Optimizing patient outcomes in interstitial lung disease through pre- and post-transplant management strategies

Abstract

Interstitial lung diseases (ILD) encompass a diverse group of over 200 chronic pulmonary disorders characterized by varying degrees of inflammation and fibrosis, which can lead to severe respiratory impairment. Lung transplantation offers a crucial therapeutic option for patients with advanced ILD, extending survival and improving quality of life. This review explores optimal management strategies in both the pre- and post-transplant phases to enhance patient outcomes. Comprehensive pre-transplant evaluation, including pulmonary function testing, imaging, and comorbidity assessment, is critical for determining transplant eligibility and timing. Post-transplant care must focus on preventing complications such as primary graft dysfunction and chronic lung allograft dysfunction, managed through tailored immunosuppression and proactive monitoring. Recent advancements in diagnostic techniques and therapeutic approaches, including emerging technologies like ex vivo lung perfusion and precision medicine, promise to further improve outcomes. The ultimate goal is to establish an evidence-based, multidisciplinary framework for optimizing ILD management and lung transplantation.

Key Words: Interstitial lung disease; Lung transplantation; Chronic lung allograft dysfunction; Pre-transplant evaluation; Immunosuppression

Core Tip: This review highlights the complexities of managing advanced interstitial lung diseases in the context of lung transplantation. Comprehensive pre-transplant evaluation and meticulous post-transplant care are essential to optimizing patient outcomes. Emerging diagnostic and therapeutic innovations, including precision medicine, offer promising avenues to enhance survival and quality of life for patients undergoing lung transplantation.

INTRODUCTION

Idiopathic pulmonary fibrosis (IPF), first recognized as a distinct clinical and pathological entity by Hamman and Rich, has since become one of the most studied forms of interstitial lung disease (ILD)[1]. Over the decades, extensive research has deepened our understanding of ILD, shedding light on its natural history, pathogenesis, and therapeutic options, particularly lung transplantation, which remains a cornerstone in managing advanced disease stages[2].

ILDs comprise a heterogeneous group of over 200 disorders, each with distinct histopathological and pathophysiological characteristics. However, in recent years, the concept of progressive pulmonary fibrosis (PPF) has emerged to encompass various ILD subtypes that, despite differing etiologies, share a common trajectory of progressive lung function decline, worsening fibrosis, and a similar clinical-radiological pattern. This shift in classification acknowledges that diseases such as IPF, fibrotic hypersensitivity pneumonitis, and some forms of connective tissue disease-associated ILD exhibit comparable progressive fibrotic behavior and response to antifibrotic therapies. Recognizing PPF as a unifying category has important therapeutic implications, allowing for the broader application of antifibrotic agents, such as nintedanib and pirfenidone, beyond IPF to other forms of progressive fibrotic ILD (fILD). These disorders range in severity and can significantly impair respiratory function by reducing the lungs' ability to transfer oxygen into the bloodstream[3]. As ILD advances, it leads to deteriorating lung capacity, compromised oxygenation, and ultimately, respiratory failure. This group of diseases is associated with considerable morbidity, reduced quality of life (QoL), high healthcare utilization, and poor survival rates. For many patients with advanced ILD, lung transplantation offers a lifeline by extending survival, restoring lung function, and improving QoL[4].

However, the management of ILD in the pre- and post-transplant periods is fraught with challenges. Patient selection, optimizing timing for transplantation, and managing co-morbidities and post-transplant complications such as allograft dysfunction remain critical areas of concern[5]. Recent advancements in diagnostic techniques, a deeper understanding of disease progression, and innovations in immunosuppressive therapy have led to improvements in outcomes. Yet, these advances have also introduced new challenges, including the long-term management of transplant recipients who face a unique set of complications due to prolonged survival[6].

While significant advancements have been made in the diagnosis and management of ILD, particularly in the context of lung transplantation, many challenges remain. Existing reviews have primarily focused on either the surgical aspects of transplantation or the pharmacological management of ILD. However, a comprehensive synthesis of pre- and post-transplant management strategies, integrating recent advancements in immunosuppressive regimens, perioperative care, and long-term post-transplant complications, is lacking. This review aims to bridge this gap by providing a holistic overview of the latest strategies to optimize patient outcomes across the lung transplantation continuum. By addressing key gaps in patient selection, pre-transplant optimization, and post-transplant surveillance, this review offers a timely and practical framework to guide clinicians in improving survival and QoL for ILD patients undergoing lung transplantation.

