Pulmonary Disease in the Older Adult – A Review of Interstitial Lung Disease (ILD)

Introduction – ILD in the Older Adult

Interstitial lung diseases (ILD) are an important group of related lung disorders that impact older adults. In addition to the lung alveoli and vasculature needed for gas exchange,¹ numerous different cell types make up the lung tissue, or interstitium.² These include immune cells,³ stromal cells to provide structure,² and stem cells and fibroblasts to support injury repair.⁴ In the healthy lung, these various cells all work together to respond to stressors and maintain lung homeostasis. However, derangements in the functions of one or more cell types in the interstitium can result in abnormal lung function, inappropriate response to injury, and disease.

The science of aging and geriatrics are integral to understanding and managing ILD in numerous ways. From an epidemiologic perspective, ILD is more common in older adults⁵ and has greater impacts on health and survival at advanced age.⁶ Aging biology is also implicated heavily in the pathogenesis of ILD and its progression.⁷ Finally, ILD in the older adult is associated with high rates of age-related comorbidities and barriers,⁸ requiring an age-friendly approach to care. Overall, effective management of ILD in the older adult requires a multidisciplinary approach that incorporates principles of both pulmonary and geriatric medicine.

Epidemiology of ILD in Older Adults

ILDs are categorized based on shared etiologies, clinical features, or treatment considerations.^9,10 Figure 1 outlines the types and subtypes of ILD by age at diagnosis. The most common types include idiopathic pulmonary fibrosis (IPF), connective tissue disease-associated ILD (CTD-ILD), hypersensitivity pneumonitis (HP), and sarcoidosis. There are also ILD cases that are unclassifiable, a phenomenon that increases with age at diagnosis.⁵ Comprehensive lists and descriptions of ILD types and subtypes can be found in relevant ILD guidelines.^9,10

Figure 1: Conceptual Representation of Interstitial Lung Disease (ILD) Incidence by Age at Diagnosis.

Rates are conceptual and not based on actual data. ILD = interstitial lung disease, IPF = idiopathic pulmonary fibrosis, CTD-ILD = connective tissue disease-associated interstitial lung disease, HP = hypersensitivity pneumonitis, SLE = systemic lupus erythematosus, DM = dermatomyositis, RA = rheumatoid arthritis, LAM = lymphangioleiomyomatosis, NSIP = nonspecific interstitial pneumonitis, COP = cryptogenic organizing pneumonia.

The overall prevalence of ILD among US adults is 200 cases of ILD per 100,000 US adults¹¹ and rises significantly with age to a peak for patients age 80-84 (>1,000 cases of ILD per 100,000). Estimates among Veteran populations are similar, with an estimated overall prevalence of 256 cases of ILD per 100,000 Veterans.¹² Over time in the US, the overall incidence and prevalence of ILD is rapidly rising,^11-14 perhaps due to the aging US population, advances in diagnosis, or increased exposure to risk factors. With regards to subtype, sarcoidosis and CTD-ILD are the most common among adults 50-59.⁵ However, as the age at diagnosis advances, sarcoidosis incidence falls while IPF and unclassifiable ILD rise and become the predominant types.⁵ CTD-ILD has a more stable distribution by age at diagnosis, but the underlying CTD-ILD subtype changes with higher rates of rheumatoid arthritis (RA) than others like systemic lupus erythematosus (SLE) or dermatomyositis (DM). It is also critical to note that, as outlined above, ILD prevalence rises with age. Thus, because IPF is the most common type of ILD among older adults, IPF is the most prevalent form of ILD overall.^9,10

ILD has a significant impact on the US health care sector, especially for older adults. For example, patients over 65 years old with IPF have an estimated 1.8 hospitalizations per year¹⁵ costing $10,400 per patient per year in inpatient costs alone.⁶ Accounting for all care, older patients with IPF have an estimated 134% higher annual health care costs compared with age-adjusted controls.⁶ Finally, ILD can be a severe life-limiting disease. Survival is highly variable in adults diagnosed with ILD and depends on many factors including ILD type, the age at diagnosis, and access to treatment. However, in IPF which is the most common subtype of disease, survival for older adults is poor with a median life expectancy of 3.8 years from diagnosis.¹⁶ Thus, ILD has a particularly large impact on the older US population.

