Recent Advances and Outcomes in Heart and Lung Transplantation

Abstract

Heart and lung transplantations are established treatments for patients with end-stage heart and lung failure, respectively. As mechanical circulatory devices, extracorporeal membrane oxygenation, organ perfusion, and transport systems advance, so do patient comorbidities and profiles of patients undergoing transplantation are becoming more complex. With the ever-increasing shortage of donor organs, marginal and high-risk donor utilization continues to rise. In this chapter, we attempt to elucidate the recent advances and outcomes in heart and lung transplantation. We also highlight how an ongoing COVID-19 pandemic affects the logistics of transplant programs.

1. Introduction

Each year, more than 4500 lung transplants are performed worldwide, over 2500 of which occur in North America itself [1]. The year 2020 faced unique challenges due to the onslaught of the COVID-19 pandemic. Social distancing, physical isolation, and travel restrictions made people increasingly hesitant to seek healthcare as hospitals were overburdened with COVID-19 patients. As the accessibility to healthcare declined, fewer candidates were added to the waitlist, and even fewer underwent a transplant. Additions to the waitlist saw a 17% decline from 2019 [2]. Procurement of organs from eligible donors was further complicated by travel bans. The dip in donor availability and infrequent healthcare access by transplant candidates ultimately led to a rise in waitlist mortality from 14.7 deaths per 100 waitlist years in 2019 to 16.1 in 2020 [2]. For those who were scheduled to receive a transplant, the health risks posed by the virus on the already frail lung transplant recipients were a major concern. In time, it was noticed that some COVID-19-infected patients could develop end-stage lung disease, which itself could require lung transplantation. Consequently, in the early half of 2021, 165 patients underwent transplantation for COVID-19 infection [2]. Another complexity was COVID-19 infection among donors. While it was initially viewed apprehensively, studies were conducted to assess the impact of transplanting organs from COVID-19-infected donors to healthy recipients. Although statistics did not disclose any impact on the early survival rates, more long-term studies are necessary [3]. Recently, Eichenberger et al. reported the safe and effective use of hearts from COVID-19-positive donors. 14 thoracic transplants in 13 recipients were performed using organs from COVID-19-positive donors. None of the recipients or healthcare members acquired COVID-19. No recipients suffered unexpected acute rejection. Patient survival was 92% to date, with graft survival 93% [4].

2. Lung-recipient characteristics

Survival among lung transplant recipients has remained stable in 2020 despite the effects of the COVID-19 pandemic as compared with the previous year. The 1-year survival was close to 90% . 61.2% of recipients who underwent a transplant in 2015 survived for 5 years, and 33.1% of recipients from 2010 survived for 10 years. When comparing within age groups, the 5-year survival was lowest for recipients aged 65 and older [2].

Due to a more inclusive candidate profile, we see a corresponding shift in the recipient characteristics. The past decade boasts of the inclusion of a larger age and BMI group as compared to the 1990s with the median age increasing to 57 from 50, and the median BMI rising from 25.0 kg/m2 to 26.5 kg/m2 [5]. As more patients have comorbidities, the patient profile is increasingly complex. The proportion of lung transplant recipients having diabetes mellitus has seen a sharp rise. Between 2010 and 2018, 20.1% of recipients had diabetes. This figure was only 6.1% as recorded in Oct 1999–Dec 2000. Patients with malignancies have also become more frequent. 7.9% of lung transplant recipients had a history of malignancy in 2010–2018 as compared to only 2.7% between 1994 and 2000 [5]. A similar trend is noted in recipients of heart transplants. Patients have increased BMI, and a greater percentage suffer from comorbidities, such as diabetes and malignancies [5].

Traditionally, lung transplants in adults have been performed mainly for chronic obstructive pulmonary disease (COPD), idiopathic interstitial pneumonia (IIP), and cystic fibrosis (CF). These formed 30.1%, 26.1%, and 15.2% of all transplants respectively from Jan 1995 to June 2018 [6]. The year 2020 saw a sharp decline in the transplants done for cystic fibrosis due to patient stabilization following cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy (Figure 1). Nevertheless, cystic fibrosis remains the number 1 indication for a lung transplant in the pediatric age group [2]. The OPTN/SRTR 2020 annual data report reflects a study rise in lung transplants performed for patients suffering from restrictive lung diseases, from 263.0 transplants per 100 waitlist years in 2019 to 308.7 in 2020. On the contrary, among adults waiting for a lung transplant, a decline is seen in patients needing transplants for obstructive lung disease (Figure 2).

Figure 1.

Deceased donor lung transplant rates among adult waitlist candidates by diagnosis group. Transplant rates are computed as the number of deceased donor transplants per 100 patient-years of wait time in a given year. Individual listings are counted separately. The other/unknown group includes a small number of heart-lung candidates prior to 2015 who did not have an a/B/C/D diagnosis group specified. (from OPTN/SRTR 2020 annual data report. HHS/HRSA).

Figure 2.

Distribution of adults waiting for lung transplant by diagnosis group. Candidates waiting for a transplant at any time in the given year. Candidates listed at more than one center are counted once per listing. Active and inactive patients are included. The other/unknown group includes a small number of heart-lung candidates prior to 2015 who did not have an a/B/C/D diagnosis group specified. (from OPTN/SRTR 2020 annual data report. HHS/HRSA.)

