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Milestones in Transplantation History

“… if there is a father of heart and lung transplantation.

then Demikhov certainly deserves this title” (C. Barnard).

The miracle of Cosmas and Damian (martyrs, 287 A.D.) depicted the first evidence of transplantation. According to tradition, these martyrs grafted the leg from a barely deceased Ethiopian onto a Caucasian patient, in order to replace his ulcerated leg. See Fig. 1.1.

Fig. 1.1
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The Healing of Justinian by Saint Cosmas and Saint Damian. Fra Angelico (circa 1438–1440) (Source: https://commons.wikimedia.org/wiki/File:Fra_Angelico_-_The_Healing_of_Justinian_by_Saint_Cosmas_and_Saint_Damian_-_WGA00519.jpg. Fra Angelico [Public domain], via Wikimedia Commons)

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In modern times, Vladimir P. Demikhov (Moscow) (Fig. 1.2a), a Russian physiologist, presented the first important stimulus in developing transplantation science: he transplanted a dog head onto the neck of another dog in 1940, and this dog survived for several days [1]. Furthermore, he performed the first lung transplantation (right inferior lobe) on a dog, and the dog survived for 7 days; it died from a pneumothorax due to a bronchial suture dehiscence [1]. Demikhov continued these attempts at transplantations in dogs (Fig. 1.2b). The complication which doomed his first lung transplant attempt became the main challenge in his following attempts; simultaneously, Demikhov demonstrated that bronchial arteries and nerves are unnecessary in the lung function of the recipient [1].

Fig. 1.2
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(a) Vladimir Demikhov (1916–1998) (Source: ITAR-TASS News Agency/Alamy Stock Photo). (b) The last dog head transplant performed by Dr. Demikhov (Source: Bundesarchiv, Bild 183–61478-0004/Weiß, Günter/CC-BY-SA 3.0)

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Alexis Carrel (University of Chicago) (Fig. 1.3) is another important pioneer in the lung transplantation field. His innovations in surgical techniques, mainly in end-to-end anastomosis (for which he received the Nobel Prize in 1912), allowed the beginning of a new era dedicated to whole organ transplantations [2]. In 1907, Carrel and C.C Guthrie (University of Chicago) performed a heterotopic heart-lung transplantation on the neck of a cat; it died 3 days later, probably from an acute rejection [3, 4].

Fig. 1.3
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Dr. Alexis Carrel (1873–1944) in 1912 (Source: https://commons.wikimedia.org/wiki/File:Alexis_Carrel_(1912).jpg#filelinks. Forms part of George Grantham Bain Collection, Library of Congress. Public Domain)

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In 1954, Joseph E. Murray (Massachusetts) performed the first human kidney transplantation on twins in order to avoid rejection problems. This experience established the first evidence of the feasibility of transplants applied to human [5]. The most important landmark in lung transplantation history was the first human single-lung transplantation performed in 1963 by the pioneer James D. Hardy (University of Mississippi) [2]. Four years later, Christiaan Barnard (University of Cape Town) (Fig. 1.4) realized the first human-to-human heart transplantation [2].

Fig. 1.4
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Dr. Christiaan Barnard (1922–2001) (Used with permission of University Stamp Co., Inc./University Archives, Westport, CT, USA)

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However, despite these and other achievements and promising results, lung transplantation developed with delay when compared to transplantation of other organs such as the heart, kidney, and liver. This was due mainly to the lung’s frailty, to the major exposure to infections from the external world, and to the absence of systemic bronchial connections after the transplantation [2].

The Pre-Hardy First Human Lung Transplant Era: Lessons Learned from Animal Models of Lung Transplantation

In 1950, Henri Metras (Marseille) described an innovative experiment concerning the venous anastomosis of a lung transplantation in a dog involving the pulmonary veins with the left atrium cuff [6]. He also demonstrated the possibility of preserving the bronchial arterial support with a connection to the subclavian artery. Furthermore, he was the first to succeed in allotransplantation [6].