Pathogenesis of ILD and the Impact of Aging

The etiologies of ILD range from foreign antigen exposure (HP) to intrinsic cell damage from autoimmunity (CTD-ILD, sarcoidosis) to idiopathic and self-perpetuating aberrant fibrosis formation (IPF).^9,10 What ILDs share in common, however, is the potential to result in progressive, irreversible pulmonary fibrosis.⁷ Thus, understanding the pathogenesis of lung fibrosis, and its relation to aging, are key to the study of ILD.

Fibrosis in the lungs and in other tissues of the body has been most closely associated with hallmarks of aging,¹⁷ and aging biomarkers show promise in advancing pulmonary fibrosis understanding.¹⁸ For example, pulmonary fibrosis is linked to loss of telomeres,¹⁹ or the non-coding ends of DNA. Short telomeres are associated with increased risk for pulmonary fibrosis development, both in familial syndromes^20,21 and sporadic disease.²² Pulmonary fibrosis is also associated with accelerated cellular senescence, or the aging-related loss of cells’ ability to replicate and differentiate. Senescent lung cells in ILD result in increased extracellular matrix deposition, increased tissue stiffness, and reduced gas exchange.²³ The immune system in ILD also shows an aging phenotype known as senescence-associated secretory phenotype (SASP)²³ that is implicated in pathogenesis. Finally, intrinsic and external insults that can accelerate cellular aging have been associated with increased risk of pulmonary fibrosis, including cigarette smoke,²⁴ Agent Orange,²⁵ metal dusts,²⁶ and urban air pollution.²⁷

This pathogenesis has immediate and long-term implications in ILD. Advances in aging biology, especially in the area of drug development, have driven pharmaceuticals in ILD. For example, the current mainstay of treatment for many forms of ILD target the fibrosis pathways implicated in aging.²⁸ New aging pathways such as drugs targeting cell senescence show initial promise in ILD as novel therapeutics.²⁹ Thus, advances in the biology of aging can inform ILD pathogenesis and vice versa.

Management Considerations

Presentation

ILD typically presents with progressive respiratory symptoms, including exertional dyspnea (reported in 90% of patients with IPF)³⁰ and chronic cough (reported in with 84% of patients with IPF).³¹ Symptom time-course can vary; some rarer forms of ILD like acute interstitial pneumonia can present quickly over weeks,³² and others like IPF typically have an indolent onset over months to years.^33,34 Insidious symptoms can pose a significant challenge. In IPF, it takes patients a median of 2.2 years from first presentation to subspecialty IPF evaluation.³⁵ A high index of suspicion is required for early identification and referral. Other non-pulmonary features at presentation may reflect the ILD subtype, such as symptoms of inflammatory arthritis in CTD-ILD. It is important to note that pulmonary fibrosis can precede systemic symptoms in CTD-ILD,³⁶ and the absence of an autoimmune disease does not rule out CTD-ILD. Additional non-pulmonary symptoms, such as weight loss or debility, can reflect advanced disease and portend a poor prognosis.³⁷

The hallmark exam finding in ILD is fine crackles on pulmonary auscultation, a finding related to underlying pulmonary fibrosis.³⁸ More advanced disease can also present with clubbing, hypoxia, and cachexia. Findings may also be present related to the underlying driver of ILD, such as adenopathy in sarcoidosis or tenosynovitis in CTD-ILD. Comorbidity including pulmonary comorbidities can be common in older adults with ILD and may contribute to challenges in diagnosis. Combined pulmonary fibrosis and emphysema, or CPFE, is a well-recognized syndrome due to overlapping risk factors including aging and tobacco use.³⁹ A diagnosis COPD or emphysema does not rule out ILD. Other pulmonary comorbidities, including the presence of pulmonary hypertension, can also complicate the presentation of ILD.

