infection and prevention of infection in kidney transplantation unit dr

Infection and prevention of Infection and prevention of infection in kidney infection in kidney transplantation unittransplantation unit

Dr. Dr.

IntroductionIntroduction

Advances in transplant medicine in recent Advances in transplant medicine in recent years have helped to years have helped to Avoid or overcome many clinical challenges in Avoid or overcome many clinical challenges in

renal transplant recipients, most notably renal transplant recipients, most notably Reducing the previous high rates of graft loss to Reducing the previous high rates of graft loss to

acute rejection,acute rejection, Ameliorating the toxicity associated with early Ameliorating the toxicity associated with early

immunosuppression regimens, and immunosuppression regimens, and Lowering infection-related mortalityLowering infection-related mortality

Transplantation Reviews 2008;22:241–51


However, new concerns have become However, new concerns have become apparent in the quest for apparent in the quest for Higher long-term graft survival rates and Higher long-term graft survival rates and Quality of life for patients Quality of life for patients

The clinician is faced with The clinician is faced with Risks for infection Risks for infection An increasingly diverse range of issues to An increasingly diverse range of issues to

consider when deciding on the consider when deciding on the Optimal immunosuppressive strategy to adopt Optimal immunosuppressive strategy to adopt

based on an individual's specific profilebased on an individual's specific profile



Questions that now need to be taken into Questions that now need to be taken into account as part of post-transplant account as part of post-transplant management includemanagement include Relative risk of complications such as Relative risk of complications such as

Emerging problem of polyomavirus-associated Emerging problem of polyomavirus-associated nephropathynephropathy

Diabetes mellitusDiabetes mellitus Time-dependent adequate dosing of adjunctive Time-dependent adequate dosing of adjunctive

therapy,therapy, Avoidance of chronic nephropathy, and Avoidance of chronic nephropathy, and Use of novel regimens to achieve balanced Use of novel regimens to achieve balanced

calcineurin inhibitor (CNI) exposurecalcineurin inhibitor (CNI) exposure


IntroductionIntroduction Despite refinements in diagnostic techniques and Despite refinements in diagnostic techniques and

discovery of new anti-microbial drugs, discovery of new anti-microbial drugs, The risk of infection amongst transplant recipients has not come The risk of infection amongst transplant recipients has not come

downdown About 70% of all RTRs experience at least one infection About 70% of all RTRs experience at least one infection

episode by 3 yearsepisode by 3 years The 2008 USRDS report showed The 2008 USRDS report showed

Increase in hospitalization rates for infection from 5.9% per 100 Increase in hospitalization rates for infection from 5.9% per 100 patient years in 2001-2003 to 6.5% per 100 patient years in patient years in 2001-2003 to 6.5% per 100 patient years in 2004-2006; 2004-2006; hospitalization rates for other causes decreased over the same hospitalization rates for other causes decreased over the same

periodperiod Infections are responsible for 18% of all deaths with Infections are responsible for 18% of all deaths with

functioning grafts in the US, and are the functioning grafts in the US, and are the Leading cause of death in the developing countriesLeading cause of death in the developing countries

RTR – Renal transplant recepients Indian J Nephrol 2010;20:171-8

IntroductionIntroduction Infection risk is even greater in the pediatric transplant Infection risk is even greater in the pediatric transplant

populationpopulation Bacterial infections are approximately twice as frequent Bacterial infections are approximately twice as frequent

as viral infections in RTRas viral infections in RTR Vascular access and urinary tract infections (UTIs) were Vascular access and urinary tract infections (UTIs) were

the most frequent bacterial infections, whereas the most frequent bacterial infections, whereas cytomegalovirus (CMV) was the commonest viral cytomegalovirus (CMV) was the commonest viral infectioninfection

Extremes of recipient age, female gender, deceased Extremes of recipient age, female gender, deceased donor source, older donor age, CMV+ve donor, time on donor source, older donor age, CMV+ve donor, time on dialysis and systemic lupus erythematosus (SLE) as the dialysis and systemic lupus erythematosus (SLE) as the cause of kidney disease increased the infection riskcause of kidney disease increased the infection risk

