Final post kt infection


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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.
  • 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
  • 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.
  • 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.
  • Infectious complications are the leading cause of morbidity and mortality in any transplant patient.
  • 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.
  • 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.
  • 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.
  • This slide compares the relative advantages offered by universal prophylaxis over pre-emptive anti-CMV therapy. Prophylaxis has been shown to be efficacious and is associated with a reduced all cause mortality. Prophylaxis may also reduce the incidence of other viral infections, as well as bacterial and protozoal opportunistic infections. Prophylaxis is easier to implement, requiring less frequent assessments, and resistance to the antiviral medication is low.
  • Universal prophylaxis, has also been shown to markedly reduce rates of co-infection with other viruses such Herpes Zoster, and reduces bacterial and protozoal infection rates. This reduces the morbidity and costs associated with these infections and improves outcomes from SOT. Hodson EM, Craig JC, Strippoli GFM, Webster AC. Antiviral medications for preventing cytomegalovirus disease in solid organ transplant recipients. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD003774. DOI: 10.1002/14651858.CD003774.pub3
  • 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.
  • 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.
  • Final post kt infection

    1. 1. Infections in Kidney Transplantation Dr. Sunil Kumar Daksh Prajapati
    2. 2. Layout Risk factors The Timeline of Posttransplant Infections Viral infections Bacterial infections Fungal infections Parasitic infections
    3. 3. Source Various articles Handbook of Gabriel M. Danovitch Various other standard text books 2010 KDIGO clinical practice guideline for the care of kidney transplant recipients
    4. 4. Kidney transplant(KT) infection – Risk factors Pretranspaltation  Comorbid illness (DM, malnutrtion, immunosupression)  Immunosuppression for chonic conditons  Unrecognized or undertreated infections  Colonization by unusual or resistant organism (VRE - stool, MRSA – nares/skin, Pseudomonas/enterobacteriace – UTI, yeast - skin)  Preoperative antibiotic exposure  Duration/frequency of hospitalization Perioperative  Complexity of surgery/requirement of re-exploration  Prolonged operative time  Graft injury or prolonged ischemia  Bleeding/multiple BT  Infected graft  Contaminated preservation fluid  Foreign body
    5. 5. Kidney transplant(KT) infection – Risk factors Post-transplantation  Graft failure/dysfunction- needing immunosuppresion  Complicated post op management – development or worsening of comorbid illness  Infection with immunomodulating viruse  Prolonged hospitalization, catheters,stents, intubation  Drains  Anastomotic breakdown  Leucopenia, thrombocytopenia, acquired hypogammaglobulinemia  Prolonged antibiotic therapy  Selected occupation/endemic infections  Lack of appropriate hand hygiene by caregivers  Marijuana abuse
    6. 6. Making clinical decision Factors that may assist in recognizing the causative organism  Timing of infection  Status of donor and recipient  State of immunosuppresion
    7. 7. The Timeline of Posttransplant Infections Nosocomial Technical Opportunistic, Relapsed, Residual Common infections HSV, CMV, HBV, HCV,Transplantation 4 Weeks LISTERIA, PCP, TOXO 6-12 Months Long-term Donor- Nosocomial derived infection Period of most intensive infection immune suppression Common Variables in Immune Suppression  Rejection, antirejection therapy, new agents  Neutropenia, lymphopenia  Viral coinfection (CMV, HCV, EBV)
    8. 8. Changing Timeline of Infection after TransplantationFishman J. N Engl J Med 2007;357:2601-2614
