Introduction

Lung transplantation (LTx) is now a well-accepted treatment option for a variety of selected end-stage lung diseases(ESLD) which improves survival rates and quality of life [1]. The International Society for Heart and Lung Transplantation Registry reports a 1 and 5-year survival of 85% and 59%, respectively, for adult lung transplant recipients transplanted since 2010 [2].

The current indications of LTx are, but not limited to, chronic obstructive pulmonary disease (COPD), interstitial lung diseases (ILDs), cystic fibrosis (CF), non-CF bronchiectasis, and pulmonary hypertension (Table 1) [3,4,5,6,7]. LTx is not usually considered in patients with acute lung injury (ALI) due to any infectious cause. However, there has been a paradigm shift in the treatment strategy in the cohort of ALI due to COVID-19 [8].

Table 1 Indications of Lung transplantation as per the ISHLT
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Three methods of LTxs are possible. These are single lung transplant through posterolateral thoracotomy, double lung transplant with a clamshell incision, and combined heart and lung transplant as enbloc through median sternotomy. Double lung transplant is routinely performed through either a clamshell or bilateral thoracotomies, depending on the surgeons’ preference or underlying disease. The surgical time required for double LTx is around 4 − 6 hours and for single LTx is around 2 − 4 hours. This is usually within the ischemic time, which is defined as the time from application of cross clamp on the donor’s aorta up until implantation of the lung to the recipient. In cases of lung transplantations alone, use of the cardiopulmonary bypass (CPB) might be indicated, but CPB is mandatory in the case of heart–lung transplantations. Over the past two decades, two-thirds of LTx were performed bilaterally as opposed to single LTx. Combined heart–lung transplantation are more challenging in terms of procuring the organs and with regards to their long-term outcomes [9].

Landmarks in Lung Transplantation

The first clinical attempt of LTx in humans was reported in 1963 by Hardy and Webb at the University of Mississippi, and the first successful HLTx for pulmonary vascular disease was reported by the Stanford group in 1981. Further to the utilization of Cyclosporine in post-transplant patients, the Toronto group reported the first successful single LTX in 1983 and first successful double LTx in 1986 [1].

The first HLTx in India was performed by Dr K M Cherian and group in 1999 [10]. On July 11, 2012, Dr. Jnanesh Thacker, performed the first successful lung transplant in India. Subsequent to this, there were few reports of heart and lung or lung transplants discretely until the mid-nineties [10,11,12]. The milestones in LTx in India are summarized in Fig. 1.

Fig. 1
figure 1

Pioneers and milestones in Thoracic Transplantation in India

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Present Situation and Challenges in India

To understand the basic concept of integrated care pathway and to anticipate challenges, the process of LTx is discussed under the following:

  1. A)

    Organ availability

  2. B)

    Recipient selection

  3. C)

    Waiting list and organ allocation

  4. D)

    Post-transplantation care

  5. E)

    Complications

Organ Availability

The criteria of the ideal donor are tabulated below (Table 2) [13]. In India, only about 20% of the multi-organ donors have a lung harvest performed [13,14,15]. Unlike abdominal solid organs, heart and lung transplantation is mainly dependent on brain dead patients. At the donor level, lungs from brain-dead donors could easily be damaged and are more susceptible to conditions resulting from direct trauma, resuscitation manoeuvers, neurogenic edema, aspiration of gastric contents, ventilator-associated barotrauma, and pneumonia.

Table 2 Donor selection criteria as per the ISHLT
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Due to a long wait for an ideal lung donor, the waiting list mortality rate tends to range from 12 to 20% [16]. In order to overcome the critical organ shortage and to decrease the mortality rate on their waiting lists, many transplant programs are now also using extended criteria donors, often named as marginal donors. By expanding or extending the donor criteria, the organ availability could be increased to over 40% without adversely affecting the results [17].

Certain measures have been proposed to improve the organ availability including using ex vivo lung perfusion(EVLP), lobar transplant, and utilizing lungs from donation after circulatory death (DCD) [18]. By perfusing and ventilating a donor lung in an ex vivo circuit, EVLP has emerged as a promising preservation technique for suboptimal donor lungs, due to its potential for reconditioning donor lungs that would otherwise fall below the acceptable threshold for transplant (Fig. 2). Although the technique has not proven to be superior to cold static preservation for standard criteria donor organs, it gives the transplant surgeons an opportunity to partly overcome the long ischemic time and enables the transplant physicians to reassess the suboptimal lungs and potentially increase the utilization [19].

