after the initial infection has resolved, and can be reactivated in the immunocompromised individual.
  • The direct effects of CMV infection, namely CMV disease, present as either CMV syndrome or as Tissue Invasive Disease. CMV syndrome presents as a Flu- or Infectious mononucleosis-like syndrome, often with neutropenia. Tissue invasive disease presents as nephritis, hepatitis, carditis, pneumonitis, pancreatitis, retinitis or colitis with the transplanted organ usually showing the greatest inflammatory pathology. Tissue invasive disease was often fatal prior to the development of anti-vial therapy.
  • Indirect effects cover those conditions that develop independently of significant CMV viremia, and that result in part is from the influence of the virus on the host’s immune response. These effects are diverse including increased graft rejection, secondary fungal and bacterial infections, post-transplant diabetes mellitus, decreased graft and patient survival, cancer. In animal models a role for CMV infection in rejection of kidney, lung, heart, and liver allografts has been shown. In addition, anti-CV prophylaxis has been shown to reduce the frequency of organ (renal) rejection in D+/R- patients.
  • The slide shows CMV infection in the liver as a micro-abscess. The central CMV inclusion body is surrounded by neutrophils. Resource:
  • Two principal strategies have been advanced for the prevention of CMV disease after organ transplantation: Universal prophylaxis where therapy to all subjects or all of a particular group of subjects such as D+/R- individuals receive prophylaxis, and pre-emptive therapy, where individuals are monitored regularly post-SOT and therapy initiated when there is evidence of CMV reactivation or infection.
  • Pre-emptive therapy requires serial monitoring via nucleic acid amplification testing or immunofluorescence assays for the pp65 (CMV) antigen.
  • Pre-emptive therapy is aimed at targeting those most at risk for CMV disease. Pre-emptive therapy has the advantage of minimizing patient exposure to antiviral drugs, which potentially reduces both risk of toxicity and reduces costs. It seems likely, though unproven, that minimizing exposure to antiviral therapy reduces the risk of SOT recipients becoming resistant to the drug. Pre-emptive therapy may also reduce the risk of late-onset disease. However, pre-emptive therapy requires increased surveillance of SOT recipients which require greater coordination of health care services and patient monitoring. Pre-emptive therapy may also be unsuccessful in high-risk patients with a rapidly increasing viral load. Pre-emptive therapy also means that low-level asymptomatic viral infection is not impeded, exposing patients to the indirect effects of CMV.
  • Late-onset CMV disease is defined as occurring > 3 month following transplantation. Late-onset CMV occurs either as a primary infection in D+/R- individuals or recurrence in R+ patients. Epidemiological studies show that late-onset CMV is associated with significant morbidity. Limaye et al. reported that CMV disease developed in 19 of 259 recipients (7% [95% confidence interval 0.04–0.11]) of a liver transplant at a median of 4.5 months post transplant. Subjects developing late onset-CMV, were more likely to develop CMV syndrome (63%) or CMV tissue-invasive disease (37%), and CMV disease was independently associated with an increased risk of mortality during the first post-transplant year (hazard ratio 14 [95% confidence interval 3.8 –54], P=0.0007). Limaye AP, Bakthavatsalam R, Kim HW, et al. Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis. Transplantation . 2004;78: 1390–1396.
  • Oral antiviral therapy is an effective means of preventing CMV disease. In this double-blind, double-dummy randomized study of 364 high-risk, seronegative (D+/R-) SOT recipients a 900 mg once-daily regimen of valganciclovir was compared with a 1g three-times daily regimen of oral ganciclovir in CMV prevention. Both regimens were effective while on prophylaxis but once prophylaxis was discontinued a substantial portion of patients developed late-onset CMV disease. The rate of investigator diagnosed CMV disease was even higher than shown here (~30%). Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Pescovitz MD. Valganciclovir Solid Organ Transplant Study Group. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant . 2004 Apr;4(4):611-620.
  • Late-onset CMV may still develop in SOT recipients despite antiviral prophylaxis. In a study of 259 recipients of a first liver transplant at the University of Washington Medical Center between January 1, 1998 and December 31, 2001, all of whom received CMV prophylaxis as well as immunosuppressive and rejection therapy, 19 subjects developed CMV disease at a median of 4.5 months post transplant. Using multivariate analysis, the investigators reported that the main risk factors for late-onset CMV disease were D+/R- [HR (95%CI)] [12.1 (1.5-94)] (1). Other studies have suggested that potent immunosuppressive therapy and acute rejection therapy leads to an increased risk of late-onset CMV disease, as well as the type of organ transplanted. (1) Limaye AP, Bakthavatsalem R, Kim HW, et al. Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis. Transplantation . 2004;78:1390-1396.
  • PML = progressive multifocal leukoencephalopathy
  • Decoy cells are uroepithelial cells with nuclear viral inclusions—can be shed from ureter or bladder…
  • Our long experience with Liposomal Amphotericin B (AmBisome) at the department of Transplantation surgery, Huddinge University Hospital, Karoliska Institute, Stockholm, Sweden. We started to use AmBisome within a compassionate trial during 1989 in both Allogeneic stem cell transplant recipients as well as within solid organ transplant recipients. Later on we initiated two randomised placeo controlled prophylactic trials among stem cell and liver transplant recipients. We have also evaluated both safety as well as efficacy among our patients.
  • We performed a retrospective analysis of our first ten years of AmBisome treatment in solid organ transplant recipients. Patient charts were retrospectivly analysed for adverse events and efficacy.
  • The majority of patients treated were liver transplant recipients, some in conjunction with stem cell or kidney transplants.
  • We examined treatment data in the different groups of patients according to prophylaxis or if the fungal infection was suspected or verified. Interestingly enough treatment for verified fungal infections was not extreme, the median total dose was 0.95 g, median max dose of 1.8 mg/kg/day for a median of 18 days, however, the ranges were wide.
  • This slide show adverse events as found during the retrospective analysis, the majority of findings are laboratory values exceeding the normal ranges. Only 9 that is 3% of reported adverse events were considered caused by AmBisome, mainly backpain as have been discussed earlier.
  • In patients with a suspected fungal infection, 18 out of 75 patients died, 10 with no trace of fungi at autopsy. Only one patient died with fungi at autopsy, but, 7 more died without any autopsy, thus the efficacy was 89% as indicated by clinical cures.
  • We have come a long way in prophylaxis, handling and treating invasive fungal infections in solid organ transplant recipients during the ten years AmBisome been available. Mortality figures have been reduced from around 77 - 100% to below 10% which is encouraging.
  • Infection In Kidney Transplant

    1. 1. Infections in Organ Transplantation <ul><li>Dr.Mahmud Javed Hasan </li></ul><ul><li>Nephrology Dept. </li></ul><ul><li>MMCH </li></ul>
    2. 2. The Timeline of Posttransplant Infections HSV, herpes simplex virus; CMV, cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; PCP, Pneumocystis carinii pneumonia; TOXO, toxoplasmosis; EBV, Epstein-Barr virus. <ul><li>Common Variables in Immune Suppression </li></ul><ul><li>Rejection, antirejection therapy, new agents </li></ul><ul><li>Neutropenia, lymphopenia </li></ul><ul><li>Viral coinfection (CMV, HCV, EBV) </li></ul>Transplantation 4 Weeks 6-12 Months Long-term Nosocomial Technical From Common to ZEBRAS HSV, CMV, HBV, HCV, LISTERIA, PCP, TOXO Period of most intensive immune suppression Donor-derived infection Opportunistic, Relapsed, Residual Nosocomial infection
    3. 3. Use of the Timeline of Posttransplant Infections <ul><li>Differential diagnosis by time posttransplantation </li></ul><ul><li>Excess epidemiologic hazard </li></ul><ul><ul><li>Nosocomial infections: Aspergillus , MRSA, VRE, clustered in time and space, by hospital, physician, clinical unit </li></ul></ul><ul><ul><li>Community-acquired: influenza and respiratory viruses, Histoplasma , Cryptococcus </li></ul></ul><ul><ul><li>Individual: gardening, travel, work related, children </li></ul></ul><ul><li>Excessive immune suppression in a program </li></ul><ul><ul><li>Too many infections, too severe, or at the wrong time on timeline in entire cohort of patients </li></ul></ul>MRSA, methicillin-resistant Staphylococcus aureus ; VRE, vancomycin-resistant enterococci.
