Curr Infect Dis Rep (2015) 17: 18 DOI 10.1007/s11908-015-0473-x
TRANSPLANT AND ONCOLOGY (M ISON AND N THEODOROPOULOS, SECTION EDITORS)
Transplant Tourism: Understanding the Risks Jennifer M. Babik & Peter Chin-Hong
Published online: 14 April 2015 # Springer Science+Business Media New York 2015
Abstract Transplant tourism is commonly defined as travel abroad for the purpose of transplantation, but the term evokes ethical and legal concerns about commercial transplantation. Due to the mismatch in supply and demand for organs, transplant tourism has increased over the last several decades and now accounts for 10 % of transplants worldwide. Patients from the USA who pursue transplantation abroad do so most commonly for renal transplantation, and travel mostly to China, the Philippines, and India. Transplant tourism puts the organ recipient at risk for surgical complications, poor graft outcome, increased mortality, and a variety of infectious complications. Bacterial, viral, fungal, and parasitic infections have all been described, and most concerning are the high rates of blood-borne viral infections and invasive, often fatal, fungal infections. Transplant and infectious diseases physicians should have a high degree of suspicion for infectious complications in patients returning from transplantation abroad.
Keywords Transplant tourism . Solid organ transplant . Kidney transplant . Commercial transplant . Immunocompromise . Travel . Infection . Hepatitis B virus . Hepatitis C virus . HIV . Cytomegalovirus . Malaria . Fungal infection . Aspergillus . Zycomycetes . Multi-drug resistant . Wound infection . Tuberculosis . Pneumocystis jiroveci
Introduction Transplant tourism is most broadly defined as travel abroad for the purposes of transplantation, although the term evokes ethical and legal concerns [1, 2]. Some transplants acquired abroad may be considered Bemotionally related^ transplants procured in foreign countries for cultural or familial reasons. However, the majority are thought to be commercial transactions [1]. In fact, the Declaration of Istanbul on Organ Trafficking and Transplant Tourism defines transplant tourism more precisely as travel for transplantation that Binvolves organ trafficking and/or transplant commercialism or if the resources (organs, professionals, and transplant centers) devoted to providing transplants to patients from outside a country undermine the country’s ability to provide transplant services for its own population^ [3]. Transplant tourism carries many risks, most notably for the recipient but also for the donor and local transplant infrastructure. In this article, we will focus primarily on the risk incurred by the recipient. Ethical concerns, while not the focus of this article, are certainly paramount and include the exploitation of living donors, the possibility that organs from deceased donors in some countries (notably, China) are procured from executed prisoners [4, 5], and the erosion of development of deceased donor systems on a local level [6].
Epidemiology
This article is part of the Topical Collection on Transplant and Oncology J. M. Babik (*) : P. Chin-Hong Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA e-mail: [email protected] P. Chin-Hong e-mail: [email protected]
All nations, with the exception of Iran, now outlaw commercial transplantation. However, due to the significant mismatch in supply and demand for organs in the developed world, the practice continues widely and has garnered considerable attention by international transplant societies [3, 7••] and the lay press [8]. In fact, transplant tourism has actually been increasing over the last 20 years in developing countries [2, 9–11] and now makes up approximately 10 % of all transplants worldwide [10].
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There are many countries where transplant tourism has occurred, but the countries with the highest number of cases are China, India, Philippines, Pakistan, and Iran (Fig. 1) [2, 11, 12, 21•]. In a study of patients on transplant waiting lists in the USA, 373 patients underwent transplantation abroad over a 20-year period between 1987 and 2006 [2]. Of these transplants, 89 % were kidney transplants. Transplants took place in 35 different countries but most took place in China (26 %), the Philippines (12 %), India (10 %), and Pakistan (4 %). Patients undergoing transplants abroad were more likely to be male, Asian, have a college or graduate level education, be from California or New York, and be a resident or nonresident alien of the USA. This last category deserves further mention, as most patients who leave the USA to acquire a transplant abroad travel to a region of shared ethnicity or religion [11–13]. Most patients who leave the USA for transplant receive living unrelated transplants [11, 12]. Although there is not a lot of data on why patients choose to travel for transplantation, a survey of transplant centers in the UK and Ireland identified several reasons, including shorter wait list times, inability to be listed in their country of residence, and having family ties or a living donor abroad [14].
Risks for the Donor Although the majority of this article will discuss the risks incurred by the transplant organ recipient, it is important to
Curr Infect Dis Rep (2015) 17: 18
mention the risks to the donor as well. Most donors involved in transplant tourism have a decline in medical and psychological health after donation [6, 15]. Despite the fact that the incentive of a commercial donor is almost always financial, these donors usually see little to no economic improvement after donation [6, 15]. In fact, many donors even see a decline in economic status due to post-operative declines in medical and emotional health [6].
Non-infectious Risks for the Recipient Logistical Challenges in Transitions of Care Multiple studies have demonstrated poor communication between the transplanting center abroad and the continuing care center in the patient’s home country, mainly related to inadequate documentation of donor information and perioperative care [4, 11, 12, 16–18••]. This includes minimal information on donor and recipient screening (including donor CMV serostatus), HLA matching, cold ischemia time, intraoperative procedures, and details of immunosuppressive regimens and antimicrobial prophylaxis. In addition, as for all types of medical tourism, accreditation of care providers may be variable, and there is a lack of liability in the case of poor outcomes [18••].
