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Chapter 304 | Interstitial Lung Disease

Disorders of the Respiratory System · Part 7 – Respiratory Disorders

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Diagnosis of ILD requires combined weight of clinical data, laboratory studies, pulmonary function testing, imaging, and histopathology.
  2. Idiopathic Pulmonary Fibrosis (IPF) is the most common ILD of unknown cause, with a 50% 3- to 5-year mortality rate.
  3. UIP pattern on HRCT (subpleural reticular changes, honeycombing, traction bronchiectasis) is diagnostic for IPF.
  4. Antifibrotic therapy (pirfenidone, nintedanib) slows lung function decline in IPF.
  5. NSIP has a better prognosis than IPF, with >80% 5-year survival.
  6. Smoking is associated with Respiratory Bronchiolitis–Interstitial Lung Disease (RB-ILD) and Desquamative Interstitial Pneumonia (DIP).
  7. Systemic Sclerosis (SSc) is the most common connective tissue disease associated with ILD.
  8. Acute Interstitial Pneumonia (AIP) is rare, often fatal, and characterized by acute respiratory distress.
  9. Lung transplantation remains the standard of care for advanced and rapidly progressive ILDs.
  10. Family history of ILD is a strong risk factor for IPF; MUC5B promoter variant and TERT variants are genetic determinants.

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🔀 Flowchart Classification of interstitial lung disease
1 🖼 Figure Chest CT imaging and interstitial lung disease
2 🖼 Figure Histopathology of interstitial lung disease
3 🖼 Figure Histopathology of interstitial lung disease
4 🖼 Figure Histopathology of interstitial lung disease
5 🖼 Figure Histopathology of interstitial lung disease

1. DEFINITION & OVERVIEW

Interstitial lung diseases (ILDs) include a large number (>200) of heterogeneous conditions that affect the lung parenchyma with varying degrees of inflammation and fibrosis. While remodeling of the interstitial space, the region between the epithelium and endothelium, tends to be the dominant site of involvement for most of the ILDs, it is important to recognize the prominent role of the alveolar epithelium and endothelial cells (including both airways and vessels) in the pathogenesis of these ILDs. Despite the diverse array of conditions, most patients ultimately diagnosed with an ILD will come to medical attention with reports of progressive exertional dyspnea or a persistent dry cough. However, because some ILDs are part of multisystem disorders, some patients will be identified based on nonrespiratory symptomatology (e.g., skin thickening in the setting of systemic sclerosis) or physical examination findings (e.g., ulnar deviation of the fingers in the setting of rheumatoid arthritis). Additionally, ILDs can also be identified incidentally based on the results of abnormal pulmonary function tests, chest x-rays (CXRs), and computed tomography (CT) studies of both the chest and abdomen (which can both visualize at least a portion of the lung parenchyma), and positron emission tomography (PET) scans.

1.1 Classification

ILDs are categorized into those of known and unknown causes. Known causes include occupational exposures (e.g., asbestosis), medications (e.g., nitrofurantoin), and those related to an underlying systemic disease (e.g., cryptogenic organizing pneumonia [COP] in the setting of polymyositis). Unknown causes of ILD include groups of rare disorders often with classic presentations (e.g., a spontaneous pneumothorax in a young female with diffuse cystic changes on a chest CT might suggest lymphangioleiomyomatosis [LAM]) and the most common group of ILDs, the idiopathic interstitial pneumonias (IIPs). Granulomatous lung diseases straddle both known (e.g., hypersensitivity pneumonitis [HP] due to chronic bird exposure) and unknown (e.g., sarcoidosis) causes and are often separated due to their unique presentations, imaging findings, and diagnostic evaluation.

