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%

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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%

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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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