Fig. 1 Countries where transplant tourism has occurred. Shown in red are the countries in which the highest numbers of transplant tourism cases have occurred (China, India, Pakistan, Philippines, and Iran). Other countries in which transplant tourism has occurred are shown in light red
Curr Infect Dis Rep (2015) 17: 18
Patient and Graft Outcomes The majority of studies show lower graft and patient survival rates in commercial kidney transplantation compared with domestic transplantation, with 1-year graft survival rates between 65–96 % and patient survival rates 78–96 % [4–6, 13, 16, 19–21•, 22]. A Canadian study showed a >2-fold increase in the risk of graft failure and death with transplant tourism (most transplants in this study were done in South and East Asia) [16]. In addition, rejection rates are up to two times higher in transplants done abroad versus domestically [11, 19]. Patients undergoing transplant abroad have an up to 23fold increased risk of hospitalization [19], with rates up to 42 % in the first 3 months after transplantation [20]. Medical and Surgical Complications Multiple studies report surgical complications, often discovered upon presentation to the home institution, including problems with the anastomosis, urinary fistulas, lymphocele, hydrocele, and urinary obstruction [6, 9, 20, 23]. A systematic review on transplant tourism outcomes showed an increased rate of post-transplant diabetes in patients who underwent transplantation abroad [21•]. Interestingly, a study in Taiwan showed that the risk of malignancy was threefold higher in the cohort of patients who underwent renal transplantation in China versus those who had their transplant domestically in Taiwan [24]. Most of these were urothelial malignancies, thought possibly secondary to the older age of the tourist group or increased rates of depleting antibodies used in this group.
Infectious Risks for the Recipient Increased Risk of Infection The majority of studies on outcomes in transplant tourism show a significant increased risk of infection in the tourism group, whose rate of infections are approximately 45–54 % versus 5 % in the non-tourist group [16, 19, 20, 25]. One study showed that transplant tourism conferred an increased risk of infection by 85-fold compared with domestic transplants [19]. These infections often occurred early in the post-transplant course [12, 20]. Bacterial, viral, fungal, and parasitic infections have all been described (Table 1). Infections in the setting of transplant tourism can be from procedural complications (such as wound infections), nosocomial infections, blood-borne pathogens, or due to a geographically restricted pathogen acquired as a donor-derived infection or acquired in the peri-transplant period while staying in an area of endemicity [18••]. The risk of nosocomial infections is significantly higher in developing countries [26]. ICU infection rates are 3.5-fold higher, and surgical site infection
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rates are twofold higher in developing countries compared to developed nations [26]. Another sobering statistic is that 39 % of injections given in the developing world are provided with reused equipment [27]. Explanations for the high rates of infection include the following: (1) many regions where transplant tourism is practiced are tropical or subtropical areas with high rates of endemic infections such as malaria, tuberculosis (TB), and other geographically restricted infections; (2) these regions often have a high prevalence of pathogens such as HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV); (3) donor infectious diseases screening is likely variable and the assays used may be substandard; (4) poor hygiene and operative conditions may exist; (5) inadequate education of patients regarding infectious risk post-transplant; and (6) lack of prophylaxis against opportunistic infections [1, 11, 12, 14, 18••, 28]. Bacterial Infections Many reports describe wound infections, often severe, in patients returning from a transplant abroad [4, 6, 9, 11, 21•, 20, 23]. These infections have been described with resistant organisms, including multi-drug resistant Pseudomonas and vancomycin-resistant Enterococcus [4, 11]. Urinary tract infections are also common, including infections with multidrug resistant Escherichia coli [16] and Acinetobacter [13]. Multi-drug resistant organisms are a significant concern in many developing countries where antibiotics can be purchased without a prescription, leading to overuse and widespread resistance [18••]. For example, ESBL rates in India are 70–90 % [18••, 29]. In addition, the New Delhi-metallo-βlactamase (NDM) carbapenemases were initially isolated in India but subsequently have been found in many other countries, often introduced by patients who have pursued medical tourism abroad, including transplantation [18••, 29]. In the absence of overt infection, travelers can also return colonized with multi-drug resistant pathogens [18••]. TB has been described in 2–15 % of patients who have procured a transplant abroad [6, 16], including a fatal disseminated case in the USA that was acquired in Pakistan [13]. Viral Infections Transplant tourism increases the risk of several viral infections, most importantly HIV, HBV, and cytomegalovirus (CMV). CMV has been reported in up to 33 % of patients returning from transplants abroad, usually occurring in the first few months after transplant [4, 6, 11, 16]. This has been attributed to very low rates of CMV prophylaxis use in this group [11, 14]. Patients returning from transplantation abroad have reportedly high rates of seroconversion with HIV (4–6 %) and HBV (2–18 %) [4, 21•, 25]. Some cases of HBV infection have been fatal [11] and others have led to local outbreaks, raising a
18 Page 4 of 6 Table 1
Curr Infect Dis Rep (2015) 17: 18
Infectious complications of transplant tourism
Pathogen
Riska
Comments
Reference
Bacterial Infections Wound infections
Unknown, likely high
[4], [6], [9], [11], [20], [21], [23]
Urinary tract infection Tuberculosis
Unknown 2–15 %
Can be severe and require surgical intervention; can be due to MDR organisms. Can be due to MDR organisms. Fatal cases have been described.