OVERVIEW OF ILDS

ILD encompass a vast and diverse group of over 200 pulmonary disorders, each marked by varying degrees of inflammation and fibrosis that affect the lung's interstitium-the space surrounding the air sacs. The heterogeneity of these diseases presents significant challenges in diagnosis and management[7]. Clinically, ILD can manifest through a broad spectrum of symptoms, ranging from mild, chronic respiratory discomfort to acute and life-threatening respiratory failure. The course of ILD can be acute, sub-acute, or chronic, and the prognosis varies widely depending on the underlying etiology, rate of disease progression, and the presence of comorbid conditions. This spectrum leads to vastly different patient outcomes, with some individuals experiencing relatively stable disease, while others face rapid progression, leading to respiratory disability or death[8].

In the past, the diagnosis of ILD was largely one of exclusion, often requiring invasive procedures like open lung biopsy to identify specific disease subtypes, particularly in cases of IPF, the most common and aggressive form of ILD. Diagnosing ILD was complicated by overlapping clinical features with other lung diseases, making it difficult to reach a timely and accurate diagnosis[9].

However, the last 15 years have seen transformative advances in diagnostic methods. Minimally invasive procedures, such as bronchoscopy with transbronchial biopsy and video-assisted thoracoscopic surgery, have become critical tools for obtaining lung tissue samples without the need for more invasive surgery. These techniques have been pivotal in allowing for earlier and more accurate diagnoses of ILD, which is crucial given that early intervention often leads to better outcomes[10].

In addition to diagnostic advances, the development of multidisciplinary consensus guidelines for ILD-particularly for IPF-has been instrumental in improving patient care. These guidelines, developed by experts in pulmonology, radiology, and pathology, have established standardized criteria for diagnosing and classifying ILD[11,12]. This collaborative approach has enabled clinicians to more accurately differentiate between subtypes of ILD, which is critical for determining the appropriate course of treatment. For instance, while IPF is a progressive and often fatal disease that requires specific antifibrotic therapy, other ILDs, such as hypersensitivity pneumonitis or sarcoidosis, may respond to immunosuppressive treatments.

INDICATIONS FOR LUNG TRANSPLANTATION IN ILD

Lung transplantation is often the last resort for patients with advanced ILD when medical management fails to halt disease progression. For these patients, the decision to proceed with transplantation hinges on a complex interplay of factors, including the severity of the disease, the presence of comorbidities, and the expected post-transplant prognosis[13]. Pulmonary hypertension (PH) is a critical consideration in the evaluation process, as it frequently accompanies ILD and significantly impacts transplant outcomes. PH in ILD patients is typically diagnosed through right heart catheterization, which measures pressure in the pulmonary vasculature. This invasive procedure remains the gold standard for diagnosing PH; however, because of its frequent occurrence in ILD patients, current recommendations advocate for the use of echocardiography as an initial, non-invasive screening tool to detect signs of PH. Echocardiography can help identify key indicators such as elevated pulmonary pressures and right heart dysfunction, which are associated with more advanced disease and poorer outcomes[14,15].

The presence of PH is associated with an increased risk of peri- and post-transplant complications, particularly due to elevated pulmonary vascular resistance (PVR). High PVR can lead to chronic organ dysfunction, including right heart failure, which significantly complicates the post-transplant recovery process. As a result, identifying and managing PH in ILD patients is crucial during the pre-transplant evaluation. Right heart enlargement and dysfunction are key indicators of severe PH, and patients exhibiting these signs must be closely monitored and carefully considered for transplantation, as these factors can complicate both the transplant surgery itself and long-term outcomes[16,17].

Beyond PH, several other considerations play an essential role in determining whether an ILD patient is a suitable candidate for lung transplantation[18]. A comprehensive pre-transplant evaluation considers disease severity, functional status, and modifiable risk factors to optimize patient outcomes. Comorbidities, including coronary artery disease, chronic kidney disease, and frailty, significantly affect post-transplant survival and must be thoroughly assessed. Additionally, age is a key consideration, as older patients tend to have reduced long-term survival, necessitating careful selection. Frailty and malnutrition are emerging risk factors that influence recovery post-transplantation, with early referral allowing time for nutritional and functional optimization. The presence of right heart dysfunction, particularly in the setting of ILD-associated PH, further complicates transplant eligibility and requires careful hemodynamic assessment[19]. Pre-transplant optimization strategies are critical in maximizing the likelihood of successful outcomes. These include implementing treatment protocols such as targeted medical therapies aimed at stabilizing lung function, supporting nutritional status to ensure that patients are physically robust enough to endure the transplant surgery and recovery, and treating any pre-existing infections that may complicate the transplant process. Symptom management, particularly in relation to dyspnea, pain, and anxiety, is another important aspect of pre-transplant care. Addressing these modifiable factors can improve not only the patient's QoL prior to transplant but also their overall post-transplant outcomes, as these symptoms, if left unmanaged, can hinder recovery[19,20].

IPF is the most common ILD leading to lung transplantation, requiring close monitoring due to its progressive and unpredictable course[21]. Frequent or severe acute exacerbations signal a more aggressive disease and worsen post-transplant outcomes, emphasizing the need for timely transplant evaluation[22].