    4. 4. Timetable of Infection After Transplantation: First Month Following Transplantation <ul><li>Infection carried by donor cells or graft </li></ul><ul><li>Present (in recipient) prior to transplantation </li></ul><ul><li>Technical complications </li></ul><ul><ul><li>Obstructed stents, organ damage in procurement </li></ul></ul><ul><ul><li>Hemorrhage, hematoma, leaks, ischemia </li></ul></ul><ul><li>Postoperative complications in complex patients </li></ul><ul><ul><li>Aspiration, pulmonary embolus </li></ul></ul><ul><ul><li>Lines, drains, catheters </li></ul></ul><ul><ul><li>Clostridium difficile colitis </li></ul></ul>
    5. 5. Early Posttransplant Infections <ul><li>Possible infections from the allograft include: </li></ul><ul><li>Tuberculosis </li></ul><ul><li>Known pathogens (screened): HBV, HCV, HIV </li></ul><ul><li>Uncommon pathogens: West Nile virus, Chagas’ disease, Toxoplasma gondii , rabies, lymphocytic choriomeningitis virus </li></ul><ul><li>Common “sticky” bacteria (may be nosocomial colonizers of donor): Pneumococcus , Staphylococcus , Streptococcus , Pseudomonas , Salmonella , Aspergillus , Candida </li></ul>HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus. Johnston L et al. Clin Infect Dis . 1999;29:819-823.
    6. 6. Vancomycin-Resistant Enterococci in Transplantation <ul><li>Among highest risk </li></ul><ul><ul><li>kidney transplant recipients, </li></ul></ul><ul><ul><li>in neutropenic patients, and </li></ul></ul><ul><ul><li>other critically ill patients (LVADs, dialysis, ventilators) </li></ul></ul><ul><li>Common bacterial pathogen after liver transplantation </li></ul><ul><li>“ Predictor” of morbidity and mortality that reflects overall “illness” of patient </li></ul><ul><li>Up to 50% of all Enterococcus faecium in United States </li></ul>LVADs, left ventricular assist devices.
    7. 7. Conditions Predisposing to Early and Nosocomial Infection <ul><li>Exogenous immune suppression </li></ul><ul><li>Intubation (>3 days) </li></ul><ul><li>Catheters (urinary, venous, balloon pumps, dialysis, other mucosal injuries) </li></ul><ul><li>Ascites, peritoneal dialysis </li></ul><ul><li>Constipation, endoscopy, Clostridium difficile colitis </li></ul><ul><li>Broad-spectrum antimicrobial agents </li></ul><ul><li>Deep vein thrombosis, atelectasis, decubitus ulcers </li></ul><ul><li>Metabolic (malnutrition/uremia/hyperglycemia) </li></ul><ul><li>Latent infections (viral and parasitic) </li></ul><ul><li>Colonization (bacterial and fungal) </li></ul>
    8. 8. Timetable of Infection After Transplantation: 2 to 6 Months Following Transplantation <ul><li>Classic “opportunistic infections” </li></ul><ul><ul><li>Pneumocystis carinii </li></ul></ul><ul><ul><li>Toxoplasma gondii </li></ul></ul><ul><li>Endemic pathogens </li></ul><ul><ul><li>Trypanosoma cruzi , Strongyloides stercoralis , Leishmania species </li></ul></ul><ul><ul><li>Geographic/endemic fungi: Histoplasma , Coccidioides </li></ul></ul><ul><ul><li>Tuberculosis </li></ul></ul><ul><li>Reactivation of latent viral infections: CMV, EBV, HSV, VZV, HBV, HCV </li></ul><ul><li>CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; VZV, varicella-zoster virus; HBV, hepatitis B virus; HCV, hepatitis C virus. </li></ul>
    9. 9. Timetable of Infection After Transplantation: >6 to 12 Months Following Transplantation <ul><li>Most patients are doing well—gradual decrease in immune suppression </li></ul><ul><li>Infections are those of the community </li></ul><ul><ul><li>Community-acquired pneumonia </li></ul></ul><ul><ul><li>Influenza, RSV, Chlamydia , Mycoplasma </li></ul></ul><ul><ul><li>Urinary tract infections </li></ul></ul><ul><ul><li>RSV, respiratory syncytial virus. </li></ul></ul>
    10. 10. Timetable of Infection After Transplantation: >6 to 12 Months Following Transplantation <ul><li>A subset with: </li></ul><ul><li>Chronic viral infection </li></ul><ul><ul><li>CMV (now uncommon) </li></ul></ul><ul><ul><li>HCV (very common) </li></ul></ul><ul><ul><li>HBV (some viral resistance and relapse) </li></ul></ul><ul><ul><li>EBV (PTLD) </li></ul></ul><ul><ul><li>Papillomavirus (warts, anogenital and squamous cell cancers) </li></ul></ul><ul><ul><li>BK virus nephropathy </li></ul></ul><ul><li>Recurrent bacterial infections (lungs) </li></ul><ul><li>Chronic anastamotic issues </li></ul><ul><li>Recurrent Clostridium difficile colitis </li></ul>CMV, cytomegalovirus; HCV, hepatitis C virus; HBV, hepatitis B virus; EBV, Epstein-Barr virus; PTLD, posttransplant lymphoproliferative disorder.