3. Lung-donation after circulatory death

With the continued shortage of donor’s lungs, donation after circulatory death (DCD) has emerged as an option in addition to conventional brain dead (BD) donation to increase the donor pool. Patients with extensive and devastating brain injury where the damage is recognized to be irreversible but who are not brain dead qualify as a potential donor, if by advance directives or family consent it is decided to withdraw life support (WLST). After withdrawal of support, death is usually declared after a 5–15-min window of no cardiac activity also called a stand-off period. In the most recent era, DCD organ use comprise 4.2% of all lung transplants. Recipient outcomes from DCD donors are equivalent to BD donors. The Maastricht classification defines DCD categories (classes I-V) according to the circumstances of the donor’s death. Controlled DCD (class III) includes patients who cannot be resuscitated and undergo WLST following cardiac arrest, determination, and organ donation [7]. Cypel et al. from Toronto described their simple method of in situ donor lung preservation for uDCD (uncontrolled DCD) where, in contrast to most of the European experience, no reinstitution of circulation (via normothermic regional perfusion or continuous chest compressions) is performed after cardiac arrest and death declaration, and only simple measures of lung protection are initiated. Of 30 cases consented for uDCD, donor’s lungs were retrieved from 16 donors, the remaining 14 lungs ultimately underwent EVLP to evaluate suitability for transplant; finally, lungs from five donors were used—four bilateral lungs and one left single-lung transplant (16.7% utilization rate from consented donors) [8].

4. Expanding the donor pool with increased-risk donors

As the criteria for the candidacy for lung transplantation keeps evolving [9], the number of people awaiting a transplant is also increasing. Based on the organ procurement & transplantation network (OPTN) Metrics, by the 52nd week of 2021, the cumulative waitlist total for lung transplantation was 3091, but only 2631 donors could be recovered. This ultimately resulted in a total of 2524 lung transplants in 2021. Due to the ever-increasing shortage of donors, expanding the donor pool has become necessary. In addition to traditional donors, strategies are now in place to procure organs from increased risk donors (IRD), which help in closing the gap substantially. In 2013, the United States Public Health Service categorized organ donors with risk factors for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) as IRDs [10].

4.1 ODD and HCV-positive donors

The ongoing opioid crisis in the United States has caused an increase in the number of overdose-related deaths, consequently increasing the number of overdose-death donors (ODD). The proportion of ODDs increased from 1.1% in 2000 to 13.4% in 2017, while trauma-death donors (TDD) and medical-death donors (MDD) saw only a marginal increase of 1.6% per year and 2.3% per year, respectively [11].

There were two major concerns with accepting organs from ODDs—the unknown outcomes, and the possibility of them being increased risk donors (IRD). Studies have measured the 1-year and 5-year survival rates after transplant for ODDs and have found that they are non-inferior as against TDDs and MDDs, which has helped attenuate the fear regarding uncertain outcomes [11]. The only remaining concern is the risk of transmission of blood-borne viruses, as a 30% prevalence of HCV among ODDs is a fairly apprehensive number [11]. The advent of direct-acting antivirals (DAA), and the availability of additional diagnostic means like nucleic acid testing (NAT), virus-specific antigens, and antibodies have offered some hope for better detection and reduction of transmission of these infections to the recipient [12].

With pretransplant mortality of 16.1 deaths per 100 waitlist years [2], there is an ever-growing need to find acceptable donor lungs. Studies have tried to assess the impact of transplanting lungs from HCV-positive donors on the waitlist numbers and post-transplant survival. Since DAAs have almost 97% HCV cure rates, several researchers have also tested the outcomes of transplanting lungs from HCV+ donors to HCV- recipients, after covering the recipient with a short course of DAAs. Patient and graft survival at 6 and 12 months have been like transplanting lungs from HCV- donors, but the odds of having acute rejection were higher in the HCV+ donor subgroup [13]. Viral load in recipients after transplantation and establishment of active HCV infection has also been researched. While some studies show undetectable HCV viral load post solid organ transplant, others have documented the establishment of infection [14, 15]. Some studies express concern over the possibility of false negative NAT and serologic testing in IRD, as seen during a window period because cases have been recorded demonstrating transmission of HCV infection during transplantation [16]. Nevertheless, with the increasing utilization of IRD lungs to the extent of 95%, HCV-positive donors potentially help shorten the donor-waitlist gap considerably [2]. While this approach shows promising results, long-term studies are needed to assess the impact on the quality of life of the recipients. Emerging modalities, such as ex vivo lung perfusion, have also led to the discovery of novel means to inactivate infections in allografts before transplantation.

5. HIV organ policy equity act

The signing of the HIV organ policy equity (HOPE) act into law in 2013 was a revolutionary move in expanding the organ donor pool as it enabled HIV-positive patients well-controlled on highly active antiretroviral therapy (HAART) to be registered as organ donors. People living with HIV (PLWH) are always at a higher risk of end-stage organ disease, more so because HAART has significantly reduced the rates of deadly opportunistic infections. Until recently, having an HIV infection was considered a contraindication for receiving a lung transplant [17]. Researchers have since found out that lung transplant survival rates and postoperative outcomes were similar in HIV-positive recipients as compared to their uninfected counterparts [18, 19]. Solid organ transplantation has therefore become the standard of care for organ failure in PLWH [20]. After clearing the way for HIV-positive transplant recipients, the HOPE act went one step ahead by allowing HIV-positive people to donate their organs to fellow individuals sharing their HIV-positive status.

Once the HOPE act was implemented in 2015, HIV-positive recipients began receiving organs from HIV-positive donors (HIV D+/R+). As of July 2021, there have been 144 true/false HIV-positive donors, which led to 300 kidney and 87 liver transplants [20]. This decision did not pass without its fair share of concerns. Healthcare professionals were worried about several plausible issues upon such transplants, particularly superinfection if the donor’s HIV strain did not match the recipients, rate of rejection, and HIV-related organ disease in the allograft [21, 22, 23]. As compared to transplanting organs from HIV-negative donor to HIV-positive recipient (HIV D−/R+), the outcomes were similar, with the only real challenge being increased rates of rejection [24].