Fig. 2
figure 2

Ex vivo lung perfusion circuit with schematic representation; note the colour code. PAP-Pulmonary artery pressure, LAP – Left atrial pressure

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Similarly, organ care system (OCS) (Fig. 3) is a portable, normothermic lung perfusion system which augments in the retrieval of standard and expanded criteria donor lungs. The Inspire trial reported benefits such as improved post-transplant outcomes compared to conventional cold storage, expanded organ retrieval range while limiting ischemic time and significantly reduced primary graft dysfunction(PGD) [20]. The OCS Lung Expand trial reported that earlier lungs had been declined for transplantation on an average of thirty five times by other transplant centers as compared to an OCS transplant center where there was eighty seven percent usage of lungs on OCS [21].

Fig. 3
figure 3

OCS Lung with schematic representatiom (reprinted with permission from Dr. Warnecke. OCS- Organ Care System

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Living lung lobe donation (LLD) is another way of increasing the supply of organs, but so far it has only been used in a handful of developed countries, and this procedure is suitable only for very selective patients.

Recipient Selection

The appropriate selection of the recipients is an important determinant for the outcomes of LTx. As per the consensus of Council of the International Society for Heart and Lung Transplantation (ISHLT) in 2021 [2], lung transplantation should be considered for adults with chronic, end-stage lung disease who meet all the following general criteria:

  • High (> 50%) risk of death from lung disease within 2 years if lung transplantation is not performed

  • High (> 80%) likelihood of 5-year post-transplant survival from a general medical perspective if there is adequate graft function [7]

All alternative therapies for the end-stage lung disease must be exhausted and contraindications excluded prior to the enlisting of these recipients [6, 22]. Disease-specific indications for lung transplantation are often more precise and should be abided to as per the ISHLT consensus statement [23, 24].

Contraindications to lung transplantation can be categorized into absolute and risk factors with high or substantially increased risk as per the ISHLT consensus statement in 2021 and are tabulated below (Table 3) [25]. In particular, colonization of the respiratory tract with multi-resistant gram-negative pathogens is often a relative contraindication [26]. In patients with Hepatitis B, LTx can be considered in cases without significant clinical, radiological, or biochemical signs of cirrhosis or portal hypertension and who are stable on appropriate therapy.

Table 3 Contraindications of lung transplantation as per the ISHLT
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Waiting List and Organ Allocation

The prospect of an improved quality of life (QOL) is the most important reason for a patient’s decision to seek a lung transplant. Financial constraints and difficulty in accessing high quality centers are the main deterrents [27, 28].

At present, there are a few transplant centers which cover a wide geographic area (Fig. 4) [4, 29]. Yet some major challenges remain, such as inappropriate timing of referrals, distance to the referring hospitals, lack of infrastructure, social taboo associated with organ donation, and lack of coordination between different centers.

Fig. 4
figure 4

Registered Lung Transplant Centres in India (as per the data from MOHAN foundation and INTRAN)

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In an ideal situation, for selected ESLD not amenable to optimal medical management (OMM), there should be a close coordination between the referring pulmonologist and the nearest transplant center. For patients who manifest rapid disease progression, the consultation should be expedited. The transplant team then evaluates the patient. A decision to enroll the patient on the waiting list is based on the clinical findings, patient’s motivation, affordability, risk–benefit analysis, and counselling. Once listed, further investigations and assessments are performed as per the published criteria (Table 4) [30, 31].

Table 4 Details required for registering the recipient (taken from the NOTTO website)
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For an effective integrated development of donation and transplantation, we need to have an efficient national transplant allocation system. In the USA, donor lung organs were allocated based on a potential recipient’s waiting list time, which was modified in the year 2005 to incorporate medical urgency and utility to optimize patient outcomes. Subsequently, lung allocation score (LAS) was developed, which predicts the probable benefit of a LTx as the difference between the probability of survival after a lung transplant and the probable survival on the waiting list [32, 33]. This system was based on the UNOS (United Network for Organ Sharing) database. Similar systems were adopted by the Scandinavian, Asian and other European centers [33, 34]. Unlike LAS, there is no unified allocation scoring system in India.

Allocation of Lung for Transplantation and Its Challenges

In India, the National Organ and Tissue Transplant Organization (NOTTO) [35] coordinates with various organizations at regional levels, Regional Organ and Tissue Transplant Organization (ROTTO); state levels, State Organ and Tissue Transplant Organization(SOTTO); and at city levels. Since its inception, NOTTO has been instrumental in the regulation and streamlining of the removal, storage, and transplantation of human organs for therapeutic purpose and in curtailing its commercial dealings in India. As per the World Health Assembly (WHA) guiding principles [36], NOTTO is also responsible for maintaining the National Registry for Organ Donation. Five ROTTOs were established in Chandigarh, Chennai, Mumbai, Kolkata, and Guwahati to serve the north, south, west, east, and northeast regions of India, respectively.

The current system in our country provides organ distribution according to waiting time, body size and blood group compatibility. The recipients are categorized under emergency and elective listings. The process of recipient selection and allocation of the donor lung is illustrated in the flow chart (Fig. 5).