    11. 11. Timetable of Infection After Transplantation: >6 to 12 Months Following Transplantation <ul><li>Chronic “ne’er do wells” with poor allograft function and higher levels of immune suppression in an attempt to preserve graft function </li></ul><ul><li>At highest risk for recurrent opportunistic infections including Nocardia asteroides, Cryptococcus , and fungal infections </li></ul><ul><li>Benefit from extended prophylaxis </li></ul>
    12. 12. Infection <ul><li>Types </li></ul><ul><ul><li>Bacterial </li></ul></ul><ul><ul><li>Fungal </li></ul></ul><ul><ul><li>Viral </li></ul></ul><ul><ul><li>Parasitic </li></ul></ul>27
    13. 13. Copyright ©2008 American Society of Nephrology Weikert, B. C. et al. Clin J Am Soc Nephrol 2008;3:S76-S86 Figure 1. Time of presentation of common viral illnesses post-transplant
    14. 14. Infection <ul><li>Prophylaxis </li></ul><ul><li>Time table of occurrence </li></ul><ul><li>Evaluation of fever </li></ul>28
    15. 15. 29
    16. 16. Classification of Infections <ul><li>Donor-derived </li></ul><ul><li>Recipient-derived </li></ul><ul><li>Nosocomial </li></ul><ul><li>Community-acquired </li></ul>
    17. 17. Donor-derived Infection <ul><li>Most are latent </li></ul><ul><ul><li>CMV, TB, T.cruzi </li></ul></ul><ul><li>Rarely can be acute </li></ul><ul><ul><li>Bacteremia/viremia at time of procurement </li></ul></ul><ul><ul><li>West Nile, rabies, HIV, hepatitis, LCV </li></ul></ul><ul><li>The majority of these are sub-clinical in healthy patients, but can be catastrophic when transplanted into an immunosuppresed patient </li></ul><ul><li>At present, routine evaluations of donors for infectious diseases relies upon serologic antibody testing, and thus sensitivity is not 100% for those that may not have had time to seroconvert </li></ul>
    18. 18. Donor-derived <ul><li>Transplantation of organs from deceased donors with viral syndromes is controversial </li></ul><ul><li>Livers with known Chagas or Hep B infection may be used as there are effective treatments for these infections </li></ul><ul><li>Hep C infected organs are sometimes transplanted into Hep C(+) donors </li></ul>
    19. 19. Fishman J. N Engl J Med 2007;357:2601-2614
    20. 20. Recipient-derived Infections <ul><li>Infections that can be treated or controlled do not necessarily preclude transplantation </li></ul><ul><li>Most commonly screened for: </li></ul><ul><ul><li>TB </li></ul></ul><ul><ul><li>syphilis </li></ul></ul><ul><ul><li>Viral: CMV, EBV, VZV, HSV, HIV, HBV, HCV </li></ul></ul><ul><li>Other things to think of </li></ul><ul><ul><li>T.cruzi, strongyloides, cryptococcus </li></ul></ul><ul><ul><li>Endemic fungi: histoplasma, coccidioides, paracoccidioides, aspergillus, blastomycosis </li></ul></ul>
    21. 21. Fishman J. N Engl J Med 2007;357:2601-2614
    22. 22. Immunizations <ul><li>Pt’s should be current on the following vaccines </li></ul><ul><ul><li>MMR </li></ul></ul><ul><ul><li>HBV </li></ul></ul><ul><ul><li>Influenza </li></ul></ul><ul><ul><li>Strep pneumoniae </li></ul></ul><ul><ul><li>Tetanus </li></ul></ul><ul><ul><li>Diphtheria </li></ul></ul><ul><ul><li>Pertussis </li></ul></ul><ul><ul><li>Polio </li></ul></ul><ul><ul><li>VZV – if never infected </li></ul></ul><ul><li>Consideration should be given to boosters for any of the above prior to transplantation as live vaccines are generally contraindicated post-transplant, and immunologic memory will become impaired </li></ul>
    23. 23. Nosocomial Infections <ul><li>MRSA </li></ul><ul><li>VRE </li></ul><ul><li>fluconazole-resistant Candida species </li></ul><ul><ul><li>associated with surgical site and indwelling catheters </li></ul></ul><ul><li>C.diff </li></ul><ul><li>Resistant gram-negative bacilli </li></ul><ul><li>Aspergillus </li></ul>
    24. 24. Community Infections <ul><li>Aspergillus </li></ul><ul><li>Nocardia </li></ul><ul><li>Cryptococcus neoformans (birds) </li></ul><ul><li>Respiratory viruses </li></ul><ul><ul><li>Secondary bacterial superinfection </li></ul></ul>
    25. 25. Monitoring Immunosuppression <ul><li>There are no specific tests currently available to determine the overall susceptibility of patients to infection… </li></ul><ul><li>… but they are on the horizon </li></ul><ul><li>Currently, the known determinants contributing to the overall risk of infection are the dose, duration, and sequence of immunosuppressive therapies </li></ul>
    26. 26. Fishman J. N Engl J Med 2007;357:2601-2614 Changing Timeline of Infection after Organ Transplantation
    27. 27. Early post-transplant period (30d) <ul><li>Opportunistic infections are rare in the first month post-transplant </li></ul><ul><li>>1 month of medical therapy is required to effectively deplete cell-mediated therapy </li></ul><ul><li>One exception is large, prolonged doses of corticosteroids </li></ul><ul><li>Infections are generally donor-derived or associated with complications from the surgery itself </li></ul>
    28. 29. Intermediate period (1-6mos) <ul><li>Viral infections and allograft rejection account for the majority of febrile episodes </li></ul><ul><li>Adherence to Bactrim and antiviral prophylaxis renders infections such as PCP, UTI’s, listeria, toxoplasmosis, and herpes very unlikely </li></ul><ul><li>Fungi, cryptococcus, T.cruzi, strongyloides can surface </li></ul><ul><li>Other: polyoma virus (BK and JC), recurrent HCV </li></ul>
    29. 31. Late post-transplant period (>6mos) <ul><li>Risk wanes as immunosuppressive therapy is tapered </li></ul><ul><li>Risk profile however, is “reset” with each episode of acute rejection </li></ul><ul><li>Chronic viral infections can cause allograft injury </li></ul><ul><ul><li>HCV  cirrhosis </li></ul></ul><ul><ul><li>BOOP in lungs </li></ul></ul><ul><ul><li>CMV  coronary vasculopathy </li></ul></ul><ul><ul><li>PTLD </li></ul></ul><ul><ul><li>Skin/anogenital cancers </li></ul></ul><ul><li>Fungi/molds, virusesn and “typical” bugs still remain on radar </li></ul>
    30. 33. Viral Infection after Renal Transplantation: Surveillance and Management
    31. 34. CMV and Solid Organ Transplantation <ul><li>CMV is still among the most important infectious complications after transplant </li></ul><ul><li>In the absence of prophylaxis, CMV reactivation can occur in over 75% of solid organ transplant recipients depending on other risk factors (1) </li></ul><ul><li>Once CMV infection is established, then its replication is highly dynamic with rapid increases in viral load </li></ul><ul><li>CMV infection may lead to tissue invasive disease </li></ul><ul><ul><li>1. Fishman JA, Rubin RH. Infection in organ-transplant recipients . N Engl J Med . 1998;338:1741. </li></ul></ul>
    32. 35. CMV Infection and Renal Transplantation Dr. Md. Shahidul Islam (Selim) MD, FACP Department of Nephrology BSMMU, Dhaka .