PRE-TRANSPLANT EVALUATION AND WORK-UP

ILD form a group of lung diseases that affect the lung parenchyma, the tissue in the lung between the air-filled sacs and the vascular structures. There is profound lung inflammation, lung remodeling or fibrosis, and gas exchange abnormalities in this group of diseases. Depending upon the nature of the lung injury and the character and severity of the lung inflammation and remodeling, although only a few syllables of similar words, their meanings are highly controversial and their clinical severity, disease behavior, and response to therapy markedly differ within this large category of lung diseases[23].

Patients with ILD more frequently undergo lung transplant than patients with any other type of chronic lung disease[5]. Prior to transplant, the patient should undergo extensive medical work-up, as the process of lung transplantation is a high-risk operation with higher rates of overall complications, including mortality, than many other types of solid organ transplantation. The pre-transplant recipient evaluation typically requires an evaluation of the patient's underlying lung disease and severity, determination of the most appropriate type of transplant operation, a search for an optimal donor, and then the patient must be given financial resources, educated, and prepared for the peri- and post-operative course. Data attests to the safety and efficacy of the transplant and management of ILD both prior to and following lung transplantation[19].

Pulmonary function tests

Pulmonary function tests (PFTs) are critical in the pretransplant evaluation for lung transplantation, offering essential insights into the severity of pulmonary impairment, risk stratification, and prioritization for transplant candidacy[24]. Parameters such as FEV₁, forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO) help characterize disease patterns, identify airflow limitations, and detect gas exchange abnormalities[25]. PFTs not only assist in determining eligibility but also serve as baseline markers for evaluating disease progression and postoperative lung function[26].

PFTs provide disease-specific metrics that inform transplant timing in ILD. A low and rapidly declining DLCO in ILD patients is a key indicator of worsening gas exchange and disease progression, signaling the need for urgent transplant evaluation. Additionally, the presence of restrictive patterns, characterized by reduced FVC and total lung capacity, reflect significant parenchymal fibrosis and loss of lung compliance, contributing to increased surgical complexity[4].

In ILD, these restrictive changes often correlate with a stiffening of the lung tissue, making mechanical ventilation and perioperative management more challenging. Moreover, a rapidly declining FVC or DLCO may serve as a predictor of imminent respiratory failure, emphasizing the importance of serial PFT monitoring to determine the optimal timing for transplantation. This is crucial, as delayed referral or prolonged wait times can lead to irreversible functional decline and increased perioperative mortality[27].

PFTs are incorporated into a comprehensive, multidisciplinary assessment, including imaging studies and hemodynamic evaluations, to ensure optimal candidate selection and timing for transplantation. They serve as an ongoing tool for monitoring changes in lung function, allowing for timely intervention and better post-transplant outcomes. Although essential, PFT results should be considered alongside clinical symptoms and comorbidities to provide a holistic view of the patient's condition and prognosis[19].

Imaging studies

Imaging plays a crucial role in diagnosing and managing ILD by characterizing the pattern of lung involvement and suggesting potential etiologies for pulmonary symptoms[28]. High-resolution computed tomography (HRCT) is the gold standard for assessing ILD, as it provides detailed visualization of lung parenchyma and can identify specific patterns such as usual interstitial pneumonia or nonspecific interstitial pneumonia, which guide diagnostic and therapeutic decisions. While conventional imaging and noninvasive magnetic resonance imaging can offer supplementary information, none of these modalities alone can definitively diagnose ILD. Often, a multidisciplinary approach that integrates HRCT findings with clinical assessment and, when feasible, tissue biopsy is necessary to confirm the diagnosis and to tailor the pretransplant strategy[29,30].

Optimizing patient outcomes in ILD through pre- and post-transplant management requires a thorough understanding of the radiographic manifestations of each subtype, as well as vigilance for peri-transplant complications[31]. The transplant team should be adept at identifying radiographic patterns that indicate disease progression, infection, or complications related to immune suppression. For instance, subtle changes in imaging may signal early recurrence of ILD, infection, or development of post-transplant lymphoproliferative disorders. This knowledge is essential to ensure timely intervention and to mitigate the risk of postoperative complications that can significantly impact patient survival and QoL[32,33].

MEDICAL MANAGEMENT AND OPTIMIZATION OF PATIENTS PRIOR TO TRANSPLANT

It is important that, while outcomes in lung transplantation have improved to some extent, too many lives are lost without adequate preparation[34]. It has been reported that in patients with ILD undergoing lung transplantation, pulmonary complications are the leading cause of death, accounting for approximately three-quarters of the cases[35]. Many patients wait too long to undergo the procedure when other non-interventional treatment modalities have long ceased to be beneficial to them, in combination with the need for transplantation[36]. It is felt that integrated interdisciplinary care optimized for the pre-transplantation patient will pay significant benefits both to the overall treatment costs for the patient in the total patient loop and to the number of organs available for transplantation given better QoL post-transplantation and ongoing patient contribution to society[37].

