Transplant Expert by Amy L. Friedman, M.D.

HAPPILY EVER AFTER FOR THE PRINCE WITH A KIDNEY TRANSPLANT

A fascinating story has just been brought to light by the local Swedish business newspaper, Dagens industri. The Swedish royal family includes an organ transplant recipient! Prince Daniel, the husband of Crown Princess Victoria, acknowledged undergoing a live donor kidney transplant in 2009 as treatment for congenital kidney disease just three months following his engagement to the Princess. His father was his donor. While other medical details were not shared, his photo suggests that he is doing quite well. And he has met the basic American measures of successful transplantation by surviving more than three years with the transplant. It appears that he is now six years out from the transplant and presumably still counting. And happily living the life of a royal.

The matter-of-fact way the issue seems to have been approached by the royal family into which he married, and by the Swedish population who appears to adore the now married couple, is extraordinary. This is hardly the first time that transplantation has touched the life of a person in the public eye. It is also not an unusual illustration of the magnificent way transplantation permits rehabilitation to a full level of function, whether royal (Prince Daniel), presidential (Ferdinand Marcos), athletic (Alonzo Mourning), musical (Charity Sunshine Tillemann-Dick), thespian (Larry Hagman), retired (Dick Cheney), or more ordinary (half a million transplants). Indeed, it is just another example of the full potential that awaits those in need of organ transplants. Meaningful, high quality life is widely achievable.

While some might be inclined to conclude that the transplant was performed simply because Daniel was soon to be a Prince, the more appropriate observation is that his own parent was the organ’s source. No other connection than family was required. And such a source is just as likely to be available to any of us, as to a Prince-to-be.

For the transplant to continue functioning as well as it appears to be, the Prince must be taking immunosuppressive medications to prevent rejection of that kidney. Years ago, there were few choices about which medications to use. Often, undesirable cosmetic consequences of those medications such as a very rounded face or exuberant facial hair growth were readily apparent. Today, however, such a broad choice of drugs is available that those undesirable outcomes are quite rare. They do not appear to be complicating Prince Daniel’s life.

The take home message from this “ordinary” royal news is that transplantation has evolved into a standard therapy with excellent results that is widely available in developed countries served by mature medical and social infrastructures. The limitations to even broader access include the woefully inadequate availability of organs (overcome through live kidney donation in Prince Daniel’s case) and the relatively high costs of surgery (in the first year) and maintenance medications (lifelong).

Half A Million – What An Accomplishment!

Survey

More than 500,000 organ transplants have been performed in the United States since October 1987, according to the United Network for Organ Sharing (UNOS) website on May 19, 2015. To put this bland statistic into perspective, there are only 34 cities in the U.S. with larger populations! And 5 entire states have no cities with even 20% (100,000) of this number of people. A mind numbing number of people who have, thus far, benefited from transplantation. But, so many more might have been saved if there had been more organs.

Transplant technologies have become such a significant component of the standard of care in medicine that the general public may no longer be amazed by transplantation, instead, simply taking it for granted. And, perhaps a sense of entitlement to having a transplant also contributes to the generally lackadaisical attitude many seem to have. Such a lack of awe is dangerous for multiple reasons. To begin, transplantation remains technically, medically and emotionally challenging. Even under the best circumstances, problems can pop up. For example, every transplant is performed under general anesthesia, an approach which has small but significant risk. And the patients undergoing transplantation are older and sicker than ever before. Why? Because medical care has become so good, because so many effective anti-rejection medications are available, and because people are living longer than ever before. All of these factors contribute to a surging group of transplant candidates who might benefit from kidney, liver, heart, lung, pancreas, intestine transplants. The U.S. list has topped 123,000 people who are currently waiting. At the current rate, 18 are dying every day. If we only had enough organs to be able to perform these transplants!

These huge numbers should help everyone to understand how important donation is.  These procedures have become so commonly needed, that at least 1/3 of people in the U.S. have a personal connection to someone who has undergone, has died waiting for, or is in need of a transplant. Beyond the ties to transplant recipients that so many of us have, it is well known that the majority of Americans are in favor of organ donation. In a 2012 government survey, 95% were strongly in support, or in support (see below)! Now it is time to make the connection between thought and action.

