Author(s): Nicole Pontee, MD, MS, Lauren Cuenant, DO, Kaitlyn Brunworth, MD
Originally published: September 20, 2014 Last updated: November 30, 2023
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Disease/Disorder

Definition

Lung transplantation is the surgical replacement of severely diseased lungs(s) to reestablish adequate lung function. Pulmonary rehabilitation is a multidisciplinary and comprehensive intervention, including exercise and educational sessions, for patients with chronic respiratory system diseases to improve health-related quality of life and functional status, promote stabilization of symptoms, and prevention of complications.

Etiology

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) remain the leading causes of lung transplantation.1 In recent years, rates of lung transplant for fibrosing disease have increased,2 with IPF surpassing COPD as the number one leading indication for lung transplantation in North America. COVID-19, and its sequelae, have emerged as a major indication for lung transplant 3.  Lung transplant rates for cystic fibrosis (CF) have decreased significantly owing to the approval of highly effective CF transmembrane conductance regulator modulator therapy. Emphysema caused by alpha-1 antitrypsin deficiency, pulmonary vascular disease, sarcoidosis, non-CF bronchiectasis, and lymphangioleiomyomatosis represent other less common indications.2,3

Epidemiology including risk factors and primary prevention

Although no data exist on the worldwide prevalence of respiratory failure requiring lung transplant, it is estimated at tens of thousands, one-third of whom have fibrotic lung diseases and another one-third of whom have severe COPD.4 In 2021, there were 2,569 adult lung transplants performed in the United States; of these, 19.7% were single lung transplants and 80.3% were bilateral. Post-transplant survival is equivalent between single and bilateral lung transplant recipients until approximately two years post-transplant, when survival for bilateral transplants becomes higher. The largest proportion of transplants occurs in recipients aged 50-64 years. The majority of transplant recipients are male. Survival rates are similar between sexes. The majority of lung transplant recipients in 2021 were White (70.6%). However, the proportion of transplants in White patients is down-trending, while rates of lung transplant in Hispanic (13.9%), Black (10.1%), and Asian (4%) recipients are on the rise. This reflects an increased interest in addressing disparities in access to transplant and promoting equity in transplantation.3

The most common risk factor for COPD is tobacco smoke; more than 10 packs per year is identified as the threshold for increased risk.5 Other risk factors included environmental exposures such as organic and inorganic occupational dusts associated with coal miners, hard rock miners, tunnel workers, industrial workers, and transportation industry workers. Additional factors included prior tuberculosis history, outdoor air pollution, respiratory infections, genetics, lower socioeconomic status, nutrition, and other medical comorbidities. Lung growth and development deficits and oxidative stress have also been linked to COPD. Influenza and pneumococcal vaccines are recommended for COPD patients to prevent respiratory tract infection.6 The US Centers for Disease Control (CDC) also recommends the Tdap vaccine (also called dTaP/dTPa) for prevention of pertussis, tetanus, and diphtheria for adults with COPD, as well as shingles vaccine and COVID-19 vaccine in line with national recommendations.6

IPF typically presents as progressive dyspnea in the sixth or seventh decades of life.7 It is a chronic and progressive disorder with a median survival time of 3-5 years after diagnosis if left untreated. There is substantial variability in the clinical course of IPF, from slow progression to acute exacerbation, rapid loss of lung function and early death. The two main risk factors for IPF are aging and cigarette smoke exposure8. The majority of patients with IPF have a history of cigarette smoking. Other risk factors include gastroesophageal reflux, chronic viral infections (Epstein-Barr virus or hepatitis C), and a family history of interstitial lung disease (ILD).7