In 1950, Vittorio Staudacher (Milan) compared allotransplantation and autotransplantation in dogs in order to better investigate the physiopathology of rejections [7]. In the same manner, A. A. Juvenelle (Buffalo University) attempted reimplantation (autotransplantation) in canine models for physiological studies [8]. This study would be continued later in 1953 by W. B. Neptune (Philadelphia), who conducted canine experiments on bronchial anastomosis and investigated post-transplant dehiscence and the resulting recipient death. He proved that the use of adrenocorticotropic hormone (ACTH) actually improved survival [9]. In 1954, Creighton A. Hardin and C. F. Kittle (Kansas) established the functional capacity of a lung allotransplant. They also demonstrated that the use of cortisone could efficiently increase the survival of the recipient [10].

Nevertheless, despite these advancements, the main issue still being debated was the role of hilar vascular and nerve structures [11]. Table 1.1 lists the most important stages of this phase: the grafted lung has normal functional pattern if part of the recipient lung remains in place, and the autonomic nerves are important for pulmonary function. However, there is no explanation regarding the reduction of lung function post-transplantation [11].

Table 1.1 Lessons from animal models of lung transplantation
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Finally, immunosuppressive therapy received attention through the work of David A. Blumenstock in 1961 (New York) and James D. Hardy in 1963 (Mississippi) [12, 13], specifically concerning the possible use of cortisone, ACTH, total body irradiation, and splenectomy.

Lessons from the First Human Lung Transplantation by Hardy

In 1963, James D. Hardy (Fig. 1.5) performed the first human lung transplantation on a prisoner affected by lung central carcinoma with nodal metastases; the left graft lung was harvested from a man who died of massive acute myocardial infarction [11, 14]. Immunosuppressive therapy , consisting of azathioprine, cortisone, and cobalt irradiation of the thymic region, was also administered [11, 14]. The patient survived for 18 days, and the death was ascribed to kidney failure and malnutrition [11, 14].

Fig. 1.5
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Dr. James D. Hardy (1918–2003): “…research became a vital part of my professional life….” (Used with permission of the University of Mississippi. Medical Center. Source: https://www.umc.edu/uploadedImages/UMCedu/Content/Administration/Institutional_Advancement/Public_Affairs/News_and_Publications/Press_Releases/2013/2013-06-10/Hardy%20in%20Scrubs.jpg)

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From 1963 to 1973, several lung transplantation attempts were performed, but with little success. Indeed, only sporadic experiments showed significant results, such as the one by Fritz Derom in 1968 (Belgium), who reported a 10-month posttransplantation survival [15].

In 1970, Frank J. Veith (New York) confirmed the feasibility of single-lung transplantation [16]. However, several troublesome issues still existed: the unadapted immunosuppression and consequent graft rejection, the infection problems, and, finally, the maldistribution of ventilation and perfusion in the grafted lung [16]. Subsequently, the anastomosis dehiscence problem became the main topic.

From 1963 to 1983, many laboratories focused their studies on [11]:

  1. 1.

    Pulmonary denervation : Based on Haglin’s work (Minneapolis, 1963), S. Nakae (Texas Southwestern) conducted studies in 1967 testing the efficiency of lung transplantation on rhesus monkeys, dogs, and cats; only rhesus monkeys had normal pattern lung ventilation after the transplantation [17]. He tested different techniques on four categories of animals from different species: mediastinal denervation with tracheal transaction and reanastomosis onto dogs, cats, and rhesus monkeys. The fourth group consisted of dogs that underwent total mediastinal denervation [17]. The conclusion of his work was that humans and primates have a different respiratory reflex compared to dogs, and, for this reason, they have a normal functional lung pattern after lung transplantation [17].

  2. 2.

    Pulmonary vascular physiology after lung transplantation : Several studies up until 1960 had underlined the frequency of pulmonary hypertension after lung transplantation and ligation of the contralateral pulmonary artery [18,19,20]. This problem was mainly due to venous anastomosis obstruction. In order to prevent this complication, Frank J. Veith and K. Richards introduced the concept of left atrium cuff in 1970 [21].

  3. 3.