Heart and lung transplants from HIV-positive donors have been approved and are highly anticipated [20]. Federal HOPE Act guidelines require participating hospitals to carry out five transplants in HIV-positive recipients before they can accept organs from HIV-positive donors. Successful implementation of the HOPE act requires the address of community-level barriers like the lack of awareness, fear of infection in personnel procuring organs from HIV-positive patients, and the fear of revelation of donor/recipient HIV status during transplantation [25]. Challenges faced while coadministering HAART and immunosuppressive therapy also need to be considered. Such studies would lay the foundation for the successful initiation of thoracic organ transplants in HIV-infected individuals from HIV-positive donors. Koval et al. reported outcomes from 29 HIV-infected thoracic transplant recipients (21 heart, 7 lungs, and 1 heart and/or lung) across 14 transplant centers from 2000 through 2016. Compared to an ISHLT registry cohort, similar 1-, 3- and 5-year patient and allograft survival was seen. However, at 1 year, significant rejection rates were high (62%) for heart transplant recipients (HTRs). Pulmonary bacterial infections were high (86%) for lung transplant recipients (LTRs) [19].

6. Ex vivo lung perfusion (EVLP)

Ex vivo lung perfusion is a technique that allows harvested donor lungs to be explanted into a system that mimics the hemodynamic status of the human body. The general design of the system involves ventilation of the allograft via endotracheal tubes and circulation of a fraction of cardiac output by means of pumps [26]. In cellular EVLP protocols like the lund protocol and organ care system, packed red blood cells mixed with a composite perfusate are allowed to flow through the lungs, while acellular EVLP protocols like toronto protocol do not use blood cells in the perfusate [27]. It enables the assessment of hemodynamic, ventilatory, and gas exchange parameters of the allograft. Biochemical values, imaging studies, bronchoscopic analysis, physical inspection, and palpation can also be performed on these organs [26]. These factors allow EVLP to be used as a tool for analyzing the allograft before transplantation, which is especially useful in the case of marginal lungs facing the threat of being rejected. EVLP thus aims to maximize the utilization of procured donor lungs [26]. In cellular EVLP, Kamal et al. described direCt lung ultrasound evaluation (CLUE) technique as a method for monitoring extravascular lung water in donor lungs during ex vivo lung perfusion (EVLP). Significant differences were found between suitable and non-suitable lungs in CLUE scores (1.03 vs. 1.85, p < 0.001), unlike the partial pressure of oxygen/fraction of inspired oxygen ratio. Standard donors had significantly better scores than marginal lungs and proning improved this score, especially in upper lobes [28].

EVLP was mainly developed to tackle the problem of ischemic-reperfusion injury, which increases the risk of development of primary graft dysfunction (PGD) [29]. The current practice involves cold preservation of allografts that facilitates a reduction in the organ’s metabolic demand. However, concerns regarding cold ischemic injury have surfaced. EVLP revolves around the principle of retaining the organ in its physiological milieu, at the human body temperature, for as long as possible [26]. Posttransplant outcomes after using EVLP have been consistently similar to traditional techniques in terms of patient and graft survival [30].

While the main role of EVLP remains the analysis of the graft, it is being creatively used to recondition the graft and even make initially rejected organs useful. In edematous lungs, EVLP allows the fluid from extravascular compartments to be drawn out, which can make the graft usable [31]. Antibiotics can be administered in the EVLP system, which ensures targeted therapy, preventing systemic adverse effects [32]. To shift the cytokine profile from pro-inflammatory to anti-inflammatory, Interleukin (IL)-10 gene therapy and stem cell therapies have been tried in porcine models by administering them to the graft using the EVLP systems [26].

Keeping in view the potential of eliminating infections from donor organs, trials began on organs harvested from HCV+ donors. Applying the age-old perspectives from blood product sterilization, researchers irradiated lungs in EVLP systems with ultraviolet C (UVC) light, which has been known for its germicidal properties [33, 34]. Similarly, another light-based sterilization technique called photodynamic therapy (PDT) uses methylene blue irradiated with red light [35]. As compared to standard EVLP, which focused simply on washing the virus away from the organ, PDT was the most effective in reducing HCV load. It cleared 98% of HCV-RNA from the perfusate and 91% from the lung tissue. The UVC group did not show any significant reduction as compared to controls [33, 36]. Despite reduced infectivity of the persistent RNA fragments noticed in in vitro analysis, UVC irradiation failed to prevent the development of viremia posttransplant in further trials [37]. Is it hypothesized that this difference arises because of the weaker penetrating power of UVC rays due to wavelength differences as compared to PDT [38]. Additionally, irradiated methylene blue provided better coverage because it could be injected into the vasculature [36].

The potential of EVLP for research and to evaluate and salvage initially rejected lungs is vast and the outcomes after using EVLP are comparable to standard lung transplantation. Multiple trials are demonstrating ingenious ways to utilize the technology clinically [27]. For example, researchers are administering targeted adenosine receptor 2B antagonists via EVLP to abolish its proinflammatory effects [39]. The use of EVLP as a platform for improving the utilization of donated lungs continues to increase.

Recently, Cypel et al. identified 10°C to be an optimal temperature for lung storage, allowing for preservation times of up to 24–36°C. Furthermore, they explored the concept of multiday lung preservation by pairing 10°C lung preservation with short cycles of EVLP in an animal model. For the first time, they were successful 3-days of lung preservation with exceptional immediate posttransplant graft function [40].

