Best Practices in the Management of Chronic Care Issues
Best Practices in the Management of Chronic Care Issues
Robert R. Redfield, MD
University of Wisconsin–Madison School of Medicine and Public Health, Madison, Wisconsin
Addressing primary care issues is extremely important in the postoperative care of the solid-organ transplant recipient. In addition to maintaining graft function, the transplant provider must address concerns about diabetes, hypertension, cancer screening, and infectious disease. This report reviews advances in transplant patient care presented at an early-morning symposium for clinicians and allied health personnel, "What to Expect Down the Road: Best Practice in the Management of Chronic Care Issues Post Transplant," held during the 2014 World Transplant Congress in San Francisco, California.
The 2014 World Transplant Congress in San Francisco showcased many ongoing advances in the field. Because solid-organ transplantation has become such a success, our patients are living longer and are subject to both common and unique primary care issues. Solid-organ transplant recipients are at risk for developing diabetes and hypertension post transplant and are at increased risk of experiencing many types of malignancies. Furthermore, as transplant patients go on to lead normal lives, they are at increased risk of developing and contracting infectious diseases, especially as they travel abroad.
CANCER AFTER SOLID-ORGAN TRANSPLANTATION: RISKS AND
Based on a presentation by Claire M. Vajdic, PhD, Associate Professor of Medicine, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
Immunosuppression is the primary risk factor for cancer among the transplant population, which recently was reported to have a cancer profile similar to that of individuals who are infected with the human immunodeficiency virus (HIV) or who have acquired immunodeficiency syndrome (AIDS).1,2 When matched for both age and gender, solid-organ transplant recipients have a two- to threefold increased risk of cancer compared with the general population.3 Cancer rates in transplant recipients are similar to those of people who are 20–30 years older who did not receive a transplant.4 Furthermore, cancer risk is inversely related to age. Younger recipients have a much greater risk of cancer development than do their older counterparts. When compared with the general population, children who have undergone an organ transplant have 15–30 times the risk of malignancy, whereas organ-transplant recipients > 65 years of age have twice the risk.4,5
Additionally, cancer risk differs with the organ transplanted. Na et al6 demonstrated an increased risk of malignancy in lung-transplant recipients when compared with heart- and liver-transplant recipients. The main reason for this difference seems to be the variation in the intensity or type of immunosuppression—individuals who receive lung transplants typically require more immunosuppression than do liver-transplant recipients.7–9 Pancreas-transplant recipients also require increased levels of immunosuppression, which is an independent risk factor for post-transplant lymphoproliferative disorder.10
Additional support for this hypothesis appears in several studies that have found a link between use of induction therapy with depleting antibodies and post-transplantation cancer risk.9–11 In addition to the degree, duration, and type of immunosuppression used and the organ transplanted, other factors likely are involved, such as prior and new exposure to viral infections and baseline accrual of cancer risk factors known to the general population.
The cancer risk reported in the literature demonstrates a wide-ranging excess cancer risk relative to the general population, especially when cancers with a viral cause are considered (Figure 1).1 Malignancies include non-Hodgkin's lymphoma; Kaposi's sarcoma; cancer of an unknown primary site; and malignancies of the skin (both melanoma and non-melanoma skin cancers, including Merkel cell carcinoma), anus, genitalia (eg, cervical cancer), lips, salivary glands, colon and rectum, liver, stomach, lungs, and thyroid gland. Interestingly, the post-transplant population does not have an increased risk of developing two common cancers—those of the prostate and breast.4
FIGURE 1 Estimates of cancer risk for solid-organ transplant recipients, by cancer site or type. HHV-8 = human herpesvirus-8; EBV = Epstein-Barr virus; H pylori = Helicobacter pylori; HBV = hepatitis B virus; HCV = hepatitis C virus; HPV = human papillomavirus. Adapted, with permission, from Grulich et al.1
Prevention and Screening
Because of this now well-established increased cancer risk, proper care of the transplant recipient should include strategies to prevent and screen for malignancy. First and foremost, immunosuppression should be minimized, if possible. Also, azathioprine therapy has been associated with an increased risk for developing non-melanoma skin cancers, lip cancer, and non-Hodgkin's lymphoma; discontinuation of azathioprine therapy should be considered if these cancers develop. Treatment with sirolimus has antineoplastic effects and should be considered in patients with a history of malignancy.12
All transplant recipients should learn about their skin and the risks of sun exposure. They should be evaluated regularly by a dermatologist for full-body skin checks and removal of suspicious lesions.