Viral Infections HIV
4–6 %
Hepatitis B virus Hepatitis C virus Cytomegalovirus
2–18 % Unknown, likely high Up to 33 %
Fungal Infections Molds
4%
Pneumocystis jiroveci
8%
Parasitic Infections Malaria
6–11 %
a
High rate of blood-borne pathogens likely due to inadequate donor screening and high background rate of infection in the community. As for HIV. Fatal cases have been described. As for HIV. Likely due to lack of prophylaxis.
[13], [16] [6], [13], [16]
[4], [21], [25]
[4], [11], [21], [25] [31] [4], [6], [11], [16]
Often disseminated, involve the CNS, or directly involve the renal graft. High rates of graft loss and death. Aspergillus accounts for 2/3 of cases, and Zygomycetes 1/4 of cases. Likely due to variable prophylaxis.
[17], [33–38]
Most common in transplants done in India; acquired via the organ, blood transfusion, or mosquito bite.
[20], [23], [39–41]
[19]
The percentage of patients who return from transplantation abroad with the specific infectious complication.
MDR multi-drug resistant
public health concern for the introduction of communicable diseases into the community from transplant tourism [30]. There also appears to be an increased risk of HCV based on the high prevalence of HCV seropositivity in patients who have undergone transplantation abroad (up to 37 % in one study), although limited pre-transplant screening in some cases makes the exact number that have been transmitted via transplantation unknown [31]. These high rates of infection with blood-borne pathogens are thought due to inadequate donor screening and/or transmission while on hemodialysis in the foreign country [25]. A study of commercial kidney donors in Pakistan showed that 24 % were HCV antibody positive and 4 % hepatitis B surface antigen positive following organ donation. It is not known if these donors had preexisting infections or acquired infection in the setting of transplant, but the former was suspected [15]. Fungal Infections Fungal infection is perhaps the most feared infectious complication of transplant tourism and occurs in approximately 4 % of patients [32]. The most common fungi reported are Aspergillus and Zygomycetes but there are also rare cases of Ramichloridium, Pseudallescheria boydii, and Trichosporon [17, 33–38]. These infections may directly involve the
transplanted kidney and can be necrotic, form abscesses, and involve the vasculature. A review of 19 fungal infections in 17 commercial renal transplants performed in Asia or the Middle East showed that 63 % were Aspergillus and 26 % were Zygomycetes [34]. All infections were extrapulmonary or disseminated with direct involvement of the graft in 35 % and infection of the CNS in 29 %. Graft loss occurred in 76 % and the overall mortality in this group was 59 %. The very high rates of direct infection of the graft were thought to be due to infection in the donor or contamination of the organ during procurement, transport, or transplantation [33, 34, 36, 38]. Presumably as a result of this mechanism of infection, transplant tourism accounts for 22 % of all donor-derived filamentous fungal infections [17]. Pneumocystis jiroveci (PCP) is also more commonly seen in the setting of transplant tourism. In one study, rates of PCP in patients undergoing transplant in China was 8 % compared to 1 % in those done domestically in Korea [19]. Similar to the case of CMV, this may be due to variable practices in prescribing prophylaxis [11, 14]. Parasitic Infections The parasitic infection that has been reported most commonly in the setting of transplant tourism is malaria. It has been most
Curr Infect Dis Rep (2015) 17: 18
frequently described in patients who received their transplants in India with a rate of 6–11 % [20, 23, 39–41]. Infections usually occur at a mean of 44 days (range 20–83) after transplantation and have been described with Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae [41]. In general, patients do well with rapid recovery following the initiation of antimalarial therapy [41]. It is presumed that the infection is acquired via the organ itself, in the setting of blood transfusion peri-operatively, or by mosquito bites within the foreign country [23]. Many other geographically restricted parasites, such as Trypanosoma cruzi and Strongyloides, have been transmitted in the setting of organ transplantation, although not necessarily in the setting of transplant tourism [28]. Prevention of Infection Most transplant physicians have no prior knowledge that their patients are planning to go overseas for the purposes of transplant tourism [14]. However, if physicians did have knowledge ahead of time, this could allow for counseling regarding the ethical (and legal) considerations involved as well as well as significant risks, both noninfectious and infectious, involved in transplant tourism [7••]. As for any other immunocompromised patient who is planning to travel, these patients could be given appropriate vaccines and other precautions about travel abroad [7••]. When these patients return to their home country after transplant abroad, it is recommended to (1) consider screening for blood-borne pathogens (HIV, HBV, and HCV) by molecular methods, (2) evaluate for bacteremia and urinary tract infection with appropriate cultures, (3) ensure adequate prophylaxis of opportunistic infections, and (4) consider screening for other endemic infections depending on the country where the transplant occurred (e.g., malaria, TB, T. cruzi, Strongyloides) [7••].