Loor et al., in the INSPIRE trial, sought to assess the safety and efficacy of normothermic portable EVLP using the OCS Lung device. It was the first prospective, multicenter, and randomized controlled study in EVLP for standard bilateral lung transplantation. The composite primary effectiveness endpoint of the trial was absence of PGD 3 within the first 72 hours after transplant and 30-day survival in the per-protocol population, with a 4% noninferiority margin [41]. The EXPAND trial was used to evaluate the efficacy of normothermic portable organ care system (OCS) lung perfusion and ventilation on donor lung use from extended-criteria donors and donors after circulatory death. OCS resulted in 87% of donor lung use for transplantation with excellent clinical outcomes [42]. A major challenge in lung transplantation is the need for ABO blood group matching. To address this challenge, Wang et al. used two enzymes, FpGalNAc deacetylase and FpGalactosaminidase, to convert blood group A lungs to blood group O lungs during ex vivo lung perfusion. The authors demonstrated successful removal of blood group A antigen with no overt changes in lung health. The authors showed reduced antibody and complement deposition, suggesting that this technique may reduce antibody-mediated injury in vivo [43].

6.1 Lung transportation

Conventional cold static preservation of donor’s lungs leads to unpredictable lung tissue cooling as also the freezing and thawing cause irreversible cellular damage. The Paragonix LUNGguard donor preservation system provides a stable temperature between 4 and 8^οC for extended preservation times. Hartwig et al. presented their initial report of a study comparing two methodologies of hypothermic storage: patients with donor lungs preserved by the LUNGguard and patients with donor lungs transported by conventional preservation methods (ice protocol) [44].

6.2 Intraoperative use of cardiopulmonary bypass (CPB) vs. ECMO for lung transplantation

The use of extracorporeal membrane oxygenation (ECMO) for intraoperative cardiopulmonary support has gained traction in recent years. There is growing experience with the preoperative use of ECMO as a bridge to a transplant in patients with refractory respiratory failure. Biscotti et al. compared differences in patient outcomes and operative parameters for extracorporeal membrane oxygenation (ECMO) versus cardiopulmonary bypass (CPB) in patients undergoing lung transplants. Intraoperatively, CPB group required more cell saver volume, FFP, platelets, and cryoprecipitate. The CPB group had higher rates of primary graft dysfunction at 24 and 72 hours. There were no differences in 30-day and 1-year survivals [45]. Hoetzenecker et al., from the Vienna lung transplant group reported their results of uniform central venoarterial ECMO in patients receiving bilateral lung transplantation. Their median time of mechanical ventilation was 29 hours, 90-day mortality was 3.1%, and 2-year survival was 86%. Thus, routine use of intraoperative ECMO resulted in excellent primary graft function and midterm outcomes in patients undergoing lung transplantation [46]. Magoulitis et al. in their meta-analysis of seven observational studies incorporating 785 patients showed that ECMO support lowered rate of primary graft dysfunction, bleeding, renal failure requiring dialysis, tracheostomy, intraoperative transfusions, intubation time, and hospital stay. However, no difference was reported between operative and ischemic time [47]. Recently, Halpern et al. in their study on patients with no or mild pulmonary hypertension, who underwent bilateral lung transplantation, reported that planned VA ECMO was associated with higher odds of textbook outcomes than planned off-pump support [48].

7. Advances in treatment of post-lung transplant complications

According to the OPTN annual report in 2020, 14.6% of lung transplant recipients developed acute rejection. 40% of recipients went on to develop bronchiolitis obliterans syndrome (BOS) by the fifth year after transplant, and 24% of recipients developed malignancy in the same period.

Chronic lung allograft dysfunction (CLAD) holds substantial weightage during the discussion of lung transplant because it is a major cause of mortality and morbidity following lung transplantation [49]. According to the ISHLT consensus report 2019, CLAD is a persistent > = 20% decline in FEV1 as compared to the recipient’s posttransplant baseline [50]. Decreases in lung functions after three months posttransplant are also attributed to CLAD. Two prominent subtypes of CLAD are BOS (bronchiolitis obliterans syndrome) and RAS (restrictive allograft syndrome) [49]. Once BOS develops, the mortality rate varies from 25 to 55% [51, 52]. Risk factors of CLAD include autoimmunity, PGD, alloimmune rejections (e.g., acute cellular rejection, antibody-mediated rejection, and lymphocytic bronchiolitis), infections (viral, bacterial, and fungal), persistent bronchoalveolar lavage neutrophilia and pathological gastroesophageal reflux (Figure 3) [31].

Figure 3.

Incidence of acute rejection by 1-year posttransplant among adult lung transplant recipients by induction agent, 2018–2019. Only the first reported rejection event is counted. Cumulative incidence is estimated using the Kaplan–Meier method. IL2-RA, interleukin-2 receptor agonist; TCD, T-cell depleting. (from OPTN/SRTR 2020 annual data report. HHS/HRSA).

Newer treatment modalities, such as extracorporeal photopheresis (which uses ultraviolet light to generate anti-inflammatory cytokines), liposomal cyclosporine, and anti-fibrotic agents, such as pirfenidone, are being assessed in the treatment of CLAD in trials.

8. Lung transplantation committee

Recently, a collaborative effort of transplant centers has led to formation of a committee. The lung transplantation committee of OPTN works regarding lung procurement, allocation, and transplantation, including medical, scientific, and ethical aspects. The goal of the committee’s work is to develop evidence-based policies aimed at reducing waitlist mortality in lung transplant candidates, increasing lung utilization, improving access to lung transplantation, and improving the health outcomes of lung transplant recipients.