Patho-anatomy/physiology

During a lung transplant, the host lung is surgically denervated. When this occurs the lung’s lymphatic drainage and circulation is altered.9 The lung receives blood supply from the pulmonary and bronchial arteries, but during lung transplantation, only the pulmonary artery circulation is reattached. The rationale behind this decision is that direct revascularization has been seen as too difficult and often unreliable to perform routinely; also, de novo regrowth of the bronchial arteries has been observed. There is some association of this alteration in lung vasculature to bronchiolitis obliterans, which is a common postoperative complication.10 Following lung transplantation there is increased airway hyperresponsiveness, altered cough reflex, and reduced mucociliary clearance. Injury to the vagus, recurrent laryngeal nerve, and superior laryngeal nerve during surgical procedure can also lead to swallowing and gastroesophageal dysfunction.11

Skeletal and respiratory muscle dysfunction is another common complication in lung transplantation. The etiology is thought to be multi-factorial due to critical illness myopathy, chronic steroid use, and injury to the phrenic nerve. Additionally, there is increased incidence of sleep disordered breathing in lung transplant recipients. Pulmonary function tests typically show the most improvement during the first year after transplant. Decline in forced expiratory volume in 1 second (FEV1) could be a sign of organ rejection, infection, airway stenosis or other issues. Patients typically experience improved exercise and functional capacity following lung transplantation, though they typically experience chronic limitations including reduced peak oxygen consumption and early onset of anaerobic threshold; a pattern compatible with skeletal muscle deconditioning.9 

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) formulated a staging system as follows:

  • Stage I: forced expiratory volume in one second (FEV1) more than 80% of expected; minimal shortness of breath with/without cough and/or sputum.
  • Stage II: FEV1 50% to 80% of predicted; moderate to severe shortness of breath on exertion, with/without cough, and sputum or dyspnea.
  • Stage III: FEV1 30% to 50% of predicted; severe shortness of breath, with/without cough, sputum or dyspnea, exacerbation, reduced exercise capacity, and fatigue.
  • Stage IV: FEV1 less than 30% of predicted; serious impairment in quality of life caused by shortness of breath with frequent exacerbation, and life threatening at times.6

According to the American Lung Association, there is no formal staging system for pulmonary fibrosis. Prognostication based on symptoms, pulmonary function tests, and imaging with high resolution CT scan is utilized to categorize disease as mild, moderate, or severe. A scoring system called the GAP Model (Gender, Age, and Physiology) was recently developed which uses gender, age and physiology to stage pulmonary fibrosis. There are multiple studies assessing the prognostic value of the GAP Model, however it is not yet widely utilized.12

Specific secondary or associated conditions and complications

Primary graft dysfunction (PGD) is a syndrome of acute lung injury that occurs within 72 hours of lung transplant and is characterized by pulmonary edema and diffuse alveolar damage. The incidence of grade 3 PGD is approximately 16.8%. PGD cases can last anywhere from 48 hours to several weeks. Acute cellular rejection (ACR) is a host lymphocyte reaction to donor antigens; the incidence of ACR is estimated at 35% of adult lung transplant recipients within the first year but it is only responsible for 4% of deaths within the first month of transplant. Antibody-mediated rejection also occurs when the recipient forms donor-specific antibodies. Bronchiolitis Obliterans Syndrome (BOS) is a manifestation of chronic lung transplant dysfunction that typically occurs within the first 3 months of transplant and is responsible for the majority of deaths in the first year after transplant. BOS occurs in greater than 50% of lung transplant recipients by year five. Recurrence of primary disease most commonly occurs in patients with sarcoidosis which recurs at a rate of 35% after transplant. Lymphangioleiomyomatosis has also been found to recur.13

There are other medical complications that commonly arise after lung transplant as an adverse effect of anti-rejection and other post-lung transplant medications. For example, calcineurin inhibitors can be implicated in the development of hypertension (HTN) and renal failure after lung transplant. The prevalence of diabetes mellitus (DM) is estimated at greater than 30% in lung transplant patients, often secondary to or exacerbated by chronic steroid and calcineurin inhibitor use. Lung transplant patients frequently suffer from steroid-induced osteopenia or osteoporosis and rapid bone loss after transplant.4 Due to immunosuppression, lung transplant patients are also at high risk for opportunistic infections such as cytomegalovirus, aspergillosis and pneumocystis jiroveci.13