Conclusion Transplant tourism is unfortunately increasing despite international policies to prohibit commercial transplantation. Transplant tourism carries the risk of surgical complications, poor graft outcomes, increased mortality, and a significant increase in infectious complications. Bacterial, viral, parasitic, and fungal infections have all been described, and of particular concern are the high rates of blood-borne viral infections and invasive, often fatal, fungal infections. Transplant and infectious diseases physicians should have a high degree of suspicion for infectious complications, including unusual infections, in patients returning from transplantation abroad. Acknowledgments The authors would like to thank Ban Hock Tan for his assistance. Dr. Chin-Hong is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through
Page 5 of 6 18 UCSF-CTSI Grant Numbers UL1 TR000004 and TL1 TR000144. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Compliance with Ethics Guidelines Conflict of Interest Jennifer Babik and Peter Chin-Hong have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Kotton CN. Transplant tourism and donor-derived parasitic infections. Transplant Proc. 2011;43(6):2448–9. 2. Merion RM, Barnes AD, Lin M, Ashby VB, McBride V, Ortiz-Rios E, et al. Transplants in foreign countries among patients removed from the US transplant waiting list. Am J Transplant. 2008;8(2): 988–96. 3. The Declaration of Istanbul on Organ Trafficking and Transplant Tourism: Transplantation. 2008; 86(8):1013–1018. 4. Kennedy SE, Shen Y, Charlesworth JA, Mackie JD, Mahony JD, Kelly JJP, et al. Outcome of overseas commercial kidney transplantation: an Australian perspective. Med J Aust. 2005;182(5):224–7. 5. Vathsala A. Outcomes for kidney transplants at the National University Health System: comparison with overseas transplants. Clin Transpl. 2010;149–160. 6. Sajjad I, Baines LS, Patel P, Salifu MO, Jindal RM. Commercialization of kidney transplants: a systematic review of outcomes in recipients and donors. Am J Nephrol. 2008;28(5): 744–54. 7.•• Kotton CN, Hibberd PL. The AST Infectious diseases community of practice. Travel medicine and transplant tourism in solid organ transplantation. Am J Transplant. 2013;13(4):337–47. Guidelines from the AST Infectious Diseases Community of Practice regarding prevention of vaccine and nonvaccine preventable illnesses in solid organ transplantation travelers, including recommendations for the management of patients returning after transplantation abroad. 8. Sack K. Transplant Brokers in Israel Lure Desperate Kidney Patients to Costa Rica. N Y Times [Internet]. 2014 [cited 2014 Dec 9]; Available from: http://www.nytimes.com/2014/08/17/ world/middleeast/transplant-brokers-in-israel-lure-desperatekidney-patients-to-costa-rica.html 9. Chugh KS, Jha V. Commerce in transplantation in third world countries. Kidney Int. 1996;49(5):1181–6. 10. WHO | WHO proposes global agenda on transplantation [Internet]. 2007 [cited 2014 Dec 12]. Available from: http://www.who.int/ mediacentre/news/releases/2007/pr12/en/ 11. Gill J, Madhira BR, Gjertson D, Lipshutz G, Cecka JM, Pham P-T, et al. Transplant tourism in the United States: a single-center experience. Clin J Am Soc Nephrol. 2008;3(6):1820–8. 12. Canales MT, Kasiske BL, Rosenberg ME. Transplant tourism: outcomes of United States residents who undergo kidney transplantation overseas. Transplantation. 2006;82(12):1658–61.
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Polcari AJ, Hugen CM, Farooq AV, Holt DR, Hou SH, Milner JE. Transplant tourism—a dangerous journey? Clin Transpl. 2011;25(4):633–7. 14. Odedra A, Green ST, Bazaz R. United Kingdom and republic of Ireland renal physicians’ experiences of patients undergoing renal transplants abroad: a questionnaire-based cross-sectional survey. Travel Med Infect Dis. 2014;12(6):702–6. 15. Naqvi S a A, Rizvi S a H, Zafar MN, Ahmed E, Ali B, Mehmood K, et al. Health status and renal function evaluation of kidney vendors: a report from Pakistan. Am J Transplant. 2008;8(7):1444–50. 16. Prasad GVR, Shukla A, Huang M, D''A Honey RJ, Zaltzman JS. Outcomes of commercial renal transplantation: a Canadian experience. Transplantation. 2006;82(9):1130–5. 17. Gomez CA, Singh N. Donor-derived filamentous fungal infections in solid organ transplant recipients. Curr Opin Infect Dis. 2013;26(4):309–16. 18.•• Chen LH, Wilson ME. The globalization of healthcare: implications of medical tourism for the infectious disease clinician. Clin Infect Dis. 2013;57(12):1752–9. An excellent review of the infections associated with medical tourism, including transplant tourism. 19. Cha R-H, Kim YC, Oh YJ, Lee JH, Seong EY, Kim DK, et al. Long-term outcomes of kidney allografts obtained by transplant tourism: observations from a single center in Korea. Nephrology. 2011;16(7):672–9. 20. Sever MŞ, Kazancioğlu R, Yildiz A, Türkmen A, Ecder T, Kayacan SM, et al. Outcome of living unrelated (commercial) renal transplantation. Kidney Int. 2001;60(4):1477–83. 21.• Anker AE, Feeley TH. Estimating the risks of acquiring a kidney abroad: a meta-analysis of complications following participation in transplant tourism. Clin Transplant. 2012;26(3):E232–41. A metaanalysis of 19 studies analyzing the infectious and non-infections complications of transplant tourism. 22. Colakolgu M, Yenicesu M, Akpolat T, Vural A, Utas C, Arinsoy T, et al. Nonrelated living-donor kidney transplantation: medical and ethical aspects. Nephron. 1998;79(4):447–51. 23. Sever M, Ecder T, Aydin AE, Türkmen A, KillÇaslan I, Uysal V, et al. Living unrelated (paid) kidney transplantation in third-world countries: high risk of complications besides the ethical problem. Nephrol Dial Transplant. 1994;9(4):350–4. 24. Tsai M-K, Yang C-Y, Lee C-Y, Yeh C-C, Hu R-H, Lee P-H. De novo malignancy is associated with renal transplant tourism. Kidney Int. 2011;79(8):908–13. 25. Prabhakar KS, Vathsala A, Woo KT. Long-term outcome of livingunrelated donor kidney transplantation. Transplant Proc. 2000;32(7):1807–8. 26. Allegranzi B, Nejad SB, Combescure C, Graafmans W, Attar H, Donaldson L, et al. Burden of endemic health-care-associated infection in developing countries: systematic review and meta-analysis. Lancet. 2011;377(9761):228–41.