    9. 9. Conditions predisposing to early and nosocomial infection Intubation (>3 days) Catheters (urinary, venous, balloon pumps, dialysis, other mucosal injuries) Ascites, peritoneal dialysis Constipation, endoscopy, Clostridium difficile colitis Broad-spectrum antimicrobial agents Deep vein thrombosis, atelectasis, decubitus ulcers Metabolic (malnutrition/uremia/hyperglycemia) Latent infections (viral and parasitic) Colonization (bacterial and fungal) Exogenous immune suppression
    10. 10. Donor derived infectionsPossible infections from the allograft include: Tuberculosis Known pathogens (screened): HBV, HCV, HIV Uncommon pathogens: West Nile virus, Chagas’ disease, Toxoplasma gondii, rabies, lymphocytic choriomeningitis virus Common “sticky” bacteria (may be nosocomial colonizers of donor): Pneumococcus, Staphylococcus, Streptococcus, Pseudomonas, Salmonella, Aspergillus, Candida
    11. 11. Donor-derived Infection Most are latent  CMV, TB, T.cruzi The majority of these are sub-clinical in healthy patients, but can be catastrophic when transplanted into an immunosuppresed patient Rarely can be acute  West Nile, rabies, HIV, hepatitis 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
    12. 12. Donor-derived Transplantation of organs from deceased donors with viral syndromes is controversial Livers with known Chagas or Hep B infection may be used as there are effective treatments for these infections Hep C infected organs are sometimes transplanted into Hep C(+) donors
    13. 13. Fishman J. N Engl J Med 2007;357:2601-2614
    14. 14. Recipient-derived Infections Infections that can be treated or controlled do not necessarily preclude transplantation Most commonly screened for:  TB  Syphilis and other STD  Viral: CMV, EBV, VZV, HSV, HIV, HBV, HCV Other things to think of  T.cruzi, strongyloides, cryptococcus  Endemic fungi: histoplasma, coccidioides, paracoccidioides, aspergillus, blastomycosis
    15. 15. Fishman J. N Engl J Med 2007;357:2601-2614
    16. 16. Immunizations Pt’s should be immunized for Consider in endemic area  MMR •Rabies, (2D)  HBV •Tick-borne (2D)  Influenza •Meningoencephalitis, (2D)  Strep pneumoniae •Japanese B encephalitis-  Tetanus inactivated (2D)  Diphtheria •Meningococcus, (2D) •Pneumococcus, (2D)  Pertussis •Salmonella typhi-  Polio inactivated. (2D)  VZV – if never infected 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
    17. 17. Monitoring Immunosuppression There are no specific tests currently available to determine the overall susceptibility of patients to infection… …but they are being developed Currently, the known determinants contributing to the overall risk of infection are the dose, duration, and sequence of immunosuppressive therapies
    18. 18. Infection Types  Viral  Bacterial  Fungal  Parasitic 27
    19. 19. Viral Infection
    20. 20. Figure 1. Time of presentation of common viral illnesses post-transplant Weikert, B. C. et al. Clin J Am Soc Nephrol 2008;3:S76-S86Copyright ©2008 American Society of Nephrology
    21. 21. CMV
    22. 22. CMV • Among all organ transplant KT pt have lowest risk for CMV disaese • CMV is still among the most important infectious complications after transplant • It is widely distributed in general population ranging from 40-97% • Once CMV infection is established, then its replication is highly dynamic with rapid increases in viral load • Transmitted by Allograft, blood products, Sexual contacts24
    23. 23. CMV and Kidney Transplantation It usually develops during the first few months of Tx. when patient is immunosuppressed. In the absence of prophylaxis, CMV reactivation can occur in over 75% of recipients depending on other risk factors It has also been implicated as a cause of acute and chronic allograft injury. CMV may play a crucial role in chronic graft vasculopathy resulting CAN, bronchiolitis and accelerated CAD
    24. 24. CMV Infection: Risk Categories in Solid Organ Transplant Recipients Donor (D) or Recipient (R) Risk Category Seropositivity (+/-) High D+/R- Intermediate D+/R+, D-/R+ Low D-/R- Fishman JA, Emery V, Freeman R, et al. Cytomegalovirus in transplantation –26 challenging the status quo. Clinical Transplantation. 2007;21:149-158.
