Download - INFECTIONS AFTER TRANSPLANTATION
INFECTIONS AFTER TRANSPLANTATION
Lora Thomas MD, MPH
September 28, 2012
Topics To Be Discussed
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 (%)
Type 1 year 3 year 1 year 3 yearRenal-LD 96 90 99 95Renal-Cad 91 80 96 89Pancreas 76 60 98 92Heart 88 81 88 82Liver 84 74 88 79Lung 82 64 83 66Heart-Lung 81 62 81 62
Data from SRTR 2009 Annual Report
Decreasing Infectious Mortality in Subsequent Cardiac Transplant Cohorts
1980-1990
PPID, chapter 304, 2000
Lack of Change in Infectious Mortalityafter Cardiac Transplantation: 1990-2000
Infection Related Mortality in Lung Transplant Recipients
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
1998 1999 2000 2001 2002 2003 2004 2005 2006
Other
Cancer
BO/Graft Dys
Infection
Proportion of All Deaths Related
to Cause
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 from infections “normal” people get
Time Scale of Infection after Transplantation
Types of Infections vary depending on time post-transplant:
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 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
Prions: Creutzfield-Jakob disease (cornea)
Gottesdiener, Ann Int Med 1989;110:1001; Dummer JS, PPID, 2004
Infectious Episodes Related to Total Time Spent in the Operating Room
Total operative time in hours
Immunosuppression and Infection- A Summary
No good marker is available for state of immunosuppression (unlike CD4 in HIV)
“Net state of immunosuppression” must be 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 drugs with different modes of action; some IV drugs are also used either for treatment of rejection or induction early post-transplant
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
Antithymocyte Globulin Rabbit Equine
Increased risk of CMV, PTLD
Anti-CD25 (IL-2 receptor) antibodies Basiliximab (Simulect®)
Infection risk not significantly increased
Anti-CD20 antibody
Rituximab (Rituxan®)HBV reactivation
Anti-CD52 antibody Alemtuzumab (Campath®)
Increased risk of CMV, Pneumocystis jirovecii pneumonia, invasive fungal infections, immunosuppression effects can last up to 12 months
Herpesvirus Infections after Transplantation
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
Epstein-Barr 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
infection in 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
antigenemia or quant. PCR Treatment: ganciclovir, foscarnet
Infection and Morbidity due to CMV in Different Transplant Groups*
Data collected in Pittsburgh before the use of antiviral medications
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Kidney Liver Heart Heart-lung
Asymptomatic infection Symptomatic infection Pneumonia
Manifestations of CMV Disease Following Cardiac Transplantation
Manifestation No. 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%
Data from Dummer, JID, 1985
Vogel et al.Br J Radiol 2006 (epub)
CMV Pneumonitis
Horger et al.AJR Am J Roentgenol 2006;187:W636
CMV Pneumonitis
Cytomegalovirus Pneumonitis: Pathology
Microabscess Caused by CMV in the Liver
CMV Colitis
jmedicalcasereports.com
CMV Retinitis - Early
Management of CMV Infection
Most patients receive preventive regimens, either post-transplant prophylaxis for 3 or more months or viral monitoring with preemptive therapy
Valganciclovir is the preferred prophylaxis 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 is simplicity. Some data supports better long term outcomes with prophylaxis
Costs of pre-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 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 highest in lung transplants and pediatric transplants (~4%)
As with CMV primary infection and level of 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 donorShe maintained excellent lung function post-transplant. 13 years later she presented with a month of headache, 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
Australas Radiol 2006;50:412
Lymphoproliferative Disease in the Abdomen related to EBV
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
Mucocutaneous Candida (Thrush and esophageal candidiasis) once common but are controlled by topical antifungals such as nystatin (“swish and swallow”)
Invasive Candida incidence varies with organ transplanted: 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. Risk factors high dose steroids, GVHD, renal dysfunction, prolonged neutropenia
Endemic fungal infections occur sporadically
Esophageal Candidiasis
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 pulmonary or no symptoms
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 InvasiveAspergillosis
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 Caused by Aspergillus in a Neutropenic Host
Hyphae of Aspergillus Invading Tissue
Vascular Invasion by Aspergillus
Pulmonary Nodule due to A. fumigatusin a Heart transplant Recipient
Aspergillus: Halo Sign
http://radiology.rsna.org
Cerebral Aspergillosis
Transplant Histoplasmosis
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 liver and spleen enlargement
Diagnosis by culture (slow), urine or blood antigen (few days) and in sickest pts by blood smear
H. Capsulatum
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
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 disseminated or extra-pulmonary; few patients have classic upper lobe cavitary changes
TB can be transmitted by donated organs but this accounts for <5% of all cases
Singh N, Patterson DL, CID, 1998;27:1266
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
BK Virus Nephropathy
Polyomavirus Infection of the Transplanted Kidney: “Decoy” Cells in the Urine
Risk Factors for Polyomavirus Nephropathy after Renal Transplantation
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
BK Virus Nephropathy: Graft Survival
Respiratory Syncytial Virus (RSV) RNA virus
Seasonal: Fall-early Spring
>90% have had primary infection 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
RSV Pneumonia
Respiratory Viral Infections
Influenza Parainfluenza Adenovirus Metapneumovirus Adenovirus Enterovirus Rhinovirus Coronavirus
Respiratory Viral Panels increasingly being used at centers
Nasopharyngeal swab, wash, BAL
Sensitivity 79% Specificity 99%
Lymphocytic Choriomeningitis Virus (LCMV) Transmission 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, abdominal pain, mental status changes
Most donors with no evidence of LCMV infection (one donor had exposure to pet hamster that tested 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 filter air and restrict visitors with colds
Enteric pathogens: avoid raw eggs, unpasteurized milk and juices, certain soft cheeses, water from streams or lakes
Varicella: if seronegative 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 starting 3 months after transplant if at baseline immunosuppression
Avoid live virus vaccines after transplant (minimum 4 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
American Journal of Transplantation 2011; 11: 2020–
2030
Questions
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