Topics To Be Discussed Infections after transplantation 衛福部疾病管制署中區傳染病防治醫療網王任賢指揮官 How are we doing in transplantation? Review basic precepts of transplant infections Discuss some classic transplant pathogens: CMV, EBV, fungal diseases, pneumocystis, TB Emerging transplant problems: polyomaviruses, RSV, respiratory viruses, arenaviruses Avoidance of infection Graft and Patient Survival After Transplantation by Organ Graft Survival (%) Patient Survival (%) Decreasing Infectious Mortality in Subsequent Cardiac Transplant Cohorts 1980 1990 1990 Type 1 year 3 year 1 year 3 year Renal LD 96 90 99 95 Renal Cad 91 80 96 89 Pancreas 76 60 98 92 Heart 88 81 88 82 Liver 84 74 88 79 Lung 82 64 83 66 Heart Lung 81 62 81 62 Data from SRTR 2009 Annual Report PPID, chapter 304, 2000 Lack of Change in Infectious Mortality after Cardiac Transplantation: 1990 2000 Infection Rl Related dmortality in Lung Transplant Recipients 100% 90% 80% Proportion of All Deaths Related to Cause 70% 60% 50% 40% 30% 20% 10% 0% 1998 1999 2000 2001 2002 2003 2004 2005 2006 Other Cancer BO/Graft Dys Infection VUMC Data
Basic Precepts of Transplant Infections Infections occur on a time scale Type and frequency of infection vary with transplant type: lung>liver>heart>kidney More surgery more infection More immunosuppression more infection Beware of donor as a source of infection especially early post transplant Transplantation does not protect frominfections normal people get Time Scale of Infection after Transplantation 0 30 days: mostly surgical infections, common bacteria, Candida, HSV 1 6 months: opportunistic pathogens, CMV, Pneumocystis, Nocardia, Aspergillus 6 months onward: common community infections, occasional opportunists, endemic fungi (histo, crypto) Frequency and Severity of Infections by Organ Type N Inf /Pt. CMV Bacteremia Fungal Inf. Death Renal 64 0.98 8% 5% 0% 0% Heart 119 1.36 16% 13% 8% 15% Liver 101 1.86 22% 16% 16% 23% H Lung 31 3.19 39% 19% 23% 45% Dummer JS, PPID, 2000, Churchill Livingstone, based on data from early 1980 s in Pittsburgh Partial List of Organisms Transmitted by Transplantation ti Infectious Episodes Related to Total Time Spent in the Operating Room Viruses: CMV and other herpesviruses, HIV, hepatitis A, B C & D, HTLV 1, WNV, Rabies, LCMV Fungi: Histoplasma, Coccidioides, Cryptococcus Protozoa: Toxoplasma, malaria, T. cruzii Bacteria: TB, nosocomial pneumonia agents (lung), urinary bacteria (kidney), bacteremic donor Pi Prions: Creutzfield Jakob Jkbdi disease (cornea) Gottesdiener, Ann Int Med 1989;110:1001; Dummer JS, PPID, 2004 Total operative time in hours
Immunosuppression and Infection A Summary No good marker is available for state tt of immunosuppression (unlike CD4 in HIV) Netstate of immunosuppression mustbeestimated estimated based on clinical status, doses or levels of drugs, and recent treatment of rejection Treatment of rejection increases clinical infection rates Patients are treated with a cocktail of oral drugswith different modes of action; some IV drugs are also used either for treatment of rejection or induction early posttransplant Dummer JS, PPID, 2000; Halloran PF NEJM 2004;351:2715 Immunosuppression and Infection Infections increase with increased intensity of immunosuppression Two major immunosuppressive drugs introduced since 1980, cyclosporine and tacrolimus, have similar infectious risk but are associated with less infection than the earlier regimen of azathioprine/steroids Two cell cycle inhibiting agents, azathioprine and mycophenylate mofetil, have similar infectious risk Risk of post transplant malignancy and CMV may be reduced with rapamycin Dummer JS, PPID, 2000 Antibody Therapy and Infection Herpesvirus Infections after Transplantation Antithymocyte Globulin Rabbit Equine Anti-CD25 (IL-2 