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Hauri AM, Armstrong GL, Hutin YJF. The global burden of disease attributable to contaminated injections given in health care settings. Int J STD AIDS. 2004;15(1):7–16. 28. Martín-Dávila P, Fortún J, López-Vélez R, Norman F, de Oca MM, Zamarrón P, et al. Transmission of tropical and geographically restricted infections during solid-organ transplantation. Clin Microbiol Rev. 2008;21(1):60–96. 29. Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect Dis. 2010;10(9):597–602. 30. Harling R, Turbitt D, Millar M, Ushiro-Lumb I, Lacey S, Xavier G, et al. Passage from India: an outbreak of hepatitis B linked to a patient who acquired infection from health care overseas. Public Health. 2007;121(10):734–41. 31. Onwubalili JK, Obineche EN, Assuhaimi S, Bassiouni M. Outcome of bought living non-related donor kidneys followed up at a single centre. Transpl Int. 1994;7(1):27–32. 32. Alkhunaizi AM, Amir AA, Al-Tawfiq JA. Invasive fungal infections in living unrelated renal transplantation. Transplant Proc. 2005;37(7):3034–7. 33. Stas KJ, Louwagie PG, Van Damme BJ, Coosemans W, Waer M, Vanrenterghem YF. Isolated zygomycosis in a bought living unrelated kidney transplant. Transpl Int. 1996;9(6):600–2. 34. Shoham S, Hinestrosa F, Moore J, O’Donnell S, Ruiz M, Light J. Invasive filamentous fungal infections associated with renal transplant tourism. Transpl Infect Dis. 2010;12(4):371–4. 35. Fadhil RAS, Al-Thani H, Al-Maslamani Y, Ali O. Trichosporon fungal Arteritis causing rupture of vascular Anastamosis after commercial kidney transplantation: a case report and review of literature. Transplant Proc. 2011;43(2):657–9. 36. Nalmas S, Bishburg E, Goldstein C. Mucormycosis in a transplanted kidney. Transpl Infect Dis. 2008;10(4):269–71. 37. Mitwalli A, Malik GH, Al-Wakeel J, Aisha HA, Al-Mohaya S, AlJaser A, et al. Mucormycosis of the graft in a renal transplant recipient. Nephrol Dial Transplant. 1994;9(6):718–20. 38. Chkhotua A, Yussim A, Sobolev V, Bar-Nathan N, Shaharabani E, Shapir Z, et al. Mucormycosis of the renal allograft: case report and review of the literature. Transpl Int. 2001;14(6):438–41. 39. Geddes CC, Henderson A, Mackenzie P, Rodger SC. Outcome of patients from the west of Scotland traveling to Pakistan for living donor kidney transplants. Transplantation. 2008;86(8):1143–5. 40. Hung CC, Chang SC, Chen YC, Yen TS, Hsieh WC. Plasmodium vivax infection in a renal transplant recipient: report of a case. J Formos Med Assoc. 1994;93(10):888–9. 41. Türkmen A, Sever MS, Ecder T, Yildiz A, Aydin AE, Erkoç R, et al. Posttransplant malaria. Transplantation. 1996;62(10):1521–3.
TRANSPLANT AND ONCOLOGY (M ISON AND N THEODOROPOULOS, SECTION EDITORS)
Transplant Tourism: Understanding the Risks Jennifer M. Babik & Peter Chin-Hong
Published online: 14 April 2015 # Springer Science+Business Media New York 2015
Abstract Transplant tourism is commonly defined as travel abroad for the purpose of transplantation, but the term evokes ethical and legal concerns about commercial transplantation. Due to the mismatch in supply and demand for organs, transplant tourism has increased over the last several decades and now accounts for 10 % of transplants worldwide. Patients from the USA who pursue transplantation abroad do so most commonly for renal transplantation, and travel mostly to China, the Philippines, and India. Transplant tourism puts the organ recipient at risk for surgical complications, poor graft outcome, increased mortality, and a variety of infectious complications. Bacterial, viral, fungal, and parasitic infections have all been described, and most concerning are the high rates of blood-borne viral infections and invasive, often fatal, fungal infections. Transplant and infectious diseases physicians should have a high degree of suspicion for infectious complications in patients returning from transplantation abroad.