Essentials of Assessment

History

  • Medical history: age, severity of respiratory disease, cough, sputum production, oxygen supplementation needs, dyspnea, history of lung infections, malignancy, prior thoracic surgeries, vaccination history, hospitalizations as a result of pulmonary issues, and assessment for any comorbid conditions (e.g., heart disease, weight loss, esophageal dysmotility, connective tissue diseases) and assessment for any conditions that would preclude patient from receiving a transplant (active infections, sepsis, or stroke or coronary event within the past 30 days).
  • Environmental history: primary or second-hand smoke exposure, high pollution environment and biomass disease fuel use in enclosed spaces.
  • Occupational history: work type and exposure to inhaled gases and/or particulate matter inhalation.
  • Psychosocial history: tobacco use or any inhaled illicit drugs, known or progressive cognitive impairments or uncontrolled psychiatric illnesses that could interfere with medication adherence, social support, and resources available.
  • Functional history: premorbid functional status, current functional status, assistive device use, and dyspnea during activity.

Physical examination

Patient assessment should focus on the following:

  • Lung auscultation to evaluate for effusion, areas of atelectasis and bronchial constriction.
  • Assessment of supplemental oxygen requirements
  • Inspection to evaluation for accessory muscle use and to assess for any deformity.
  • Heart auscultation to assess for cardiac/valvular disease.
  • Examination of the muscle bulk for any signs of atrophy or cachexia including measurement of BMI.
  • Manual muscle testing to assess strength focusing on muscles used for ambulation.

Both before and after transplant, examination should also focus on signs of comorbid and secondary diseases (e.g., diabetes, renal disease, neurologic examination, gastrointestinal involvement).

Functional assessment

  • Mobility: six-minute walk test, FIM, and cardiopulmonary exercise study.
  • Multidimensional prognostic model: BODE index (BMI, airflow limitation as measured by forced expiratory volume in 1 second (FEV1), dyspnea and six-minute walk test)
  • Self-care: index of independence in activities of daily living, instrumental activities of daily living, Barthel Index of activities of daily living, and FIM.
  • Cognition/behavior/affective state evaluation tools: Minnesota Multiphasic Personality Inventory-2, clinical interview, Montreal Cognitive Assessment, among others.

Laboratory studies

Pretransplant evaluation includes laboratory analysis of hepatic and renal function to assess for potential multi-visceral transplant candidacy. Viral serologies are also measured in order to assess compatibility with donor serologies to decrease risk for reactivation and viremia.

During the posttransplant period, surveillance of immunosuppressant levels for dose titration is indicated, and its frequency will be dictated based on the patient’s clinical status. Monitor for electrolyte disturbance, such as hypomagnesemia and hypophosphatemia, among others. Further laboratory monitoring and workup should be tailored to what is indicated for each individual patient.

Imaging

The needs for imaging will be dictated by the patient’s clinical status and time frame posttransplant. The following are some of the most used:

  • Chest radiographs with a selection of views depending on the suspected diagnosis. Useful to assess for lung expansion, donor size mismatches, pulmonary infection, presence of pneumo/hemothoraces, effusions, and/or diaphragmatic paralysis. Routine follow-up radiographs are usually done serially during the first 3 months posttransplant.
  • Fluoroscopic examination to rule out diaphragmatic paralysis, if suspected, posttransplant.
  • Chest computed tomography (CT), both non-contrast and contrast enhanced, is useful to assess the presence of common pulmonary pathology, such as effusions and consolidation, among others. CT is useful for confirming and quantifying infiltrates, selecting appropriate regions of the lung for bronchoscopy, and determining the response to specific antimicrobial treatment. It is also useful to evaluate for well-established complications of transplant such as vascular and bronchial anastomotic abnormality, lung torsion, pulmonary embolism, rejection, infection and bronchiolitis obliterans.