receptor) antibodies Basiliximab (Simulect ) Anti-CD20 antibody Rituximab (Rituxan ) Anti-CD52 antibody Alemtuzumab (Campath ) Increased risk of CMV, PTLD Infection risk not significantly increased HBV reactivation Increased risk of CMV, Pneumocystis jirovecii pneumonia, invasive fungal infections, immunosuppression effects can last up to 12 months Up to 35% of patients develop oral or genital herpes simplex infection in the first 2 3 weeks after transplantation; rare invasive or primary infections may be fatal Herpes zoster or shingles occurs in up to 1/3 of transplant recipients. Chicken pox can be fatal EB virus is associated with lymphoma after transplantation. Risk is 0.3 4%, may be 10 times higher with primary infection Human herpes virus 8 associated with Kaposi s sarcoma after transplantation Cytomegalovirus has been the single most important pathogen in transplant recipients Labial Herpes Intraoral Herpes Simplex
Herpes Simplex Esophagitis Herpes Simplex: Donor Transmitted Disease Cytomegalovirus and Transplantation At one time CMV was the most important serious infection after transplantation Now largely controlled by antivirals Usually occurs 30 90 days after transplantation Manifestations: Fever most common, but sometimes invasive infectionin bowel, liver, lung or retina Risk factors for disease are primary infection (usually donor derived), level of immunosuppression, organ transplanted (lung) Diagnosis used to be by viral culture, now most often by blood antigenemiaor quant. PCR Treatment: ganciclovir, foscarnet Infection and Morbidity due to CMV in Different Transplant Groups * 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Kidney Liver Heart Heart-lung Asymptomatic infection Symptomatic infection Pneumonia Data collected in Pittsburgh before the use of antiviral medications Manifestations of CMV Disease Following Cardiac Transplantation Manifestation No.of of Patients % of Patients Fever > 38º 17 100% Atypical Lymphs > 3% 15 88% Interstitial Changes (CXR) 8 47% WBC <4,000 8 47% Platelets < 100,000 7 41% SGPT > 40 IU 7 41% Abdominal Pain 7 41% Myalgia 2 12% Arthralgia 2 12% Dt Data from Dummer, JID, 1985
CMV Pneumonitis CMV Pneumonitis Vogel et al.br J Radiol 2006 (epub) Horger et al.ajr Am J Roentgenol 2006;187:W636 Cytomegalovirus Pneumonitis: Pathology Microabscess Caused by CMV in the Liver CMV Colitis CMV Retinitis i i Early jmedicalcasereports.comcom
Management of CMV Infection Most patients receive preventive regimens, either post transplant prophylaxis for 3 or more monthsor or viral monitoring with preemptive therapy Valganciclovir is the preferred prophylaxis p in the USA; some oral ganciclovir is also used. High dose valacyclovir is also used but more outside than inside the USA Advantage of prophylaxis hl is simplicity. it Some data dt supports better long term outcomes with prophylaxis Costsof of pre emptive emptive therapy are potentially lower and late CMV disease is less likely with pre emptive therapy Treatment of CMV disease is usually with IV ganciclovir or oral valganciclovir Epstein Barr Virus (EBV) and Transplantation Epstein Barr virus can cause lympho proliferative p disease after transplantation Some cases are polyclonal proliferations that respond to reduction of immunosuppression; others are true lymphomas Risk varies by transplant group lowest in renal transplants (~0.3%) and highestinlung in transplants and pediatric transplants (~4%) As with ihcmv primary infection i and level lof immunosuppression are the main risks Transplant Lymphoma Case A 41 year old woman received a heart lung transplant for cystic fibrosis in 1993 in North Carolina. She was EBV seronegative at the time of transplantation. She converted to EBV after transplantation possible from the donor She maintained i excellent lung function posttransplant. 13 years later she presented with a month of headache, h low grade fevers and malaise. Exam showed only left sided ptosis. An MRI scan of the head showed numerous enhancing lesions in the brain. Initial MRI Scan of the Brain Lymphoproliferative Disease in the Abdomen related to EBV Australas Radiol 2006;50:412