 

A WHOLE LOTTA HOPE

After an organized, well fought, and fully bi-partisan effort, the HOPE (HIV Organ Policy Equity) Act became U.S. law, signed by President Obama on November 21, 2013. This new legislation removes the previously existing legal barrier to all research on the transplantation of HIV-positive organs in humans.  Present at the legislative signing were the President-elect of the American Society of Transplant Surgeons, Dr. Peter Stock and the President of the American Society of Transplantation, Dr. Dan Salomon. As previously noted HIV-positive transplant candidates had been legally prohibited from receiving HIV-positive organs by the Organ Transplant Amendments Act of 1988, even though cautious exploration of this strategy (a logical potential step in expansion of the too small pool of donor organs) was widely supported.The logic thread is based on successful transplant outcomes with Hepatitis C. With this infectious disease, organs from infected (or potentially infected) donors are transplanted into recipients known to already be infected with the same virus. This clever strategy, while avoiding the transmission of a new disease (since the recipients are already infected with it) and thereby causing a brand new problem at the time of transplantation, is actually a means of successfully expanding the too small pool of deceased donor organs. Of course, the recipients must be informed about the donor’s infection and asked for consent in advance – many (but not all) do agree to proceed. Long term results of liver and kidney transplants for previously infected recipients have been equivalent for those receiving either Hepatitis C -ve or +ve organs. And, future results in both circumstances may prove even better with the advent of new, highly effective anti-viral Hepatitis C drugs. So, instead of completely wasting the organs from a Hepatitis C +ve donor, they are ADDED to those effectively transplanted – saving lives.

Now, it will be possible to explore the possibility of transplanting HIV +ve organs into HIV +ve recipients. In fact, we have long had better anti-retroviral therapies (to treat HIV) than anything available for Hepatitis C. Yet the 1988 law had halted all potential progress. But not now! So, let’s move forward…….consider further broadening the breadth of donors (maybe even living donors who are HIV +ve?) and helping a specific subset of transplant candidates. This was/is a win-win for all.

WHAT EVER HAPPENED TO DICK CHENEY?

Time can fly, especially for transplant recipients. Remember the buzz and controversy surrounding former Vice President Richard Cheney’s heart transplant on March 24, 2012 at the age of 71? That news story essentially quieted down after a few weeks. No-one at the national level seemed to notice when the major transplant landmarks of one year graft and patient survival were happily met 4 months ago. And there has been no celebration of his high level return to political life that has occurred insidiously, with interviews and occasional speechs (Dick Cheney full return to active politics 6/16/13 ) popping up. There has been no attribution of his active lifestyle to either the deceased donor’s gift, or to the hard work of the transplant team, in part or in whole. What has happened is quite simple. He has re-engaged in his life. Transplantation, the donor’s heart, the amazing anti-rejection medications (which the Vice President must be taking reliably) are combining to restore a man’s ability to live his life. Whether his politics match yours or not, he is living up to his own previous standards of outspoken opinions on hot, important topics. This is the magic of transplant. If the VP is lucky (and adheres to medical advice and medications, etc) we won’t have particular reason to notice his next benchmarks at 3 years either!

In follow-up of a different transplant, Grzegorz is not a name that will ring bells for most of us. But you will surely recognize the images taken shortly after he received Poland’s first face transplant on May 15, 2013. You will also recall the horrific story of a stone cutting machine causing the trauma that induced his emergent need for that transplant. The terrific follow-up news came today that he has gone home, breathing and eating on his own a mere 11 weeks after the transplant. The report is that he is also speaking, although the words are still a bit difficult to understand. His speech is expected to improve as the nerves regenerate to the muscles in the transplanted face. The process is likely already underway as he is experiencing pins and needles in his cheeks. Although standardized goals and benchmarks have not yet been fully established for face transplants, 1 and 3 year patient and graft survival are likely to be selected. We will surely breathe a collective sigh of relief when Grzegorz meets the first of these, won’t we?

The final follow-up to be reviewed in this posting is not a happy one, but pertains to a story that is likely also familiar to you, the live donor kidney that was inadvertently discarded and wasted in a tragic human error in 2012. Both the live donor and recipient are reportedly well. A transplant did subsequently occur with a different kidney, but the family has now sued the original transplant hospital.