The process of lung transplantation can be time-consuming, but preparation prior to transplantation is vital for the overall health and healing of the recipient. This period is an important tool not only for the treatment of symptoms but also for maximizing the ability to undergo transplantation when the appropriate time comes. There may be conditions that make a wait time shorter, and quality reasons for delaying to allow for the right match and best condition to maximize outcome. A major stress to the patient is the forced wait for an appropriate organ. During this crucial period of time and the hospitalization for transplant, if the patient is in good physical condition, both the recipients and the outcomes will very likely be better. Post-operative inflammation, polypharmacy, and mechanical ventilation threaten health and strength, and having a physically fit patient can only help the process go more smoothly[37].

Pharmacological therapies

ILDs can respond to anti-inflammatory or immunosuppressive therapies over time. Even when organ transplantation is not an immediate consideration, these medications may reduce symptom burden and, depending on the underlying disease pathology, may slow the progression of the disease[38]. Corticosteroids such as prednisone are commonly prescribed for individuals with known hypersensitivity pneumonitis or specific autoimmune conditions[39]. Immunosuppressive agents like azathioprine and mycophenolate mofetil (MMF) are frequently used as first-line treatments for patients with ILD associated with autoimmune diseases (e.g., rheumatoid arthritis, scleroderma)[40].

In contrast, antifibrotic agents such as pirfenidone and nintedanib are often the first-line therapies for idiopathic forms of ILD, such as IPF[41]. Pirfenidone has demonstrated efficacy in stabilizing disease progression even in severe ILD cases. Consequently, it may be considered as a temporizing treatment in a multi-step therapeutic strategy, rather than being reserved solely for advanced disease or pre-transplant evaluation[42]. Pirfenidone is typically administered at a dose of 801 mg three times daily, while nintedanib is generally dosed at 150 mg twice daily[43,44]. If side effects occur, the nintedanib dose may be reduced to 100 mg twice daily[44]. Recent evidence supports the continued use of antifibrotic agents as part of pre-transplantation management in patients with ILD, as they do not significantly increase the risk of postoperative complications. A systematic review and meta-analysis evaluating the impact of antifibrotics on lung transplantation outcomes found no significant association between their use and complications such as surgical wound dehiscence, bronchial anastomotic issues, major bleeding, or primary graft dysfunction (PGD). These findings challenge prior concerns regarding the potential perioperative risks of antifibrotic therapy and suggest that their continued use may help stabilize disease progression without adversely affecting transplant outcomes. Given their role in reducing pulmonary function decline in fILDs, maintaining antifibrotic therapy up to the time of transplantation may optimize patient outcomes across the treatment continuum[45].

Pulmonary rehabilitation

The importance of structured pulmonary rehabilitation in post-lung transplant care is well established[46]. Routine rehabilitation programs have been shown to significantly enhance pulmonary function, QoL, mental health, and overall physical capacity in lung transplant recipients. Such programs typically involve supervised, progressive respiratory and whole-body exercises, contributing to notable improvements in functional capacity and physical activity levels[47].

Maintaining a robust exercise regimen is essential for maximizing post-transplant recovery and long-term outcomes. Incorporating high-intensity exercise strategies into rehabilitation has been associated with superior gains in exercise capacity compared to standard programs. These benefits include enhanced peak performance, improved exercise tolerance, and increased endurance during cardiopulmonary activities, indicating that tailored rehabilitation approaches may better support patients' recovery trajectories[48].

Pulmonary rehabilitation is also recognized for its value in pre-transplant settings. Engaging in pre-transplant rehabilitation can expedite post-operative recovery, facilitate earlier weaning from mechanical ventilation, and promote faster extubation[49]. Patients who undergo pre-transplant rehabilitation tend to demonstrate better physical performance and reduced complications in the early post-transplant phase[48].

SURGICAL CONSIDERATIONS AND TECHNIQUES IN LUNG TRANSPLANTATION

Thoracic surgeons have grand responsibilities in the care of patients with ILD. Their role in the management of ILD involves not only assessing patients referred for lung transplantation with a multidisciplinary team, but overseeing the complex operative strategies to remove native, abnormal tissue and replace it with donor organs. ILD includes a wide diversity of conditions, not all of which require lung transplantation, but many of these have familial tendencies or sporadically occur in association with certain syndromes characterized by multiorgan involvement[50].

Types of lung transplantation procedures

During the lung transplant evaluation process, each patient is evaluated individually and discussion and consideration of all the patient's unique personal and medical issues. The decision about which type of lung transplant to have will vary among patients and their healthcare team, mainly based on the patient's lung disease, the degree of illness, and availability of donor organs[51].