    25. 25. CMV Pathogenesis • Viral factors • Host factors – replication dynamics – CD4+, CD8+ T-cell – immune evasion – NK cell, B-cell, neutropenia – viral heterogeneity – exogenous – viral co-infections immunosuppression/ lymphocyte depletion – D/R immune status27
    27. 27. CMV Infection Latent CMV infection Active CMV infection (viral replication) Direct Indirect effects effects29
    28. 28. Direct Effects of CMV Infection Direct Effects CMV Viral Syndrome Tissue Invasive • Fever, malaise, myalgias Disease • Leukopenia, • Hepatitis thrombocytopenia, and other • Pneumonitis(most serious) laboratory abnormalities • Colitis(diagnostic endoscopy) • Carditis • Nephritis • Pancreatitis • Retinitis30
    29. 29. Indirect Effects of CMV Infection Indirect Effects Altered host immune response • Graft rejection; graft dysfunction • Opportunistic infections: Bacterial fungal superinfection • Decreased graft and patient survival • Herpesvirus interactions: EBV/PTLD31
    30. 30. Diagnosis of CMV Pretransplantation screening  CMV – IgM, IgG Disease  Culture based – Tissue culture  PCR  New era for CMV diagnosis by the PP65 antigenemia assay. This test is sensitive and specific.  Quantitative method is used for monitoring response
    31. 31. Anti-CMV Therapy  Valganciclovir: a prodrug form of ganciclovir with improved oral bioavailability(=Ganciclovir)  Ganciclovir: intravenous or oral  Foscarnet: is an inhibitor CMV DNA polymerase (UL54) ‒ Useful for ganciclovir resistant CMV ‒ Major limitation is nephrotoxicity  Cidofovir: inhibits viral DNA polymerase ‒ Useful for ganciclovir resistant CMV  Maribavir: is an investigational agent that prevents viral encapsidation and nuclear egress33
    32. 32. Ganciclovir  Adverse effects: – Hematologic: neutropenia, anemia, thrombocytopenia(additive with Azathiopurine) – Gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, flatulence, anorexia – Neurologic: headache, confusion, hallucination, seizures – Other: pain and phlebitis at injection site (due to high pH), sweating, rash, itch, increased serum creatinine and blood urea concentrations  Toxicity: – Human carcinogen, teratogen, and mutagen – Inhibits spermatogenesis – Increased seizure threhold on use with Imipenem  Pharmacokinetics: – 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)  5-10 mg/kg/d in two divided dose for 4-6 weeks for treatment34
    33. 33. Valganciclovir  Dose :  Oral 900mg BD for mild to moderate CMV disease for 14-21 days  Pt with severe tissue invasive disease, who fail to achieve a reduction in viral load after 7 days should receive iv ganciclovir  Weekly monitoring of viral load  Adverse effects: – Similar to ganciclovir – Myelosuppression is one of the main side effects that may limit prolonged use of valganciclovir  Pharmacokinetics: – Oral bioavailability ~ 60% • Fatty foods significantly increase the bioavailability – Eliminated as ganciclovir in the urine, with a half-life of about 4 hours35
    34. 34. CMV Prevention • Two strategies • Universal prophylaxis – Therapy from the time of transplant to all patients or a subgroup of patients at high risk for CMV disease • Pre-emptive therapy – Patients are monitored at regular intervals for early evidence of CMV replications guided by laboratory monitoring – Treatment is started when CMV viral load or antigenemia reaches a certain threshold – Useful for low/intermediate risk – In patients with CMV disease, we suggest weekly monitoring of CMV by NAT or pp65 antigenemia.(2D)36
    35. 35. Pre-emptive Therapy CMV disease TEST _ _ _ + + + + + + + _ _ 0 4 8 12 weeks Initiate pre-emptive therapy to prevent CMV disease37
    36. 36. Prophylaxis vs. Pre-emptive Therapy Prophylaxis Pre-emptiveEvidence of efficacy +++ ++Indirect effects/mortality ++ +Other viruses + for some ?Ease ++ +/-Late onset disease ++ -Resistance Low Very Low 38
    37. 37. Effects of Anti-CMV Prophylaxis on Concomitant Infections 39 Hodson EM, et al. Lancet. 2005;365:2105-2115.