Life goes on. When donation and transplantation are the causes of life going on for recipients we should be especially grateful. Not necessarily mentioning it at every moment of every day……..but at least acknowledging from time to time that life can never be taken for granted. And when someone gives so that one or more recipients may benefit, a beautiful thing has taken place.

EVEN MORE HOPE !

An earlier post on June 19, 2013 delved deeply into the rationale behind the HOPE Legislation currently in the U.S. Congress to permit cautious exploration of the use of HIV +ve donor organs for transplantation into HIV +ve recipients, along with appropriate observational research. At that time the Senate had unanimously passed the bill but the House of Representatives was just beginning to take action.Now there is good news that on 7/17/13 the Energy and Commerce Committee of the House of Representative also voted unanimously to pass H.R. 698. Additional co-sponsors have also signed on to Representative Lois Capps’ bill – now at a total of 51 (12% of the 435 Representatives). Now we await action from the entire House of Representatives.

This legislation is an important bipartisan effort, supported by multiple medical, patient and social organizations because it represents a potential win-win for everyone. Expansion of the organ donor pool, carefully supervised clinical research with informed consent of the participating subjects, oversight by the government, support of the major transplant organizations, potential reduction of transplant candidate deaths, etc.

Keep tuned to this blog for updates as additional steps happen. It is beginning to look like this legislative action may become real in the not too distant future.

TRANSPLANT JARGON EXPLAINED

    A GLOSSARY OF TRANSPLANT TERMINOLOGY

    • allocation – algorithm for distribution of a deceased donor organ
    • allograft – a donor organ from a non-identical member of the same species (e.g., parent to child)
    • autograft – a donor organ from a genetically identical member of the same species (e.g., between clones or identical twins)
    • cold ischemia – time between cessation of blood flow to the donor organ and restoration of blood flow during transplantation
    • en bloc – organs that remain anatomically connected (e.g., 2 pediatric kidneys still attached to the aorta and vena cava)
    • DCD – Donor after Circulatory Death is a deceased organ donor whose death was declared based on cessation of cardiac activity
    • deceased donor – a human being whose organs have been removed after death for the purpose of transplantation
    • delayed graft function (DGF) – a newly transplanted organ that is alive (receiving blood flow) but has not yet begun to function (e.g., a transplanted kidney that is not yet making urine)
    • donor service area (DSA) – the geographic region that is the smallest unit of organ allocation and is served by one OPO
    • EPTS (estimated post transplant survival) – a formula based on four medical factors about the transplant candidate (age, time on dialysis, presence of diabetes, history of a prior transplant) that determines the statistical likelihood of survival of a patient in comparison to other patients 
    • expanded criteria donor (ECD) – a deceased organ donor who meets the UNOS definition of a less than optimal donor because of age, cause of death or medical history. In general, these organs are more vulnerable to all types of transplant related injury than standard criteria organs.
    • graft – organ +/- tissue that is transplanted
    • KDPI – kidney donor profile index is a numerical measure that combines ten dimensions of information about a donor, including clinical information and demographics, to express the quality of the donor kidney relative to other donors.(optn KDPI source info). Ranging from 1-100%, a value of 75% means that this kidney has a relative risk of failing that is higher than 75% of deceased donor kidneys.
    • immunosuppression – pharmacologic or biologic therapy administered to diminish the strength of the response of the immune system
    • import – an organ that has been recovered in a different UNOS region or DSA and transported in to the transplant center and patient. Importanting an organ prolongs the cold ischemia period.
    • LYFT (life years from transplant) – the statistical quality adjusted survival benefit provided by the transplantation of a given organ to a given recipient
    • multi-visceral – a transplant in which more than one abdominal organ is transplanted, usually involving the liver +/- pancreas, duodenum, stomach, small intestine
    • NOTA (National Organ Transplant Act) – federal legislation, P.L. 98-507,  enacted in 1984 to address the organ donation shortage and to improve organ matching and placement. The act and its amendments establish the national registry for organ matching and call for a transplant network to be operated by a non-profit organization under federal contract.
    • opo (organ procurement organization) – a private, non-profit organization responsible for increasing donor registration in the assigned donor service area and for coordinating the donation process in the service area hospitals.
    • OPTN (organ procurement and transplantation network) – established by the U.S. congress when it enacted the National Organ Transplant Act (NOTA), this is a unified transplant network to be operated by a private, non-profit organization under federal contract.
    • rejection – recognition and attack of the transplanted organ and tissue by the host’s immune system
    • standard criteria donor (SCD) – a deceased organ donor who does not meet the UNOS definition of an expanded criteria donor. In general, these organs are most likely to function promptly after transplantation, and most likely to continue functioning for may years.
    • SRTR  (Scientific Registry of Transplant Recipients) – the primary source of transplant data in the U.S., containing information from 1988 and later. These data are developed from mandatory transplant center reports and are used by multiple regulatory agencies and researchers.
    • tolerance – a host’s immune system’s failure to recognize and respond to a specific donor’s organ (or other stimulus) while retaining all other functions
    • Thrombosis – the condition of blood clot blocking flow through a blood vessel
    • UNOS (United Network for Organ Sharing) – the private, non-profit organization that manages the nation’s organ transplant system under contract with the federal government.
    • VCA (vascularized composite allograft) -multiple tissues such as muscle, bone, nerve and skin that are transplanted as a functional unit and require the surgical attachment of blood vessels (e.g., a hand or face).
    • xenograft – a donor organ from a member of a different species (e.g., pig to human)