Human Herpes Virus 8 and Kaposi s Sarcoma (KS) Most recently discovered Herpesvirus Endemic in Central Africa (50%); also somewhat in Near East and around Mediterranean (10%); rare in USA Strongly associated with KS in AIDS and transplantation May respond to reduction of immunosuppression Fungal Infection after Transplantation Esophageal lcandidiasis i Mucocutaneous Candida (Thrush and esophageal candidiasis) once common but are controlled by topical antifungalssuch as nystatin ( swish and swallow ) Invasive Candidaincidenceincidence varies with organtransplanted: bone marrow = liver>>lung=pancreas>heart=renal Cryptococcal infection occurs in 0.5 2.0 % of organ recipients usually at least 6 months out and often quite late; rare in bone marrow recipient Aspergillus: bone marrow>lung>liver>>heart=renal. li l Risk factors high dose steroids, GVHD, renal dysfunction, prolonged neutropenia Endemic fungal infections occur sporadically Candidiasis in Transplantation Cryptococcal Infection after Transplantation Commonly presents either with pulmonary or central nervous system disease Pulmonary: usually presents with lung nodule(s) on CXR with mild pulmonaryoror nosymptoms CNS disease presents as meningitis with gradual evolution of headache and neurological findings that are often subtle Occasionally associated skin lesions Diagnosis with invasive procedures (bronchoscopy, lumbar puncture and cryptococcal antigen) Disease can usually be controlled but some patients stay on antifungals for prolonged durations, even lifelong
Pulmonary Cryptococcosis Budding Cryptococcus neoformans Strongly Positive India Ink Smear Large Ulcer on Arm Caused by Cryptococcus Skin Lesions Due to Cryptococcus Mortality of Invasive Aspergillosis i Organ Transplanted % Incidence % Mortality (3 month) Allo HSCT 12.8% 71% Auto HSCT 1.1% 42% Lung 2% 22% Liver 1.9% 45% Heart 1.3% <10% Kidney 0.4% 25% Trans Infect Dis 2010
Pulmonary Infiltrates t Caused dby Aspergillus in a Neutropenic Host Hyphae of Aspergillus Invading Tissue Vascular Invasion by Aspergillus P l N d l d t A f i t Pulmonary Nodule due to A. fumigatus in a Heart transplant Recipient Aspergillus: Halo Sign Cerebral Aspergillosis http://radiology.rsna.org
Transplant Histoplasmosis H. Capsulatum Soil fungus seen mostly in south central USA. Occurs in about 0.5 1% in endemic areas Transplant patients often have multisystem disease with fever, pneumonia, lymph node enlargement, low blood counts and liverand spleen enlargement Diagnosis by culture (slow), urine or blood antigen (few days) and in sickest pts by blood smear Histoplasmosis: Miliary Pattern Millet Seeds Pneumocystis Infection and Transplantation Pneumocystis pneumonia once occurred in 5 10% of transplant patients, now controlled with prophylaxis Typically presented with fever, hypoxemia and diffuse pneumonia 2 6 months after transplantation t ti Diagnosis usually required bronchoscopy with lavage of lung alveoli Treatment with sulfa trimethoprim or pentamadine was usually successful in clearing the organism but some patients died during period of hypoxemia Two to three sulfa tablets a week prevent it Radiographic Picture of Pneumocystis Pneumonia Cysts of Pneumocystis in a Lung Biopsy