1.2 Diagnostic Approach

A generally accepted central tenet of ILD diagnosis is that the combined weight of clinical data, laboratory studies, pulmonary function testing, imaging findings, and histopathology (if obtained) are jointly required to make a confident diagnosis. No single piece of data confers a diagnosis alone. For example, a lung biopsy demonstrating the usual interstitial pneumonia (UIP) pattern is helpful in diagnosing a patient with idiopathic pulmonary fibrosis (IPF) but is also present in some connective tissue diseases (CTDs) (e.g., RA-associated ILD). In light of this challenge, most ILD centers recommend a multidisciplinary approach to the diagnosis (and, in some cases, the management) of ILDs. An example of a multidisciplinary approach is a conference attended by pulmonologists, rheumatologists, radiologists, and pathologists where all of the data generated on a patient can be discussed and reviewed jointly by those with unique sets of expertise in the care of patients with ILD.

2. EPIDEMIOLOGY

Although there is variability within different demographic groups, most studies demonstrate that IPF, sarcoidosis, and ILDs related to CTDs as a group are among the most common forms of ILD. The age of onset of clinical symptoms has a strong influence on the pretest probability that IPF, in particular, is present. IPF occurs most commonly in patients aged >60 and is quite rare among patients aged <50. Other common ILDs, such as sarcoidosis and CTD-associated ILD, and less common ILDs, such as LAM and pulmonary Langerhans cell histiocytosis (PLCH), tend to present between the ages of 20 and 40. Sex has some influence on the likelihood of various ILDs. LAM (and the related disorder tuberous sclerosis) is a disorder that is frequently diagnosed in young women. Many CTD-associated ILDs are more common among women, except for RA-associated ILD, which is more common among men. IPF and occupational/exposure-related ILDs are more common among men.

2.1 Prevalence

IPF prevalence increases with age and is estimated at 50–200:100,000. IPF is commonly diagnosed in the fifth or sixth decade of life, affects men more than women, and is frequently associated with a history of smoking or other environmental exposures. IPF is a variably progressive disease that carries a poor prognosis with an estimated 50% 3- to 5-year survival.

2.2 Risk Factors

Family history of ILD (of almost any type) is important to ascertain. The percentage of pulmonary fibrosis that is familial, as opposed to idiopathic, varies by study, and could be as high as 20%. Despite the variability, most studies suggest the presence of a close relative with an IIP is among the strongest risk factors for IPF. Family studies have consistently noted familial aggregation of diverse forms of IIP (such as IPF, nonspecific interstitial pneumonia [NSIP], and desquamative interstitial pneumonia [DIP] running in the same family) and, in some cases, other forms of ILD. To date, the most well-replicated genetic factors for pulmonary fibrosis (a promoter variant of a mucin gene [MUC5B]) and various genetic determinants known to influence telomere length (e.g., variants in the telomerase reverse transcriptase gene [TERT]) appear to be associated with both familial and idiopathic forms of pulmonary fibrosis similarly.

3. ETIOLOGY & PATHOPHYSIOLOGY

ILDs include a diverse group of lung pathologies that can be subclassified into those disorders of unknown cause (e.g., IIPs) and those of known cause (e.g., sometimes referred to as secondary interstitial pneumonias [CTD-associated ILDs]). Although this remains a useful approach to classifying these disorders, it is important to recognize that genetic studies are challenging this classification. For example, numerous ILDs commonly listed as having an "unknown cause" have been determined to have significant genetic underpinnings (e.g., IPF and LAM), while the pathophysiologic processes that result in ILDs of "known cause" (e.g., CTD) remain incompletely understood. Diagnosis is based on combined information obtained from a patient's clinical presentation, measures of pulmonary function, imaging, immune serologies, and histopathology. It is important to remember that prognosis and treatment vary widely by disorder (and disease extent). In some cases, medical therapy that is felt to be effective for some ILDs has been proven to be harmful for others. Medical treatments range from immune modulators to antifibrotic medications, whereas lung transplantation remains the standard of care for patients with advanced and rapidly progressive ILDs.

3.1 Genetic Factors

Genetic studies demonstrate that a significant portion of familial and sporadic pulmonary fibrosis or IPF may be explained, in part, by genetic factors. The most well-replicated genetic factors for pulmonary fibrosis include a promoter variant of a mucin gene [MUC5B] and various genetic determinants known to influence telomere length (e.g., variants in the telomerase reverse transcriptase gene [TERT]).

