Jefferson Jones, MD MPH Medical Officer

1. Notification of Donor-Derived Tuberculosis — CDC’s Office of Blood, Organ, and Other Tissue Safety Jefferson Jones, MD MPH Medical Officer California TB Controller Association Conference March 12, 2019

2. Outline • Organ transplantation in the United States • Regulation of organ transplantation • Reporting organ donor-derived disease • CDC’s Office of Blood, Organ, and Other Tissue Safety (BOOTS) • Reporting organ donor-derived tuberculosis • Interaction of BOOTS and partner organizations • Case studies

3. Organ supply in United States • Number of deceased donors and transplants increasing • Waiting list also increasing • >124,000 on waiting list • ~Additional 1 person per 10 minutes • 5,661 on waiting list died during 2018 • 20 deaths per day https://optn.transplant.hrsa.gov/data/view-data-reports/

4. Balancing Resources —Differences between blood and organs SAFETY AVAILABILITY For blood, the emphasis is on safety, and availability is less of a concern. For organs, the emphasis is on availability, and safety is less of a concern.

5. National Organ Transplant Act • Passed in 1984 • Established Organ Procurement and Transplantation Network (OPTN) • Directs organ allocation • Links all organizations involved in donation and transplantation • Establishes transplant policies • Contracted by HRSA to United Network for Organ Sharing (UNOS) • Established Organ Procurement Organizations • Evaluate donor and recovers organs • Coordinate matching organs to recipient

6. Regulation of organ transplantation • Health Resources and Services Administration (HRSA) regulates solid organ transplantation • OPTN forms policy and collects data • Food and Drug Administration regulates human cells, tissues, and cellular and tissue-based products (e.g., skin, muscle, bone, valves, corneas) • Regulate infectious disease testing • Hospital regulators (CMS, CMS-approved organization)

7. Ad Hoc Disease Transmission Advisory Committee (DTAC) • Part of OPTN patient safety program • Examine and classify potential donor-derived transmission of infection or malignancy • Educate transplant community • Help change policy and improve processes • Membership includes CDC, HRSA, transplant centers, transplant infectious disease, laboratory experts, organ procurement organizations

8. Role of CDC • CDC not regulatory agency • Through HRSA agreement member of DTAC, investigates potential infectious disease transmissions • Nationally notifiable diseases in donor or recipient • Multiple ill recipients • Encephalitis in donor or recipient(s) • Unknown syndrome • Goal is it determine whether infection was transmitted from donor to recipient(s) • ~ 50 case investigations annually are referred to CDC

9. Reporting to DTAC • OPTN policy that all suspected donor-derived disease should be reported • Passive reporting by transplant centers and OPO’s to OPTN/UNOS (referred to DTAC for review) • No standardized criteria for what specific data to report • Any infectious disease or malignancy suspected to be transmitted to an organ recipient from the organ donor (at discretion of clinical team or OPO) • Trigger to report can include recipient illness or in some cases, suspected donor disease (at time of organ recovery or retrospectively)

10. Pathogens of special interest- reportable for suspected or confirmed donor or recipient illness • Acute Flaccid Myelitis • Amebic encephalitis • Anaplasma or Ehrlichiosis • Anthrax • Arboviral Infections • Babesiosis / Babesia microti • Brucellosis / Brucellaspecies • California Serogroup Virus Diseases • Chagas / Trypanosoma cruzi (T. cruzi) • Chikungunya Virus Disease • Coccidioidomycosis (Coccidioides species) /Valley Fever • Enterovirus D68, A71 • Fungi/Mold (if growing from sterile site o e.g. blood culture excluding Candida species) • Hantavirus • Hepatitis A • Hepatitis B (active only) * • Hepatitis C (acute, past or present)2 • Histoplasmosis • HIV Infection • Influenza-associated pediatric mortality • Lymphocytic choriomeningitis virus (LCMV) • Leptospirosis / Leptospira Fever, Crimean-Congo Hemorrhagic Fever • Listeriosis / Listeria monocytogenes • Lyme disease / Borrelia species • Malaria / Plasmodiumspecies • Measles / Rubeola • Microsporidia • Middle East Respiratory Virus(MERS) • Mumps • New WorldArenavirus • Pandemic Influenzastrains • Plague / Yersinia pestis • Poliomyelitis, paralytic • Poliovirus infection,nonparalytic • Q fever / Coxiellaburnetii • Rabies, animal or human • Rubella / German Measles • Severe Acute Respiratory Syndrome (SARS)- Associated Coronavirus Disease • Smallpox/Variola • Spotted Fever Rickettsiosis • Strongyloides • Tuberculosis (TB) o e.g. Identified through a culture or DNA probe in the organ donor or other evidence suggesting by active TB • Tularemia / Francisellatularensis • Varicella / Chickenpox • Viral Hemorrhagic Fevers • West Nile Virus Disease • Zika virus