Tuberculosis after Transplantation Uncommon (< 1%) in developed world compared to developing world (2 10%) 2/3 of cases occur in first year; most thought to be due to reactivation but only 20% in pts with +PPD ½ of cases disseminatedor extra pulmonary; few patients have classic upper lobe cavitary changes TB can be transmitted dby donated dorgans but tthis accounts for <5% of all cases Polyomaviruses and Transplantation Two related small DNA viruses (JC & BK); serology shows 60 80% of humans infected in childhood JC causes progressive multifocal leukoencephalopathy (PML) in immunosuppressed patients Polyomaviruses (esp. BK but also JC) found by culture in urine of 10 45% of renal and bone marrow transplant patients; occasionally in normal hosts In 1980 s polyomaviruses shown to cause ureteral stenosis (renal TX) and hemorrhagic cystitis (BM Tx) In recent years polyomavirus (mostly BK) shown to cause severe nephropathy in 2 4% of renal recipients Singh N, Patterson DL, CID, 1998;27:1266 BK Virus Nephropathy Polyomavirus Infection of the Transplanted Kidney: Decoy Cells in the Urine Risk Factors for Polyomavirus Nephropathy after Renal Transplantation BK Virus Nephropathy: Graft Survival Generally strongest risk factor is detection of virus; in one study just finding BKV in urine had an odds ratio of 68 for nephropathy Demographic risk factors are older age, male gender and caucasian ethnicity Polyomavirus nephropathy is associated with level of immunosuppression, but findings are variable. Ramos et al. J Am Soc Nephrol 2002;13:2145 51
Respiratory Syncytial y Virus (RSV) RSV Pneumonia RNA virus Seasonal: Fall early Spring >90% have hd had primary infection i by age 2 Reinfection common throughout life More severe disease seen in stem cell and lung transplant recipients Rhinorrhea, sinus congestion, sore throat usually precede pneumonia Respiratory Viral Infections Influenza Respiratory Viral Panels Parainfluenza increasingly being used at Adenovirus centers Metapneumovirus Nasopharyngeal swab, wash, BAL Adenovirus Sensitivity 79% Enterovirus Specificity i 99% Rhinovirus Coronavirus Lymphocytic Choriomeningitis Virus (LCMV) Transmission i by Organ Donation Multiple cases reported of LCMV transmission through organ transplantation Fevers in recipients began between 3 and 22 days after transplantation: other symptoms included peri incisional rash, headache, h abdominal pain, mental tlstatus tt changes Most donors with no evidence of LCMV infection (one donor had exposure to pet hamster thattestedtested positive) Only one known survivor had reduction in immunosuppression and ribaviron treatment NEJM 2006;354:2235 LCMV In Transplant Patients Kidney Skin NEJM 2006;354:2235 Prevention of Exposure to Infection Hospital exposures: usually just standard infection control. Bone marrow units may HEPA filterair and restrict visitors with colds Enteric pathogens: avoid raw eggs, unpasteurized milk and juices, certain soft cheeses, water from streams or lakes Varicella: ifseronegativeavoid avoid contact with chickenpox or shingles Zoonoses: avoid cat litter, bird cages, avoid jobs with frequent animal contact
Prevention of Exposure to Infection Respiratory viruses: avoid persons with colds, public places during flu outbreaks, vaccinate family members Prevention of Exposure to Infection Continued Airborne molds: avoid barns, silos, chicken coops etc. STD s: Practice safer sex Exotic infections: Before international travel outside Canada or W. Europe, confer with infectious disease expert Vaccination after Transplantation No clear evidence connecting vaccination to rejection episodes Inactivated vaccines safe to use starting3 monthsafter transplant if at baseline immunosuppression Avoid live virus vaccines after transplant (minimum4 weeks from live vaccine to transplantation) Influenza: inactivated seasonal vaccine recommended, insufficient data to support use of high dose influenza vaccine, adjuvant, or booster dose 多謝聆聽 American Journal of Transplantation 2011; 11: 2020 2030