    Dehiscence of bronchial anastomosis : This complication was the focal point of interest of the “Toronto Lung Transplantation Group,” the main thoracic surgical center in Toronto, founded by F. Griff Pearson in 1968 (Fig. 1.6) and later directed by Joel D. Cooper (Fig. 1.7). It was Joel D. Cooper who in 1978 first performed a right lung transplantation in a 19-year-old man who was ventilator-dependent and affected by pulmonary failure due to inhalation injuries sustained during a home fire [22]. A veno-venous extracorporeal membrane oxygenator (ECMO) was previously positioned and maintained for few days after the transplant [22]. The patient survived for 17 days and died from bronchial anastomosis dehiscence [22]. The autopsy reported circumferential area of necrosis, poor healing of pulmonary artery, and atrium anastomosis [22].

Fig. 1.6
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Dr. F. Griff Pearson (1926–2016). Removal of kidneys, donor for lung transplant (Used courtesy of University Health Network Archives, Toronto, Canada)

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Fig. 1.7
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Drs. Thomas Todd, Joel Cooper, Alec Patterson, and Griffith Pearson (seated). Toronto General Hospital Division of Thoracic Surgery (1987) (Used with permission of Joel D. Cooper, MD, FACS, Chief of Thoracic Surgery, Department of Surgery, University of Pennsylvania Health System)

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Due to the results of the Toronto Centre experiments and different trials from similar groups, the human transplant program was temporarily interrupted in order to assess the bronchial anastomosis in laboratory studies [2, 11].

The 1970s to the Early 1990s: The Bronchial Anastomosis Era—Lung Transplantation Dilemma

In 1981, M. Goldberg (Toronto Group) first evaluated the combined use of cortisone and azathioprine after lung transplantation in canine models and reported bronchial anastomosis damage associated with this technique; later, he analyzed these drugs separately in order to underline the sensitivity of bronchial dehiscence to steroids [23]. Another study compared the use of different immunosuppression drugs in dogs: in the first group, dogs were treated with a combination of steroid and azathioprine; in the second group, only cyclosporine A was used; the third control group was composed of untreated dogs [24]. This analysis revealed that the correct regimen for healing anastomosis for dogs was with cyclosporine A [24].

At this time, important efforts were focused on finding a method providing bronchial arterial blood flow to the anastomosis site. R. M. Stone in 1966 (Toronto Group) demonstrated the restoration of bronchial circulation in only 4 weeks in dogs following a primary phase of cyanosis, edema, and secretion retention mainly due to irregular bronchial mucosa blood supply [25].

In 1970, N. L. Mills (New York) proposed the connection of the left bronchial artery and the intercostal arteries to the aorta as an alternative solution for left lung transplantation [26]. The control group of dogs without reimplantation evidenced more postoperative complications, such as ulcerations, poor healing anastomosis, and stenosis [26].

F. Griff Pearson (Toronto), using angiography in 1970, demonstrated the bronchial artery reconstruction after 4 weeks from lung asportation and reimplantation in dog models, thanks to the connection of the bronchial arterial channels into the bronchial wall [27]. This result was also successively confirmed by J. J. Rabinovich (Moscow) through left inferior lung lobe autotransplantation [28].

In 1977, Stanley S. Siegelman (New York) analyzed allotransplantation versus autotransplantation/reimplantation in canine models in a manner that was different from previous studies [29]. He noticed that, during the second week after the transplant, an arterial network develops around the bronchial anastomosis and that, after 31 days, a copious arterial pattern is generally present behind the anastomosis [29]. Furthermore, he announced that no correlation existed between the possible regeneration of bronchial flow and bronchial anastomosis dehiscence: some animals with bronchial flow restoration had bronchial dehiscence in any case, but the opposite situation was also observed [29].

Hence, the cause of the lung transplantation dilemma could be attributed to two different sources: the immunosuppression therapy and the correlated rejection. With Goldberg’s study in mind, O. Lima and Joel D. Cooper (Toronto) introduced the omentopexy technique in 1982: using an omental pedicle appropriately vascularized and able to avoid infections, the bronchial anastomosis was reinforced and its healing facilitated [30].

After all these experimental results, the Toronto Lung Transplantation Group restarted its attempts of lung transplantation in humans.