    33. 36. Introduction <ul><li>CMV infection is a major cause of morbidity and mortality after solid organ Tx. </li></ul><ul><li>It is widely distributed in general population ranging from 30-70% </li></ul><ul><li>It usually develops during the first few months of Tx. when patient on immunosuppressed. </li></ul><ul><li>It has also been implicated as a cause of acute and chronic allograft injury. </li></ul><ul><li>CMV may play a crucial role in chronic graft vasculopathy resulting CAN, bronchiolitis and accelerated CAD. </li></ul>
    34. 37. CMV Infection: Risk Categories in Solid Organ Transplant Recipients * D+/R+ generally at higher risk than D-/R+ Fishman JA, Emery V, Freeman R, et al. Cytomegalovirus in transplantation – challenging the status quo . Clinical Transplantation . 2007;21:149-158. Risk Category Donor (D) or Recipient (R) Seropositivity (+/-) High D+/R- Intermediate* D+/R+, D-/R+ Low D-/R-
    35. 38. CMV Pathogenesis <ul><li>Viral factors </li></ul><ul><ul><li>replication dynamics </li></ul></ul><ul><ul><li>immune evasion </li></ul></ul><ul><ul><li>viral heterogeneity </li></ul></ul><ul><ul><li>viral co-infections </li></ul></ul><ul><li>Host factors </li></ul><ul><ul><li>CD4+, CD8+ T-cell </li></ul></ul><ul><ul><li>NK cell, B-cell </li></ul></ul><ul><ul><li>exogenous immunosuppression </li></ul></ul><ul><ul><li>D/R immune status </li></ul></ul>
    37. 40. Co-Infection <ul><li>Factors contributing </li></ul><ul><li>to risk for infection: </li></ul><ul><li>Viral factors </li></ul><ul><li>Immunosuppression </li></ul><ul><li>Co-infection </li></ul>CMV INFECTION CMV DISEASE Increasing viral load
    38. 41. CMV Infection Latent CMV infection Active CMV infection (viral replication) Direct effects Indirect effects
    39. 42. Direct Effects of CMV Infection <ul><li>CMV Viral Syndrome </li></ul><ul><li>Fever, malaise, myalgias </li></ul><ul><li>Leukopenia, thrombocytopenia, and other laboratory abnormalities </li></ul><ul><li>Tissue Invasive Disease </li></ul><ul><li>Hepatitis </li></ul><ul><li>Pneumonitis </li></ul><ul><li>Colitis </li></ul><ul><li>Carditis </li></ul><ul><li>Nephritis </li></ul><ul><li>Pancreatitis </li></ul><ul><li>Retinitis </li></ul>Direct Effects
    40. 43. Indirect Effects of CMV Infection <ul><li>Altered host immune response </li></ul><ul><li>Graft rejection; graft dysfunction </li></ul><ul><li>Opportunistic infections: Bacterial fungal superinfection </li></ul><ul><li>Decreased graft and patient survival </li></ul><ul><li>Herpesvirus interactions: EBV/PTLD </li></ul>Indirect Effects
    41. 44. CMV Hepatitis
    42. 45. Anti-CMV Therapy <ul><li>Valganciclovir : (Valcyte®) a prodrug form of ganciclovir with improved oral bioavailability </li></ul><ul><li>Foscarnet : (Foscavir  ) is an inhibitor CMV DNA polymerase (UL54) </li></ul><ul><ul><li>Useful for ganciclovir resistant CMV </li></ul></ul><ul><ul><li>Major limitation is nephrotoxicity </li></ul></ul><ul><li>Cidofovir : (Vistide  ) inhibits viral DNA polymerase </li></ul><ul><ul><li>May be useful for ganciclovir resistant CMV but not well studied in organ transplant recipients </li></ul></ul><ul><li>Maribavir : is an investigational agent that prevents viral encapsidation and nuclear egress </li></ul><ul><li>Ganciclovir : (Cytovene® and Cymevene®) is a synthetic analogue of 2-deoxyguanosine, that competitively inhibits the incorporation of dGTP by viral DNA polymerase–intravenous or oral </li></ul>
    43. 46. Ganciclovir <ul><li>Adverse effects : </li></ul><ul><ul><li>Hematologic: neutropenia, anemia, thrombocytopenia </li></ul></ul><ul><ul><li>Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, flatulence, anorexia </li></ul></ul><ul><ul><li>Neurologic: headache, confusion, hallucination, seizures </li></ul></ul><ul><ul><li>Other: pain and phlebitis at injection site (due to high pH), sweating, rash, itch, increased serum creatinine and blood urea concentrations </li></ul></ul><ul><li>Toxicity : </li></ul><ul><ul><li>Human carcinogen, teratogen, and mutagen </li></ul></ul><ul><ul><li>Inhibits spermatogenesis </li></ul></ul><ul><li>Pharmacokinetics : </li></ul><ul><ul><li>Oral ganciclovir: poor absorption – (~ 5% fasting and ~ 8% with food) </li></ul></ul><ul><ul><li>90% of plasma ganciclovir is eliminated unchanged in the urine with a half-life of 2-6 hrs, depending on renal function (elimination takes over 24 hours in end-stage renal disease) </li></ul></ul>
    44. 47. Valganciclovir <ul><li>Adverse effects : </li></ul><ul><ul><ul><li>Similar to ganciclovir </li></ul></ul></ul><ul><ul><ul><li>Myelosuppression is one of the main side effects that may limit prolonged use of valganciclovir </li></ul></ul></ul><ul><li>Pharmacokinetics : </li></ul><ul><ul><ul><li>Oral bioavailability ~ 60% </li></ul></ul></ul><ul><ul><ul><ul><li>Fatty foods significantly increase the bioavailability </li></ul></ul></ul></ul><ul><ul><ul><li>Eliminated as ganciclovir in the urine, with a half-life of about 4 hours </li></ul></ul></ul>
    45. 48. CMV Prevention <ul><li>Pre-emptive </li></ul><ul><ul><li>Guided by laboratory monitoring for evidence of early viral replication; treatment is started when CMV viral load or antigenemia reaches a certain threshold </li></ul></ul><ul><li>Universal prophylaxis </li></ul><ul><ul><li>Therapy from the time of transplant to all patients or a subgroup of patients at risk for CMV disease </li></ul></ul>
    46. 49. Pre-emptive Therapy + + + + + _ _ + + _ 0 4 8 12 weeks Initiate pre-emptive therapy to prevent CMV disease CMV disease TEST _ _
    47. 50. Pre-emptive Therapy <ul><li>Advantages : </li></ul><ul><ul><li>Minimizes drug exposure </li></ul></ul><ul><ul><li>This may potentially decrease toxicity and costs </li></ul></ul><ul><ul><li>Theoretically lower risk of resistance </li></ul></ul><ul><ul><li>Less late-onset disease: may allow development of cell-mediated immune response </li></ul></ul><ul><li>Disadvantages : </li></ul><ul><ul><li>Logistically more difficult to coordinate </li></ul></ul><ul><ul><li>May be unsuccessful in preventing progression to active disease in high-risk patients due to rapid doubling time </li></ul></ul><ul><ul><li>May not eliminate the indirect effects of CMV </li></ul></ul>
    48. 51. Late Onset CMV Disease Definition <ul><li>CMV disease occurring > 3 months post transplant </li></ul><ul><li>May be primary infection (D+/R-) or recurrence (R+) </li></ul><ul><li>In epidemiology studies associated with significant morbidity (including graft dysfunction) and occasional mortality (indirect effects) (1) </li></ul><ul><li>Incidence 3%-17%; In IMPACT study 37% with 3 months of prophylaxis in D+/R- </li></ul>Limaye, AP, et al. Transplantation . 2004;78(9):1390-1396 .
    49. 52. CMV Prophylaxis: Late-Onset Disease Prophylaxis period Patients With No CMV Disease (%) 0 10 20 30 40 50 60 70 80 90 100 Time (days) 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 364 D+/R- SOT patients Ganciclovir (oral) Valganciclovir Paya, et al. Am J Transplant . 2004;4:611-620.
    50. 53. Late Onset CMV Disease in High-Risk Groups <ul><li>CMV D+/R- individuals (1) </li></ul><ul><li>CMV R+ on potent immunosuppression; anti-lymphocyte therapy </li></ul><ul><li>Therapy of acute rejection </li></ul><ul><li>Lung transplant highest risk; kidney, liver lower risk </li></ul>1. Limaye AP, et al. Transplantation . 2004;78:1390-1396.