For anogenital cancers, patients should be offered vaccination, be counseled on safe sexual practices, and undergo cervical screening. Also, transplant recipients should avoid tobacco smoking to minimize the risk of lung cancer and undergo a routine colonoscopy for colon cancer screening; patients with primary sclerosing colitis and ulcerative colitis should be screened more frequently.
In summary, cancer continues to be an important post-transplant complication, particularly as organ recipients live longer and continue to use immunosuppressants. There is emerging evidence regarding risk factors; thus, strategies for prevention can be developed. Where possible, it is important to minimize immunosuppression to reduce these risks.
HYPERTENSION, HYPERGLYCEMIA, AND THE METABOLIC SYNDROME
Based on a presentation by Kymberly D. Watt, MD, Associate Professor of Medicine, Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
The term metabolic syndrome describes a collection of modifiable risk factors for cardiovascular disease characterized by obesity, physical inactivity, and insulin resistance (Table 1). Because the side effects of most routine immunosuppressive therapies include glucose intolerance, hypertension, and hyperlipidemia, the incidence of metabolic syndrome among transplant recipients on maintenance immunosuppression is higher than that in the general population and makes preoperative assessment and treatment of these parameters all the more important.13,14 The incidence of metabolic syndrome following transplant can be as high as 50%.15
Metabolic syndrome is a predictor of poor outcomes (Figure 2).16 This collection of modifiable cardiovascular disease risk factors—and a cause of death among people with a functioning graft—usually is a consequence of underlying cardiovascular disease. Thus, screening and identification of metabolic syndrome in transplant recipients are crucial to optimizing post-transplant care.
FIGURE 2 Effect of metabolic syndrome during 12 months post transplant on kidney allograft survival (a) and freedom from coronary heart disease (b). Adapted, with permission, from Israni et al.16
Once the syndrome is identified, affected patients should practice aggressive lifestyle modifications. Appropriate medical and surgical interventions should be used to reduce weight and blood pressure and improve lipid and glucose parameters. Specifically, goals of therapy include a hemoglobin A1c level < 7%, a fasting blood sugar level = 70–130 mg/dL (3.9–7.2 mmol/L), blood pressure < 140/90 mm Hg in nondiabetic patients or < 130/80 mm Hg in diabetic patients, and a low-density lipoprotein cholesterol level < 130–160 mg/dL (3.4-4.2 mmol/L). Bariatric surgery pre- and post-transplant is safe and effective, although the risks are slightly higher than those seen in the general population.17
In summary, metabolic syndrome is common both before and after transplant and impacts patient morbidity and mortality. Control of weight gain is central to managing metabolic syndrome and for treating dyslipidemia, hypertension, and diabetes. In addition to aggressive lifestyle modifications and pharmacotherapy, considerations should also be made for bariatric surgery.
MINIMIZING EXPOSURE RISKS IN GLOBAL TRAVEL
Based on a presentation by Deepali Kumar, MD, MSC, FRCP(C), Transplant Infectious Diseases Clinic, Multi-Organ Transplant Program, University Health Network, and Associate Professor of Medicine, University of Toronto, Toronto, Ontario, Canada.
Prophylaxis of infection in transplant patients is extremely important. When traveling abroad, the transplant recipient needs to take appropriate precautions. Patients routinely seek advice regarding travel prophylaxis from their transplant providers, although, more often than not, the counseling about travel abroad is inadequate.18 Instead, these individuals should seek counseling from a knowledgeable practitioner in travel medicine; such an encounter also allows a review of routine immunizations that may have been overlooked.
Information on routine vaccinations in immunocompromised hosts is summarized in Table 2.19 According to the Centers for Disease Control and Prevention, overall considerations for vaccine recommendations (eg, destination, likely risk of exposure to disease) are the same for immunocompromised travelers as for any other traveler. In general, live vaccines are contraindicated in solid-organ transplant recipients on immunosuppression, but their use is generally safe in close household contacts who are immunocompetent. The live vaccines include attenuated influenza vaccines (intranasal formulations) and varicella (smallpox), herpes zoster, measles, mumps, rubella, yellow fever, Bacillus Calmette-Guérin (BCG), and Salmonella typhi (oral formulation) vaccines. Intravenous administration of immunoglobulin may provide protection against measles, mumps, rubella, varicella, hepatitis A, and rabies when vaccination is contraindicated or time to develop immunity is insufficient.