Fig. 5
figure 5

Flow chart demonstrating the recipient selection criteria and donor lung allocation system. ESLD- End stage lung disease, OMM- Optimum Medical management, MDT- Multidisciplinary team

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Present Scenario in India

The national deceased organ donor rate is < 1 per million population(pmp) compared to about 20–35 pmp in more developed countries [13]. This low rate can be attributed to the lack of awareness among the general public and due to the social taboo and religious beliefs associated with organ donation. Many state-level governmental organizations have been formed to promote organ donation of which the Transplant Authority of Tamil Nadu (TRANSTAN), and The Cadaveric Transplantation Advisory Committee (CTAC) formed by the Andhra Government, warrants special mention. A highly successful transplant scheme called “Jeevandan” was introduced by the AP government in 2013, augmenting the cadaveric organ donation program four times more than the national average [29]. Similar organizations and programs were later launched in other states like the Maharashtra Confederation for Organ Transplant (MCFOT), Zonal Transplant Coordination Centre (ZTCC), “Jeevasarthakathe” in Karnataka, and “Mrithasanjeevani” programme in Kerala.

A very popular non-governmental organization, MOHAN foundation, made a significant positive impact in the cadaveric organ donation through patient education, providing support for organ failure patients and by forming the Indian network of Organ sharing (INOS). This scheme lead to a greater than twofold increase of deceased organ donors from 340 in 2013 to 875 in 2018 [12] reiterating the impact and need for such schemes and a centralized organ procurement organization [35].

Post-transplantation Care

Follow-up care after lung transplantation is initially overly complex, requiring a high level of patient cooperation. With limited fully fledged transplant centers in the country, the patients will have to reside in the same city for a few weeks in order to closely monitor the patients, identify potential complications, and treat them preemptively.

The immunosuppression therapy after lung transplantation comprises of a triple combination of calcineurin inhibitor (cyclosporine or tacrolimus), purine synthesis antagonist (azathioprine or mycophenolate mofetil), and prednisolone [3]. The dosage of the calcineurin inhibitors (CNI) is controlled according to its blood levels. In the first year, the target levels of CNI in order to avoid acute rejection after lung transplantation are high and hence increased risk of toxicity. CNI are metabolized via the hepatic cytochrome P450 system. Interactions with other medications can seriously affect CNI blood levels. Hence, close coordination with the transplant center is essential. Our robust program is fortunate to have fully trained teams deployed in various parts of the country to avoid potentially long journeys to the main hub for aftercare.

Complications

The complications are summarized below [Fig. 6]. In-hospital mortality was reported to be fifteen percent. Primary graft dysfunction (PGD) is the most dreaded complication in the first month [15]. The clinical picture mimics acute respiratory distress syndrome with a very high mortality rate, ranging from thirty to fifty percent. Infection was reported to be the second leading cause of death, although the morbidities were more observed in developing countries [30].

Fig. 6
figure 6

Early and late complications after Lung transplantation. CMV- Cytomegalovirus, HSV - Herpes simplex virus, RSV – Respiratory syncytial virus, CNI- Calcineurin inhibitor

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Acute Transplant Rejection

Acute rejection, which is common in the first year, is rarely a life-threatening complication. Patients often present with non-specific symptoms including cough, shortness of breath, pyrexia, hypoxemia, pleural effusion, interstitial infiltrates, or a decline in lung function. Histologically, lymphocytic infiltration of the terminal bronchioli and accompanying vessels is seen. The acute rejection is usually completely reversible.

Chronic Organ Dysfunction

Bronchiolitis obliterans syndrome (BOS) and non-CMV-associated infections are the main causes of death in the long-term. BOS appears as a progressive obstructive ventilation disorder triggered by repeated acute rejections, viral infections, poor adherence to therapy, aspiration, and gastroesophageal reflux. Histologically, obliteration of the bronchioles is seen.

If the suspected triggers are managed appropriately, long-term therapy with azithromycin can result in better outcome in terms of improvement in lung function. However, in cases of progressive BOS with severe respiratory failure, the possibility of re-transplantation should be considered.

Rehabilitation

Pulmonary rehabilitation and general physiotherapy are integral parts of a successful transplant program. Multiple variables influence the post-operative results including the pre-operative constitution, transplant function, complications, and immunosuppression. The potential long-term risks necessitate a structured rehabilitation, which is conducted either at the main hub or designated associated hospitals. We have a structured program and conduct seminars for patients and their relatives, where we impart knowledge about transplantation, pharmacotherapy, and the influence of transplantation on living conditions. We also provide psychological support for the patients to help them adhere to therapy and cope with illness.