    If you don’t see the term you were seeking, please ask for an explanation by submitting a COMMENT.

      AMERICAN LEGISLATORS SLOWLY JOINING THE IMMUNOSUPPRESSIVE DRUG COVERAGE EFFORT

      U.S. congressional efforts are slowly in process, seeking to close the ridiculous catch-22 that ensnares kidney transplant recipients 36 months after transplantation. This bureaucratic trap halts Medicare coverage of their expensive immunosuppressive medications but resumes payment for dialysis when the resulting rejection causes the kidney to fail. In two prior postings on this blog; March 7, 2013 and  May 27, 2013 status reports on the Senate and House versions of the Comprehensive Immunosuppressive Drug Coverage for Kidney Transplant Patients Act of 2013 were provided.

      Today’s report is that additional co-sponsors have “signed on” to each bill. The Senate bill, initially introduced by Senator Durbin from Illinois, now has 11 co-sponsors. This means that 12/100 Senators, or 12% have committed to supporting the bill. Another 88 to go! Are your Senators on board? Use this Senate link to check whether both of your Senators have “signed on”. If they have not, please give them a phone call……or send them an e-mail. Ask them to sign on to S.323 (the formal # for this bill in the Senate).

      The current status in the House of Representatives is that 67 members have “signed on” to co-sponsor Representative Michael Burgess’ original bill. This makes a total of 68/435, or 16% who have committed to supporting the bill.   Use this House link to determine whether your Representative is on the list and, if not, contact him/her. Ask for support of H.R. 1428.

      Together we can make a difference. Legislators DO respond to their constituents. If we make it very clear that this Catch-22 is unacceptable, that we insist on change, and that we hold our own politicians accountable, we can be the agents of change. Take a few moments to take the simple steps outlined above. And, pass the link for this blog to someone else who will help make the change. We do have this power. You have this power. Please use it.

      FACE + HAND TRANSPLANTS : NEW NAME, NEW REGULATORY NICHE

      Clinical transplantation has moved forward in leaps and bounds, surpassing the speed of the U.S.  government in addressing regulatory standards for new transplant types. This is neither an irrelevant nor a minor issue and has just been definitively addressed by the Final Rule published in the July 3, 2013 Federal Register. The National Organ Transplant Act (NOTA) originally enacted in 1984 had defined a specific list of transplant organs based on all of the transplant types that were performed in that era. The Organ Procurement and Transplantation Network (OPTN) and United Network for Organ Sharing (UNOS) oversee and regulate those types of organ transplantation with a fully developed set of bylaws for member institutions and policies that determine how transplants are undertaken. These transplants currently include:

      ORGAN TRANSPLANTS
      Kidney
      Liver
      Heart
      Lung
      Pancreas
      Intestine (any part of the intestinal tract)

      In contrast, human cells or tissue for transplantation are under the regulatory jurisdiction of the Food and Drug Administration (FDA) under Section 361 of the Public Health Service Act and 21 CFR parts 1270 and 1271.  Examples (not inclusive) of Cell and Tissue “Implants/Transplants” include:

      CELL + TISSUE “IMPLANTS/TRANSPLANTS” 
      Bone
      Skin
      Cornea
      Ligaments
      Stem cells
      Peripheral blood
      Cord blood
      Oocytes
      Semen