There are several things to consider while discussing and determining which type of lung transplant a patient may need. The following is a list of some of the baseline criteria that your healthcare team may use when determining which type of lung transplant a patient will receive: (1) Age; (2) Size of a patient's chest cavity; (3) State of patient's overall health; (4) How close the patient lives to the transplant center; and (5) The patient's specific lung disease and its severity[13].

There are two main types of lung transplant procedures: The single lung transplant (SLT), in which the patient receives only one lung, and the double lung transplant (DLT), where both native lungs are removed and replaced with one lung from a donor on each side[52]. The choice of lung transplant procedure depends on a variety of factors, including the patient's size, disease state, age, and a number of medical and anatomic criteria[19]. Particularly for individuals with advanced ILD, DLT is the preferred approach, largely because bilateral involvement is typical in these diseases[53]. Multiple studies have demonstrated important survival benefits for patients needing a transplant facing lung transplantation compared to SLT[54,55].

In particular, a large-scale analysis of the United Network for Organ Sharing (UNOS) registry found that patients with IPF who received DLT had significantly better median survival (65.2 months vs 50.4 months for SLT, P < 0.001). The survival benefit was particularly evident beyond the first post-transplant year, suggesting that DLT may offer long-term advantages in graft durability and functional capacity[55].

Specific patient populations may benefit differentially from each approach. Younger patients and those with higher functional reserves tend to derive greater benefit from DLT, as it provides better post-transplant pulmonary function and lower risk of chronic lung allograft dysfunction (CLAD). However, in older patients (> 65 years), those with significant comorbidities, or patients with high surgical risk, SLT remains a reasonable alternative, reducing operative time and potential perioperative complications. Given the ethical and logistical challenges of donor lung allocation, patient selection for SLT vs DLT should be individualized, balancing the survival advantage of DLT against donor lung availability and surgical risk[54].

Post-transplant care and complications

Lung transplantation requires a comprehensive post-transplant management strategy to ensure the longevity and functionality of the transplanted organ. Close monitoring and timely intervention are crucial to address both immediate and long-term complications that may arise.

In the post-transplant period, regular imaging surveillance is critical for monitoring disease recurrence, identifying malignancies, and detecting infections or other complications. Imaging follow-up, primarily through HRCT, should be tailored to the patient’s individual risk profile, taking into account the likelihood of original disease recurrence and the potential for new-onset pulmonary conditions due to immune suppression. Such a comprehensive imaging strategy enables early detection and prompt management, ultimately supporting long-term graft function and overall survival in ILD patients undergoing lung transplantation[33].

In the immediate postoperative period, patients are at high risk for PGD, a form of acute lung injury that typically manifests within 72 hours post-transplant and is a leading cause of early morbidity and mortality. The management of PGD involves optimizing ventilator support, managing fluid status, and, in severe cases, employing extracorporeal membrane oxygenation as a bridging therapy. In addition to PGD, acute rejection episodes are a common complication within the first year post-transplant. These episodes are managed through immunosuppressive regimens, typically involving corticosteroids, calcineurin inhibitors (CNI), and antiproliferative agents to mitigate the immune system’s response against the donor lung. Tailoring immunosuppressive therapy is essential to reduce the risk of rejection while balancing the potential for adverse effects, such as infections or drug toxicity[56,57].

Long-term management in lung transplant recipients focuses on the prevention and early detection of CLAD, the leading cause of late graft failure. CLAD encompasses two main phenotypes: Bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), each with distinct pathological and clinical features. While BOS is characterized by small airway inflammation and fibrosis leading to airflow obstruction, RAS is associated with fibrotic remodeling in the lung parenchyma, resulting in restrictive physiology and rapid functional decline. The development of CLAD is often precipitated by recurrent infections, acute rejection episodes, or gastroesophageal reflux disease, necessitating a multidisciplinary approach for management[58,59]. Strategies such as aggressive treatment of infections, prophylactic therapies, and consideration of experimental interventions, including extracorporeal photopheresis and total lymphoid irradiation, are being explored to manage CLAD. Furthermore, lifestyle modifications, pulmonary rehabilitation, and psychological support are critical components of post-transplant care to improve overall outcomes and QoL in lung transplant recipients[60].

Recent studies indicate that a significant proportion of patients with fILD exhibit underlying telomere dysfunction (TL) due to pathogenic variants in telomere-related genes or shortened telomere length. These patients tend to present with earlier disease onset, rapid progression, and a worse prognosis, often leading to earlier referral for lung transplantation. While initial studies suggested that TL patients may have poorer post-transplant outcomes, recent systematic data indicates that patient and graft survival in TL recipients does not appear to be unequivocally inferior to those with non-TL. However, these patients may face higher risks of post-transplant complications, including cytopenias, airway complications, and cytomegalovirus (CMV) reactivation. Given the increasing recognition of telomeropathies in ILD, further research is needed to refine patient selection criteria for transplantation and optimize post-transplant management in this unique population[61].

