Introduction

Pulmonary fibrosis (PF) is an end-stage interstitial lung disease that causes inflammation and scarring around the tiny air sacs called alveoli in the lungs. Although there is no common cause, pulmonary fibrosis may be triggered by allergens, chemicals, radiation and environmental factors. As idiopathic pulmonary fibrosis advances, these scars stiffen the lungs, making it difficult to breathe. The most advanced stage of the condition leads to a life-threatening condition; while there is no cure for end-stage pulmonary fibrosis, lung transplantation is a potentially lifesaving treatment option for some patients. This article explores considerations for lung transplantation. 

Pulmonary fibrosis

To regain normal organ function after injury or illness, normal tissue architecture must be restored. Pulmonary wound repair is an extremely dynamic process involving immunology, structural biology, and airway physiology. All three must collaborate for successful repair to occur. In lung conditions, an acute inflammatory response to injury or infection can disrupt the epithelial and endothelial integrity, leading to oedema (excessive accumulation of fluid). In idiopathic pulmonary fibrosis, agents such as allergens, toxic chemicals, radiation or other persistent irritants cause dysregulated healing. In the process of scarring, inflammation results in a local environment rich in chemokines, pro-inflammatory, angiogenic, fibrogenic cytokines, growth factors and tissue-destructive enzymes.^1,2,3 The dysregulated healing process can result in an increased accumulation of extracellular matrix components (proteins) and fibrotic lesions, when connective tissue replaces healthy tissue, leading to fibroplasia. The repeated inflammation, tissue destruction and tissue regeneration result in damage, replacing the healthy tissue cells which normally supply the essential nutrients. Recurrent inflammation damages lung cells called parenchymal cells, leading to excessive collagen deposition, scar tissue formation and ultimately, pulmonary fibrosis.⁴

Steps in lung scarring and damage

• Initial lung injury (including autoimmune disease or idiopathic causes)
• Inflammatory response
• Dysfunctional repair (persistent inflammation, overactive fibroblasts)
• Excessive collagen deposition
• Disrupted extracellular matrix
• Loss of lung function

The scar tissues accumulate in the lungs, it replace structures in the alveoli, and stiffen the lungs, hindering normal systolic and diastolic function during breathing. The reduced surface area for gas exchange makes it increasingly difficult for oxygen to enter the bloodstream and for carbon dioxide to be expelled from the lungs. The scarring process transforms the healthy lung tissue into dense, fibrotic tissue, ultimately leading to debilitating symptoms of end-stage pulmonary fibrosis.

What are the impacts of scarring on lung function?

The consequences of the scarring process in the pulmonary process have a devastating impact on lung function, hindering the lung’s ability to perform vital gas exchange duties. They include:  

• Reduced elasticity: The scar tissues become stiff and inflexible, reducing the elastic recoil, and making it harder for them to expand during inhalation
• Alveolar damage: When the scar tissue accumulates, it replaces and engulfs alveol structures
• Decreased gas exchange: Loss of lung surface area, damages the alveolar walls, this results in hypoxemia (low oxygen) and hypercapnia (high carbon dioxide)
• Laboured breathing: complications caused by the scarring causes the respiratory muscles to work harder to overcome lung stiffness and adequate ventilation The increased workload leads to Dyspnea (shortness of breath)
• Respiratory muscle fatigue
• Pulmonary hypertension:  a secondary complication caused by the increased workload on the lungs

Characteristics signs and symptoms of end-stage pulmonary fibrosis

• Dyspnea: shortness of breath 
• Difficulty breathing: leads to debilitating fatigue 
• Cough: becomes less productive, little phlegm in the end stage disease
• Shortness of breath: leads to difficulty eating and increased metabolic demand causes weight loss
• Digits clubbing: may occur with advanced lung disease
• Low blood oxygen levels: can cause cyanosis (blue/grey skin or lips)

Diagnosis of pulmonary fibrosis

Diagnosis of PF begins with a doctor taking a medical history, including asking about the individual’s symptoms, risk factors and family history. The following tests may also be performed: 

• Assessment of the lung function by listening for abnormal breathing sounds with a stethoscope
• Imaging: chest X-ray and computed tomography (CT) scans can reveal characteristic patterns of scarring in the lungs
• Pulmonary function tests: assess lung volumes, air flow rates, and gas exchange capacity
• Blood tests may be performed to rule out other conditions 
• Lung biopsy

Early diagnosis of PF is crucial, as it allows for earlier intervention and management of symptoms. However, symptom onset is usually gradual, so PF can be challenging to diagnose in the early stages. By the time patients reach the end stage, the scarring process is typically extensive, and treatment options are limited.