      Face, hand, larynx, and abdominal wall transplants are all examples of transplants that did not clearly fit into either of the two pre-existing categories. Agreeing with advocates within the transplant community, the Secretary of Health and Human Services issued this Final Rule that has formally created a new category of Vascularized Composite Allografts (VCA), (allograft = transplant between non-identical members of the same species) that is defined based on functions below (ischemia is a period of interrupted blood, see below):

      VASCULARIZED COMPOSITE ALLOGRAFTS 

      1. Vascularized – requires blood flow by surgical connection
      2. Contains multiple tissue types
      3. Recovered from a human donor as an anatomical/structural unit
      4. Transplanted into a human recipient as an anatomical/structural unit
      5. Minimally manipulated or processed (but may be cut or shaped)
      6. For homologous use (i.e., to be used for the same purpose in the recipient as it was in the donor)
      7. Subject to ischemia and therefore stored only temporarily
      8. Subject to allograft rejection and generally requiring immunosuppression

      The Final Rule also clearly stipulates that VCA transplants fall under the jurisdiction of the OPTN/UNOS, not the FDA. Major implications of this definition are that VCA transplants may only be performed at OPTN member institutions in good standing. New policies specifically applicable to VCA transplants clearly need to be developed by the OPTN/UNOS.

      Because of the unique issues pertaining to donor consent for these specific transplant types, wherein donor identification may be retained (e.g., fingerprints and facial identifiers), the Final Rule implies that donor specific consent should be undertaken on a case-by-case basis. This is the current ad hoc practice. But new issues of allocation will arise if the number of transplants begins to grow substantially. For example, there is no other transplant type in which skin color may be relevant!

      Overall, a new field of medicine is currently developing at a very rapid pace. This one step is an important one. It will be challenging and exciting as others are made. Stay tuned.

      KIDNEY TRIAGE BECOMING MORE SEVERE

      Acknowledging reality, the Board of Directors of the United Network for Organ Sharing (UNOS)  accepted recommended changes to the allocation policy for deceased donor kidneys throughout the U.S. at its meeting on June 24-25, 2013. This policy determines how a specific kidney is offered to a specific waiting patient by defining how the UNOS computer generates the specific list in response to availability of a donor.  In the context of the extraordinary discrepancy between people waiting and the number of organs available, several fundamental problems are intended to be improved with the amended policy (see below).

      A key change involves implementation of the Kidney Donor Profile Index (KDPI) as a measure of the risk of kidney failure after transplantation, with 100% being the worst and 1% the best possible values. An organ with a KDPI of 20% is more likely to function than 80% of transplanted kidneys – pretty darned good. Since one would not like to transplant an organ that is likely to fail, the KDPI is used as a direct measure of donor kidney quality.

      Waiting candidates are stratified into 4 groups based on the KDPI and a second formula, the estimated post-transplant survival (EPTS).  This not-so-subtle means of including the candidate’s statistical life expectancy following transplantation is a major step in the allocation scheme, taken in order to maximize the number of life years for the kidney following transplantation (LYFT).  It is based on the candidate age, length of time on dialysis, prior transplantation and presence of diabetes. However, the new policy amendment will incorporate the EPTS to advantage just those 20% of candidates with the best likely survival.

      Now, combining the KDPI and EPTS will lead to the 20% of best KDPI organs being matched to pediatric patients and adult patients with the best EPTS. Pediatric patients are still given an advantage for organs with a KDPI up to 35%. Between KDPI of 35-85% adult recipients are addressed by the standard allocation factors already in effect. Above 85% broad sharing (beyond local areas) will be undertaken promptly in order to avoid discarding potentially transplantable organs.

      These changes have been neither reactive nor rapid, but have followed years of debate and formal procedure that included opportunities for input from all stakeholders. Nonetheless, the starkness of  including some healthier candidates while excluding sicker ones from access to the best kidneys, is not lost on anyone involved. This “cherry-picking” of transplant candidates is a deeply distasteful but necessary response to the lack of sufficient resources. Please take a moment to register your opinion about these changes by answering the poll at the bottom right of this webpage – thanks.