11. Determining donor-derived disease • Levels include proven, probable, possible, unlikely, and excluded • Depends on presence of disease in single or multiple recipient(s), pretransplant studies, and molecular testing • Proven: Same disease in donor and recipient and either • Proof of identical disease (e.g., molecular testing) OR • Evidence of negative disease pretransplant and in multiple recipients • OPTN/UNOS Disease Transmission Advisory Committee

12. Disease reporting by transplant centers and OPOs • Variable by center • Bronchoscopy, blood, urine culture reported • Certain organisms frequent, treated by standard antimicrobial prophylaxis, and no associated with significant morbidity/mortality • Donor infection might be unrecognized • Some diseases are rare and infrequently encountered • Some donors have no evidence of infectious cause of death • Difficulty in linking donor and recipient infections • Suspecting donor-derived disease responsibility of transplant centers/OPO • Some infections difficult to recognize and diagnose in recipient • Geographic distance • Timeliness of information

13. Variability of Reporting Suspected Donor-derived Diseases by Organ Procurement Organizations OPTN/UNOS DTAC-Cases reported through 2013.

14. DTAC reports 2008–2012 PDDTE: Potential donor-disease transmission events

15. Suspected Donor-derived disease reports to the DTAC: 2005-2011 DTAC: Disease Transmission Advisory Committee DDD: Donor-derived disease Data includes cases classified as possible, probable or proven from 2005-2007 as published in AJT, and all reviewed cases from 2008-2011. *Including TB, non-TB mycobacteria

16. Reporting donor-derived TB to DTAC • Laboratory performs TB test and result is positive • Laboratory or transplant center reports result to local health department • If transplant center suspects donor-derived disease, it reports to OPTN • OPTN refers to DTAC • If CDC Office of Blood Organ and Other Tissue (BOOTS) accepts, it coordinates investigation

17. CDC BOOTS TB investigation partners • Public health jurisdictions for donor and each recipient • State epidemiologist • State TB controller • Organ Procurement Organization • Transplant Centers • CDC Division of TB Elimination • CDC Infectious Disease Pathology Branch

18. CDC BOOTS TB Investigation Points of Contact • Public health agencies for donor and each recipient • Organ Procurement Organization (Donor information) • Clinical history • Next-of-kin interview • Laboratory testing • Transplant Centers • CDC Division of TB Elimination • CDC Infectious Disease Pathology Branch • Autopsy results • Tissue specimens • Donor medical records

19. CDC BOOTS TB Investigation Points of Contact • Public health agencies for donor and each recipient • Organ Procurement Organization • Transplant Centers (recipient information) • Clinical history, symptoms, laboratory results, imaging • Confirm public health informed • CDC Division of TB Elimination • CDC Infectious Disease Pathology Branch • Recipient medical records • Tissues for testing

20. CDC BOOTS TB Investigation Points of Contact • Public health agencies for donor and each recipient • To determine if recipient disease is donor-derived • Risk factors for TB • Case provided by health department • Organ Procurement Organization • Transplant Centers • CDC Division of TB Elimination • CDC Infectious Disease Pathology Branch • If isolate available, confirm isolate sent for genotyping

21. CDC BOOTS TB Investigation Points of Contact • Public health agencies for donor and each recipient • Organ Procurement Organization • Transplant Centers • CDC Division of TB Elimination • Provide genotyping results and interpretation • Liaison to state/local health departments • CDC Infectious Disease Pathology Branch

22. CDC BOOTS TB Investigation Points of Contact • Public health agencies for donor and each recipient • Organ Procurement Organization • Transplant Centers • CDC Division of TB Elimination • CDC Infectious Disease Pathology Branch • Testing of available donor and recipient tissues

23. Case study • Lung recipient with positive MTB PCR of BAL. Liver and kidney recipient hospitalized for fever of unknown origin. • Confirm liver and kidney (and other organs) recipient transplant teams aware of possible exposure. • Recipients have symptoms or TB? TB risk factors? • Donor have symptoms or TB? TB risk factors? • Genotype of isolates match? Genotype specific to geographic location or population? • Any donor tissue available for testing?

24. Case study • Lung recipient has positive MTB PCR of BAL. No other recipients with positive tests or symptoms. • How many months after transplant? • Lung recipient have symptoms or TB? TB risk factors? • Lung donor have symptoms or TB? TB risk factors? • Genotype of lung recipient specific to geographic location? • Any donor tissue available for testing?