RTR – Renal transplant recepients Indian J Nephrol 2010;20:171-8


Guidelines are constantly being refined to outline the Guidelines are constantly being refined to outline the most practical and appropriate screening processes to most practical and appropriate screening processes to minimize donor-related infectionsminimize donor-related infections

Conversely, attention to implementing preventive Conversely, attention to implementing preventive measures such as pretransplant vaccination in organ measures such as pretransplant vaccination in organ transplant recipients also represents an important step in transplant recipients also represents an important step in optimizing safe organ donation and retentionoptimizing safe organ donation and retention

Newer host-related challenges, such as the Newer host-related challenges, such as the Increasing prevalence of obesity, and system-related problems, Increasing prevalence of obesity, and system-related problems,

such as healthcare-acquired infections, represent other such as healthcare-acquired infections, represent other challenges for successful infection prevention challenges for successful infection prevention


Several areas related to infections in organ Several areas related to infections in organ transplant recipients aretransplant recipients are Unresolved and controversial, and Unresolved and controversial, and

Recognized emerging issues include Recognized emerging issues include Donor-derived infection (eg, rabies, West Nile virus, Donor-derived infection (eg, rabies, West Nile virus,

lymphocytic choriomeningitis virus [LCMV]),lymphocytic choriomeningitis virus [LCMV]), Impact of pandemic influenza in the organ transplant Impact of pandemic influenza in the organ transplant

recipient,recipient, Drug-resistant infections (including multidrug-resistant Drug-resistant infections (including multidrug-resistant

tuberculosis), and many others…tuberculosis), and many others…


Remaining up-to-date with the latest Remaining up-to-date with the latest findings relating to such a variety of findings relating to such a variety of complex areas is a demanding taskcomplex areas is a demanding task



We shall discuss today regardingWe shall discuss today regarding Various infections which may occur post renal Various infections which may occur post renal

transplantation as well astransplantation as well as Strategies of prevention of infections…Strategies of prevention of infections…

The phases in the "timetable of infections" The phases in the "timetable of infections" according to time elapsed since transplantation and the risk status of the patient. The according to time elapsed since transplantation and the risk status of the patient. The risk status changes in any stage if any of the modifiers are present risk status changes in any stage if any of the modifiers are present

Indian J Nephrol 2010;20:171-8

Infection in renal transplant recipientInfection in renal transplant recipient

The possibility of infection needs to be The possibility of infection needs to be considered in all febrile presentations of considered in all febrile presentations of RTRRTR

Fever may occasionally be absent, and Fever may occasionally be absent, and symptoms may solely be related to one or symptoms may solely be related to one or more organ systemsmore organ systems

The presentation may be different in RTR The presentation may be different in RTR compared to the general population compared to the general population



The possibility of infections with unusual, often exotic, The possibility of infections with unusual, often exotic, organisms and the high likelihood of polymicrobial organisms and the high likelihood of polymicrobial infections necessitate a multidisciplinary approach with infections necessitate a multidisciplinary approach with involvement of other specialists including the ID teaminvolvement of other specialists including the ID team

Early and aggressive use of imaging techniques such as Early and aggressive use of imaging techniques such as Ultrasound, computed tomography (CT) scans or magnetic Ultrasound, computed tomography (CT) scans or magnetic

resonance imaging (MRI), and invasive procedures like resonance imaging (MRI), and invasive procedures like bronchoalveolar lavage, imaging guided aspiration and/or bronchoalveolar lavage, imaging guided aspiration and/or biopsies for obtaining specimens for histological and/or biopsies for obtaining specimens for histological and/or microbiological examination microbiological examination Are essential for accurate diagnosis Are essential for accurate diagnosis


Serologic tests are of limited value since Serologic tests are of limited value since antibody response is attenuated in the antibody response is attenuated in the immunocompromised hostimmunocompromised host

Quantitative nucleic acid based assays are Quantitative nucleic acid based assays are sensitive, quick, and useful for detection of sensitive, quick, and useful for detection of subclinical infection, assessing response to subclinical infection, assessing response to therapy and identifying drug resistancetherapy and identifying drug resistance