    38. 38. Universal prophylaxisAcyclovir, ganciclovir, valacyclovir, valgancilovir and immune- globulin.Acyclovir: Possesses comparatively poor vitro activity against CMV at clinically achievable levels.Ganciclovir:  Use in D+ & R-ve patients immediate after Tx.Valacyclovir:  Oral 8 gm per day for 3 months  Less effective than gancyclovir. All prophylaxsis for 3mth or 6 wk after tt with T cell depleting antibody (Dose adjustment necessary for all)
    39. 39. Guidelines for CMV prevention in kidney recipientsGroup: Recommendations:* Kidney * Oral ganciclovirD+ve/R-ve for 3 months/IV ganciclovir 1-3 M*Kidney R+ve * As aboveStart prophylaxis within 10 days post Tx. And continue for 100 days
    40. 40. Polyvalent I/V ImmunoglobulinThe efficacy of I/V Ig in KT has been investigated.Unclear status
    41. 41. Late Onset CMV Disease Definition • CMV disease occurring > 3 months post transplant • May be primary infection (D+/R-) or recurrence (R+) • Incidence 3%-17% • In IMPACT study 37% with 3 months of prophylaxis in D+/R-43 Limaye, AP, et al. Transplantation. 2004;78(9):1390-1396.
    42. 42. CMV Prophylaxis: Late-Onset Disease 100 Valganciclovir 90 364 D+/R- patients Patients With No CMV Disease (%) 80 70 60 Ganciclovir (oral) 50 40 30 20 10 Prophylaxis period 0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 Time (days)44 Paya, et al. Am J Transplant. 2004;4:611-620.
    43. 43. Herpes Simplex Virusand Varicella Zoster Virus
    44. 44. HSV & HZV Seroprevalence for HSV-1 in the adult population is as high as 60 percent, while VZV rates can be as high as 90 percent Infection in the renal transplant patient is usually caused by reactivation of latent virus. Within 6 weeks HSV infection usually presents with oral or genital lesions, but in some instances can cause esophagitis,hepatitis, encephalitis or pneumonitis
    45. 45. HSV & HZV ZV reactivation usually presents as dermatomal zoster, but can disseminate In the absence of prophylaxis, HSV and VZV may be seen early The incidence of HSV in renal transplant recipients is estimated to be approximately 53% and VZV 4 to 12% Due to high seroprevalence in the adult population, serologies are rarely helpful in the setting of active infection.
    46. 46. HSV & HZV Diagnosis  Direct fluorescence antibody for HSV and VZV from vesicular lesions or PCR from CSF or visceral tissue samples.  Treatment  Disseminated infections involves intravenous acyclovir,   Less severe infection ; oral acyclovir, valacyclovir, or famciclovir  Acyclovir resistance - foscarnet, cidofovir, and topical trifluridine -monitoring of KFT  VZV immunoglobulin ASAP but no later than 96 hr  If immunoglobulin is N/A or more than 96 h have passed, a 7-day course of oral acyclovir begun 7–10 days after varicella exposure. (2D)
    47. 47. Epstein Barr Virus
    48. 48. Epstein Barr Virus EBV remains latent in lymphocytes following primary infection. Can cause replication and clonal expansion of the B cells that serve as its primary reservoir and other cell lines as well. However, a competent immune system, specifically T cell response, prevents these cells from propagating. 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
    49. 49. Epstein Barr Virus & PTLD Risk of development of PTLD,  with higher incidence rates observed in patients receiving cytolytic therapies,  including antithymocyte globulin and  OKT3 Occur more commonly in pediatric kidney recipient EBV seropostive donor and recipient both are at increased risk of PTLD PTLD most commonly occurs in the first year post transplant