3.2 Pathogenesis

Remodeling of the interstitial space, the region between the epithelium and endothelium, tends to be the dominant site of involvement for most of the ILDs. It is important to recognize the prominent role of the alveolar epithelium and endothelial cells (including both airways and vessels) in the pathogenesis of these ILDs.

4. CLINICAL FEATURES

Most patients ultimately diagnosed with an ILD will come to medical attention with reports of progressive exertional dyspnea or a persistent dry cough. However, because some ILDs are part of multisystem disorders, some patients will be identified based on nonrespiratory symptomatology (e.g., skin thickening in the setting of systemic sclerosis) or physical examination findings (e.g., ulnar deviation of the fingers in the setting of rheumatoid arthritis). Additionally, ILDs can also be identified incidentally based on the results of abnormal pulmonary function tests, chest x-rays (CXRs), and computed tomography (CT) studies of both the chest and abdomen (which can both visualize at least a portion of the lung parenchyma), and positron emission tomography (PET) scans. It is important to remember that ILDs can be associated with high rates of morbidity and mortality, and although prognosis depends on both disease extent and specificity, this fact makes these important disorders to recognize in a timely manner.

4.1 Symptoms

Progressive dyspnea, most frequently noted with exertion, is the most common complaint in patients presenting with an ILD. Despite this fact, both research studies of general population samples and clinical experiences of asymptomatic patient referrals with abnormal chest CT imaging patterns have also demonstrated that some patients, even those with more extensive disease, may not report dyspnea. Cough, particularly a dry cough, is also common and can be the most prominent symptom in patients with IPF. Cough is often reported in other ILDs, particularly those with prominent airway involvement including sarcoidosis and HP. Cough with hemoptysis is rare and could suggest an ILD associated with diffuse alveolar hemorrhage (DAH) (e.g., Goodpasture's syndrome), GPA, or LAM. Cough with hemoptysis could also suggest a secondary pulmonary infection that can be seen in patients with traction bronchiectasis and in those receiving immunosuppressive therapy. Chest pain is rare in most of the ILDs, with the exception of sarcoidosis, where chest discomfort is uncommon. Fatigue is common to all of the ILDs.

4.2 Physical Examination

End-inspiratory fine crackles, or rales, noted at the lung bases are found in most patients with IPF and may be one of the earliest signs of the disease. However, rales are nonspecific and can be found in many forms of ILD and other disorders. Wheezing is uncommon in most forms of ILD but can be present in some disorders, such as sarcoidosis, HP, and eosinophilic GPA. Signs of advanced disease include cyanosis, digital clubbing, and cor pulmonale.

4.3 History

Age: The age of onset of clinical symptoms has a strong influence on the pretest probability that IPF, in particular, is present. For example, IPF occurs most commonly in patients aged >60 and is quite rare among patients aged 65 without strong evidence for an alternate diagnosis, atypical chest CT findings are still more likely to result in a histopathologic diagnosis of UIP (a pathologic hallmark of IPF) than they are to result in an alternate IIP diagnosis. Other common ILDs, such as sarcoidosis and CTD-associated ILD, and less common ILDs, such as LAM and pulmonary Langerhans cell histiocytosis (PLCH), tend to present between the ages of 20 and 40.

Sex: Although less influential than age, sex has some influence on the likelihood of various ILDs. LAM (and the related disorder tuberous sclerosis) is a disorder that is frequently diagnosed in young women. Many CTD-associated ILDs are more common among women, except for RA-associated ILD, which is more common among men. IPF and occupational/exposure-related ILDs are more common among men.

Duration of Symptoms: Acute presentations (days to weeks) of ILD are unusual and are commonly misdiagnosed as more common diseases such as pneumonia, a chronic obstructive pulmonary disease (COPD) exacerbation, or heart failure. ILDs that can present acutely include eosinophilic pneumonia, acute interstitial pneumonia (AIP), HP, and granulomatosis with polyangiitis (GPA). An acute exacerbation of IPF as the initial presentation of this disease should also be a consideration given its prevalence. ILDs most commonly have a chronic indolent presentation (months to years) typified by IPF. However, subacute presentations (weeks to months) can occur in most of the ILDs but, in the right context, could suggest sarcoidosis, CTD-associated ILD, drug-induced ILD, or COP.