Travelers who cannot tolerate recommended immunizations or prophylaxis should consider deferring their trip. For solid-organ transplants, the risk of infection is highest during the first year after transplant, so transplant patients should consider postponing travel to high-risk destinations until after that time.
There is no evidence that vaccines increase the risk of allograft rejection. Guidelines from the American Society of Transplantation's Infectious Diseases Community of Practice suggest that transplant centers restart vaccination 3–6 months after transplant. For transplant recipients, vaccination may result in a less vigorous immunologic response, especially early after surgery, when the immunosuppressive load is highest. It is still generally worthwhile to vaccinate, however, since many patients develop some type of response and, thus, protection against disease.
Vaccination Recommendations and Contraindications
Vaccines to be considered for travel are listed in Table 2.19 Hepatitis A can be a devastating illness in transplant patients. The risk of hepatitis A in nonimmune travelers to the developing world can be as high as 1:200.20 Therefore, patients should be vaccinated against this virus before traveling; if they do not have time or do not respond to active immunization, they should receive immunoglobulin before traveling.
Each year, approximately 400 cases of typhoid fever (Salmonella enterica subspecies I, serovar Typhimurium) are reported in the United States. The majority of S typhi infections are related to international travel. Transplant patients may have severe complications during infection with S typhi and should be immunized against typhoid before any travel to endemic areas.
Polio essentially has been eradicated from the Western hemisphere. Occasionally, outbreaks of vaccine-associated polio occur due to activation of live attenuated poliovirus from the oral polio vaccine. Wild-type virus still exists in sub-Saharan Africa and South Asia, and transplant recipients need protection when traveling to those areas. Childhood polio vaccination should be adequate; however, if 10 years have passed since the last dose of polio vaccine was given, booster immunization is advisable, especially for travelers to endemic areas. Encouragingly, immunity appears to be well maintained after transplant patients are revaccinated.21
Meningococcal vaccine is indicated for individuals traveling to areas of the world with known outbreaks of meningococcal disease (eg, sub-Saharan Africa, Saudi Arabia for the Muslim pilgrimages of Hajj). Proof of vaccination is required for this pilgrimage.
Yellow fever is a mosquito-borne illness endemic to South America and sub-Saharan Africa. The fatality rate from this infection is high, and no specific treatment exists. Only a live attenuated vaccine is available; transplant patients should be cautious about traveling to endemic areas. If travel is mandatory, it should be avoided during peak infection months.
Pre-exposure rabies immunization may be indicated for travelers expecting to be exposed to suspicious animals. However, transplant patients may not mount an adequate antibody response to the rabies vaccine. Human rabies immunoglobulin should be given after all risk exposures.22
Immunization against Japanese encephalitis is appropriate for individuals traveling to rural, endemic areas of Asia, especially during periods of increased transmission.
BCG is a live, attenuated vaccine intended to prevent tuberculosis. BCG should not be administered to transplant patients, since it may cause disseminated infection.
Transplant patients also should be educated about travelers' diarrhea, which affects approximately 50% of travelers to developing regions. Travelers' diarrhea can be life-threatening for transplant patients. Travelers who have undergone transplant surgery should carry ciprofloxacin or azithromycin for self-treatment of symptoms lasting more than a few days. Patients who experience fever, vomiting, or bloody stools while traveling should consider seeking medical attention. Trimethoprim-sulfamethoxazole is not effective against travelers' diarrhea, due to high levels of resistance. Travelers should be counseled about food and water precautions; in general, they should drink bottled or boiled water and avoid consuming raw foods that cannot be peeled and ice.
Malaria is a significant risk for travelers to endemic areas. There is no evidence that the incidence of malarial infection is higher or that severity of the disease is worse in immunocompromised hosts other than asplenic patients. Therefore, asplenic patients should be aware of their increased risk of morbidity and mortality from malaria. Otherwise, standard prophylactic precautions should be taken.