The Successful Lung Transplantation Era: From the Mid-1990s to the Present

In 1982, Bruce A. Reitz and Norman E. Shumway (Fig. 1.8) performed the first three heart-lung transplantations in humans at the University of Stanford [31]. The three recipients were affected by primary pulmonary hypertension, Eisenmenger’s syndrome, and transposition of the great vessels, respectively. In all the cases, cyclosporine A was the immunosuppression therapy: it became the primary agent for immunosuppression [31]. It was generally associated with azathioprine or mycophenolate, followed by induction therapy with basiliximab. The survival range of these three attempts was from 12 h to 23 days [31]. The Stanford Group underlined the importance of preserving the vagus nerves and the left recurrent laryngeal nerve during recipient dissection [31].

Fig. 1.8
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Dr. Norman E. Shumway (1923–2006) (inset and at patient’s left) performing the first adult US heart transplant with Dr. Edward Stinson, January 7, 1968 (Source: http://bulletin.facs.org/wp-content/uploads/2012/05/Shumway.jpg. Used with permission of the American College of Surgeons, Chicago, IL, USA)

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In 1982, the Toronto Group performed a right lung transplantation on a patient with respiratory failure due to an accidental paraquat poisoning; the left lung also ended up being transplanted [32]. However, paraquat induced generalized myopathy which caused the patient’s death 3 months later [32]. The selection criteria of the recipient came under scrutiny, and, at this time, only patients affected by idiopathic pulmonary fibrosis and end-stage disease without important comorbidities and who were not ventilator-dependent could be treated by transplantation [2].

November 7, 1983, marked the beginning of the successful lung transplantation era with a right lung transplant in a patient who survived for nearly 5 years: the bronchial anastomosis was performed using omentopexy, and immunosuppression with azathioprine, cyclosporine, and steroid was introduced [2, 33]. After nearly 5 years, the patient died from transbronchial biopsy complications [2, 33].

For patients affected by cystic fibrosis or chronic obstructive pulmonary diseases (COPD ) with bilateral impairment, a heart-lung transplant was at this point under consideration [2, 11]. However, there were several areas of concern: heart transplant was unnecessary; heart or/and lung rejection could develop simultaneously or separately; postoperative follow-up was more complicated; a right heart dysfunction could be reversible after lung transplantation [2, 11].

In light of these concerns, J. H. Dark introduced, in 1986, the en bloc double-lung transplantation with distal tracheal anastomosis, pulmonary artery anastomosis at the main pulmonary artery level, and venous anastomosis with the left atrium cuff [34]. This procedure was complicated due to the necessity of the cardiopulmonary bypass but also due to the possible tracheal anastomosis dehiscence [2]. Consequently, the Toronto Group introduced the sequential bilateral lung transplant , implanting each lung separately with transverse bilateral thoracosternotomy incision [2].

With regard to bronchial anastomosis , Joel D. Cooper in 1987 described the use of an interrupted or running sutures with Prolene® (Ethicon, Somerville, NJ, USA) for the cartilaginous portion and interrupted sutures with Vicryl® (Ethicon, Somerville, NJ, USA) for the membranous portion (the “end-to-end bronchus anastomosis”) associated with the omentopexy by the omental mobilization with a small upper abdominal midline incision and its placement in subxiphoid position [35]. The omentopexy was successively abandoned in place of local tissue used to surround bronchial anastomosis [2].

J. H. Calhoon and J. K. Trinkle introduced the “telescoped bronchus anastomosis ”: a running suture for the posterior and membranous part of the bronchus and an interrupted figure-of-eight suture for the anterior portion [36]. Considering that generally there is some size discrepancy between the two bronchial stumps, the anastomosis telescopes one ring [36], and the donor bronchus was invaginated into the recipient bronchus by one or two cartilaginous rings [37]. This new technique did not use omentopexy, avoided the laparotomy, and reduced surgical time [36].

E. S. Garfein described the superiority of the end-to-end bronchus anastomosis versus the telescoped one in 2001: a higher incidence of anastomotic complications was seen for the telescoped versus the end-to-end anastomosis, in particular ischemia, dehiscence, and severe stenosis [37]. At this point, certain centers adopted the end-to-end anastomosis, and others adopted the telescoped one, with the range of complications slightly higher for the telescoped anastomosis [37].