9. Lung microbiome

The characteristics of the lung microbiome, its influence on the human body and disease processes, and the techniques to alter the local microbiome, serve as a large reservoir of untapped knowledge. Studies have been constantly trying to understand the differences between the microbiome of a healthy lung and a diseased one. 16S rRNA sequencing studies have disclosed that the lung microbiome is derived majorly from the oropharynx, with prevotella, veillonella, and streptococcus spp. being the most frequent colonizers [53, 54]. Consequently, it has been postulated that disruption of the oropharyngeal microbiome will reflect in the lung and ultimately make it more susceptible to pathogen colonization [55]. It is also being hypothesized that a healthy lung microbiome is based on the property of the organisms to be transient, owing to the dynamicity attributed to breathing and microaspiration. The microbial ecosystem of the lung is maintained delicately by a balance between the entry and active clearance by the cells of the lung. When the mechanisms of clearance fail, the organisms become persistent and disease ensues. It remains to be elucidated as to whether dysbiosis is a cause or effect of the disease [56]. Conventional literature believed that certain disease processes or exposures had a singular effect on the host. Recent studies, while acknowledging its effect on the microbiome independently, go beyond this idea and hypothesize that even without external influences, the microbiome and the host continually modulate each other [57].

Researchers have analyzed the oropharyngeal microbial pattern in patients with end-stage lung diseases, before and after lung transplantation. While waiting for transplantation, it was found that oropharyngeal wash samples of patients with advanced lung diseases had an increased facultative organism dominant microbial burden. Aerobic bacteria were decreased, alongside an overall reduction in richness and diversity. The microbiome stabilized after transplantation briefly, tending toward healthy lung levels. Nevertheless, 6 months after transplantation, it reverted to the severe dysbiosis-like state that existed before transplantation in the diseased lung [55]. If dysbiosis at oral sites indeed precedes/causes dysbiosis in the lungs, then these observations remind us of the increased risk of infections due to pathogen colonization posttransplantation, adding to the problems caused by an immunosuppressed state.

Studies have been working toward establishing and elaborating on the relationship between the altered microbiome and the complications after lung transplant. The most worrisome ones are primary graft dysfunction (PGD), acute rejection (AR), and chronic lung allograft dysfunction (CLAD). Lungs that had enrichment of oral-type taxa, before procurement from the donor and immediately after reperfusion in the recipient, have been seen to develop PGD. Aspiration of these microbes is hypothesized to prime the allografts for PGD [58]. Similarly, it is also observed that higher bacterial load after transplant is correlated with the development of CLAD, although no particular taxa were implicated [59]. These discoveries are promising as the microbiome can prove to be a potentially modifiable risk factor.

It is well known that inflammatory episodes happen in the allograft after transplantation, despite adequate immunosuppression [60]. Long-term immunosuppression and antibiotic therapy posttransplantation may make the local ecosystem more permissive to the overgrowth of certain immunostimulatory bacteria, which otherwise would have been cleared by the host immunity and controlled by the healthy microbiome [61, 62].

Inflammation can also be triggered by imbalances in the levels of normal commensals, which means that it is not necessary that a pathogenic invasion occurs for a disease process to ensue. For example, the Prevotella community is a part of the normal lung microbiome and is generally considered less stimulatory, but its overrepresentation can cause tissue remodeling [63]. In lung transplant recipients, an association between the dominant bacteria and the type of immune reaction was observed. When the dysbiosis was firmicutes or proteobacteria dominant, pulmonary leukocytes expressed inflammatory genes; while pro-remodeling effects were displayed by a Bacteroidetes-dominant dysbiosis [63]. Similarly, in the case of pathogens, virulence does not necessarily equate with immunogenicity. S. Pneumoniae, which is the most common cause of community-acquired pneumonia, had a lower stimulatory effect on macrophages in comparison with S.aureus or P.aeruginosa [63]. Hyperammonemia syndrome (HS) is an uncommon but fatal disorder that can affect up to 4% of lung transplant recipients. It is imperative that patients with this syndrome should be screened for ureaplasma species and treated with the appropriate antibiotics for this infection [64].

10. Gut-lung axis

The effects of the gut microbiome on local and systemic immunity are well studied, and the documentation of its influence on the brain led to the coining of the term “gut-brain axis.” Investigators are now trying to find out if such a relationship also exists between the microbiome of the gut and the lung. Several studies indicate that such “gut-lung axis” may indeed exist. For example, gut microbiome dysbiosis caused by antibiotic administration in the early years of life was seen to increase the risk of allergic airway disease [65]. Fecal microbiomes in patients with chronic obstructive pulmonary disease differed from healthy control subjects in terms of taxonomic microbial representation and their metabolites [66]. Murine models that were dietarily supplemented with short-chain fatty acids (SCFA) by adding acetate to their drinking water showed reduced inflammatory infiltrates in their lungs. Au contraire, those receiving a low-fiber diet had lower SCFAs in their circulation and higher airway reactivity [67].

It has been recently found in clinical and animal studies that derangement in the gut microbiome can impact outcomes related to allograft dysfunction after transplantation of the liver and small bowel [68, 69]. To understand whether gut microbiome can impact lung allograft rejection as well mice model studies were conducted. The donors as well as recipients were pretreated with oral antibiotic gavages to reduce microbial load. Those that were pretreated had reduced severity of rejection, while the majority of the controls showed moderate–severe lung allograft rejection. The Bacteroidetes to firmicutes ratio was increased in the gut microbiome of the mice who experienced milder rejection [70]. Previous studies have tried to establish a causal link between CD4+ T lymphocytes and chronic lung allograft rejection in animal models after lung transplantation [71]. This would mean that a depletion of CD4+ T cells would improve the outcomes related to allograft rejection. However, an emerging hypothesis suggests that a reduced dendritic cell activation may instead be the origin of the decreased generation of graft-reactive T cells [70].