    51. 54. Importance of CMV Infection <ul><li>Infectious disease syndrome (fever, pneumonia, hepatitis, retinitis. </li></ul><ul><li>Increased additional opportunistic infections. </li></ul><ul><li>Acute and chronic graft injury. </li></ul><ul><li>Tx. recipients are high-risk of CMV disease. </li></ul><ul><li>Ganciclovir is the antiviral chemotherapy use in both therapeutic and prophylaxis against CMV. </li></ul>
    52. 55. Risk factors of CMV disease <ul><li>Risk of CMV disease is height in D+ve/R-ve solid organ Tx. recipient who are lack of cellular and humoral immunity. </li></ul><ul><li>Other risk factors one recipient over all state of immunosuppression (drugs, dose, duration) & various host factors (age, comorbidity, neutropenia) </li></ul><ul><li>Induction therapy. </li></ul><ul><li>Lowest risk of CMV disease in R-ve /D -ve setting. </li></ul>
    53. 56. Laboratory diagnosis <ul><li>Serologic assays (CMV IgA & IgM) are useful for delineating risk at the time of Tx. </li></ul><ul><li>New era for CMV diagnosis by the PP65 antigenemia assay. This test is heigher sensitive and specific. </li></ul><ul><li>CMV PCR assays. </li></ul><ul><li>Molicular diagnostic test by CMV- DNA or RNA. </li></ul>
    54. 57. Clinical Presentation of CMV Disease <ul><li>Asymptomatic / Prolong irregular fever. </li></ul><ul><li>Multi organ involvement features like RTI, Hepatobiliary and CNS are important . </li></ul>
    55. 58. Prevention <ul><li>Two strategies are commonly used for CMV prevention: </li></ul><ul><li>Universal prophylaxis </li></ul><ul><li>Preemptive therapy. </li></ul><ul><li>In universal prophylaxis involves antiviral therapy to all at risk patients beginning at or immediate post Tx. for a defined time period. </li></ul><ul><li>In preemptive therapy, patients are monitored at regular intervals for early evidence of CMV replications by laboratory assess and initiate antiviral therapy. </li></ul>
    56. 59. Universal prophylaxis <ul><li>Acyclovir, ganciclovir, valacyclovir, valgancilovir and immune- globulin. </li></ul><ul><li>Acyclovir: Possesses comparatively poor vitro activity against CMV at clinically achievable levels. </li></ul><ul><li>Ganciclovir: </li></ul><ul><li>Both I/V & oral preparations are available. </li></ul><ul><li>5-10 mg/kg/d in two divided dose for 4-6 weeks for treatment and 2-4 weeks for prophylaxis in normal renal function. </li></ul><ul><li>Use in D+ & R-ve patients immediate after Tx. </li></ul><ul><li>Oral ganciclovir achieve significantly lower serum level in compared with I/V ganciclovir (dose 1000 mg tds for 3 m.) </li></ul><ul><li>Valacyclovir: (1) Oral 8 gm per day for 3 months </li></ul><ul><li> (2) Less effective than gancyclovir. </li></ul>
    57. 60. Polyvalint I/V Immunoglobulin <ul><li>The efficacy of I/V Ig in solid organ Tx. has been investigated. </li></ul>
    58. 61. Guidelines for CMV prevention in SOT recipients. <ul><li>Organ/group: Recommendations: </li></ul><ul><li>* Kidney, liver, pancreas, * Oral ganciclovir </li></ul><ul><li>heart. D+ve/R-ve. for 3 months/IV ganciclovir 1-3 M. </li></ul><ul><li>*Kidney, liver , pancreas, * As above. </li></ul><ul><li>heart. R+ve. </li></ul><ul><li>Start prophylaxis within 10 days post Tx. And continue for 3 months. </li></ul>
    59. 62. BK virus-associated nephropathy
    60. 63. BK virus-associated nephropathy <ul><li>Double-stranded DNA polyoma virus </li></ul><ul><ul><li>JC -> PML </li></ul></ul><ul><ul><li>SV40 -> renal disease in immunodeficient monkeys </li></ul></ul><ul><li>1971: BK virus first isolated from a kidney transplant recipient with ureteral stricture </li></ul><ul><li>1 st reported case of nephropathy in 1993 (Pitt), graft failure in 3 months* </li></ul><ul><li>Affects ~8% of renal transplant recipients </li></ul><ul><li>30-60% of affected allografts fail of BKVAN within 1 year </li></ul>* Purighalla R, et al. Am J Kid Dis 1995.
    61. 64. Epidemiology <ul><li>Estimated that 80-90% of adult population has been exposed to BK virus </li></ul><ul><li>Probably multiple routes of transmission, but respiratory secretions predominate </li></ul><ul><li>Primary infection may be asymptomatic, mild URI, cystitis… </li></ul><ul><li>Enters latent phase, in urogenital tract, lymphoid tissue, brain </li></ul>
    62. 65. Pathogenesis <ul><li>BK replication (viruria) occurs during states of immune suppression </li></ul><ul><ul><li>Pregnancy </li></ul></ul><ul><ul><li>Malignancy </li></ul></ul><ul><ul><li>HIV </li></ul></ul><ul><ul><li>Diabetes </li></ul></ul><ul><ul><li>Transplantation </li></ul></ul><ul><li>Viremia (13-20%) & nephropathy (5-8%) are unique to the post-kidney transplant setting </li></ul>
    63. 66. Clinical manifestations <ul><li>Risk factors: </li></ul><ul><ul><li>Older, male, White, diabetic recipient </li></ul></ul><ul><ul><li>More HLA mm, ACR, DGF </li></ul></ul><ul><ul><li>Net state of immune suppression </li></ul></ul><ul><li>Asymptomatic allograft dysfunction </li></ul><ul><li>Suspect BK when rejection does not resolve with usual therapy </li></ul>
    64. 67. Diagnosis <ul><li>Viruria precedes viremia and nephropathy </li></ul><ul><ul><li>Urine cytology </li></ul></ul><ul><ul><li>Urine PCR </li></ul></ul><ul><li>Viremia </li></ul><ul><ul><li>More specific for nephropathy </li></ul></ul><ul><li>Screening protocols increasingly used </li></ul><ul><li>Renal biopsy is gold standard </li></ul>
    65. 68. BK nephritis <ul><li>Variable degree of interstitial inflammation, fibrosis, atrophy </li></ul><ul><li>Nuclear inclusions </li></ul><ul><li>Similar in appearance to cellular rejection </li></ul><ul><li>Immunohistochemistry useful </li></ul>
    66. 69. Treatment <ul><li>Reduce immune suppression </li></ul><ul><ul><li>Stop antiproliferative </li></ul></ul><ul><ul><li>Stop steroids </li></ul></ul><ul><ul><li>Cut CNI and antiproliferative doses by 50% </li></ul></ul><ul><li>Noteworthy that all other treatments for BKVAN include reducing IS… </li></ul><ul><ul><li>Cidofovir </li></ul></ul><ul><ul><li>Leflunomide </li></ul></ul>
    67. 70. Herpes Simplex Virus and Varicella Zoster Virus
    68. 71. <ul><li>Herpes simplex (HSV) and Varicella zoster (VZV) are both alpha herpes viruses with a double stranded DNA core. </li></ul><ul><li>Seroprevalence for HSV-1 in the adult population is as high as 60 percent, while VZV rates can be as high as 90 percent </li></ul>
    69. 72. <ul><li>Infection in the renal transplant patient is usually caused by reactivation of latent virus. </li></ul><ul><li>HSV infection usually presents with oral or genital lesions, but in some instances can cause esophagitis,hepatitis, encephalitis or pneumonitis </li></ul>