    50. 50. Serologies for EBV Serologies for EBV of both donor and recipient should be obtained before transplant. Allograft recipients who are EBV negative before transplant and receive an organ from a seropositive donor are at greatest risk for PTLD; Currently there is no single standard strategy to prevent PTLD. In some centers, high-risk individuals are screened regularly for the presence of EBV viremia and immunosuppression decreased when viremia is observed. Effective prevention of CMV may also prevent EBVinfections A recent trial demonstrated that CMV Ig did not prevent the onset of PTLD in high risk recipients
    51. 51. PTLD Definitive diagnosis of PTLD requires histopathologic confirmation, preferably of tissue obtained by excisional biopsy. In the case of CNS PTLD, analysis of CSF for EBV PCR and cytology should be performed. Although viremia may be noted at the time of PTLD, its detection cannot be used to confirm or refute the diagnosis. Staging is performed by histologic type (monoclonal versus polyclonal, T cell versus B cell) and location (allograft, other organ, metastasis). Often the Ann Arbor classification, used for other non-Hodgkin lymphomas, is utilized
    52. 52. Human Herpesvirus-6, Human Herpesvirus-7,and Human Herpesvirus-8
    53. 53. HHV-6,7,8 HHV-6 is a cofactor for CMV Human Herpes Virus 8 (HHV8) is a gamma herpes virus that has been associated with Kaposis Sarcoma(30 month), primary effusive lymphoma, and Multicentric Castlemans Disease (lymphoproliferative disorder) Routine screening of HHV 6 & 8 are not performed
    54. 54. Hepatitis B and C
    55. 55. Hepatitis B 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 HBsAb titer o10 mIU/ml receive booster vaccination to raise the titer to X100 mIU/ml. All HBsAg positive pt should undergo live  biopsy, because it is difficult on clinical ground only to estimate severity of liver disease in CKD(AST tend to be spuriously low)
    56. 56. HBsAg +ve Biopsy liverDecompensated Cirrhosis or Precirrhosis Mild Histology cirrhosis Preclude RT LKT No replication Replication RT Antiviral therapy RT Antiviral therapy
    57. 57. Hepatitis B Risk factor for progression of HBV related liver disease  Alcohol  Infection- ↑ duration, ↑ HBV DNA, genotype C, coinfection with hepatitis C & D, HIV, immunosuppresion  Calcineurin inhib & Azathioprine All pt with Hep B should receive antiviral therpy after transplantation (Only 5% fail to recover) Tenofovir or entecavir are preferable to lamivudine Adefovir or tenofovir for KTRs with lamivudine resistance (>5 log10 copies/ml rebound of HBV-DNA). Dose reduction is needed – Lamivudine, Adefovir, IFN During therapy with antivirals, measure HBV DNA and ALT levels every 3 months to monitor efficacy and to detect drug resistance. Screen for hepatocellular carcinoma every 12 m with liver ultrasound and alpha feto-protein
    58. 58. HCV Graft dysfunction NODAT(40%)
    59. 59. Anti HCV +ve HCV RNA -ve HCV RNA +ve Liver Bx Normal LFT Normal Hepatitis Cirrhosis or precirrhosis Antiviral Rx Defer transplant orList for renal transplant consider combined liver- kidney transplant HCV RNA -ve HCV RNA +ve Pt by pt decision
    60. 60. HCV Cyclosporin inhibit HCV replication, Azathioprine & Antilymphocye therapy ↑ replication For sustained virological response IFN & ribavirin should be co administered very carefully because of risk of hemolytic anemia and its metabolites are not cleared by HD Dose modification needed - Ribavirin Measure ALT monthly for the first 6 m & every 3–6 months,thereafter Perform imaging annually to lookfor cirrhosis and hepatocellular carcinoma. Test HCV-infected patients at least every 3–6 months for proteinuria. (Not Graded)
    61. 61. West Nile Virus West Nile Virus is a flavivurus that causes a febrile illness, associated with encephalitis, and can be fatal  To prevent infection, summer seasonal screening should be considered for donors before transplant Preventive measures regarding mosquito bites Treatment not standardized - reduction in immunosuppression  