Unlike the gut microbiome, where microbial sampling is relatively easier due to their presence in the feces, determining the ecosystem of the lung is complicated by factors like lower biomass, the possibility of contamination during sample collection, interference by environmental factors, and the lack of knowledge about the fungal and viral component of the microbiome. Researchers have been citing the possibility of a metagenomic dark matter due to the presence of a large proportion of unidentified sequences arising during virome studies. This may indicate that we may come across undiscovered species of viruses in the future [72]. For example, recently, metagenomic sequencing from the respiratory tract of healthy as well as sick subjects led to the discovery of a new family of DNA viruses called redondoviridae [73].

More techniques are needed to profile the lung microbiome more accurately, to understand how the interactions affect the host, to establish causality between dysbiosis and specific disease processes, and to observe the resolution of symptoms after the reestablishment of the original microbiome. It would be interesting to see how therapeutic alteration of the microbiome can impact not only the outcomes of lung transplantation but also chronic disease processes in general. Trials are now being proposed to observe the effect of therapies like probiotic administration and fecal microbiota transplantation in the context of respiratory diseases [74]. If endotypes can be targeted specifically, it could open up multiple avenues tailored to deliver a personalized benefit [75]. The prospects of lung microbiome research are certainly promising but long-term studies will be necessary to ascertain the benefits quantitatively.

11. Bioengineering

Bioengineered lungs could change the landscape of lung transplantation as they counter the challenges posed by the long waitlist [76]. These techniques revolve around harvesting a lung sample and decellularizing it. The scaffold (acellular or artificial or hybrid) is then recellularized with stem or differentiated cells [77]. The matured and functional organ is then implanted into the host. EVLP systems serve as a good conduit to allow the maturation of the engineered graft [76, 78, 79, 80]. The fusion of current methods with emerging single-cell technologies and advanced 3D printing modalities could pave way for newer developments [81]. Substantial efforts are necessary to refine the existing engineering techniques and to convert preclinical studies to clinical trials in order to manifest this idea as a utilitarian alternative [76]. The idea of the bioengineered lung which appeared like utopian fiction decades ago could soon become reality [81].

12. Recent advances in heart transplantation

As a testament to improved survival statistics, heart transplant recipients have had an improved prognosis over the years. Since 2015, adult long-term mortality rates have witnessed a downward trend. Similarly, pretransplant mortality rates have also declined since 2009 [2]. However, this scenario was complicated by the COVID-19 pandemic, where we saw an increase in the 6-month and 1-year mortality rates during the first year of the pandemic. Pretransplant mortality also slightly increased in 2020 (Figure 4) [2]. Heart transplant candidates have notable changes in demographic patterns over the years. Candidates over 65 years of age have increased from 11.9% in 2009 to 15.9% in 2020. The prevalence of obesity has increased among heart transplant candidates. As of 2020, more than 40% of candidates have a BMI equal to or more than 30 kg/m2 [2]. Cardiomyopathy remains the most common indication for an adult heart transplant, while congenital heart disease remains the leading diagnosis in the pediatric age group. Notably, candidates receiving transplantation for a diagnosis of coronary artery disease have declined [2]. Continued efforts of the entire healthcare system have helped in improving transplant-related outcomes despite the current COVID-19 pandemic. Fewer candidates have been removed from the waitlist because of death or being too sick to receive transplants as compared to 2018 [2]. The number of multiple organ transplants has also increased, which is appreciated in heart-kidney transplants, while heart-lung transplants have remained stable [2]. In 2020, despite there being lesser new listings for heart transplants, the eventual number of heart transplants performed increased [2].

Figure 4.

Patient death among adult heart transplant recipients. All adult recipients of deceased donor hearts, including multi-organ transplants (from OPTN/SRTR 2020 annual data report. HHS/HRSA).

The number of deceased heart donors continues to increase. The discard rate of recovered organs remains extremely low at 1%, despite a slight rise in 2020. An upward trend is noted in the proportion of IRDs [2]. In the case of heart transplants, the use of mechanical circulatory support (MCS) as a bridge to transplant has dramatically increased over the years. In 2020, 36.4% of candidates had ventricular assist devices (VAD) at listing. This number was just 16.4% in 2010 [2].

To address the issue of waitlist mortality, the year 2018 witnessed new heart allocation criteria, as approved by the united network for organ sharing (UNOS). These criteria prioritized the sickest patients. The older 3-tier system (status 1A, 1B, and 2) was changed to a 6-tier one (status 1–6) [82]. Stable patients supported by LVAD were ranked lower (status 4) as compared to those receiving VA-ECMO and IABP, status 1 and 2, respectively [83].

Traditionally, for prolonged support, ventricular assist devices needed to be placed after securing surgical access. This was especially true when candidates were being bridged to transplant [84]. Recently, more research is being done on assist devices that can be implanted percutaneously. After the UNOS heart allocation policy change, the use of percutaneous devices like Impella jumped from 1% in 2015 to 4% in 2019 among transplant patients [85]. Impella is a catheter-based ventricular assist device for unloading the left ventricle and consequently increasing cardiac output. It was initially used to support patients with cardiogenic shock after acute myocardial infarction [86]. Due to its relative ease of insertion, it is now being considered as an alternative to support candidates waiting for a heart transplant. As compared to recipients who did not receive circulatory support, patients bridged to transplant using Impella 5.0/5.5 showed a similar 30-day and 6-month mortality [84, 87, 88].