Early predictions of outcomes

Decreased 1-year survival has been associated with the number of human leukocyte antigen mismatches, primary pulmonary hypertension and pulmonary fibrosis, pretransplant psychologic illness, clinical status, mechanical ventilator dependency, and age over 60 years. Transplant recipient selection criteria vary from center to center; nonetheless, because of lung allocation scoring system changes, increased transplant recipient age has been observed and associated with decreased survival.

Environmental

Particulate aspiration and gases (biomass fuel, diesel exhaust, etc.) have been identified as triggering agents for airflow limitation, therefore contributing to COPD and COPD-like illnesses. During the posttransplant stage, some patients will possibly require droplet precautions and/or contact precautions caused by the development of viral infections or resistant bacteria during their hospital stay. The proper hand-washing technique is the most advocated infection control measure per the Centers for Disease Control guidelines. Some immunocompromised patients with neutropenia benefit from positive air pressure and a high-efficiency particulate filter. Some transplant centers will, after discharge, require the avoidance of enclosed spaces/densely populated spaces, favor face mask use until steroids are tapered to the lowest possible dose, and require the avoidance of handling pet feces and plants.14 When handling materials with a higher chance of contamination such as soil, moss and manure, gloves should be worn. Shoes, long sleeves and pants should be worn while participating in activities such as gardening, yard work and being in parks and heavily wooded areas. As for possible percutaneous infectious exposure, body piercing and tattoos should be obtained from reputable centers with strict adherence to sterile technique. As for all activities mentioned above, extra caution should be taken during periods of enhanced immunosuppression. The same can be said for times when community spread of viral illness is increased.15

Social role and social support system

Pretransplant, an evaluation is conducted to determine whether the patient has support from family/friends or access to care services for transition to the community posttransplant. A patient’s cognitive abilities will be crucial regarding medication management to yield a higher rate of success posttransplant and help prevent complications. Household contacts should be educated on good hygiene practices such as hand washing, coughing and sneezing etiquette. Additionally, all close contacts should remain up to date on standard immunizations and yearly influenza vaccine.

Professional issues

A close evaluation of the patient’s medical needs, tolerance to activity, and need for supplemental oxygen is vital to establish goals for the rehabilitation process, inpatient or outpatient. Accurate documentation and coding will safeguard proper reimbursement and accounting for the patient’s complexity during evaluation and management.

As for patient professional considerations, lung transplant recipients have a lower pretransplant incidence of employment as compared to other solid organ transplant (SOT) recipients such as kidney, heart and liver. Studies have suggested return to work rates around 28% in lung transplant patients. Additionally, compared to other SOT recipients, lung recipients are less likely to return to work posttransplant.16 Some factors shown to positively affect return to work include pretransplant employment, self-reporting being physically able to work, greater posttransplant improvement in percent predicted forced vital capacity, and posttransplant 6-minute walk > 550 meters.17 Return to work becomes much less likely one-year post-transplant. For individuals desiring returning to work in fields such as construction, outdoors and healthcare, individualized occupational counseling is important. For transplant recipients working with animals, work should be avoided during times of maximal immunosuppression. If returning to work, it is important to properly use personal protective equipment to limit any possible dangerous exposure. Additionally, while some patients may be willing to pursue work in other areas, some are tied to previous lines of work for various reasons such as psychological, social, financial and maintenance of health insurance or other benefits. Coworkers may also be encouraged to stay up to date on regularly scheduled and seasonal vaccinations such as influenza. Professional rehabilitation, including the help of a social worker, may be started prior to transplant.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Current pulmonary rehabilitation guidelines have been published by the American College of Chest Physicians and American Association of Cardiovascular and Pulmonary Rehabilitation.18 The GOLD has also published guidelines on the diagnosis, management, and prevention of COPD. Pulmonary rehabilitation is recommended both before and after transplantation to improve the quality of life, symptoms and to prevent further loss of function.  A systematic review in 2017 provided evidence that candidates awaiting lung transplant had improved quality of life and exercise capacity after engaging in pulmonary rehabilitation.19 Additionally, transplant candidates with severe and progressive lung disease have also demonstrated preserved exercise capacity and training volumes when participating in pulmonary rehabilitation. There is also a growing body of evidence of pulmonary rehab’s survival benefits