Studies have documented the adverse impact of Studies have documented the adverse impact of subclinical CMV and Epstein-Barr virus (EBV) subclinical CMV and Epstein-Barr virus (EBV) viremia on graft function viremia on graft function




The non-specific nature of presentation The non-specific nature of presentation often necessitates the initiation of broad-often necessitates the initiation of broad-spectrum therapy before a specific spectrum therapy before a specific etiologic diagnosis can be madeetiologic diagnosis can be made

Development of CMV or EBV disease Development of CMV or EBV disease indicates over immunosuppression and indicates over immunosuppression and should prompt reduction in should prompt reduction in immunosuppressive drug dosage.immunosuppressive drug dosage.


Prevention of Post-transplant InfectionsPrevention of Post-transplant Infections

Adoption of preventive strategies has Adoption of preventive strategies has considerably reduced the burden of infection in considerably reduced the burden of infection in RTRRTR

This process starts before transplantation with This process starts before transplantation with Pre-transplant screening of donors and recipients, Pre-transplant screening of donors and recipients, Avoidance of use of blood products, Avoidance of use of blood products, Use of leukocyte filters during transfusions, Use of leukocyte filters during transfusions, Treatment of pre-existing infections, Treatment of pre-existing infections, Immunoprophylaxis (vaccination), and Immunoprophylaxis (vaccination), and Continues after transplantation with tailored Continues after transplantation with tailored

chemoprophylaxis and surveillance chemoprophylaxis and surveillance



Donor screening Donor screening Aimed at preventing transmission of latent infections Aimed at preventing transmission of latent infections

including locally prevalent ones, e.g., tuberculosis and including locally prevalent ones, e.g., tuberculosis and schistosomiasis, via the infected organschistosomiasis, via the infected organ

Organs from with hepatitis (B or C) (HBV or Organs from with hepatitis (B or C) (HBV or HBC) or HIV infected donors are not used for HBC) or HIV infected donors are not used for transplanttransplant Recently, some centers have started using organs Recently, some centers have started using organs

from HCV or HIV positive donors for recipients who from HCV or HIV positive donors for recipients who already harbor these infections after informed consent already harbor these infections after informed consent is obtainedis obtained



A recent analysis showed that A recent analysis showed that The adjusted hazard ratio for death among The adjusted hazard ratio for death among

HCV positive recipients of kidneys from HCV HCV positive recipients of kidneys from HCV antibody positive donors was lower compared antibody positive donors was lower compared to those who remained on dialysisto those who remained on dialysis

HBV core antibody-positivity indicates a HBV core antibody-positivity indicates a low risk of transmission, and low risk of transmission, and kidneys from these donors can be used in kidneys from these donors can be used in

HBV antibody-positive recipientsHBV antibody-positive recipients



Issues related to Issues related to Timing (if performed during the window period, i.e., between the Timing (if performed during the window period, i.e., between the

infection and seroconversion) infection and seroconversion) Host (poor antibody response in the immunocompromised Host (poor antibody response in the immunocompromised

patient with end stage renal disease) or patient with end stage renal disease) or Organism (genetic change, e.g., HBV precore mutant) Organism (genetic change, e.g., HBV precore mutant)

Can result in a false negative serologic testCan result in a false negative serologic test Nucleic acid based assays are not subject to these errorsNucleic acid based assays are not subject to these errors

Uncommon pathogens for which screening is not Uncommon pathogens for which screening is not performed routinely (rabies, SARS, West Nile virus) can performed routinely (rabies, SARS, West Nile virus) can be transmitted through a contaminated allograftbe transmitted through a contaminated allograft



Vaccination Vaccination Recommendations for vaccination in transplant Recommendations for vaccination in transplant

recipients are based largely on data from general recipients are based largely on data from general populationpopulation

Vaccination status should be reviewed at initial Vaccination status should be reviewed at initial evaluation of chronic kidney disease (CKD), and all evaluation of chronic kidney disease (CKD), and all vaccinations recommended for the general population vaccinations recommended for the general population should be administeredshould be administered