Medications: Many medications have been associated with ILD, and to complicate matters further, many medications commonly used to treat inflammatory and granulomatous lung disease are also associated with ILD development (e.g., methotrexate, azathioprine, rituximab, and the tumor necrosis factor α–blocking agents). Specific medications in many classes are also known to cause ILD, including antibiotics (e.g., nitrofurantoin), antiarrhythmics (e.g., amiodarone), and many of the antineoplastic agents (e.g., bleomycin).

Family History: A family history of ILD (of almost any type) is important to ascertain. The percentage of pulmonary fibrosis that is familial, as opposed to idiopathic, varies by study, and could be as high as 20%. Despite the variability, most studies suggest the presence of a close relative with an IIP is among the strongest risk factors for IPF. Family studies have consistently noted familial aggregation of diverse forms of IIP (such as IPF, nonspecific interstitial pneumonia [NSIP], and desquamative interstitial pneumonia [DIP] running in the same family) and, in some cases, other forms of ILD.

Social History: A history of smoking is nearly always present in some forms of ILD (e.g., respiratory bronchiolitis and DIP—sometimes not referred to by pathologists jointly as smoking-related ILD) where it is felt to be causative. A history of smoking is also noted in approximately three-quarters of IPF patients. Occupational and environmental exposure histories are also important to obtain as they might identify exposures known to cause pulmonary fibrosis (e.g., significant asbestos exposure) or HP (pigeon breeder's lung).

5. DIFFERENTIAL DIAGNOSIS

Owing to a variety of clinical presentations, as well as overlapping imaging and histopathologic findings, ILDs can be difficult to diagnose. A generally accepted central tenet of ILD diagnosis is that the combined weight of clinical data, laboratory studies, pulmonary function testing, imaging findings, and histopathology (if obtained) are jointly required to make a confident diagnosis. No single piece of data confers a diagnosis alone. For example, a lung biopsy demonstrating the usual interstitial pneumonia (UIP) pattern is helpful in diagnosing a patient with idiopathic pulmonary fibrosis (IPF) but is also present in some connective tissue diseases (CTDs) (e.g., RA-associated ILD). In light of this challenge, most ILD centers recommend a multidisciplinary approach to the diagnosis (and, in some cases, the management) of ILDs. An example of a multidisciplinary approach is a conference attended by pulmonologists, rheumatologists, radiologists, and pathologists where all of the data generated on a patient can be discussed and reviewed jointly by those with unique sets of expertise in the care of patients with ILD.

5.1 Common ILDs

IPF, sarcoidosis, and ILDs related to CTDs as a group are among the most common forms of ILD. IPF is the most common ILD of unknown cause. Other common ILDs, such as sarcoidosis and CTD-associated ILD, and less common ILDs, such as LAM and pulmonary Langerhans cell histiocytosis (PLCH), tend to present between the ages of 20 and 40.

5.2 Rare ILDs

LAM and pulmonary Langerhans cell histiocytosis (PLCH) are less common ILDs. Granulomatous lung diseases straddle both known (e.g., hypersensitivity pneumonitis [HP] due to chronic bird exposure) and unknown (e.g., sarcoidosis) causes and are often separated due to their unique presentations, imaging findings, and diagnostic evaluation.

6. INVESTIGATIONS & DIAGNOSIS

The initial diagnostic approach to diffuse parenchymal lung disease is often broader than a focus on ILD and should include an evaluation for alternate causes, including cardiovascular disease (e.g., heart failure), diffuse infections (e.g., pneumocystis pneumonia), and malignancy (e.g., bronchoalveolar cell carcinoma). This chapter will focus on the diagnostic evaluation that helps to distinguish among the various forms of ILD.