Transplant recipients who intend to travel overseas should seek advice from a healthcare provider familiar with travel medicine, the patient's immunocompromised state, and the various immunosuppressive medications being taken. Appropriate travel vaccines greatly depend on the patient's itinerary. Administration of live vaccines generally is contraindicated. Use of immunoglobulin may protect against measles, mumps, rubella, varicella, hepatitis A, and rabies when vaccination is contraindicated or there is insufficient time to develop immunity. Prophylactic measures are necessary for illnesses that cannot be prevented by vaccination, such as travelers' diarrhea and malaria.
- Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370:59–67.
- Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011;306:1891–1901.
- Giordano TP, Henderson L, Landgren O, et al. Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA. 2007;297:2010–2017.
- Webster AC, Craig JC, Simpson JM, Jones MP, Chapman JR. Identifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15,183 recipients. Am J Transplant. 2007;7:2140–2151.
- Chapman JR, Webster AC, Wong G. Cancer in the transplant recipient. Cold Spring Harb Perspect Med. 2013;3:a015677.
- Na R, Grulich AE, Meagher NS, McCaughan GW, Keogh AM, Vajdic CM. Comparison of de novo cancer incidence in Australian liver, heart and lung transplant recipients. Am J Transplant. 2013;13:174–183.
- Collett D, Mumford L, Banner NR, Neuberger J, Watson C. Comparison of the incidence of malignancy in recipients of different types of organ: a UK Registry audit. Am J Transplant. 2010;10:1889–1896.
- Euvrard S, Kanitakis J, Pouteil-Noble C, et al. Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation. J Am Acad Dermatol. 1995;33:222–229.
- Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in Australian heart transplant recipients. J Am Acad Dermatol. 1999;40:27–34.
- Caillard S, Lamy FX, Quelen C, et al. Epidemiology of posttransplant lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French registry and analysis of subgroups of lymphomas. Am J Transplant. 2012;12:682–693.
- Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant. 2004;4:222–230.
- Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med. 2005;352:1317–1323.
- Laish I, Braun M, Mor E, Sulkes J, Harif Y, Ben Ari Z. Metabolic syndrome in liver transplant recipients: prevalence, risk factors, and association with cardiovascular events. Liver Transplant. 2011;17:15–22.
- Hricik DE. Metabolic syndrome in kidney transplantation: management of risk factors. Clin J Am Soc Nephrol. 2011;6:1781–1785.
- Pagadala M, Dasarathy S, Eghtesad B, McCullough AJ. Posttransplant metabolic syndrome: an epidemic waiting to happen. Liver Transplant. 2009;15:1662–1670.
- Israni AK, Snyder JJ, Skeans MA, Kasiske BL; PORT Investigators. Clinical diagnosis of metabolic syndrome: predicting new-onset diabetes, coronary heart disease, and allograft failure late after kidney transplant. Transpl Int. 2012;25:748–757.
- Modanlou KA, Muthyala U, Xiao H, et al. Bariatric surgery among kidney transplant candidates and recipients: analysis of the United States renal data system and literature review. Transplantation. 2009;87:1167–1173.
- Boggild AK, Sano M, Humar A, Salit I, Gilman M, Kain KC. Travel patterns and risk behavior in solid organ transplant recipients. J Travel Med. 2004;11:37–43.
- Kotton CN, Ryan ET, Fishman JA. Prevention of infection in adult travelers after solid organ transplantation. Am J Transplant. 2005;5:8–14.
- Ryan ET, Kain KC. Health advice and immunizations for travelers. N Engl J Med. 2000;342:1716–1725.
- Ljungman P, Aschan J, Gustafsson B, Lewensohn-Fuchs I, Winiarski J, Ringden O. Long-term immunity to poliovirus after vaccination of allogeneic stem cell transplant recipients. Bone Marrow Transplant. 2004;34:1067–1069.
- Gibbons RV, Rupprecht CE. Postexposure rabies prophylaxis in immunosuppressed patients. JAMA. 2001;285:1574–1575.
Dr. Redfield is Instructor of Surgery and Senior Fellow in Abdominal Transplant Surgery, Department of Surgery, University of Wisconsin–Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, Wisconsin.