Diagnosis

Effective, early diagnosis is critical to the management of ILD. For the older adult, it is important to distinguish ILD from normal declines in aerobic fitness with aging, from other lung disease, and from cardiac comorbidities that are more common in older adults (like congestive heart failure and coronary artery disease).⁴⁰ Pulmonary physiology can be determined through the performance of pulmonary function tests (PFT). It is important to note that lung function declines with age, but normalized estimates of lung function compared against age-matched controls can aid differentiating between normal aging and pathology.⁴¹ PFTs in ILD most commonly reveal a restrictive physiology phenotype, marked by low forced vital capacity (FVC) on spirometry and low total lung capacity (TLC) on lung volume assessment. Patients with ILD may also have reduced diffusion capacity (DLCO) depending on the severity of disease.

When history, exam, and PFTs suggest ILD, the cornerstone of diagnosis is the chest CT scan. CT imaging is superior to X ray imaging with a greater sensitivity and specificity in identifying ILD.⁴² Advances in CT technology and techniques have also greatly improved including high-resolution CT studies with ILD protocols employing supine/prone and inspiratory/expiratory phases.⁴³ CT findings supportive of pulmonary fibrosis include reticular opacities, traction bronchiectasis, and honeycombing. Numerous other abnormalities can be present depending on the underlying ILD subtype including ground glass opacities, nodular opacities, cysts, and adenopathy.

Determining the subtype of ILD is critical for determining the appropriate pharmacologic treatment strategy and in assessing prognosis. CT imaging findings are key, with different radiographic patterns supporting different ILD subtypes. For example, IPF has a defined typical radiographic appearance, the Usual Interstitial Pneumonia (UIP) pattern.³⁴ Other testing is key including autoimmune serologies (CTD-ILD)⁹ and screening for relevant exposures (HP).⁹ These diagnostic tests alone are often sufficient to make a diagnosis of ILD including the subtype.⁴⁴ However, when diagnostic uncertainty remains, lung biopsy may be performed but requires special considerations for the older adult. Surgical lung biopsy such as video-assisted thoracic surgical (VATS) biopsy is often required to provide sufficient tissue for an ILD diagnosis. However, the overall mortality rate of a VATS biopsy is 1-2% and may be higher for older patients,⁴⁵ meaning many older adults with ILD cannot tolerate a biopsy and may have unclassifiable disease. Fortunately, advances in technology including bronchoscopic cryobiopsy show promise in assisting ILD diagnosis while reducing severe complications.^46,47 Ultimately, the gold-standard practice for determining ILD subtype is through a multi-disciplinary discussion of pulmonologists, radiologists, and pathologists with ILD expertise.⁹ Thus, prompt subspecialty referral is critical for older patients with suspected or confirmed ILD.

Treatment - Pharmacotherapy

New and emerging therapies hold promise in ILD, but currently only two classes of medications have FDA indications in ILD. The first class of medications are known as antifibrotics because they target fibrosis pathways and consist of two drugs: pirfenidone and nintedanib. Pirfenidone is approved for use in patients with IPF after trials showed pirfenidone significantly slows annual lung function decline,^48,49 and pooled trial analysis supports a significantly reduced mortality compared with placebo.⁵⁰ Nintedanib similarly is approved for patients with IPF with randomized control trials showing a significant reduction in annual FVC decline^51,52 and pooled trial analysis supporting a significant survival benefit.⁵³ However, nintedanib importantly also has demonstrated benefit and approval in patients with scleroderma-associated ILD⁵⁴ and patients with progressive pulmonary fibrosis (PPF).⁵⁵ PPF represents a phenotype of or progression of ILD through clinical symptoms, PFTs, and imaging, regardless of the underlying ILD subtype. Overall, older adults with any of the above ILD types or phenotypes should be evaluated for antifibrotic therapy.