Pediatric CKD patients should be vaccinated against Pediatric CKD patients should be vaccinated against varicella, influenza, hepatitis B and varicella, influenza, hepatitis B and PneumococcusPneumococcus



Vaccination Vaccination Vaccines should be administered early to CKD Vaccines should be administered early to CKD

patients, since patients, since Poor immune memory in advanced stages of CKD and after Poor immune memory in advanced stages of CKD and after

transplantation results in weak antibody response transplantation results in weak antibody response

Pre-transplant vaccination may not be feasible in Pre-transplant vaccination may not be feasible in children and in areas with limited dialysis facilities, children and in areas with limited dialysis facilities, Necessitating post-transplant vaccinationNecessitating post-transplant vaccination Experts agree that Experts agree that

Inactivated vaccines are safe when administered after Inactivated vaccines are safe when administered after transplantationtransplantation

Use of live vaccines, however, is controversialUse of live vaccines, however, is controversial



Vaccination Vaccination A couple of studies demonstrated the safety A couple of studies demonstrated the safety

of varicella and measles vaccines in small of varicella and measles vaccines in small number of patients after transplantation, butnumber of patients after transplantation, but The balance of opinion suggests that the risks of The balance of opinion suggests that the risks of

live vaccines outweigh potential benefits and live vaccines outweigh potential benefits and hence should not be used hence should not be used


Prevention of Post-transplant InfectionsPrevention of Post-transplant InfectionsRecommended vaccinations after renal transplantationRecommended vaccinations after renal transplantation

Indian J Urol 2009;25:161-8


Recommended vaccines for renal transplant recipients Recommended vaccines for renal transplant recipients



Data on the clinical efficacy of individual vaccines is Data on the clinical efficacy of individual vaccines is limitedlimited

Observational studies have documented the salutary Observational studies have documented the salutary effect of pre-transplant vaccination on the course of effect of pre-transplant vaccination on the course of varicella infection after transplantationvaricella infection after transplantation

Post-transplant influenza and pneumococcal Post-transplant influenza and pneumococcal vaccinations lead to protective antibody titers in a vaccinations lead to protective antibody titers in a majority of RTRmajority of RTR

The antibody response is weak for post-transplant The antibody response is weak for post-transplant hepatitis B vaccinehepatitis B vaccine Antibody titers should be monitored with booster vaccination Antibody titers should be monitored with booster vaccination

once the titers fall below 10 IU/ml once the titers fall below 10 IU/ml



The American Society of Transplantation The American Society of Transplantation suggests suggests Delaying resumption of vaccinations after Delaying resumption of vaccinations after

transplantation until the immunosuppressive drug transplantation until the immunosuppressive drug dosage has been reduced to the lowest maintenance dosage has been reduced to the lowest maintenance levels and documentation of vaccine efficacy by levels and documentation of vaccine efficacy by serologic assaysserologic assays

There is no consensus on the frequency of There is no consensus on the frequency of monitoring; monitoring; Annual verification is sufficient in most instancesAnnual verification is sufficient in most instances

Vaccination is desirable for pathogens that may be Vaccination is desirable for pathogens that may be encountered while traveling to endemic areas as long encountered while traveling to endemic areas as long as the recommended vaccinations are inactivatedas the recommended vaccinations are inactivated



ChemoprophylaxisChemoprophylaxis Drugs provide effective protection against a variety of Drugs provide effective protection against a variety of

potential pathogens in RTRpotential pathogens in RTR One single strength tablet of cotrimoxazole protects One single strength tablet of cotrimoxazole protects

against against Bacterial UTI, Bacterial UTI, Pneumocystis cariniiPneumocystis carinii pneumonia (PCP), pneumonia (PCP),

ToxoplasmaToxoplasma, , ListeriaListeria and Nocardia and Nocardia It is be used for 6-12 months after transplantation, the period of It is be used for 6-12 months after transplantation, the period of

maximum risk for PCP and Nocardia, and graft pyelonephritis, maximum risk for PCP and Nocardia, and graft pyelonephritis, bacteremia and poor graft function following UTIbacteremia and poor graft function following UTI