Keywords Transplant tourism . Solid organ transplant . Kidney transplant . Commercial transplant . Immunocompromise . Travel . Infection . Hepatitis B virus . Hepatitis C virus . HIV . Cytomegalovirus . Malaria . Fungal infection . Aspergillus . Zycomycetes . Multi-drug resistant . Wound infection . Tuberculosis . Pneumocystis jiroveci
Introduction Transplant tourism is most broadly defined as travel abroad for the purposes of transplantation, although the term evokes ethical and legal concerns [1, 2]. Some transplants acquired abroad may be considered Bemotionally related^ transplants procured in foreign countries for cultural or familial reasons. However, the majority are thought to be commercial transactions [1]. In fact, the Declaration of Istanbul on Organ Trafficking and Transplant Tourism defines transplant tourism more precisely as travel for transplantation that Binvolves organ trafficking and/or transplant commercialism or if the resources (organs, professionals, and transplant centers) devoted to providing transplants to patients from outside a country undermine the country’s ability to provide transplant services for its own population^ [3]. Transplant tourism carries many risks, most notably for the recipient but also for the donor and local transplant infrastructure. In this article, we will focus primarily on the risk incurred by the recipient. Ethical concerns, while not the focus of this article, are certainly paramount and include the exploitation of living donors, the possibility that organs from deceased donors in some countries (notably, China) are procured from executed prisoners [4, 5], and the erosion of development of deceased donor systems on a local level [6].
Epidemiology
This article is part of the Topical Collection on Transplant and Oncology J. M. Babik (*) : P. Chin-Hong Division of Infectious Diseases, Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA e-mail: [email protected] P. Chin-Hong e-mail: [email protected]
All nations, with the exception of Iran, now outlaw commercial transplantation. However, due to the significant mismatch in supply and demand for organs in the developed world, the practice continues widely and has garnered considerable attention by international transplant societies [3, 7••] and the lay press [8]. In fact, transplant tourism has actually been increasing over the last 20 years in developing countries [2, 9–11] and now makes up approximately 10 % of all transplants worldwide [10].
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There are many countries where transplant tourism has occurred, but the countries with the highest number of cases are China, India, Philippines, Pakistan, and Iran (Fig. 1) [2, 11, 12, 21•]. In a study of patients on transplant waiting lists in the USA, 373 patients underwent transplantation abroad over a 20-year period between 1987 and 2006 [2]. Of these transplants, 89 % were kidney transplants. Transplants took place in 35 different countries but most took place in China (26 %), the Philippines (12 %), India (10 %), and Pakistan (4 %). Patients undergoing transplants abroad were more likely to be male, Asian, have a college or graduate level education, be from California or New York, and be a resident or nonresident alien of the USA. This last category deserves further mention, as most patients who leave the USA to acquire a transplant abroad travel to a region of shared ethnicity or religion [11–13]. Most patients who leave the USA for transplant receive living unrelated transplants [11, 12]. Although there is not a lot of data on why patients choose to travel for transplantation, a survey of transplant centers in the UK and Ireland identified several reasons, including shorter wait list times, inability to be listed in their country of residence, and having family ties or a living donor abroad [14].
Risks for the Donor Although the majority of this article will discuss the risks incurred by the transplant organ recipient, it is important to
Curr Infect Dis Rep (2015) 17: 18
mention the risks to the donor as well. Most donors involved in transplant tourism have a decline in medical and psychological health after donation [6, 15]. Despite the fact that the incentive of a commercial donor is almost always financial, these donors usually see little to no economic improvement after donation [6, 15]. In fact, many donors even see a decline in economic status due to post-operative declines in medical and emotional health [6].
Non-infectious Risks for the Recipient Logistical Challenges in Transitions of Care Multiple studies have demonstrated poor communication between the transplanting center abroad and the continuing care center in the patient’s home country, mainly related to inadequate documentation of donor information and perioperative care [4, 11, 12, 16–18••]. This includes minimal information on donor and recipient screening (including donor CMV serostatus), HLA matching, cold ischemia time, intraoperative procedures, and details of immunosuppressive regimens and antimicrobial prophylaxis. In addition, as for all types of medical tourism, accreditation of care providers may be variable, and there is a lack of liability in the case of poor outcomes [18••].