    70. 73. <ul><li>ZV reactivation usually presents as dermatomal zoster, but can disseminate, causing similar visceral complications. </li></ul><ul><li>In the absence of prophylaxis, HSV and VZV may be seen early with HSV observed even in the first post transplant month and VZV as early as 1 to 6 mo post transplant  </li></ul><ul><li>The incidence of HSV in renal transplant recipients is estimated to be approximately 53% and VZV 4 to 12% </li></ul>
    71. 74. <ul><li>Diagnosis </li></ul><ul><ul><li>Direct fluorescence antibody for HSV and VZV from vesicular lesions or </li></ul></ul><ul><ul><li>PCR from CSF or visceral tissue samples. </li></ul></ul><ul><li>Due to high seroprevalence in the adult population, serologies are rarely helpful in the setting of active infection. </li></ul><ul><li>  Treatment </li></ul><ul><ul><li>Disseminated infections involves intravenous acyclovir,  </li></ul></ul><ul><ul><li>Less severe infection ; oral acyclovir, valacyclovir, or famciclovir </li></ul></ul><ul><ul><li>Acyclovir resistance has been rarely reported in some strains; foscarnet, cidofovir, and topical trifluridine may be considered for treatment ofresistant virus, although careful monitoring of renal function is required </li></ul></ul>
    72. 75. Epstein Barr Virus
    73. 76. <ul><li>Epstein Barr Virus (EBV) is a gamma herpes virus with a double stranded DNA core; similar to other herpesviruses, </li></ul><ul><li>EBV remains latent in lymphocytes following primary infection. </li></ul><ul><li>EBV can cause replication and clonal expansion of the B cells that serve as its primary reservoir and other cell lines as well. </li></ul><ul><li>However, a competent immune system, specifically T cell response, prevents these cells from propagating. </li></ul><ul><li>When T cell function is impaired, as is the case in renal transplant patients, this surveillance system can fail and post transplant lymphoproliferative disorder (PTLD) can develop </li></ul>
    74. 77. <ul><li>Risk of development of PTLD, </li></ul><ul><ul><li>with higher incidence rates observed in patients receiving cytolytic therapies, </li></ul></ul><ul><ul><ul><li>including antithymocyte globulin and </li></ul></ul></ul><ul><ul><ul><li>OKT3 </li></ul></ul></ul>PTLD most commonly occurs in the first year post transplant
    75. 78. Serologies for EBV <ul><li>Serologies for EBV of both donor and recipient should be obtained before transplant. </li></ul><ul><li>Allograft recipients who are EBV negative before transplant and receive an organ from a seropositive donor are at greatest risk for PTLD; </li></ul><ul><li>consequently it is most commonly seen in pediatric and young adult populations. </li></ul><ul><li>Currently there is no single standard strategy to prevent PTLD. </li></ul><ul><li>In some centers, high-risk individuals are screened regularly for the presence of EBV viremia and immunosuppression decreased when viremia is observed. </li></ul><ul><li>Effective prevention of CMV may also prevent EBVinfections, primarily by limiting the impact of CMV on immune regulation </li></ul><ul><li>A recent trial demonstrated that CMV Ig did not prevent the onset of PTLD in high risk recipients </li></ul>
    76. 79. <ul><li>Definitive diagnosis of PTLD requires histopathologic confirmation, </li></ul><ul><li>preferably of tissue obtained by excisional biopsy. </li></ul><ul><li>In the case of CNS PTLD, analysis of CSF for EBV PCR and cytology should be performed. </li></ul><ul><li>Although viremia may be noted at the time of PTLD, its detection cannot be used to confirm or refute the diagnosis. </li></ul><ul><li>Staging is performed by histologic type (monoclonal  versus  polyclonal, T cell  versus  B cell) and location (allograft, other organ, metastasis). </li></ul><ul><li>Often the Ann Arbor classification, used for other non-Hodgkin lymphomas, is utilized </li></ul>
    77. 80. Human Herpesvirus-6, Human Herpesvirus-7, and Human Herpesvirus-8
    78. 81. <ul><li>Human Herpes Virus 8 (HHV8) is a gamma herpes virus that has been associated with Kaposi's Sarcoma, primary effusive lymphoma, and Multicentric Castleman's Disease (lymphoproliferative disorder) </li></ul>
    79. 82. Hepatitis B and C
    80. 83. <ul><li>Patients with chronic renal failure, notably those receiving hemodialysis, may be at increased risk for Hepatitis B. </li></ul><ul><li>Consequently all nonimmune patients with chronic renal failure should be vaccinated with Hepatitis B vaccine and immunity verified with Hepatitis B surface antibody screening following completion of the vaccination series  </li></ul>
    81. 84. West Nile Virus <ul><li>West Nile Virus is a flavivurus that causes a febrile illness, associated with encephalitis, and can be fatal </li></ul><ul><li>  To prevent infection, seasonal screening should be considered for donors before transplant by serologic and/or nucleic acid testing. </li></ul><ul><li>Additionally all transplant recipients should be counseled in preventive measures regarding mosquito bites, including the use of protective clothing and DEET containing insect repellants. </li></ul><ul><li>Treatment for West Nile intransplant recipients has not been standardized but should include a reduction in immunosuppression along with supportive care  </li></ul>
    82. 85. Fungal infections in solid organ transplantation recipients
    83. 86. <ul><li>Incidence of major invasive fungal infection(IFI) among Kidney recipient patient: </li></ul><ul><li>Aspergillus:0-26% </li></ul><ul><li>Candida:76-95% </li></ul><ul><li>Cryptococcus:0-39% </li></ul><ul><li>Other fungi:0-39% </li></ul>Hand book of renal transplant:( Gabriel)
    84. 87. <ul><li>Incidence of fungal infections in renal transplant recipient s is less than other SOT but mortality high : </li></ul><ul><ul><li>Pathogen city of organism </li></ul></ul><ul><ul><li>Site of infection </li></ul></ul><ul><ul><li>Impaired host inflammatory response </li></ul></ul><ul><ul><li>Limited diagnostic tools </li></ul></ul><ul><ul><li>Potential for rapid clinical progression </li></ul></ul><ul><ul><li>Failure to recognize a “high risk” patients </li></ul></ul><ul><ul><li>Co morbid disease (renal failure and DM) </li></ul></ul>Hand book of renal transplant:( Gabriel)
    85. 88. <ul><li>Risk factor for colonization with yeast and molds after KT: </li></ul><ul><ul><li>Corticosteroid therapy </li></ul></ul><ul><ul><li>Broad spectrum antibiotic </li></ul></ul><ul><ul><li>Domiciliary exposure </li></ul></ul><ul><ul><li>Presence of urinary catheter </li></ul></ul><ul><ul><li>Endotracheal tube </li></ul></ul>Hand book of renal transplant:( Gabriel)
    86. 89. Fungal growth on: <ul><li>Skin </li></ul><ul><li>Mucosal surfaces </li></ul><ul><li>Within gastrointestinal tract </li></ul>Hand book of renal transplant:( Gabriel)
    87. 90. Common fungal <ul><li>Common  </li></ul><ul><ul><li>Candida spp. </li></ul></ul><ul><ul><li>Aspergilous spp </li></ul></ul><ul><ul><li>C. neoformans </li></ul></ul>Hand book of renal transplant:( Gabriel)