At different disease stages

Pretransplant: Previous studies have shown that VO2 max and exercise capacity of transplant patients is significantly limited by impaired oxidative capacity of peripheral skeletal muscle. Therefore, pulmonary rehabilitation should begin as soon as possible to optimize cardiopulmonary function. Additionally, there is evidence to suggest that pulmonary rehabilitation can lead to better outcomes. A study published in 2013 in the Journal of Heart and Lung Transplantation, found that a greater final 6-minute walking distance was associated with a shorter hospital stay following lung transplant.20 The goal is to improve endurance and activity tolerance to promote a better functional recovery and prevent complications posttransplant.

Posttransplant:  During the inpatient stay, the rehabilitation process should be started early, once the patient is stabilized. Activities should start with functional mobility (e.g., bed mobility, transfers, gait) and include treadmill training, with a progressive increase in distance, resistance, and inclination as tolerated. Supplemental oxygen weaning to the minimum necessary should be reassessed frequently. Resistance exercises involving large muscle groups should also be started, taking into account limitations due to sternal precautions. Breath retraining, control, respiratory muscle strength training (RMST) and pulmonary hygiene techniques are also part of this phase. Lung transplant patients may experience dysphagia, which can lead to malnutrition and worse outcomes, and should also be addressed during inpatient rehabilitation.  Following completion of an inpatient rehabilitation stay, lung transplant recipients benefit from direct enrollment in a formal pulmonary rehabilitation outpatient program, which entails a closely monitored and individually tailored exercise program of 36 sessions focused on cardiovascular endurance building and strength training.  Exercise training post-lung transplantation can benefit muscle strength, exercise capacity and bone mineral density in this population. 

Coordination of care

Arrangements for surveillance bronchoscopies and biopsies during acute inpatient rehabilitation requires close work with the transplant team. The transplant and infectious disease teams are typically responsible for titrating immunosuppressant drugs and surveillance for infectious processes. The rehabilitation team’s key role is in the identification and facilitation of functional progress, as well as monitoring symptoms, and clinical changes in the patient during the rehabilitation process. Good communication among team members is essential.

Patient & family education

Pulmonary rehabilitation helps to ensure that patient exercise and equipment use is safe and effective. Education is provided to both the patient and their caretakers to promote independence and address knowledge gaps. Additionally, while exercise capacity, muscle function, physical performance and mobility are assessed in rehabilitation, therapists may also help identify psychosocial issues which can concurrently be treated.

Emerging/unique interventions

COPD Assessment Test (CAT): The CAT is a questionnaire for people who have COPD. It can help assess the impact the disease has on a patient’s life and monitor changes over time. It has demonstrated reliability and validity and is responsive to interventions. 

Clinical COPD Questionnaire (CCQ): The CCQ is a ten-item questionnaire focused on patients’ quality of life. It has been shown to have a better correlation with the SGRQ and CAT compared to the modified Medical Research Council (mMRC) and FEV1. It has demonstrated reliability and validity and may be a reasonable alternative to more time-consuming health-related quality of life questionnaires.  St. George’s Respiratory Questionnaire (SGRQ): This questionnaire contains 50 items which are designed to evaluate the perceived well-being of patients with obstructive pulmonary disease. It is disease specific, validated and has demonstrated internal consistency.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Managing a transplant patient in the rehabilitation unit includes, but is not limited to, the following:

  • Airway normalization (oxygen weaning and decannulation)
  • Surveillance bronchoscopy coordination and follow-up
  • Immunosuppressant monitoring and management coordination
  • Protection from, assessment for and coordinating management of infectious processes in the immunosuppressed patient
  • Post-operative wound care (including drain management)
  • Prevention of, surveillance for and management coordination of complications (e.g., venous thromboembolisms, arrhythmias, pleural effusions, neuropathies, dysphagia, rejection and hemorrhage).
  • Minimize disability and facilitate functional recovery through therapies, training and strength-building
  • Nutritional optimization
  • Comorbidity management (such as anticoagulation, diabetes, arthritis, and hypertension)
  • Symptom management (pain, anxiety, dyspnea)
  • Home care and outpatient therapies coordination
  • Arrangements for medical equipment and therapies needed post discharge (DME, spirometer, nebulizer etc.)

Cutting Edge/Emerging and Unique Concepts and Practice

With the emergence of FDA approved gene therapies, such as for SMA or LCA, in addition to the introduction of CRISPR-based gene editing techniques, medicine is closer than ever to preventing and treating genetic factors predisposing patients to causes of respiratory disease and transplantation, such as cystic fibrosis and alpha-1 antitrypsin deficiency. Next generation DNA sequencing has also greatly reduced the cost and accelerated the timeline for better understanding which medical therapies work best for which patients, and possibly providing targets for rational drug design or gene therapy to improve symptoms and response to medications, such as matrix metalloproteinase-12, gene transfer of interleukin 2 and interferon gamma to decrease airway hyperresponsiveness, or beta-2-adrenergic receptor gene, single nucleotide polymorphisms and insertion-deletion polymorphism of the hemopoietic cell kinase gene.

We are also encountering new causes for respiratory failure and lung transplantation, such as e-cigarette, or vaping product use-associated lung injury (EVALI), and the SARS-CoV-2 virus (COVID-19). Both of these pathologies present with unique physiologies and comorbidities complicating both pre- and post-transplantation rehabilitation. Efforts are ongoing to adjust and optimize practices for these new diseases. Such adjustments have included the necessary growth of telemedicine, allowing access and refinement of home pulmonary rehabilitation programs for the outpatient and maintenance phases.  Wearable devices, such as smart watches, permit O2 and heart rate monitoring and documentation inexpensively and passively, providing rehabilitation teams with a wealth of data to further improve interventions and systems of care.

Gaps in The Evidence-Based Knowledge

Most research regarding pulmonary rehabilitation has focused on patients with COPD, however in the past decade, trials evaluating other diseases, such as pulmonary fibrosis, have expanded and improved upon our knowledge base. Unfortunately, though the benefits to function and short-term quality of life metrics are clear, much of the pulmonary rehab literature is focused on establishing efficacy in improving immediate physiologic and satisfaction-based outcomes, and suffers from a number of design flaws, from inadequate power to inadequate control groups, to establish evidence-based guidelines for best practices or length of stay. Only in the last decade have studies even begun to assess the value added to medical systems and society through reducing pre- and post-operative complications, reducing disability, and facilitating return to employment, but the potential in these fields is profound. Lastly, though a current and intense focus of research, the very novelty of COVID-19 and EVALI preclude rigorous evaluation of longitudinal outcomes. Further research in the form of double-blind multicenter randomized controlled trials, in these and other types of chronic pulmonary diseases and their outcomes-based response to pulmonary rehabilitation, pre- and post-lung transplantation, is recommended.

References

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Original Version of the Topic

Melissa M. Alvarez Perez, MD. Pulmonary Rehabilitation Before and After Pulmonary Transplantation. 9/20/2014

Previous Revision(s) of the Topic

Matthew Adamkin, MD, Blake Fechtel, MD, Dylan Lewis, DO, Katrina Slater, DO. Pulmonary Rehabilitation Before and After Pulmonary Transplantation. 3/23/2021

Author Disclosures

Nicole Pontee, MD, MS
Nothing to Disclose

Lauren Cuenant, DO
Nothing to Disclose

Kaitlyn Brunworth, MD
Nothing to Disclose