Each issue of the CoramClick provides an in-depth focus on timely and practical solutions. In this issue of the Click we are focusing on solid organ transplantation. Full, printable issues of the Click are available in the CoramClick archive for easy reference!

	Solid Organ Transplantation Over the past 40 years, the field of organ transplantation has evolved from an experimental therapy option for a few select patients to an accepted treatment modality for thousands of individuals with end stage organ failure.		Bug of the Month: Cytomegalovirus (CMV) CMV is the most common infection occurring after transplantation, as well as one of the most to expensive to treat.
	Cardiac and Lung Transplantation Since their beginnings, both cardiac and lung transplantation have undergone many changes, resulting in more transplants being performed annually, as well as increased survival rates.		Do You Know? What is the approximate additional treatment cost for the transplant patient who develops cytomegalovirus (CMV) disease?   a) $14,200   b) $34,200   c) $54,200
	Common ICD-9 Codes and V-Codes A list of the most widely used ICD-9 codes and V-codes for disease states linked to potential transplant candidates.		Resource Center Links to more information regarding solid organ transplantation.
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Solid Organ Transplantation

Over the past 40 years, the field of organ transplantation has evolved from an experimental therapy option for a few select patients to an accepted treatment modality for thousands of individuals with end stage organ failure. Currently, heart, lung, liver, kidney, pancreas and intestinal transplantation as well as many combined organ transplants are performed annually in the United States (Table 1) with steadily improving survival rates. These advances have been made possible through improved surgical techniques, the development of supportive care therapies and advances in immuno- suppressive therapies.

One challenge, however, that is faced by all clinicians working with this unique patient subset is the overall care management cost (Table 2). Heart and lung transplants are the most expensive solid organ transplants performed. This issue of the CoramClick will focus on these two transplant types, reviewing volume, survival statistics, complications, care management recommendations and resources.

Cardiac and Lung Transplantation

So much has changed since that first heart transplant in 1967. Currently, greater than 2,000 heart transplants are performed each year, with reported one and three year survival rates of 85.6 percent and 79.5 percent respectively. On the other hand, approximately 4,000 patients nationally are awaiting the option of a heart transplant and only about 60 percent will receive an organ within one year.

Typically, the most common two diagnoses for heart failure leading to the need for transplant are ischemic cardiomyopathy (45 pecent) or nonischemic cardiomyopathy (44 percent), including peripartum, inflammatory, familial, infiltrative and idiopathic causes. Other potential diagnoses include congenital anomalies, refractory ventricular dysrhythmias, valvular disease and re-transplantation.

The diagnosis of end stage heart failure does not automatically make a patient a heart transplant candidate. A complete evaluation must be performed to determine if the patient has other medical or surgical options that may provide a better long-term survival. A thorough history and physical exam, numerous laboratory and radiologic exams, and patient or disease specific consultations help establish the risk-to-benefit ratio. The evaluation period also serves as an invaluable time for patient and caregiver education so that an informed decision can be made about the heart transplant process and pre- and post-transplant patient responsibilities. Patient compliance with the mandatory prescribed daily immunosuppressive medications, follow-up appointments and self-care are all essential for both short and long-term transplant success.

Once a patient is determined to be a candidate for heart transplant, his or her name is placed on the national heart transplant list, and the wait begins. This is, not surprisingly, an anxious time. The patient’s blood type, height, weight and severity of illness will impact how long it takes for them to receive a transplant. During this waiting period, patients may require intravenous inotrope therapy or even a ventricular assist device placed as a “bridge to transplant”. Patients are classified on the waiting list as either a status 1A, 1B or 2. Historically, patients requiring continuous intravenous inotrope therapy or a left and/or right ventricular assist device were required to remain in the hospital. Today, these treatments can often be provided at home while the patients maintain their 1B status.

Once patients receive a heart, they remain at risk for numerous actual and potential complications. These might include one or several occurrences such as rejection, infection, vasculopathy, hypertension, metabolic disorders (e.g. hyperlipidemia, obesity, osteoporosis, and diabetes mellitus), renal insufficiency, gastrointestinal disorders, malignancy and decreased exercise tolerance. Of these complications, it is infection (bacterial, fungal, viral, protozoal) that is the major cause of morbidity and mortality during the first 12 months post-transplant. The risk being primarily associated with the degree of immunosuppression, the surgical procedure, exposure to nosocomial infections and a pre-transplant diminished level of functioning. The most common site of infection is the lung. The most common pathogen is cytomegalovirus (CMV) which is associated with the highest morbidity and mortality. Other worrisome post-transplant viral pathogens include: Epstein-Barr, HHV 1 and 2, and Varicella Zoster. Common bacterial pathogens include Listeria monocytogenes, Norcardia asteroides, Pneumocystis jiroveci (formerly pneumocystis carinii), and typical and atypical mycobacteria. Aspergillus and candida species comprise the most common post-transplant fungal infections. Most infections are treatable with the appropriate antimicrobial, although morbidity and mortality can be significant.