    88. 91. Geographical mycosis: <ul><li>Geographical mycosis: </li></ul><ul><ul><li>Histoplasma </li></ul></ul><ul><ul><li>Coccidioides </li></ul></ul><ul><ul><li>Blastomyces </li></ul></ul><ul><ul><li>Occur under clinical circumstances: </li></ul></ul><ul><ul><li>Immunomodulating viral inf </li></ul></ul><ul><ul><li>Reactivation </li></ul></ul><ul><ul><li>Ch. Graft dysfunction </li></ul></ul><ul><ul><li>During treatment of post transplant malignancies </li></ul></ul>Hand book of renal transplant:( Gabriel)
    89. 92. Renal transplantation <ul><li>Candida species: 95% </li></ul><ul><ul><li>GI tract </li></ul></ul><ul><ul><li>Disseminated infection: <5% </li></ul></ul><ul><ul><li>Risk factors: </li></ul></ul><ul><ul><ul><li>Diabetes </li></ul></ul></ul><ul><ul><ul><li>Prolonged pretransplant dialysis </li></ul></ul></ul><ul><ul><ul><li>Rejection </li></ul></ul></ul><ul><ul><ul><li>Tacrolimus suppression </li></ul></ul></ul><ul><li>Invasive aspergillosis infrequent </li></ul>Hand book of renal transplant:( Gabriel)
    90. 93. Candida <ul><li>Occurs most commonly during the 1 st month following transplant associated with; </li></ul><ul><ul><li>Technical complexities </li></ul></ul><ul><ul><li>Complication KT surgery </li></ul></ul><ul><ul><li>Early rejection </li></ul></ul><ul><ul><li>Enhanced immunosuppression </li></ul></ul><ul><li>Sources: </li></ul><ul><ul><li>Endogenous: Source of colonization </li></ul></ul><ul><ul><li>Exogenous: lack of hand washing of health workers </li></ul></ul>Hand book of renal transplant:( Gabriel)
    91. 94. <ul><li>Most common species: </li></ul><ul><ul><li>C. albicans </li></ul></ul><ul><li>Others: </li></ul><ul><ul><li>C. Glabrata </li></ul></ul><ul><ul><li>C tropicalis </li></ul></ul><ul><ul><li>C. krusei </li></ul></ul>Hand book of renal transplant:( Gabriel)
    92. 95. Candidal colonization Pulmonary tree Bowel Vagina Esophageal / GI
    93. 96. Candida: Infection sites C. parapsilosis C. tropicalis C. albicans C. krusei C. glabrata
    94. 97. SPECTRUM OF INVASIVE CANDIDA INFECTIONS candidemia organ infection acute Candida septicemia prompt empiric cover candidemia eliminate risk factor specific cover acute disseminated candidiasis prompt empiric cover ‘ hepato- splenic’ candidiasis specific cover beware of toxicity
    95. 98. MODEL FOR INVASIVE CANDIDIASIS antibiotics injury selection GI tract GI tract insult translocation infection Candida species Normal commensal flora Disease Central venous catheter
    96. 99. Candida: From colonisation to infectious disease in a neutropenic patient COLONISATION MUCOSAL INVASION DISSEMINATION ORGAN INFECTION 1 2 3
    97. 100. Renal candidosis
    98. 101. PROGNOSTIC FACTORS IN CANDIDEMIA NUCCI & ANAISSIE Clin Infect Dis 2002; 34:591-9 Associated with death: -more severe clinical symptoms -persisting neutropenia -organ involvement - high age Beter survival if: * catheter is removed *neutropenic patients given antifungals
    99. 102. Aspergillosis
    101. 104. Invasive aspergillosis <ul><li>Liver recipients: 1-4.5% </li></ul><ul><li>Kidney recipients: 0.5-2.2% </li></ul><ul><li>Lung or lung-heart recipients: 18% </li></ul>
    102. 105. Renal aspergillosis
    103. 106. Invasive aspergillosis in solid-organ transplantation <ul><li>Type Donor Time of IA after Tx </li></ul><ul><li>Renal Cadevar 21st day </li></ul><ul><li>Renal Cadevar 23rd day </li></ul><ul><li>Renal Live 26th day </li></ul><ul><li>Ergin et al. Transplant International 2003; 16: 280-286 </li></ul>
    104. 107. Invasive aspergillosis in solid-organ transplantation: risk factors <ul><li>Pulse steroid </li></ul><ul><li>OKT3 </li></ul><ul><li>Antibiotic use </li></ul><ul><li>Organ failure </li></ul><ul><li>Retransplantation </li></ul><ul><li>Thrombocytopenia </li></ul><ul><li>CONSTRUCTION </li></ul><ul><li>Ergin et al. Transplant International 2003; 16: 280-286 </li></ul>
    105. 108. Invasive aspergillosis in solid-organ transplantation: diagnosis <ul><li>Radiology: chest X-ray and CT: no halo sign </li></ul><ul><li>Microbiology </li></ul><ul><ul><li>Respiratory secretions: BAL/biopsy </li></ul></ul><ul><ul><ul><li>Direct microscopy </li></ul></ul></ul><ul><ul><ul><li>culture </li></ul></ul></ul><ul><ul><li>Serological surveillance </li></ul></ul><ul><ul><ul><li>ELISA for galactomannan </li></ul></ul></ul><ul><li>PCR </li></ul><ul><li>Ergin et al. Transplant International 2003; 16: 280-286 </li></ul>
    106. 109. Invasive aspergillosis in solid-organ transplantation: Treatment <ul><li>Conventional amphoterin B: 20-83% response </li></ul><ul><li>?iv itraconazole: limited data </li></ul><ul><li>Lipid formulations of ampho B </li></ul><ul><li>5 mg/kg/day liposomal ampho B </li></ul><ul><li>Surgical intervention </li></ul><ul><li>Prophylaxis </li></ul><ul><li>Ergin et al. Transplant International 2003; 16: 280-286 </li></ul>
    107. 110. Zygomycosis in SOT <ul><li>Median 2 months post-transplant </li></ul><ul><li>Most cases occur within 6 months of transplant </li></ul><ul><li>Rhinocerebral form </li></ul><ul><li>76% diabetes and corticosteroids </li></ul><ul><li>56% mortality </li></ul>
    108. 111. Where do filamentous fungi come from? <ul><li>Mycological surveillance </li></ul><ul><li>Patient </li></ul><ul><li>Home/work environment </li></ul><ul><li>Hospital: air, water </li></ul>
    109. 112. Aspergillus is in the air!
    110. 113. Nosocomial aspergillosis
    111. 114. Aspergillus is in tea!
    112. 115. Dust
    113. 116. Air sampling
    114. 117. Air sampling culture plates
    115. 118. Patient’s house: home sweet home
    116. 119. Who diagnoses fungal infections? Infectious Disease Physician Clinician Microbiologist Pharmaceutical Industry Pathologist
    117. 120. Diagnosis: The site of infection <ul><li>Skin </li></ul><ul><li>Oral cavity </li></ul><ul><li>Alimentary tract </li></ul><ul><li>Airways </li></ul><ul><li>Lungs </li></ul><ul><li>Liver/spleen </li></ul><ul><li>CNS </li></ul><ul><li>Disseminated </li></ul>
    118. 121. Impact of diagnostic markers on treatment decisions <ul><li>HRCT </li></ul><ul><li>Aspergillus galactomannan </li></ul><ul><li>Glucan </li></ul><ul><li>Mannan </li></ul><ul><li>DNA/RNA: PCR </li></ul>
    119. 122. Clinical haste Microbiology answer question
    120. 123. Prophylaxis <ul><li>AmBisome </li></ul><ul><li>Itraconazole </li></ul>
    121. 124. Prevention of fungal infection in transplantation <ul><li>Issues: </li></ul><ul><ul><li>Candida remains major complication in intra-abdominal solid organ transplantion where bowel is surgically manipulated. </li></ul></ul><ul><ul><li>Aspergillus main fungal complication in lung transplant recipients </li></ul></ul><ul><li>Intra-abdominal: fluconazole: 100-400 mg/day 1-3 months post liver Tx </li></ul><ul><li>Lung Tx: </li></ul><ul><ul><li>inhaled liposomal ampho B </li></ul></ul><ul><ul><li>Itraconazole </li></ul></ul><ul><ul><li>Avoidance of exposure </li></ul></ul>