Immunosuppressive regimens

The management of immunosuppressive regimens in lung transplantation has evolved significantly, with newer strategies aimed at balancing the need for effective rejection prophylaxis while minimizing adverse effects such as infection and drug toxicity[62]. Traditionally, triple therapy involving a CNI, an antiproliferative agent, and corticosteroids forms the cornerstone of post-transplant immunosuppression. Tacrolimus has largely replaced cyclosporine as the preferred CNI due to its superior efficacy in reducing acute rejection episodes and better long-term graft survival. However, tacrolimus carries its own risks, including nephrotoxicity, neurotoxicity, and the potential for post-transplant diabetes mellitus. The antiproliferative agents-most commonly MMF or azathioprine-are used to further suppress T-cell activation and proliferation, though their use must be carefully monitored for cytopenias and gastrointestinal intolerance. Corticosteroids, although effective, are tapered to the lowest feasible dose due to their long-term complications, such as bone demineralization and hyperglycemia. Emerging data suggest that individualized immunosuppressive regimens, tailored based on genetic and pharmacokinetic profiles, may offer a more personalized approach to improving outcomes while minimizing toxicity[63,64].

Efforts are focusing on optimizing CNIs and exploring newer agents such as mTOR inhibitors (e.g., sirolimus), which have shown potential in reducing the incidence of CLAD. The ultimate goal is to maintain allograft function with the minimal effective immunosuppression that reduces the risk of both rejection and infection[65]. As the field advances, ongoing clinical trials are investigating novel immunosuppressants, cellular therapies, and biomarkers to further refine and personalize post-transplant immunosuppression strategies[66,67] (Table 1).

Table 1 Pharmacological agents used pre- and post-transplantation and their characteristics.

Pharmacological agent	Advantages	Disadvantages	Potential side effects	Ref.
Prednisone	Effective for hypersensitivity pneumonitis and autoimmune ILD	Long-term use leads to osteoporosis, hyperglycemia, and adrenal suppression	Hypertension, osteoporosis, hyperglycemia, mood changes	[39]
Azathioprine	Used for autoimmune-associated ILD, suppresses immune response	Risk of bone marrow suppression and hepatotoxicity	Bone marrow suppression, hepatotoxicity, nausea	[40]
Mycophenolate mofetil	First-line for autoimmune ILD, better tolerance than azathioprine	Risk of gastrointestinal side effects and leukopenia	Leukopenia, GI distress, increased infection risk	[40]
Pirfenidone	Slows disease progression in fibrotic ILDs	Photosensitivity, gastrointestinal intolerance	Nausea, rash, weight loss, fatigue	[41,42]
Nintedanib	Reduces lung function decline in fibrotic ILDs	Diarrhea, hepatic toxicity, increased risk of bleeding	Diarrhea, hepatic enzyme elevation, loss of appetite	[41,44]
Tacrolimus	Reduces acute rejection rates in lung transplantation	Nephrotoxicity, neurotoxicity, risk of post-transplant diabetes	Kidney dysfunction, hyperkalemia, diabetes	[62,63]
Sirolimus	Potentially reduces incidence of chronic lung allograft dysfunction	Delayed wound healing, risk of pneumonitis	Mouth ulcers, thrombocytopenia, lung toxicity	[65]

GI: Gastrointestinal; ILD: Interstitial lung disease.

Infection prophylaxis

Infection prophylaxis is a critical component of the management strategy for ILD patients both pre- and post-lung transplantation, as infection remains a leading cause of morbidity and mortality in this population[68]. Due to their immunocompromised state and prolonged exposure to immunosuppressive therapies, patients on the transplant waiting list are at heightened risk for colonization and infection with multidrug-resistant organisms (MDROs) such as methicillin-resistant Staphylococcus aureus, nontuberculous mycobacteria, and resistant gram-negative bacteria[69]. Pre-transplant evaluations should include comprehensive microbiological screening, focusing on identifying occult infections through serial sputum cultures, HRCT scans, and, when needed, bronchoalveolar lavage (BAL) to detect lower respiratory tract pathogens[70]. Routine testing for fungal infections, such as Aspergillus species, using galactomannan and beta-D-glucan assays, should also be part of the pre-transplant evaluation to prevent unexpected complications during the post-transplant phase[71]. Given the dynamic risk of infection in this group, surveillance strategies should be individualized, and any new or worsening radiographic findings should prompt immediate evaluation and initiation of targeted antimicrobial therapy.