13. Donation after circulatory death, organ care system, and normothermic regional perfusion

The standard cold ice transport of donor’s hearts results in unpredictable myocardial cooling leading to irreversible suppression of diastolic function and protein denaturation. The recently introduced Paragonix SherpaPak Cardiac Transport System incorporates a novel nested canister system in concert with proprietary thermal cooling to provide physical and thermal protection for donor’s hearts. Results of 1-year transplant survival analysis of GAURDIAN registry showed that despite longer ischemic times and higher proportions of temporary MCS devices, numerically higher 1-year survival was seen in the cohort with sherapak usage [89]. Dhittal et al. pioneered the technique of DCD heart procurement. Their technique allows for rapid decompression of the systemic venous system and subsequent cardioplegia administration. Following infusion of supplemented cardioplegia, the heart is explanted first and instrumented onto the portable extracorporeal TransMedics organ care system (OCS), where its viability and suitability for transplantation can be assessed [90].

13.1 Organ care system

An OCS heart is a portable extracorporeal heart perfusion and monitoring system. The aorta is connected to the aortic line, the pulmonary artery is connected to the pulmonary artery line (PA line), the left atrium is opened, and the left ventricle is vented via a left ventricle vent. The superior and inferior vena cava are ligated. Blood from the PA line and LV vent goes to the reservoir and is pumped to the gas exchanger where it is oxygenated, passed through a warmer, and returned to the heart through the aortic line. It allows continuous monitoring of aortic pressure, lactate level, and coronary blood flow of the graft. The advantages of OCS are:

1. It enables the donor heart to be transported for long distances, thereby increasing the donor pool.

2. The aortic perfusion on the OCS system can act as a surrogate to diagnose significant coronary artery disease in the donor’s heart.

3. Increasing the pool of marginal donor hearts (hearts with left ventricular hypertrophy, EF 40–50%, downtime more than 20 minutes, and donor age > 55 years).

   In the EXPAND trial, out of 93 such marginal hearts, 75 hearts were transplanted (81% utilization rate). The mean cross-clamp time and OCS perfusion time were 381 minutes and 279 minutes, respectively. In this study, the 30-day survival was 95%, the incidence of severe primary graft dysfunction within 24 hours of transplant was 11%, and the overall and graft survival at 24 months was 82% and 95%, respectively.

4. It provides a platform to assess DCD hearts prior to implantation.

However, the present limitation of the OCS is the additional cost of resources and personnel required for its application as well as its transportation is more complicated [91].

13.2 Normothermic regional perfusion

The alternate method of DCD heart procurement is normothermic regional perfusion (NRP) wherein VA-ECMO is utilized (by cannulating aorta and right atrium) to maintain the thoracic organ perfusion to allow them to recover warm ischemia. The advantages of NRP are:

1. It restores heart function by reducing myocardial injury.

2. Reduces time spent by the organ in warm ischemia.

3. Allows visual assessment of heart and other organs prior to procurement.

The utilization of NRP for DCD requires significant resources and coordination between the donor hospital, procurement teams, and organ procurement organizations [92].

14. Post-heart transplant rejection surveillance

Between 2018 and 2019, 23.6% of recipients of heart transplants suffered from acute rejection in one year [2]. Even though the gold standard for posttransplant rejection surveillance is an endomyocardial biopsy, there have been exciting developments in the past decade in molecular noninvasive diagnostic surveillance. Such novel molecular techniques have the capacity to facilitate early diagnosis, improve the accuracy of diagnosis and decrease the frequency of invasive interventions for the diagnosis of allograft rejection [93].

14.1 Microarray technology

This technology examines endomyocardial biopsy samples at a molecular level to diagnose acute cellular rejection (ACR) as well as antibody-mediated rejection (AMR) [94]. Molecules called rejection associated transcripts (RAT) are identified to assess mRNA expression. Probabilities of developing ACR and AMR are then deduced. This technique was first implemented in patients who underwent kidney transplants. Halloran et al. later found out that similar RAT expression was observed in heart biopsy specimens, thus leading to the extrapolation of the idea in heart transplantation. This technique aims to tackle the main drawback of traditional histopathologic biopsies, which is interobserver variability in reporting findings [93, 95].

Currently, microarray technology is employed by the molecular microscope diagnostic system, which does an unsupervised archetypal analysis and predicts a normal, ACR, AMR, or injury pattern based on the assignment of scores [95]. This technology has been found to be effective in predicting molecular rejection [96]. The utility of intragraft mRNA transcripts as an addendum to the histopathology reports of endomyocardial biopsies can pave way for a newer modus operandi in diagnosing cardiac transplant rejection [93].

14.2 Gene expression profiling

Gene expression profiling (GEP) is done using peripheral blood leukocytes. It is done after 55 days posttransplant and has a high negative predictive value for moderate to severe rejection [93, 97]. Thus, it is used as an effective screening tool in stable posttransplant patients for diagnosis of rejection [93]. Allomap (CareDx) is the presently utilized gene expression profiling test in the clinical domain, which assigns a score of 0–40. A watershed score of > = 34 signals a higher probability of ACR [93, 98]. According to both IMAGE and E-IMAGE (early-IMAGE) clinical trials, GEP was found non-inferior to routine endomyocardial biopsy surveillance techniques, thus demonstrating similar clinical composite outcomes and rates of rejection [99, 100]. However, its use is limited only to the detection of ACR. Additionally, it also harbors a poor positive predictive value [93]. The CARGO-II trial proposed that a score less than 34 can imply a low risk of rejection [101]. Allomap can be utilized to time an early steroid weaning in patients with a lower risk of rejection [93].