There are important treatment considerations for antifibrotics in the older adult. Both pirfenidone and nintedanib have high rates of gastrointestinal side effects including nausea, anorexia, and diarrhea. These medications also carry a risk of liver injury requiring ongoing monitoring of liver enzymes. There are also drug-specific side effects including photosensitivity and rash in pirfenidone^48,49 and increased risk of thrombotic disease including arterial thrombus and myocardial infarction for nintedanib.^51,52 It is important to recognize side effect intolerance rises with age; older patients prescribed antifibrotics are more likely to require dose reductions or drug discontinuation.⁵⁶ Formal strategies for improving medication tolerability for older patients with ILD are lacking.

The only other class of medications specifically approved for ILD are immunosuppressants in patients with autoimmune disease. While some forms of immune-mediated ILD (primarily scleroderma-ILD) have dedicated trials evaluating specific agents,^57-59 much of the evidence and practice for immunosuppression in ILD is off-label and taken from rheumatology literature and guidelines. Potential therapies for ILD in conditions like CTD-ILD or sarcoidosis include corticosteroids as well as steroid-sparing agents like azathioprine, mycophenolate, methotrexate, rituximab, and other agents. It is important to note that immunosuppression is not indicated for all forms of ILD and may even be harmful. For example, for patients with IPF, a randomized control trial of prednisone, azathioprine, and inhaled n-acetylcysteine was stopped early due to increased mortality with these agents,⁶⁰ and as a result chronic immunosuppression is avoided in IPF. For forms of ILD that do not align with the above indications for antifibrotics or immunosuppression, the role of pharmaceuticals is limited to treating comorbid conditions (such as pulmonary hypertension).⁶¹

Treatment – Additional Modalities

Several additional modalities exist for older patients with ILD including supporting cardiopulmonary fitness and aerobic capacity. Pulmonary rehabilitation entails a protocolized regimen of medically supervised exercise and mobility education, and it has been shown to reduce reported symptoms of dyspnea, increase exercise capacity, and improve quality of life in ILD⁶² including in IPF.^63,64 Additional support can be provided by screening for hypoxia, in particular exertional hypoxia. Supplemental oxygen increases exercise capacity in patients with ILD and exertional hypoxia, although there do not appear to be any additional benefits on disease progression or mortality.⁶⁵ Nonetheless, screening for functional limitations and exertional hypoxia should occur regularly.

Symptom palliation is also appropriate and beneficial for many patients with advanced or rapidly progressive disease. As mentioned previously, dyspnea and cough are common and severe in many forms of ILD, and existing therapies like antifibrotics do not reverse existing fibrosis or improve existing symptoms. Palliative care provides expertise with ILD symptom management, goals of care, caregiver support and care transitions.⁶⁶ Specific drugs including opioid medications have demonstrated efficacy in managing dyspnea and cough in pulmonary fibrosis at low doses with low rates of serious adverse events.⁶⁷ Outpatient palliative care engagement in patients with ILD can help align treatment decisions with patient values, resulting in reduced emergency room visits and fewer admissions.⁶⁸ Early, ambulatory palliative care can improve high-value care and improve quality of life for older adults with ILD

Finally, for patients who progress to end-stage lung disease, lung transplantation is a consideration. ILD is now the leading indication for lung transplantation⁶⁹ and can extend survival and improve quality of life with careful candidate selection. However, age is a significant risk factor for reduced post-transplant survival. Lung transplant recipients ≥65 at transplantation have a median survival of 4.4 years.⁷⁰ Transplant decision-making for older patients with ILD is complex.

Treatment – Age-Related Considerations in ILD

Utilizing national frameworks like the 4M framework,⁷¹ we can see that geriatric syndromes are common in patients with ILD. With regards to medications, patients with ILD have high rates of polypharmacy (53-58% with ≥5 medications) and high medication complexity scoring.⁷² With regards to mobility, studies of patients with IPF or related conditions show 26% are frail and 56% are pre-frail,⁷³ both of which are associated with increased mortality. With regards to mentation and mental health, cognitive impairment and mood disorder are common in ILD. Rates of cognitive impairment and dementia in ILD are not well defined, but small cohort studies have shown worse cognitive assessment scores in older patients with ILD compared healthy age-matched controls.⁷⁴ For mood disorder, 43% of patients with IPF meet depression criteria including 8% with severe depression.⁷⁵ Worse depression scoring is associated with more advanced disease severity and lower quality of life.⁷⁵ Patients with ILD also experience high rates of age-related adverse health events; 40% of older patients with IPF reported two or more such events including dizziness/falls, urinary incontinence, and physical frailty.⁷⁶