Prophylactic antimicrobial regimens are tailored based on the patient’s colonization status, exposure history, and anticipated immunosuppressive needs. Standard prophylaxis often includes broad-spectrum antibacterial agents and antifungal prophylaxis, particularly for patients with preexisting colonization or those who have received prolonged corticosteroid therapy[69]. For viral infections, CMV prophylaxis is typically initiated with valganciclovir, along with prophylactic trimethoprim-sulfamethoxazole for Pneumocystis jirovecii pneumonia prevention[69]. Influenza and pneumococcal vaccinations are imperative for all ILD patients awaiting lung transplantation, as they reduce the risk of severe respiratory infections and associated complications[72]. In addition, vaccination for herpes zoster may be considered for patients with a history of varicella infection or high-risk exposure[73]. Peri-transplant strategies also involve preemptive reduction of corticosteroid doses when feasible, as high-dose steroids are associated with an increased risk of both bacterial and fungal infections. For patients with chronic steroid exposure (e.g., prednisone > 5 mg/day), prophylaxis against Pneumocystis and mold infections with agents such as voriconazole or posaconazole is often warranted. After transplantation, prophylaxis must be maintained for a defined period depending on the patient's risk factors and the presence of ongoing immunosuppression[74,75].

Infection prophylaxis extends beyond pharmacologic measures to include environmental precautions and infection control practices. Hospitalized pre-transplant patients should be placed in contact isolation if colonized or infected with MDROs to prevent cross-transmission[76]. Outpatient management should emphasize good hygiene practices and avoidance of high-risk exposures, such as construction sites, which can harbor Aspergillus spores[77]. For patients on the transplant waiting list, respiratory infections should be aggressively managed with early initiation of broad-spectrum antibiotics and antifungals until pathogen-specific susceptibilities are known[78]. Ultimately, effective infection prophylaxis in lung transplant candidates requires a multidisciplinary approach, integrating pulmonologists, infectious disease specialists, and transplant coordinators to optimize outcomes and reduce the risk of life-threatening infections in this vulnerable population.

REHABILITATION AND LONG-TERM FOLLOW-UP

The follow-up care for ILD patients, both pre- and post-lung transplantation, must be meticulously structured to ensure optimal outcomes and timely management of complications. In the pre-transplant phase, patients should have individualized follow-up schedules every 3-6 months, with a comprehensive assessment of physical condition, lung function, and disease behavior to promptly detect acute exacerbations or complications[21]. Post-transplantation, the frequency of follow-up should be highest during the initial three months, with clinic visits scheduled every 1-2 weeks, and subsequently spaced to monthly or every two months in the first year, depending on patient stability and absence of complications[79]. Routine surveillance during these visits should include PFTs, high-resolution chest imaging, and bronchoscopy with BAL when necessary to identify early signs of infection or CLAD[80]. Persistent complications such as BOS, renal dysfunction due to CNI nephrotoxicity, and infections remain a primary concern, necessitating a coordinated, multidisciplinary approach involving transplant specialists, pulmonologists, and rehabilitation experts. The long-term follow-up strategy should also involve periodic reassessment of immunosuppressive drug levels, monitoring for drug-specific adverse effects, and adjusting dosages accordingly to prevent both rejection and systemic toxicity[81].

Physical therapy and exercise programs

Rehabilitation programs are integral to the management of ILD patients, particularly those on the lung transplant waiting list, as they have been shown to significantly improve exercise capacity, muscle strength, and overall QoL[82]. Effective pulmonary rehabilitation should encompass endurance training, strength training, and flexibility exercises, along with patient education on breathing techniques, energy conservation, and nutritional optimization[83]. While pre-transplant rehabilitation is not universally incorporated into standard care due to logistical barriers such as time constraints, distance to rehabilitation centers, and insurance coverage, its potential benefits in reducing preoperative deconditioning and improving postoperative outcomes are well-established[48]. A structured rehabilitation program initiated early in the transplant evaluation process is associated with shorter hospital stays, faster recovery post-surgery, and improved survival rates[48].

Post-transplant, rehabilitation focuses on enhancing physical performance, reducing the risk of complications, and promoting long-term adherence to healthy lifestyle changes. Techniques such as diaphragmatic breathing, postural training, and gradual aerobic exercise can help mitigate the effects of deconditioning, minimize dyspnea, and prevent muscle atrophy[9]. The integration of home-based exercise programs can support continuous improvement, particularly for patients with limited access to formal rehabilitation centers[46,47] (Figure 1).

Figure 1 Post-transplant rehabilitation strategies. Created with Chat GPT tool.