Since the transplanted heart is foreign to the patient, and the body’s natural response is to reject anything not innate, patients require life-long immunosuppression to prevent rejection. Immunosuppressive regimens vary between transplant centers and doses may change depending on the patient’s clinical situation. Cyclosporine or tacrolimus are the cornerstones of treatment and are usually administered in combination with other immunosuppressive agents.

While infection remains a major issue throughout the first post-transplant year, the major impediment to long-term heart transplant survival is coronary artery vasculopathy (CAV). CAV is the primary reason for graft failure after the first year post-transplant and is the most common indication for re-transplantation. However, despite the challenges, cardiac transplantation offers an option for extended life expectancy as well as improved quality of life for many patients with end stage heart failure.

Lung Transplantation

Over the past 20 years, the number of patients receiving lung transplants has grown to approximately 1,400 annually. Unfortunately, the number of patients waiting for lung transplantation has also expanded dramatically, and there are currently close to 2,800 patients on the list.

The decision to pursue lung transplantation comes only after careful screening by a lung transplant center to determine if the patient has severe end-stage pulmonary disease for which there is no alternative treatment, progressive disability and a life expectancy of two years or less. The patient must also be willing to accept the risks of surgery, the responsibilities of follow-up care and be physically able to undergo the surgical procedure. Candidacy is determined by extensive pre-transplant screening to evaluate the patient’s overall health and identify any actual or potential risks. Once candidacy is determined, patients are placed on a wait list until a donor lung becomes available. Depending on the underlying disease, a patient may be a candidate for a dual heart-lung transplant. Average wait list times vary by center and by patient-specific characteristics (blood type, size, diagnosis).

About three years ago, prioritization on the wait list for allocation of donated lungs changed. Instead of patients being prioritized by their clinical status, patients are now classified into several groups (see table below). This allocation system is based on survival benefit and urgency versus time on the wait list. In fact, the number of patients on the lung transplant wait list has dropped 18 percent since the new allocation system went into effect, and the national average wait time has dropped to 202 days. Deaths while on the lung transplant wait list have decreased more than 50 percent since 2000, with the most notable changes occurring following the implementation of the new allocation system.

Improved quality of life and prolonged survival are two of the key benefits for patients undergoing lung transplantation. Each lung transplant center maintains survival statistics, but in general those patients who survive the first year are more likely to survive three years or longer. The current national one year survival rate is approximately 83 percent.

The major risks post-transplant are rejection and infection. Immunosuppressive medications will be prescribed to prevent rejection and lifelong compliance is essential. In addition to the effect of immunosuppressive medications, lung transplant recipients are more susceptible to pulmonary infections related to the loss of the cough reflex, secondary to denervation. Patients are closely monitored and aggressively treated for suspected and actual infections.

The utilization of high tech home care is common in both pre- and post- lung transplantation. Nutrition support (enteral and parenteral) therapy is often prescribed to maximize the pre-transplant nutrition, which promotes post-transplant healing and functional status. Antimicrobial therapies are often prescribed pre-transplant for many of the diseases such as cystic fibrosis with which patients that are susceptible to infection. Additionally, augmentation therapy for patients with alpha-1 antitrypsin deficiency is utilized pre-transplant and may continue post-transplant depending on the transplant center’s protocol. Post-transplant home care can also include anti-infective therapies, nutrition support, IVIG and pain management.

Common ICD-9 Codes and V-Codes

Below is a list of some of the most widely used ICD-9 codes and V-codes for disease states linked to potential transplant candidates. Please note that this list is not all-inclusive.

Bug of the Month: Cytomegalovirus (CMV)

Image courtesty of the CDC

Overview:
Cytomegalovirus (CMV) is a virus in the herpes family. Infection with CMV commonly occurs early in life, and by adulthood over half of the population is positive for CMV antibodies, indicating prior infection. After the initial (primary) infection, the virus remains latent. It can re-activate (secondary infection) in the immunocompromised host. In the immunocompetent host, CMV typically presents with asymptomatic viremia with IgM seroconversion and elevated titers. Patients may present with mild flu-like symptoms. In the immunosuppressed host, patients may present with more serious symptoms, including fever, decreased white cell counts, mono-like symptoms, esophagitis, gastritis, enterocolitis, pneumonitis, retinitis and hepatitis. CMV is isolated from a variety of body fluids including tears, blood, urine, saliva, breast milk, semen and transplanted organs.

Viral transmission can occur transplacentally, person-to-person, in blood products or from donor to recipient in organ, blood cell or bone marrow transplantation. CMV is the single most significant infection occurring after transplantation. The National Institute of Medicine estimates that 2,800 transplant patients acquire CMV infection annually, resulting in 160 deaths. CMV infection is also one of the most expensive infectious diseases to treat in the United States, with an annual direct hospital cost of over $1 billion.

CMV is the most common congenital infection in the United States, affecting approximately 40,000 newborns each year. Congenital CMV can lead to permanent damage, including hearing loss, blindness and moderate to severe mental retardation. Historically, for patients with HIV and AIDS, eventual infection with CMV was almost inevitable. Since the use of highly active antiretroviral therapy (HAART) in HIV disease, both the incidence and severity of CMV have dramatically decreased.