    122. 125. Successful management <ul><li>Prompt recognition of infection </li></ul><ul><li>Adjustment of level of immunosuppression </li></ul><ul><li>Antifungal therapy and surgery </li></ul>
    123. 126. Treatment <ul><li>Conventional amphotericin B </li></ul><ul><ul><li>1-1.5 mg/kg/day </li></ul></ul><ul><ul><li>Nephrotoxicity big issue </li></ul></ul><ul><ul><ul><li>30% </li></ul></ul></ul><ul><ul><ul><li>18% require haemodialysis </li></ul></ul></ul><ul><li>Liposomal amphotericin B </li></ul><ul><ul><li>Much reduced nephrotoxicity </li></ul></ul><ul><ul><li>Superior efficacy </li></ul></ul><ul><li>Itraconazole: iv formulation: little data </li></ul><ul><li>Voriconazole/caspofungin: little data. </li></ul><ul><li>Singh 2003 Infect Dis Clin N Am 17; 113-134. </li></ul>
    124. 127. Strategies for dealing with systemic fungal infectious disease
    125. 128. Optimal antifungal management? 0 36 37 38 39 40 41 Temperature (°C) Treatmen t Disease likelihood Culture + Tissue + Galactomannan + PCR + -7 0 7 14 21 28 35 42 49 56 63 -14 0.1 1 10 Days after transplant Granulocytes (log 10 x10 9 /L) Empirical Possible Prophylaxis Remote Specific Proven Pre-emptive Probable disease
    126. 129. Todays choices: IPA -7 0 7 14 21 28 35 42 49 56 63 -14 0.1 1 10 Days after transplant Granulocytes (log 10 x10 9 /L) 0 5 10 15 Galactomannan ratio 36 37 38 39 40 41 Temperature (°C) Galactomannan + Itraconazole AmBisome Caspofungin Voriconazole Antibacterial therapy
    127. 130. Largest experience with AmBisome <ul><li>More than 10 years experience in 383 patients. </li></ul><ul><li>Two double blind placebo controlled randomized trials with AmBisome as prophylaxis </li></ul><ul><ul><li>Allogeneic & autologous BMT </li></ul></ul><ul><ul><li>Liver transplant recipients </li></ul></ul><ul><li>Three retrospective analyses of treatment with respect to safety and efficacy </li></ul><ul><ul><li>Allogeneic BMT recipients (5 years) (79 patients) </li></ul></ul><ul><ul><li>Solid organ transplant recipients (10years) (196 patients) </li></ul></ul><ul><ul><li>Child recipients of transplant (7 years) (61 patients) </li></ul></ul><ul><ul><li>Tollemar and colleagues, Huddinge Hospital, Stockholm </li></ul></ul>
    128. 131. AmBisome treatment Solid organ transplant recipients, 10 year data J. Tollemar Huddinge Hospital, Stockholm
    129. 132. SOT patients <ul><li>Patients treated between Jan 1989 - March 1999 </li></ul><ul><li>196 solid organ transplant recipients </li></ul><ul><li>220 episodes of AmBisome treatment </li></ul><ul><ul><li>56 for a verified infections </li></ul></ul><ul><ul><li>79 for a suspected infections </li></ul></ul><ul><ul><li>85 as prophylaxis </li></ul></ul><ul><li>106 males </li></ul><ul><li>90 females </li></ul><ul><li>Median age was 42 years, range 1 - 72 </li></ul><ul><li>J. Tollemar, Huddinge Hospital, Stockholm </li></ul><ul><li> </li></ul>
    130. 133. SOT patients <ul><li>123 liver (LTX) transplant recipients </li></ul><ul><li>3 liver and bone marrow transplant recipients </li></ul><ul><li>5 liver and kidney transplant recipients </li></ul><ul><li>42 kidney (KTX) transplant recipients </li></ul><ul><li>21 kidney & pancreas (KPTX) transplant recipients </li></ul><ul><li>1 kidney and insulin islet transplantation recipient </li></ul><ul><li>1 pancreas (P) transplant recipients </li></ul><ul><li>J. Tollemar, Huddinge Hospital, Stockholm </li></ul><ul><li> </li></ul>
    131. 134. AmBisome treatment data in SOT <ul><li> Fungal Infection </li></ul><ul><li>AmBisome treatment Verified Suspected Prophylactic </li></ul><ul><li>Duration (days), </li></ul><ul><li> mean ± SD (median) 23±17(18) 18±15 (14) 16±19 (7) </li></ul><ul><li>range 4-81 1-80 1-83 </li></ul><ul><li>Max. dose (mg), </li></ul><ul><li>mean ± SD (median) 2.0±1 (1.8) 1.7±0.9 (1.4) 1.4±0.8 (1.0 ) </li></ul><ul><li> range 0.7-5.5 0.7-5 0.6-6 </li></ul><ul><li>Total dose (g), </li></ul><ul><li>mean ± SD (median) 1.7±1.7 (0.95) 1.4±1.3 (1.1) 0.6±0.5 (0.4) </li></ul><ul><li>range 0.05-8.1 0.06-8 0.03-2.4 </li></ul><ul><li>J. Tollemar, Huddinge Hospital, Stockholm </li></ul><ul><li> </li></ul>
    132. 135. Adverse events in SOT <ul><li>335 adverse events were reported </li></ul><ul><li>9 (3%) were regarded as caused by AmBisome treatment </li></ul><ul><ul><li>6 Lumbago </li></ul></ul><ul><ul><li>2 Lumbago combined with chills </li></ul></ul><ul><ul><li>1 Lumbago with dyspnea </li></ul></ul><ul><li>No anaphylactic reaction was reported </li></ul><ul><li>224 (67%) of the adverse events were regarded as probably related to AmBisome </li></ul><ul><li>112 (33%) of the adverse events were regarded as not related to AmBisome </li></ul><ul><li>J. Tollemar, Huddinge Hospital, Stockholm </li></ul><ul><li> </li></ul>
    133. 136. Efficacy: Suspected FI in SOT <ul><li>75 patients recieved 79 episodes of treatment for suspected FI </li></ul><ul><li>57 patients survived with clearance of symptoms and 10 died with no FI at autopsy </li></ul><ul><li>7 patients died, no autopsy was performed </li></ul><ul><li>1 patient died with FI at autopsy ( Aspergillus. fum ) </li></ul><ul><li>Efficacy was shown in 67 out of 75 patients, 89 % </li></ul><ul><li>J. Tollemar, Huddinge Hospital, Stockholm </li></ul><ul><li> </li></ul>
    134. 137. Conclusion: solid organ transplantation <ul><li>10 years experience of Ambisome treatment in solid organ transplant recipients at one single center has revealed: </li></ul><ul><li>AmBisome treatment was safe </li></ul><ul><li>AmBisome treatment was efficacious as seen as survival or mycotic clearance in 92% of proven fungal infections in SOT patients </li></ul><ul><li>Efficacy in suspected FI was 89 % clinical cures </li></ul><ul><li>J. Tollemar, Huddinge Hospital, Stockholm </li></ul><ul><li> </li></ul>
    135. 138. Liposomal amphotericin B is safe and effective in the treatment of invasive mycosis in organ transplant patients <ul><li>140 patients SOT </li></ul><ul><ul><li>12 (8%) IFI: 11 Candida; 1 Aspergillus </li></ul></ul><ul><ul><ul><li>Liver (3) </li></ul></ul></ul><ul><ul><ul><li>Pancreas and kidney (4) </li></ul></ul></ul><ul><ul><ul><li>Kidney (5) </li></ul></ul></ul><ul><ul><li>Liposomal ampho B: 1-5 mg/kg/day </li></ul></ul><ul><ul><ul><li>Duration: 1-21 days </li></ul></ul></ul><ul><ul><ul><li>10 patients completed </li></ul></ul></ul><ul><ul><ul><ul><li>1 death </li></ul></ul></ul></ul><ul><ul><ul><ul><li>1 rejection </li></ul></ul></ul></ul><ul><ul><ul><ul><li>8 infection cleared </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Merhav et al. 2001, Transplantation Proceedings 33: 2937-2938 </li></ul></ul></ul></ul>
    136. 139. Future Strategy Against Probable Invasive Fungal Infection ? susceptible Empirical or positve GM test AmBisome Fluconazole AmBisome glucan synthesis inhibitor (IV) or new azole orally no response risk of aspergillosis C U L T U R E R E S U L T
    137. 140. Thank for your attention