The risk of UTIs increases after stoppage of prophylaxis, but late The risk of UTIs increases after stoppage of prophylaxis, but late infections are usually benigninfections are usually benign Ciprofloxacin also provides effective prophylaxis for UTI and Ciprofloxacin also provides effective prophylaxis for UTI and

cotrimoxazole protects against PCP even when taken three times a cotrimoxazole protects against PCP even when taken three times a week, but once a day cotrimoxazole is preferred due to its week, but once a day cotrimoxazole is preferred due to its convenience convenience



Cytomegalovirus Cytomegalovirus CMV impacts the course of RTR in several CMV impacts the course of RTR in several

waysways CMV disease presents with a "flu-like" illness, CMV disease presents with a "flu-like" illness,

with or without tissue invasion, manifested as with or without tissue invasion, manifested as bone marrow suppression, hepatitis, colitis, bone marrow suppression, hepatitis, colitis, interstitial pneumonia or CNS involvementinterstitial pneumonia or CNS involvement Through its immunomodulatory properties, CMV Through its immunomodulatory properties, CMV

infection also increases the risk of invasion by infection also increases the risk of invasion by opportunistic organisms and allograft rejection opportunistic organisms and allograft rejection



Cytomegalovirus Cytomegalovirus Without prophylaxis, 10-60% of RTR develop CMV Without prophylaxis, 10-60% of RTR develop CMV

disease, but risk is not equal in alldisease, but risk is not equal in all Risk stratification is on the basis of recipient and Risk stratification is on the basis of recipient and

donor CMV serostatus at the time of transplantationdonor CMV serostatus at the time of transplantation Seronegative recipients who receive organs from Seronegative recipients who receive organs from

seropositive donors (D+R−) have a 40-50% chance of seropositive donors (D+R−) have a 40-50% chance of developing the diseasedeveloping the disease

Endogenous reactivation leading to CMV disease occurs in Endogenous reactivation leading to CMV disease occurs in 10-15% of seropositive recipients (D+/−R+)10-15% of seropositive recipients (D+/−R+)

The figure may be higher in those who receive The figure may be higher in those who receive antilymphocyte therapyantilymphocyte therapy

The risk is negligible in with D−R− transplantsThe risk is negligible in with D−R− transplants



CytomegalovirusCytomegalovirus Systematic reviews have shown that prophylaxis Systematic reviews have shown that prophylaxis

with with Oral or intravenous ganciclovir, valganciclovir, Oral or intravenous ganciclovir, valganciclovir,

acyclovir or valacyclovir acyclovir or valacyclovir reduces the incidence of CMV disease, CMV-associated reduces the incidence of CMV disease, CMV-associated

mortality, all cause mortality and clinically important mortality, all cause mortality and clinically important opportunistic infectionsopportunistic infections

One analysis found that prophylaxis significantly One analysis found that prophylaxis significantly reduced the rate of graft rejection, but the other did reduced the rate of graft rejection, but the other did notnot



CytomegalovirusCytomegalovirus Oral valganciclovir and intravenous ganciclovir are equally Oral valganciclovir and intravenous ganciclovir are equally

efficacious in preventing CMV infection and diseaseefficacious in preventing CMV infection and disease Similarly, oral and intravenous ganciclovir yielded similar resultsSimilarly, oral and intravenous ganciclovir yielded similar results

Ease of administration makes oral valganciclovir the preferred Ease of administration makes oral valganciclovir the preferred agentagent The recommended dose is 900 mg/d, but recent studies have The recommended dose is 900 mg/d, but recent studies have

shown that 450 mg/d is also effective for preventionshown that 450 mg/d is also effective for prevention

Prophylaxis also reduces the risk of herpes simplex and zoster Prophylaxis also reduces the risk of herpes simplex and zoster diseasedisease Acyclovir is less effective and should be restricted to situations Acyclovir is less effective and should be restricted to situations

where ganciclovir/valganciclovir cannot be used due to economic where ganciclovir/valganciclovir cannot be used due to economic reasonsreasons



CytomegalovirusCytomegalovirus The exact duration of prophylaxis is not clearThe exact duration of prophylaxis is not clear