QoL and psychosocial support

Psychosocial support and QoL interventions are essential for ILD patients throughout the transplant process. Depression, anxiety, and feelings of social isolation are prevalent among these patients, significantly impacting their overall well-being[84]. Comprehensive mental health services, including transplant-specific psychiatric support and counseling, should be integrated into the care plan to address these issues. Transplant candidates and recipients often face unique stressors, such as uncertainty about donor availability, the physical challenges of pre-transplant preparation, and the post-operative burden of lifelong immunosuppressive therapy[85]. Establishing a structured support system, which may include peer support groups, multidisciplinary support teams, and family counseling, can significantly mitigate these stressors and improve QoL. Furthermore, routine psychological assessments should be conducted to identify early signs of emotional distress or cognitive impairment, which can impact adherence to medical regimens and rehabilitation programs. Addressing these psychosocial factors not only improves patient satisfaction and QoL but is also associated with better adherence to medical recommendations, reduced hospital readmissions, and improved survival outcomes[86,87].

Emerging technologies and therapies in ILD and lung transplantation

Emerging technologies and therapeutic advancements are rapidly transforming the landscape of ILD and lung transplantation. One promising area is the development of precision medicine approaches, such as the use of genetic profiling and biomarkers to guide therapeutic decisions and predict transplant outcomes[88]. In particular, gene therapy holds potential for targeting specific molecular pathways involved in lung fibrosis and allograft dysfunction[89]. Recent studies have explored the role of mitochondrial-based therapies in mitigating fibrosis by modulating cellular energy metabolism and promoting tissue repair[90]. Additionally, advancements in regenerative medicine, such as ex vivo lung perfusion (EVLP) and bioengineered lungs, offer the possibility of improving donor organ quality and expanding the donor pool, which remains a limiting factor in lung transplantation[91]. Novel immunosuppressive strategies, including the use of monoclonal antibodies and cellular therapies, are also under investigation to reduce the incidence of CLAD while preserving immune function[67]. As these innovations continue to evolve, they have the potential to significantly enhance the management of ILD and post-transplant care, ultimately improving patient outcomes and QoL.

Ethical and legal considerations in lung transplantation

The ethical and legal dimensions of lung transplantation are complex, particularly given the scarcity of donor organs and the high mortality associated with advanced ILD[92]. Ethical principles of beneficence, justice, and autonomy must guide patient selection and organ allocation to ensure fair and equitable access to transplantation[93]. The UNOS and the Lung Allocation Score (LAS) system in the United States are designed to prioritize candidates based on disease severity and urgency, while also considering post-transplant survival[93]. However, disparities in organ allocation still exist, with certain patient populations, such as racial minorities and those from lower socioeconomic backgrounds, facing barriers to timely transplantation[94]. Strategies to address these inequities include expanding public awareness about organ donation, revising allocation policies to reflect broader criteria, and improving access to transplant evaluation and care for underserved populations[94]. Additionally, ethical considerations extend to the management of high-risk transplant recipients, including those with a history of non-adherence or significant comorbidities, as these factors may influence both short- and long-term outcomes[95]. A balanced, transparent approach that incorporates both clinical judgment and ethical principles is necessary to optimize the utilization of donor organs and achieve the best outcomes for all patients[92].

Allocation of organs

The allocation of donor lungs for ILD patients remains a topic of significant debate, given the complexity of determining which patients are most likely to benefit from transplantation. The LAS system aims to allocate organs based on a combination of medical urgency and expected post-transplant survival, but accurately predicting outcomes in ILD patients can be challenging due to the heterogeneous nature of the disease[96]. Emerging research suggests that incorporating additional variables, such as frailty scores, QoL metrics, and biomarkers of disease activity, may improve the predictive accuracy of the LAS and promote more equitable organ allocation[97]. Furthermore, strategies to increase the donor pool, such as the use of marginal or extended criteria donors, EVLP for donor lung assessment, and advancements in organ preservation, are critical to addressing the current organ shortage[98]. Ultimately, a multifaceted approach that considers both ethical principles and clinical factors is essential for optimizing lung allocation and ensuring that the limited donor organs are utilized to achieve the greatest benefit for patients with ILD.

CONCLUSION

Lung transplantation remains a life-saving intervention for patients with advanced ILD, providing significant improvements in survival and QoL. Comprehensive pre- and post-transplant management is vital to ensuring optimal patient outcomes. Key strategies include early and accurate diagnosis, timely transplant listing, and meticulous perioperative care to address complications like PGD and CLAD. Immunosuppressive regimens must be tailored to balance rejection prevention with minimizing adverse effects, such as infections. Future research should focus on refining patient selection criteria, developing personalized immunosuppression protocols, and incorporating emerging therapies like gene-based treatments. Technological advancements such as EVLP have the potential to expand the donor organ pool and reduce waitlist mortality. Establishing a robust, multidisciplinary approach that integrates advancements in precision medicine will be pivotal in addressing ongoing challenges and achieving better long-term outcomes for ILD patients undergoing lung transplantation.

ACKNOWLEDGEMENTS

During the preparation of this work, AI tool Chat GPT was used to improve the readability and language of the manuscript, and subsequently, the authors revised and edited the content produced by the AI tool as necessary, taking full responsibility for the ultimate content of the present manuscript.