14.3 Donor-derived cell-free DNA

This noninvasive modality of investigation is based on the cell death of the graft tissue, which releases donor-derived cell-free DNA (dd cfDNA) in the recipient’s blood. The percentage of donor-derived cell-free DNA is titrated against the total cell-free DNA in the recipient’s blood, detecting both ACR and AMR. It has also been found that dd cfDNA leads to earlier detection of acute rejection in asymptomatic patients compared to endomyocardial biopsy. The figure given below depicts the correlation between the percentage of dd cfDNA with ACR, AMR, and echocardiographic findings [93].

A study was conducted in Canada during the global COVID-19 pandemic utilizing noninvasive surveillance techniques for heart transplant rejection, thus ensuring minimal hospital exposure to patients. The study used cell-free DNA and gene expression profiling as a substitute for the invasive endomyocardial biopsy. The results were then harnessed for personalized titration of immunosuppressive therapy in patients. Noninvasive rejection surveillance was associated with the ability to lower immunosuppression, increase satisfaction, and reduce anxiety in HT recipients, minimizing exposure for patients and providers during a global pandemic [102].

15. Xenotransplantation

Xenotransplantation could act as a bridge to allotransplantation to tide over the crisis posed by the ever-growing waitlist. Recent developments have been in the domain of genetically engineered pigs functioning as donors for human recipients. Naturally occurring human antibodies commonly target 3 carbohydrate antigens in pigs among which galactose-a1,3-galactose is postulated to be particularly important. Removal of galactose-a1,3-galactose as antigen from pig yields a GTKO (alpha 1,3-galactosyltransferase knockout) pig. With the advent of novel gene editing techniques, double and triple-knockout pigs, engineered after the elimination of multiple carbohydrate coding genes were created.

Relatively species-specific complement pathway regulatory proteins (CPRP) like CD55, CD59, and CD56 attenuated complement-mediated injury and improved graft survival in various nonhuman primate models. These were introduced into the genome of pigs. Despite the addition of hCPRP (human complement pathway regulatory proteins) modification in GTKO pigs; the grafts were affected by microvascular thrombosis. This was probably due to a disharmony of thromboregulatory molecules like pig thrombomodulin and pig endothelial protein C receptor, which could be of a lower antithrombotic efficacy than their human counterparts. CD47 functions as a self-recognition marker in humans, which serves to inhibit phagocytosis. The Introduction of CD47 in the genome of pigs has shown better outcomes. Recently on January 7, 2022, the University of Maryland performed the first clinical heart xenotransplantation in a 57-year-old man, from a genetically engineered pig having 10 genetic modifications. He lived with a reasonable heart function for 2 months following the transplant but went on to develop graft dysfunction and ultimately, death. This event has however infused euphoria in the field of xenotransplantation and thoracic organ transplant academia. Similarly, in June/July 2022, Moazami et al. from New York University Langone successfully performed two further xenotransplants (pig hearts into humans) utilizing 10 genetic modifications, including four porcine gene “knockouts” to prevent rejection and abnormal organ growth as well as six human transgenes (“knock-ins”) to promote expression of proteins that regulate important biologic pathways that can be disrupted by incompatibilities between pigs and humans.

Conflict of interest

The authors have nothing to disclose.

Abbreviations

COPD	chronic obstructive pulmonary disease
IIP	idiopathic interstitial pneumonia
CF	cystic fibrosis
CFTR	cystic fibrosis transmembrane conductance regulator
BMI	body mass index
ECMO	extracorporeal membrane oxygenation
OPTN	organ procurement & transplantation network
IRD	increased risk donor
HIV	human immunodeficiency virus
HBV	Hepatitis B virus
HCV	Hepatitis C virus
ODD	overdose death donor
TDD	trauma death donor
MDD	medical death donor
DAA	direct acting antivirals
NAT	nucleic acid testing
HOPE	HIV organ policy equity
HAART	highly active antiretroviral therapy
PLWH	people living with HIV
HIV D+/R + transplant from HIV+ donor to HIV+ recipient.
HIV D−/R + transplant from HIV- donor to HIV+ recipient.
EVLP	ex vivo lung perfusion
PGD	primary graft dysfunction
UVC	ultraviolet C
PDT	photodynamic therapy
ISHLT	international society for heart and lung transplants
CLAD	chronic lung allograft dysfunction
BOS	bronchiolitis obliterans syndrome
RAS	restrictive allograft syndrome
rRNA	ribosomal ribonucleic acid
AR	acute rejection
SCFA	short-chain fatty acids
CD4+ T lymphocytes.
DNA	deoxyribonucleic acid
MCS	mechanical circulatory support
VAD	ventricular assist device
UNOS	united network for organ sharing
IABP	intra-aortic balloon pump
VA-ECMO	veno-arterial extracorporeal membrane oxygenation
ACR	acute cellular rejection
AMR	antibody-mediated rejection
RAT	rejection-associated transcripts
mRNA	messenger ribonucleic acid
GEP	gene expression profiling
IMAGE Trial	invasive monitoring attenuation through gene expression trial
E-IMAGE Trial	early-invasive monitoring attenuation through gene expression trial
CARGO-II Trial	cardiac allograft rejection gene expression observational trial -II
CfDNA	cell-free DNA
Dd cfDNA	donor-derived cell-free DNA
CPRP	complement pathway regulatory proteins
hCPRP	human complement pathway regulatory proteins
GTKO	alpha 1,3-galactosyltransferase knockout
WLST	withdrawal of life-sustaining treatment
OCS	organ care system
NRP	normothermic regional perfusion
DCD	donation after circulatory death