The current recommendations suggest 3 months, extended to 6 months The current recommendations suggest 3 months, extended to 6 months in those receiving antilymphocyte inductionin those receiving antilymphocyte induction

A recent meta-analysis did not find a difference in outcomes whether A recent meta-analysis did not find a difference in outcomes whether the treatment was for less or more than 6 weeksthe treatment was for less or more than 6 weeks

A recently recognized effect of prophylaxis has been to delay the onset A recently recognized effect of prophylaxis has been to delay the onset of CMV diseaseof CMV disease

Over 90% of disease in patients who receive prophylaxis is now seen Over 90% of disease in patients who receive prophylaxis is now seen after 90 daysafter 90 days

Late onset disease is an independent predictor of mortality and graft Late onset disease is an independent predictor of mortality and graft lossloss

Widespread prophylaxis also carries the risk of development of Widespread prophylaxis also carries the risk of development of resistanceresistance In a recent study, 15% of late onset disease was due to drug resistant In a recent study, 15% of late onset disease was due to drug resistant

strainsstrains



Epstein-Barr Virus Epstein-Barr Virus Hepatitis B Hepatitis B BK VirusBK Virus



Antifungal Prophylaxis Antifungal Prophylaxis The risk of The risk of CandidaCandida infection as a result of increased infection as a result of increased

oral colonization is heightened in the early post-oral colonization is heightened in the early post-transplant period, during periods of intensified transplant period, during periods of intensified immunosuppression such as after treatment for immunosuppression such as after treatment for rejections or after prolonged courses of broad-rejections or after prolonged courses of broad-spectrum antibioticsspectrum antibiotics

Prophylactic topical antifungals such as nystatin or Prophylactic topical antifungals such as nystatin or clotrimazole help eradicate the colonization without clotrimazole help eradicate the colonization without producing systemic adverse effects producing systemic adverse effects


Emerging Infections in TransplantationEmerging Infections in Transplantation

Recent years have seen the identification of disease due Recent years have seen the identification of disease due to a number of organisms hitherto not seen in RTRto a number of organisms hitherto not seen in RTR

Clinical syndrome may be a result of primary infection Clinical syndrome may be a result of primary infection due to transmission via the donor organ or following due to transmission via the donor organ or following environmental exposure, or secondary to reactivation of environmental exposure, or secondary to reactivation of latent infection following immunosuppressionlatent infection following immunosuppression

Infection may be asymptomatic, or present with either Infection may be asymptomatic, or present with either mild self-limiting febrile illness or severe multisystem mild self-limiting febrile illness or severe multisystem diseasedisease

Diagnosis is usually made by molecular techniquesDiagnosis is usually made by molecular techniques Treatment includes lowering of immunosuppression and Treatment includes lowering of immunosuppression and

use of intravenous immunoglobulin or antiviral agents. use of intravenous immunoglobulin or antiviral agents.


Emerging Infections in TransplantationEmerging Infections in Transplantation


Opportunistic infections after renal transplantationOpportunistic infections after renal transplantation


Opportunistic organisms after renal Opportunistic organisms after renal transplantationtransplantation


ConclusionsConclusions

Infections remain a major problem in the Infections remain a major problem in the transplant populationtransplant population

They are a main cause of death with They are a main cause of death with functioning graft, and cause a number of functioning graft, and cause a number of other complications that increase morbidityother complications that increase morbidity

Molecular diagnostic techniques have Molecular diagnostic techniques have allowed earlier identification and better allowed earlier identification and better monitoring of infectionsmonitoring of infections

ConclusionsConclusions

Prophylactic strategies include vaccination and Prophylactic strategies include vaccination and targeted post-transplant chemoprophylaxistargeted post-transplant chemoprophylaxis

Use of drugs carries the risk of late and resistant Use of drugs carries the risk of late and resistant infectionsinfections

A high index of suspicion and early and A high index of suspicion and early and aggressive use of diagnostic techniques are aggressive use of diagnostic techniques are essential for accurate diagnosis and improved essential for accurate diagnosis and improved outcomesoutcomes