    62. 62. Adenovirus Causes  Hemorrhagic cystitis  Fever  Renal dysfunction  Pneumonia  Hepatitis Definitive diagnosis – renal biopsy (Granulomatous interstitial nephritis, ground glass intranuclear inclusion body) TT –Ribavirin with or without IVIG
    63. 63. Parvovirus B19 Causes  Refractory anemia  Pancytopenia  Thrombotic microangiopathy  Fibrosing cholestatic hepatitis  Encephlitis  Graft dysfunction 80% in first three month Diagnosis  Bone marrow – Giant proerythroblast  Confirm by detection of B19 in serum by PCR  High dose IVIG x 10 days  Reduction of immunsuppresion
    64. 64. Bacterial infections
    65. 65. Bacterial infections UTI – Prophylaxsis for 6 m with TMP-SMX Even low level of bacteriuria can lead to septicemia  2 set of blood culture should be obtained Surgical site infection – 2-25%
    66. 66. Vancomycin-Resistant Enterococci in Transplantation Common bacterial pathogen after kidney transplantation “Predictor” of morbidity and mortality that reflects overall “illness” of patient VRE may not be detectable from a single stool culture and 3 samples should be obtained at weekly interval for 3 weeks before discontinuing search for VRE
    67. 67. Clostridium difficile infection With in 2 weeks - diarrhea Diarrhea occur in 13% of kidney transplant  Infectious agent 41%  Medications 34%
    68. 68. Bacterial infection contd.. Nocardia  Early rejection, ↑imunnosupp, neutropenia, uremia  1-6 m after acute or subacute chest presentation  High dose TMP-SMX 15mg/kg for at least 12 month TB  RIF>ETH – neutropenia  INH increase levels of cyclosporin, tacrolimus. RIF decrease these level  Interactions are predictable occurs in 1-3 days of initiating ATT, dose adjustment needed  Consider substituting rifabutin for rifampin to minimize interactions with CNIs and mTORi
    69. 69. Bacterial infection contd.. Legionella  Urinary antigen test 70-100% specific  Tt for 21 days Rhodococcus  Months to years after Tx  D/d with PTB Mixed infection
    70. 70. Fungal infections
    71. 71. Fungal infections Incidence of fungal infections in renal transplant recipients is less than other SOT but mortality high :  Limited diagnostic tools  Potential for rapid clinical progression Risk factor for colonization with yeast and molds after KT:  Corticosteroid therapy  Broad spectrum antibiotic  Co morbid disease  Domiciliary exposure Hand book of renal transplant:( Gabriel)
    72. 72. Fungal infectionsClincal scenario where fungal infection is seen 1. Presence of urinary catheter 2. Endotracheal tube 3. Immunomodulating viral inf reactivation 4. Ch. Graft dysfunction 5. During treatment of post transplant malignancies Hand book of renal transplant:( Gabriel)
    73. 73. Extent of problem Incidence of major invasive fungal infection(IFI) among Kidney recipient patient:2. Candida:76-95%3. Cryptococcus:0-39%4. Other fungi:0-39%5. Aspergillus:0-26% Hand book of renal transplant:( Gabriel)
    74. 74. Candida Occurs most commonly  Sources: during the 1st month  Endogenous: Source of following transplant colonization associated with  Exogenous: lack of hand washing of health workers Hand book of renal transplant:( Gabriel)
    75. 75. Candidal colonization Esophageal / GIPulmonary tree Vagina Bowel
    76. 76. Disseminated infection: <5%Kidney candidiasis: 0.5-2.2%
    77. 77. PROGNOSTIC FACTORS IN CANDIDEMIA Associated with death: -more severe clinical symptoms -persisting neutropenia -organ involvement -↑ age Beter survival if: *catheter is removed *neutropenic patients given antifungals
    78. 78. Aspergillosis