In 2002, C. Schröder introduced a modified intussuscepting technique to avoid complications (malacia, granulation tissue, or subcritical stenosis) that still remained with end-to-end or telescoped anastomosis [38]. The modified technique uses a running suture for the membranous portion, just three U stitches (at 0°, 90°, and 180°) and two or three figure-of-eight sutures in between; it allows for an improved coaptation of the bronchial walls and reduces the ledge of the bronchus that protrudes into the lumen of the other one [38].

At this juncture, new issues arose: the selection of donor and recipient; the best timing for transplant and allocation system, lung preservation, and immunosuppression; and the diagnosis of/therapy for rejection [2]. Lung transplantation at this time was indicated for all end-stage pulmonary diseases [39]: pulmonary vascular diseases, obstructive lung pathologies, and restrictive lung diseases.

In 1990, Stanford University performed the first lung transplant from a living donor : a 45-year-old mother donated a third of her right lung to substitute for the whole right lung of her 12-year-old daughter affected by bronchopulmonary dysplasia [40]. This option was not accepted as a rule due to the high risk to the pulmonary reserve of the donor [41]. However, the lack of organ donors imposed the introduction of best lung preservation strategies [41]: as reported by Thomas M. Egan (Fig. 1.9), “improved methods for preservation will increase the supply of suitable lungs…efficient use of donor organs remains of paramount importance” [39]. In the beginning, the Toronto Group used hypothermic cold saline solution before adopting the Euro-Collins solution to rinse lungs [2]. Later, S. Fujimura demonstrated the preservation of dog lungs for more than 24 h with a low-potassium dextran solution [2, 39]. This became known as the “Fujimura solution ” and was used in the following years to flush lungs during the preservation period [2, 39].

Fig. 1.9
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Dr. Thomas M. Egan (Source: https://www.med.unc.edu/ct/images/Egan%20photo%202%202-11.jpg. Used with permission of University of North Carolina Health Care)

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Changes in the Allocation of Donor Lung to Recipient in 1986: Allocation Prioritized Based on Severity of the Recipient Status Rather Than the Order of Listing

In 1986, the Health Resources and Services Administration (HRSA) in the United States introduced the Organ Procurement and Transplantation Network (OPTN) to create a connection between the solid organ donation organizations and the transplantation system [42]. Prior to this, the United Network for Organ Sharing (UNOS) operated the OPTN, under a contract with the HRSA [42]. The Scientific Registry for Transplant Recipients (SRTR) with the OPTN supported the scientific and clinical status of solid organ transplant in the United States [42]. In 1990, the donor lung allocation system was based on ABO match and cumulative time on the waiting list; first, the candidate was placed into the donor service area of the donor hospital and thereafter into an area 500 nautical miles distant from this hospital [42]. In 1998, the “final rules” of the allocation system based on clinical criteria and medical urgency were drafted, with the purpose of sharing organs and reducing the number of deaths on the waiting list [43]. Finally, in 2005, a new system of allocation was created by the OPTN, the Lung Allocation Score (LAS): a donor priority was assigned based on a score calculated using the waiting list survival (urgency criteria) and the 1-year survival after transplant; this score has been regularly updated; is still in use in the United States, Germany, and the Netherlands; and is used by the Eurotransplant Program when the match is outside of the donor’s country [2].

Information sharing internationally in the field of heart and lung transplant became mandatory at this point in order to improve knowledge in this field; therefore, in 1981, Norman E. Shumway founded the International Society for Heart and Lung Transplantation (ISHLT) , a voluntary registry and data sharing organization and a source for classifications and guidelines that are still used to this day [2].

In 1993, the ISHLT introduced the concept of bronchiolitis obliterans syndrome (BOS) as a chronic allograft dysfunction in order to address post-lung transplantation dysfunction [2]. Recently, restrictive allograft syndrome was recognized as a new form of chronic lung rejection [2]. Regarding immunosuppression therapy, the associated use of calcineurin inhibitor, steroid, and either azathioprine or mycophenolate mofetil has continued as a drug strategy after lung transplantation [2].