      NO GUARANTEE WITH THIS ORGAN

      Any donated human organ or tissue may harbor an unwanted, undiscovered or unrecognized infection, malignancy or other disease. With the transplant, irregardless of the best intentions and most up to date testing, that disease is donated too and may cause serious illness(even death) in a recipient. To minimize this risk, to allow assessment of the risk, and to facilitate informed judgement about whether or not to proceed……in advance of the transplant….. are the objectives. But risk cannot be completely eliminated.

      The U.S. Centers for Disease Control and Prevention (CDC) has just issued long awaited guidelines for use in preventing the transmission of Hepatitis B (hep B),  Hepatitis C (hep C) and HIV through organ transplantation. They are based on currently available evidence and expert opinions, and formally update guidelines last published in 1994. An essential difference between organ donation and blood or tissue donation led to the restriction of these new guidelines only to the former field. In organ donation transplantation must proceed within hours of the procurement of the donated material that might bear infection. In contrast, both blood and tissue are typically recovered, processed and stored for a longer period of time varying from multiple days to even months or longer. During that interval definitive testing and further risk reduction can clearly be performed.

      This rapid time frame within which results of any laboratory testing must be available so that organ procurement and transplantation are not unduly delayed defines different ground rules than in most medical scenarios. For example, only a few labs throughout the country perform the most specialized testing (nucleic acid testing -NAT) for Hep B, Hep C and HIV with 24/7/365 availability and rapid turn around. Blood samples are typically sent by courier to one of these labs when testing of a deceased donor is required. Of course, these steps do increase the cost of transplantation.

      A practical approach was, by necessity, taken by the U.S. Public Health Service in developing the guidelines. For example, if one of the test results indicates the presence of  Hep B, Hep C or HIV when the virus is really not present (a false positive result), the inappropriate exclusion of the organ donor would be a serious consequence costing one or more lives. The need to balance the potential benefit to be gained from a successful transplant, with the statistical risk of using the possibly infected organ is acknowledged in the guidelines. Thus, it might be reasonable to use a liver from a donor who is suspected of having a false positive test if the liver candidate is at death’s door and no other organs are available. But, it would not be reasonable to use the same donor’s tissue without clarification of the possible infection.

      Wisely, these guidelines also delve deeply into the important issue of involving the patient or family (if the patient is unable) through education when transplantation is only a concept, and through full informed consent when the detailed risks and benefits are known. This is a codification of the timing and content of informed consent similar to other approaches in this tightly regulated field.

      Behavioral factors that increase the donor’s risk of infection with Hep B, Hep C or HIV include sex with an infected person in the preceding 12 months, male-male sex within the preceding 12 months, people who have had sex with a person in exchange for money or drugs in the preceding 12 months, people who have had sex with a person who injected drugs in the preceding 12 months, a child < 18 months born to an infected or at risk mother, a child who has been breastfed within the preceding 12 months by an infected or at risk mother, people who injected drugs in the preceding 12 months, people in lockup, jail, prison or a juvenile correctional facility > 72 hours in the preceding 12 months, and people newly diagnosed with a sexually transmitted disease in the preceding 12 months.

      For any transplant that involved an increased risk of transmission of Hep B, Hep C or HIV, surveillance testing of the recipient for the first year is recommended. If infection does occur, treatment can be initiated as early as possible with the intent of staving off serious illness. 

      Today, these are the most common severe viral infections that concern transplant recipients. But previously, similar donor transmitted infection with the cytomegalovirus (CMV) and the Epstein Barr virus (EBV) were also highly problematic, at times even causing fatalities. Now these infections are much more manageable because of the anti-viral medications available for use.

      If all of these details seem frightening, the real statistic that new (de novo) Hep B, Hep C or HIV infection through transplantation is very rare should be reassuring. The newly available document has simply formalized screening practices that have already become routine at many transplant programs for the protection of patients. Patients are entitled to be familiar with any unusual risks posed by the specific donor whose organ they are being offered (if they are so fortunate). Patients should feel empowered to ask about unusual issues with their donor (if they have not already been informed, which should happen). 

      Remember that the only way to have no risk at all is to have no transplant. If a transplant does happen, the human donor’s organ has been assessed with a risk/benefit ratio tailored to the specific recipient who should have been informed and should have intentionally opted to proceed. Of course, the transplant team would not typically offer an organ that they did not consider acceptable for that patient. But, in the end, it must be the patient (and/or the family) who agrees to go ahead.