    80. 80. Renal aspergillosis
    81. 81. Invasive aspergillosis : diagnosis Radiology: chest X-ray and CT Microbiology  Respiratory secretions: BAL/biopsy  Direct microscopy  culture  Serological surveillance  ELISA for galactomannan PCR
    82. 82. Invasive aspergillosis: Treatment Conventional amphoterin B: 20-83% response ?iv itraconazole: limited data Lipid formulations of ampho B  5 mg/kg/day liposomal ampho B Surgical intervention
    83. 83. Zygomycosis Median 2 months post-transplant Most cases occur within 6 months of transplant Rhinocerebral form 76% diabetes and corticosteroids 56% mortality
    84. 84. Prophylaxis AmBisome Itraconazole Prophylaxsis with systemic antifungal agent is not recommended after uncomplicated KT, it may be indicated in those with persistent candiduria.  Azole Ambisome for a period of risk for infection Those with past history fo endemic mucosis, radiographic e/o healed leison – life long azole
    85. 85. Successful management Prompt recognition of infection Adjustment of level of immunosuppression Antifungal therapy and surgery
    86. 86. Treatment Conventional amphotericin B  1-1.5 mg/kg/day  Nephrotoxicity big issue  18% require haemodialysis Liposomal amphotericin B  Much reduced nephrotoxicity  Superior efficacy Itraconazole: iv formulation: little data Voriconazole/caspofungin: little data. (apppears to be superior to Amb)
    87. 87. Future Strategy Against Probable Invasive Fungal Infection? C Fluconazole U le p tib L s ce T suEmpirical U or R AmBisome E positve risk of aspergillosis AmBisome test R E no S re U sp glucan synthesis o ns inhibitor (IV) or L e new azole orally T
    88. 88. PNEUMOCYSTIS JIROVECII PNEUMONIA PCP prophylaxis with daily TMP-SMX for 3–6 months after transplantation. and for 6wk after treatment for acute rejection Diagnosed by BAL and/or lung biopsy be treated with high-dose intravenous TMP-SMX, corticosteroids, and a reduction in immunosuppressive medication Treat with corticosteroids for KTRs with moderate to severe PCP (as defined by PaO2 o70mmHg in room air or an alveolar gradient of 435mmHg)
    89. 89. Parasites
    90. 90. Malaria Usually severe Pyrexia, which may lack the typical periodicity or rigors Anemia is severe, being typically hemolytic and occasionally hemophagocytic, often associated with thrombocytopenia Acute graft dysfunction may occur as a consequence of the hemodynamic consequences of falciparum infection*. Whether the immune response to malarial infection has an impact on subsequent rejection is unknown Antimalarial drugs can be used safely Drug-drug interactions must be taken into consideration as those between quinine & chloroquine with cyclosporine * *Barsoum RS. Malarial acute renal failure. J Am Soc Nephrol 2000.;11(11):2147-54 Tan HW, Ch’ng SL. Drug interaction between cyclosporine A and quinine in a renal transplant patient with malaria. Singapore Med J 1991; 32: 189-190 Nampoory MR, Nessim J, Gupta RK, Johny KV. Drug interaction of chloroquine with ciclosporin. Nephron 1992; 62: 108-109
    91. 91. Schistosomiasis Recrudescence of schistosomal glomerulopathy has been reported in an endemic area in South America, where mesangioproliferative glomerulonephritis with schistosomal antigen deposits developed in a recent kidney transplant recipient who originally had been infected with S. mansoni. Prophylactically treat patients with such infection
    92. 92. Toxoplasmosis gondii Lack of T cell immunity Diagnosis by PCR Protected when given TMP-SMX for P. carnii
    93. 93. Approach to the kidney transplant pt with fever Infection Graft rejection Drug allergy Non infective systemic inflammatory response  Pancreatitis  Pulm. Embolism  Cytokine release syndrome
    94. 94. Thank you