At this point, the topic of bronchial artery revascularization after lung transplantation was being revisited, and it is important to mention several developments. Since H. H. J. Schreinemakers [44, 45], who reemphasized the possible role of bronchial ischemia in airway healing impairment and previously described the use of an intercostobronchial artery pedicle [46], different attempts were subsequently published. L. Couraud described the possible use of a vein graft [47, 48]. In 1993, R. C. Daly and Magdi H. Yacoub described the possible use of the left internal thoracic artery in double-lung transplantation to obtain an immediate revascularization of the whole tracheobronchial tree [49]. In 1994, they showed analogous data concerning the single-lung transplantation [45]. In 1996, M. A. Norgaard highlighted the convincing results of the correlation between the healing bronchial airway and bronchial artery revascularization and the long-term patency of the mammary artery [50]. Lastly, the wide experience of Copenhagen Group showed the use of mammary artery for single-/double-lung transplantation or heart-lung transplant [48, 51].

The entire role and long-term outcome of bronchial revascularization should be confirmed by future multicenter studies [52].

In order to increase the donor organ number, different strategies have been introduced, such as extending donor criteria and/or using deceased cardiac donors (DCD) [53]. The field of normothermic ex vivo lung perfusion (EVLP) developed in response to questionable and injured lungs in order to expand donor criteria [53]. The first report of normothermic ex vivo organ experiences was described by Alexis Carrel and C. A. Lindbergh in 1935 [53, 54], while the first EVLP was presented by D. W. Jirsch in 1970 [55]. However, these experiences failed due to the loss of the lung alveolar-capillary barrier, the onset of edema, and the vascular resistance increase during EVLP [53]. The Steen Solution (XVIVO Perfusion, Göteborg, Sweden) was introduced as lung perfusion to maintain the fluid in the intravascular space and supply nutrients for pulmonary homeostasis [56,57,58]. At this juncture, the main issue was the duration of the preservation period, which was less than 60 min. Hence, in 2008, the Toronto Group introduced a new EVLP method in order to extend this time to longer than 12 h and, thus, gain time to assess, recondition, and repair the donor lungs [53, 59]. Actually, the Toronto method is the one most used for the EVLP: it consists of creating an optimal environment for the donor lung operation, a protective ventilation setting without circuit-induced injuries (using flow parameter to prevent mechanical shear stress), and adopting a perfusate with a chemical composition appropriate for homeostasis [53]. See Fig. 1.10.

Fig. 1.10
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Cypel ex vivo lung circuit. EVLP normothermic lung circuit allowing both functional assessment and repair. Note insert’s red tank indicating a hypoxic gas. For more information see Cypel M, Liu M, Rubacha M, Yeung JC, Hirayama S, Anraku M, Sato M, Medin J, Davidson BL, de Perrot M, Waddell TK, Slutsky AS, Keshavjee S. Functional repair of human donor lungs by IL-10 gene therapy. Sci Transl Med. 2009;Oct 28:1(4):4ra9; and Steen S, Ingemansson R, Eriksson L, Pierre L, Algotsson L, Wierup P, Liao Q, Eyjolfsson A, Gustafsson R, Sjöberg T. First human transplantation of a nonacceptable donor lung after reconditioning ex vivo. Ann Thorac Surg. 2007;83(6):2191–4 (Used with permission of Dr. James G. Chandler and the American College of Surgeons, from http://bulletin.facs.org/2012/01/sanctity-2/#.WqBgCGrwaM9)

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Despite the controversy that emerged at the beginning of DCD attempts due to the frailty of the donor lungs, there were reports of successes; starting with one first reported in 1995 by R. B. Love [60], later attempts also confirmed positive results, as demonstrated by G. I. Snell in 2008 [61] and successive ones by Jeremie Reeb [62] and Marcelo Cypel [63]. Thus, a new category of lung donor developed: the uncontrolled donation after circulatory determination of death donor (uDCDD) associated with the use of EVLP. Good postoperative outcomes have been reported [53, 64, 65].