Long-Term Results

The results of the transplant centers are published annually internationally [21]. The statistics of Lung transplantation in India can be retrieved through the NOTTO website [35]. Lung transplantation is not a cure, but a therapy, that cannot achieve the life expectancy of the normal population; however, 51% of lung transplant patients worldwide are still alive after 5 years. European centers achieve a 5-year survival rate of over 60%. Overall median survival in the most recent era (i.e., 2009–2016) is 6.7 years, compared to 6.5 years and 4.7 years in 2002–2009 and 1992–2001, respectively [25]. The median survival rate according to underlying pulmonary disease differs markedly; patients with CF as an indication for lung transplant have superior survival (median 9.9 years) compared to all other groups. We have recently implemented a Quality of Life and objective assessment for all the transplant patients using General Health Questionnaires and World Health Organization Quality of Life assessment models. This will be published in due course.

Novel COVID-19 Challenge

Globally, as of December 2022, more than 657 million confirmed cases of COVID-19, including 6.3 million deaths have been reported to WHO [37]. Although several organs can be affected by COVID-19, the lungs are the primary site of disease and hence the impacts of the pandemic on lung transplantations are three-folds. Approximately ten percent of the patients with SARS-CoV-2 had been reported to have progressed to ARDS requiring mechanical ventilation [38]. Mortality of this cohort had exceeded more than twenty percent, and hence there was a surge in early utilization of extracorporeal circulation and consideration for LTx. Organ donation had however drastically reduced during the pandemic, as reflected in the activity report worldwide [2]. New guidelines were prepared for COVID screening for donors and recipients by NOTTO. Reduction in available donors reduced lung retrieval rates as compared to other solid organs and stretched healthcare resources led to further reduction in LTx in India. Our resolute eighteen-bedded, isolated intensive care unit for transplant patients was filled with COVID patients on ECMO. The semi-urgent and elective patients on the waiting list developed ARDS because of SARS-CoV-2 infection. In our center, seven out of twenty-four patients on the waiting list from March 2020 to October 2020 (29%), developed SARS-CoV infection. Out of these seven patient, three (42%) recovered and underwent bilateral LTx successfully, three patients expired (42%), and 1 patient is still awaiting LTx [27]. Our team performed the first double LTx for a post-COVID patient in India [39]. As of December 2021, our team had performed twenty-seven double LTx on post-COVID patients (Fig 7). Currently, as the COVID pandemic is stabilizing, organ donations have started increasing in India, which brings a ray of hope to the wait-listed patients.

Fig. 7
figure 7

a Explanted post COVID Lung. b Post COVID Lung with secondary heart disease for HLTx

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Our Experience in India

Our team performed two hundred and two LTx from April 2017 to November 2021 (Table 5). Interstitial lung disease (ILD) constituted the most common diagnosis among 109 (57%) patients, followed by bronchiectasis in 11 (5.4%) and primary pulmonary hypertension (PPH) in 9 (4.45%) patients. Chronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis were the common ILDs. Eight (6.06%) patients needed preoperative mechanical ventilation, and 14 (10.61%) needed preoperative ECMO in the pre-COVID era. This changed significantly during the pandemic with the majority requiring mechanical ventilation and ECMO prior to transplant. Among the population in our study, 81.6% participants had bilateral LTx, 13.8% had HLTx, and 4.45% had single LTx. The mean days on ventilator were 7.13 SD 8.43, mean ICU stay was 15.76 SD 11.66 days, and mean duration of hospital stay was 28.61 SD 22.35. The overall mortality rate was 19.7% in the pre-COVID era but increased to 27.2% during the pandemic.

Table 5 Summary of pre-operative demographic variables with procedural data and post-operative variables of Lung transplantation performed by our team
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Future in LTx

There has been a significant surge in LTx in the last decade as per the ISHLT report. In India, we witnessed many positive changes since 2017, thanks to the relentless efforts of transplant teams, governmental organizations, and NGOs [40]. Social media should be used constructively in the promotion of organ donation. We need to have a central lung allocation system coordinating with the SOTTOs with a LAS system based on priority, in order to have a fair distribution of the donor organs.

EVLP for LTx was used by our team,for the first time in India, in December 2021 [39], which could potentially pave the way to increase the utilization of donor lungs and hence more LTx. Lungs from DCD donors should also be promoted by streamlining the legislations and training the appropriate team members.

Take Home Message

Lung transplantation is still the only option that can be offered to the majority of selected end-stage lung disease patients with presumed modest improvements in quality-adjusted survival. However, it is a lengthy process with most of the recommendations based on International Society for Heart and Lung Transplant. Further streamlining of recipient selection will ensure better outcomes. Donor pool expansion methods are still in developing stages. The waiting period for the transplant should be used to improve muscle status, correct weight issues, and refresh the vaccination status. Follow-up care requires a high level of patient cooperation and should be done in close contact with the transplant center.