Lung transplant

The first person with end-stage pulmonary fibrosis to get a successful lung transplantation in 1983, the patient survived with a good quality of life for more than 5 years.¹² Since then, all patients with end-stage lung disease can be candidate for lung transplantation, when certain requirements are met.⁵ Though there have been considerable advances in the management of patients with pulmonary fibrosis, lung transplantation remains the only therapeutic option to restore lung function and improve the quality of life. Historically, chronic obstructive pulmonary disease (COPD) has been the main indication for lung transplantation, which has been replaced by pulmonary fibrosis.⁶ So new criteria and waiting lists have been developed to prioritize the lung allocation for the persons who would get the transplantation at first. The UK UK Lung Allocation Score is based on the risk of dying and the percentage of increase in survival after the transplantation. 

Indications of lung transplant

• If the individual is at high risk of death (over 50% chance in the next two years without transplant)
• If the individual has a high probability (more than 80%) of surviving at least 90 days after transplantation
• If the individual has a high probability (more than 80%) of surviving 5 years after transplantation of any general medical condition

Contraindications of lung transplant

• Age: Individuals over the age of 65 years
• Morbid obesity (BMI over 40)
• Tuberculosis: an infection of the lungs
• Bacteria or viruses not controlled with antibacterial or antiviral medication
• Chest wall deformity
• Coronary heart disease
• Hemorrhagic diathesis (easy bruising/bleeding) 
• Osteoporosis (weakened bones)
• Portal hypertension (increased blood pressure in the portal vein)
• Psychiatric disorders and/or poor social support
• Recent tumor history
• Dysfunction of a major vital organ 
• Previous pulmonary resection surgery

Pre-transplant evaluation

Those who meet the criteria and with few contraindications are considered for the lung transplantation procedure. It is important to identify the adequate time for referral to a lung transplant unit and accomplish the best management before the intervention. The survival expectancy has to carefully be assessed before the transplant because lung transplantation is a very complex and demanding process. The exact time to include the patient in the waiting list is difficult, as some individuals may deteriorate rapidly. Even though the UKLAS has reduced the waiting time and increased the number of patients getting the transplantation, the mortality rates on the waiting list are still higher, 14-67% than observed in other diagnostic groups.⁷ 

Criteria for inclusion in the waiting list

• Decrease of more than or equal to 10% of forced vital capacity (the volume of air forced out during exhalation) during 6 months of follow-up
• Decrease of more than or equal to 15% of the diffusing capacity for carbon monoxide (DLCO) test during 6 months of follow-up
• Blood oxygen desaturation of less than 88% or distance of less than 250 m during the six-minute walk test, or descent of more than 50 m distance walked, during 6 months of follow-up
• Pulmonary hypertension (high blood pressure in the pulmonary arteries) 
• Hospitalisation due to pneumothorax (collapsed lung)
• Exacerbation or clinical deterioration of symptoms

Transplantation window

There are two important clinical decisions that have to be made: when to refer the patient to a transplant unit, and when to include the claimant on the transplant waiting list. The status of survival after transplantation has to be taken into consideration in the selection criteria for referral. The study shows that 5-year post-transplant survival is around 50 % the mean life expectancy of pulmonary fibrosis after the diagnosis is 3 years and five-year survival is around 30-35%.^8,9 Based on the above data, survival is possible for end-stage pulmonary fibrosis patients, if the individual is referred early.

Stages of the lung transplant process

• Pre-listing evaluation: thorough evaluation by a multidisciplinary medical team to assess the function, overall health, and suitability for transplant
• Waiting list placement: The individual is placed on a national waiting list for a compatible donor lung, although the waiting time can vary depending on blood type, lung size, and disease severity
• Comorbidities i.e. cardiovascular disease and gastroesophageal reflux can negatively affect the post-transplant progress, so must be detected and corrected prior to the surgery to minimize the risks
• The call for transplant: the patient receives immediate notification when a suitable donor is available and is prepped for surgery
• Lung transplant surgery
• Post-operative care: intensive monitoring of the patient for several days, gradual recovery and rehabilitation focused on strengthening and regaining the lung function
• Immunosuppressant therapy: transplant patients require lifelong immunosuppressant medication to prevent rejection
• Follow-up care: regular follow-ups with transplant specialists and adherence to a strict medication regimen are critical for long-term success
• Post-transplant investigations are also necessary, as chronic lung allograft dysfunction remains a progressive and incurable complication^{10, 11}  

Summary

Pulmonary fibrosis (PF) is characterised by recurrent inflammation, leading to scarring and difficulty breathing. Lung transplantation is a treatment option for end-stage PF. The number of lung transplants due to pulmonary fibrosis has increased in recent years, mainly after the development of the UKLAS, although the waiting list mortality remains high. Therefore, it is important that individuals diagnosed with pulmonary fibrosis are evaluated as early as possible. Lung transplantation can be a lifesaving treatment, replacing the damaged lungs with healthy donor organs. However, it is not a one-size-fits-all solution, there has to be a rigorous evaluation to ensure the transplant goes to patients who will benefit most, and waiting times may be long.