Fig. 1 Countries where transplant tourism has occurred. Shown in red are the countries in which the highest numbers of transplant tourism cases have occurred (China, India, Pakistan, Philippines, and Iran). Other countries in which transplant tourism has occurred are shown in light red
Curr Infect Dis Rep (2015) 17: 18
Patient and Graft Outcomes The majority of studies show lower graft and patient survival rates in commercial kidney transplantation compared with domestic transplantation, with 1-year graft survival rates between 65–96 % and patient survival rates 78–96 % [4–6, 13, 16, 19–21•, 22]. A Canadian study showed a >2-fold increase in the risk of graft failure and death with transplant tourism (most transplants in this study were done in South and East Asia) [16]. In addition, rejection rates are up to two times higher in transplants done abroad versus domestically [11, 19]. Patients undergoing transplant abroad have an up to 23fold increased risk of hospitalization [19], with rates up to 42 % in the first 3 months after transplantation [20]. Medical and Surgical Complications Multiple studies report surgical complications, often discovered upon presentation to the home institution, including problems with the anastomosis, urinary fistulas, lymphocele, hydrocele, and urinary obstruction [6, 9, 20, 23]. A systematic review on transplant tourism outcomes showed an increased rate of post-transplant diabetes in patients who underwent transplantation abroad [21•]. Interestingly, a study in Taiwan showed that the risk of malignancy was threefold higher in the cohort of patients who underwent renal transplantation in China versus those who had their transplant domestically in Taiwan [24]. Most of these were urothelial malignancies, thought possibly secondary to the older age of the tourist group or increased rates of depleting antibodies used in this group.
Infectious Risks for the Recipient Increased Risk of Infection The majority of studies on outcomes in transplant tourism show a significant increased risk of infection in the tourism group, whose rate of infections are approximately 45–54 % versus 5 % in the non-tourist group [16, 19, 20, 25]. One study showed that transplant tourism conferred an increased risk of infection by 85-fold compared with domestic transplants [19]. These infections often occurred early in the post-transplant course [12, 20]. Bacterial, viral, fungal, and parasitic infections have all been described (Table 1). Infections in the setting of transplant tourism can be from procedural complications (such as wound infections), nosocomial infections, blood-borne pathogens, or due to a geographically restricted pathogen acquired as a donor-derived infection or acquired in the peri-transplant period while staying in an area of endemicity [18••]. The risk of nosocomial infections is significantly higher in developing countries [26]. ICU infection rates are 3.5-fold higher, and surgical site infection
Page 3 of 6 18
rates are twofold higher in developing countries compared to developed nations [26]. Another sobering statistic is that 39 % of injections given in the developing world are provided with reused equipment [27]. Explanations for the high rates of infection include the following: (1) many regions where transplant tourism is practiced are tropical or subtropical areas with high rates of endemic infections such as malaria, tuberculosis (TB), and other geographically restricted infections; (2) these regions often have a high prevalence of pathogens such as HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV); (3) donor infectious diseases screening is likely variable and the assays used may be substandard; (4) poor hygiene and operative conditions may exist; (5) inadequate education of patients regarding infectious risk post-transplant; and (6) lack of prophylaxis against opportunistic infections [1, 11, 12, 14, 18••, 28]. Bacterial Infections Many reports describe wound infections, often severe, in patients returning from a transplant abroad [4, 6, 9, 11, 21•, 20, 23]. These infections have been described with resistant organisms, including multi-drug resistant Pseudomonas and vancomycin-resistant Enterococcus [4, 11]. Urinary tract infections are also common, including infections with multidrug resistant Escherichia coli [16] and Acinetobacter [13]. Multi-drug resistant organisms are a significant concern in many developing countries where antibiotics can be purchased without a prescription, leading to overuse and widespread resistance [18••]. For example, ESBL rates in India are 70–90 % [18••, 29]. In addition, the New Delhi-metallo-βlactamase (NDM) carbapenemases were initially isolated in India but subsequently have been found in many other countries, often introduced by patients who have pursued medical tourism abroad, including transplantation [18••, 29]. In the absence of overt infection, travelers can also return colonized with multi-drug resistant pathogens [18••]. TB has been described in 2–15 % of patients who have procured a transplant abroad [6, 16], including a fatal disseminated case in the USA that was acquired in Pakistan [13]. Viral Infections Transplant tourism increases the risk of several viral infections, most importantly HIV, HBV, and cytomegalovirus (CMV). CMV has been reported in up to 33 % of patients returning from transplants abroad, usually occurring in the first few months after transplant [4, 6, 11, 16]. This has been attributed to very low rates of CMV prophylaxis use in this group [11, 14]. Patients returning from transplantation abroad have reportedly high rates of seroconversion with HIV (4–6 %) and HBV (2–18 %) [4, 21•, 25]. Some cases of HBV infection have been fatal [11] and others have led to local outbreaks, raising a
18 Page 4 of 6 Table 1
Curr Infect Dis Rep (2015) 17: 18
Infectious complications of transplant tourism
Pathogen
Riska
Comments
Reference
Bacterial Infections Wound infections
Unknown, likely high
[4], [6], [9], [11], [20], [21], [23]
Urinary tract infection Tuberculosis
Unknown 2–15 %
Can be severe and require surgical intervention; can be due to MDR organisms. Can be due to MDR organisms. Fatal cases have been described.
Viral Infections HIV
4–6 %
Hepatitis B virus Hepatitis C virus Cytomegalovirus
2–18 % Unknown, likely high Up to 33 %
Fungal Infections Molds
4%
Pneumocystis jiroveci
8%
Parasitic Infections Malaria
6–11 %
a
High rate of blood-borne pathogens likely due to inadequate donor screening and high background rate of infection in the community. As for HIV. Fatal cases have been described. As for HIV. Likely due to lack of prophylaxis.