Discussion

A review of ILD in the older patient shows many recent advances but also areas for future investigation. First, much of our understanding of ILD treatment is derived from the study of younger patients; many of the landmark pharmacotherapy clinical trials^48,49,51,52 had relatively younger age distributions and sometimes specifically excluded older patients. Dedicated efficacy studies of these therapeutics in older adults with ILD are lacking. In addition, we do not fully understand the impact of aging and geriatric syndromes as they pertain to the management of ILD. Factors like cognition and medication burden merit greater study in older adults with ILD including how they can inform patient-centered treatment plans. Finally, we lack evidence-based interventions or guidance for improving care delivery for older adults with ILD. Age-friendly care frameworks exist that make health systems better equipped to meet the needs of older adults,⁷¹ but we lack dedicated studies informing for how to make ILD care age-friendly. We need age-friendly innovations in ILD care followed by rigorous evaluation to advance care for older adults with ILD.

Summary

Interstitial lung diseases (ILD) are a group of diverse conditions that affect the tissue of the lung with the potential to cause irreversible pulmonary fibrosis, high morbidity, progressive respiratory failure, and death. Aging is implicated in the pathogenesis of ILD and the development of pulmonary fibrosis. ILD incidence rises with age, driven by higher incidence of certain subtypes like idiopathic pulmonary fibrosis (IPF) that offset declines in other subtypes. Effective management of ILD involves early recognition of the disease, pharmacotherapy targeting fibrosis and drivers of lung injury, pulmonary rehabilitation, and symptom palliation. Age-related geriatric syndromes such as medication burden, reduced mobility, and neuropsychological comorbidity are common in older adults with ILD and have important impacts on treatment. Future work remains to overcome existing gaps in knowledge for how best to care for older adults with ILD.

Figure 2: Diagnosis and Management of Interstitial Lung Disease (ILD) in the Older Adult.

ILD = interstitial lung disease, PFTs = pulmonary function tests, FVC = forced vital capacity, TLC = total lung capacity, DLCO = diffusion capacity for carbon monoxide, CT = computed tomography, IPF = idiopathic pulmonary fibrosis, UIP = usual interstitial pneumonia, CTD-ILD = connective tissue disease-associated interstitial lung disease, HP = hypersensitivity pneumonitis, PPF = progressive pulmonary fibrosis.

Clinics Care Points.

• Interstitial lung diseases (ILD) are a group of diverse conditions that affect the tissue of the lung with the potential to cause irreversible pulmonary fibrosis, high morbidity, progressive respiratory failure, and death.

• Aging is implicated in the pathogenesis of ILD and the development of pulmonary fibrosis.

• ILD incidence rises with age, driven by higher incidence of certain subtypes like idiopathic pulmonary fibrosis (IPF) that offset declines in other subtypes.

• Effective management of ILD involves early recognition of the disease, pharmacotherapy targeting fibrosis and drivers of lung injury, pulmonary rehabilitation, and symptom palliation.

• Age-related geriatric syndromes such as medication burden, reduced mobility, and neuropsychological comorbidity are common in ILD in older adults and have important impacts on treatment.

Synopsis.

Interstitial lung diseases (ILD) are a group of diverse conditions of critical importance to the care of the older adult that can cause pulmonary fibrosis, respiratory failure, and death. Aging and geriatric principles are key factors in the epidemiology, pathogenesis, and management of ILD. Effective management of ILD for the older adult includes prompt diagnosis and referral for treatment, including pharmacotherapy, pulmonary rehabilitation, and symptom palliation. Age-related geriatric syndromes are also key to recognized and address to deliver age-friendly ILD care. Important gaps remain in how best to tailor and deliver care for older adults with ILD.