Diagnosis
CMV is difficult to diagnose by signs and symptoms alone. The differential diagnosis includes a past history, viral cultures from blood, urine or sputum (may take one to six weeks to culture positive), histopathology (tissue biopsy and culture) and serological monitoring. Serological monitoring includes anti-viral titers, polymerase chain reaction (PCR) and monitoring for leucopenia, thrombocytopenia and lymphocytosis.

Treatment
Treatment for CMV infection is divided into three categories, prophylaxis, pre-emptive therapy and therapeutic regimens. Prophylactic therapy is generally not recommended in HIV patients, and selective prophylaxis is generally recommended in transplant patients, depending on CMV antibody status and immunosuppressant therapy protocols. The optimal duration of prophylaxis therapy is not known. Pre-emptive therapy should begin when CMV is detected serologically.

Therapeutic intervention is used for systemic disease, intravenous (IV) agents including ganciclovir (Cytovene®), foscarnet (Foscavir®) and cidofovir (Vistide®) or, if failing these or with either relapsed or CNS disease, ganciclovir with foscarnet or ganciclovir plus cidofovir. Therapy is typically long term and requires long-term IV access. Oral ganciclovir has been used for prophylaxis and treatment but, due to its poor oral availability and potential adverse effects, oral valganciclovir (Valcyte®), with an area under the curve (AUC) comparable to that of IV ganciclovir, is often the treatment of choice. Valganciclovir is often the treatment of choice for prophylaxis of CMV in advanced HIV disease or for patients with a CMV infection while HAART is being initiated. Resistance can develop to ganciclovir, foscarnet and cidofovir. Resistance is, however, less of an issue in HIV patients as compared to transplant patients, again due to the use of HAART in HIV. Clinical prognosis is based on the viral load and lymphatic response. Patients are treated until the viral load is sufficiently low.

CMV and Transplant — Special Considerations
CMV infection in transplant patients has both direct and indirect effects. The direct effects include infection, flu-like syndromes, hepatitis, gastritis, CNS disease, retinitis and pulmonitis. Indirect effects are an increased risk of opportunistic infection, atherosclerosis (in heart transplant), obliterative bronchiolectasis (in lung transplant) and acute and chronic rejection. CMV may also contribute to the risk of post-transplant lymphoproliferative disease. In addition, it has been cited as an independent risk factor for mortality (four-fold increase) post-liver transplant.

The risk of CMV infection in transplant patients is based on the CMV status of both the recipient and donor.

What is the approximate additional treatment cost for the transplant patient who develops cytomegalovirus (CMV) disease?
   a) $14,200   b) $34,200   c) $54,200

Answer – b) $34,200
The approximate additional treatment cost for the transplant patient who develops CMV disease is $34,200. This underscores the importance of surveillance monitoring and prophylactic or preemptive treatment for high risk patients, especially those who are CMV negative and receiving a CMV positive organ.

Workplace Partnership for Life
Thousands of U.S. corporations, organizations and associations have joined the Workplace Partnership for Life program in a collaborative effort to create a “donation friendly America”. The Federal Government, under the U.S. Department of Health and Human Services, developed this unique program to promote organ donation awareness. Participants in the program offer their employees or members an opportunity to learn about, discuss, and make decisions concerning the donation of organs, tissue, marrow and blood. Many of the participating organizations have created innovative donation awareness programs, and examples of these successful efforts can be found at www.organdonor.gov. Additionally, this website provides information about how your company or organization can join The Workplace Partnership for Life program as well as numerous transplant resources.

Transplant Program and OPO-Specific Reports
You can view the Scientific Registry of Transplant Recipients program-specific reports online by visiting their website at www.ustransplant.org/csr/current/csrdefault.aspx. These reports include statistics about organ donation and recovery, wait list activity such as transplant rate, and post-transplant outcomes such as graft and patient survival. These reports are published every six months with revised data about each Organ Procurement Organization and Transplant Program operating in the United States.

United Network for Organ Sharing
The United Network for Organ Sharing (UNOS) website, www.unos.org, contains a great deal of information regarding transplants. UNOS is a nonprofit organization that maintains the national Organ Procurement and Transplantation Network (OPTN) under contract with the Health Resources and Services Administration of the U.S. Department of Health and Human Services. On their website, you can find news, resources, data, reports and even job postings in the transplant community. The lung allocation system and method of patient ranking can also be found on the site. Another website developed by UNOS is www.transplantliving.org, which offers information for transplant patients. The site can also be personalized to help better manage specific health information needs.

Bibliography

• Havlir, D.V. Preventing opportunistic infections in the HAART era. Medscape General Medicine 1(3), 1999.
• Pescovitz, M.D. Prevention and treatment of cytomegalovirus in solid organ transplant recipients: the clinical and economic impact of evolving strategies. Am J Health Syst Pharm 60(23); S3-S4, 2003.
• Schnitzler, M.A. Costs and consequences of cytomegalovirus disease. Am J Health Syst Pharm 60(23); S5-S8, 2003.