[13], [16] [6], [13], [16]
[4], [21], [25]
[4], [11], [21], [25] [31] [4], [6], [11], [16]
Often disseminated, involve the CNS, or directly involve the renal graft. High rates of graft loss and death. Aspergillus accounts for 2/3 of cases, and Zygomycetes 1/4 of cases. Likely due to variable prophylaxis.
[17], [33–38]
Most common in transplants done in India; acquired via the organ, blood transfusion, or mosquito bite.
[20], [23], [39–41]
[19]
The percentage of patients who return from transplantation abroad with the specific infectious complication.
MDR multi-drug resistant
public health concern for the introduction of communicable diseases into the community from transplant tourism [30]. There also appears to be an increased risk of HCV based on the high prevalence of HCV seropositivity in patients who have undergone transplantation abroad (up to 37 % in one study), although limited pre-transplant screening in some cases makes the exact number that have been transmitted via transplantation unknown [31]. These high rates of infection with blood-borne pathogens are thought due to inadequate donor screening and/or transmission while on hemodialysis in the foreign country [25]. A study of commercial kidney donors in Pakistan showed that 24 % were HCV antibody positive and 4 % hepatitis B surface antigen positive following organ donation. It is not known if these donors had preexisting infections or acquired infection in the setting of transplant, but the former was suspected [15]. Fungal Infections Fungal infection is perhaps the most feared infectious complication of transplant tourism and occurs in approximately 4 % of patients [32]. The most common fungi reported are Aspergillus and Zygomycetes but there are also rare cases of Ramichloridium, Pseudallescheria boydii, and Trichosporon [17, 33–38]. These infections may directly involve the
transplanted kidney and can be necrotic, form abscesses, and involve the vasculature. A review of 19 fungal infections in 17 commercial renal transplants performed in Asia or the Middle East showed that 63 % were Aspergillus and 26 % were Zygomycetes [34]. All infections were extrapulmonary or disseminated with direct involvement of the graft in 35 % and infection of the CNS in 29 %. Graft loss occurred in 76 % and the overall mortality in this group was 59 %. The very high rates of direct infection of the graft were thought to be due to infection in the donor or contamination of the organ during procurement, transport, or transplantation [33, 34, 36, 38]. Presumably as a result of this mechanism of infection, transplant tourism accounts for 22 % of all donor-derived filamentous fungal infections [17]. Pneumocystis jiroveci (PCP) is also more commonly seen in the setting of transplant tourism. In one study, rates of PCP in patients undergoing transplant in China was 8 % compared to 1 % in those done domestically in Korea [19]. Similar to the case of CMV, this may be due to variable practices in prescribing prophylaxis [11, 14]. Parasitic Infections The parasitic infection that has been reported most commonly in the setting of transplant tourism is malaria. It has been most
Curr Infect Dis Rep (2015) 17: 18
frequently described in patients who received their transplants in India with a rate of 6–11 % [20, 23, 39–41]. Infections usually occur at a mean of 44 days (range 20–83) after transplantation and have been described with Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae [41]. In general, patients do well with rapid recovery following the initiation of antimalarial therapy [41]. It is presumed that the infection is acquired via the organ itself, in the setting of blood transfusion peri-operatively, or by mosquito bites within the foreign country [23]. Many other geographically restricted parasites, such as Trypanosoma cruzi and Strongyloides, have been transmitted in the setting of organ transplantation, although not necessarily in the setting of transplant tourism [28]. Prevention of Infection Most transplant physicians have no prior knowledge that their patients are planning to go overseas for the purposes of transplant tourism [14]. However, if physicians did have knowledge ahead of time, this could allow for counseling regarding the ethical (and legal) considerations involved as well as well as significant risks, both noninfectious and infectious, involved in transplant tourism [7••]. As for any other immunocompromised patient who is planning to travel, these patients could be given appropriate vaccines and other precautions about travel abroad [7••]. When these patients return to their home country after transplant abroad, it is recommended to (1) consider screening for blood-borne pathogens (HIV, HBV, and HCV) by molecular methods, (2) evaluate for bacteremia and urinary tract infection with appropriate cultures, (3) ensure adequate prophylaxis of opportunistic infections, and (4) consider screening for other endemic infections depending on the country where the transplant occurred (e.g., malaria, TB, T. cruzi, Strongyloides) [7••].
Conclusion Transplant tourism is unfortunately increasing despite international policies to prohibit commercial transplantation. Transplant tourism carries the risk of surgical complications, poor graft outcomes, increased mortality, and a significant increase in infectious complications. Bacterial, viral, parasitic, and fungal infections have all been described, and of particular concern are the high rates of blood-borne viral infections and invasive, often fatal, fungal infections. Transplant and infectious diseases physicians should have a high degree of suspicion for infectious complications, including unusual infections, in patients returning from transplantation abroad. Acknowledgments The authors would like to thank Ban Hock Tan for his assistance. Dr. Chin-Hong is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through
Page 5 of 6 18 UCSF-CTSI Grant Numbers UL1 TR000004 and TL1 TR000144. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Compliance with Ethics Guidelines Conflict of Interest Jennifer Babik and Peter Chin-Hong have no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.
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