6.1 Pulmonary Function Tests

Most forms of ILD will eventually result in a restrictive deficit in pulmonary function testing. A restrictive deficit is typified by a reduced total lung capacity (TLC) and symmetrically reduced measures of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). A reduction in the diffusing capacity of the lung for carbon monoxide (DLCO) is also common and may precede a reduction in lung volumes; however, there is more measurement variability in DLCO measurement and the test is less specific for ILD. A reduced FEV1/FVC ratio, which is diagnostic of airway obstruction, is unusual in many forms of ILD but can be present as an isolated finding or in conjunction with an additional restrictive deficit in ILDs involving the airways such as sarcoidosis, HP, and LAM. Although pulmonary function testing is rarely diagnostic, reductions in lung function help to characterize the extent of disease, and evidence for a decline in repeated measures of pulmonary function (e.g., FVC) has been correlated with an elevated mortality rate.

6.2 Chest Imaging

Chest X-Ray: Findings on CXR can be the first clinical indication that an ILD might be present. For example, enlarged hilar lymph nodes and a pattern of central nodular opacities in the mid to upper lung zones can suggest sarcoidosis. A basilar reticular pattern, with small cystic spaces, in the absence of clinical evidence for heart failure, might suggest IPF. With a few exceptions, CXRs alone rarely lead to a specific diagnosis.

Chest CT: High-resolution CT (HRCT) chest imaging is now considered to be standard of care in the initial evaluation of a patient with a suspected ILD. HRCT can be diagnostic for some ILDs (e.g., IPF) in the right clinical context and may preclude the need for, and spare the patient the risk of, a lung biopsy. HRCT also helps to define the extent of the ILD, determine the presence of more concerning features suggestive of advanced disease (e.g., honeycombing), provide information on coexisting diseases (e.g., emphysema and lung cancer), and when not diagnostic, provide the most useful locations for obtaining lung biopsy specimens.

6.3 Lung Biopsy

Fiberoptic Bronchoscopy: A bronchoscopy can be helpful in establishing a specific ILD diagnosis, and can help to establish an alternate diagnosis, in select cases. Examination of serial lavage fluid can be helpful in establishing DAH, which can be present in ILDs with vasculitis (e.g., GPA), and in some cases, cellular examination can suggest a specific diagnosis (eosinophilia >25% in chronic eosinophilic pneumonia or fat globules in macrophages in lipoid pneumonia). Transbronchial lung biopsies and lymph node biopsies (particularly in sarcoidosis) can lead to a confident diagnosis in patients with likely granulomatous lung disease (e.g., sarcoidosis and HP). However, in general, bronchoscopically obtained tissue samples are often felt to be insufficient to diagnose most of the IIPs. To date, studies have been mixed on whether bronchoscopically obtained cryobiopsies, which can result in yields larger than those obtained by transbronchial forceps biopsies, could improve the diagnostic yield of bronchoscopy; however, the precise role of cryobiopsies in the diagnostic workup of ILD has yet to be determined.

Surgical Lung Biopsy: A surgically obtained lung biopsy specimen can help solidify the diagnosis of ILD. In many cases, these are now obtained through a video-assisted thoracoscopic (VATS) approach (as compared to an open thoracotomy), which tends to reduce the length of operative times and hospital stays. The diagnostic yield of biopsies tends to be higher if obtained prior to treatment. The desire to obtain a surgical lung biopsy should be weighed against the risks, which can include a short-term mortality rate of as high as 5%. These risks are reported to be higher in biopsies of patients ultimately diagnosed with IPF and in those presenting acutely.

6.4 Laboratory Studies

Laboratory studies can be particularly helpful in the workup for an underlying CTD-associated ILD. As noted previously, these tests can reveal the presence of an underlying CTD as the cause of an ILD (e.g., a positive anti-cyclic citrullinated peptide [anti-CCP] antibody for RA) even when no other symptomatology or physical examination findings suggestive of the disorder are present. However, the cost-effectiveness and the extent of laboratory testing that should be ordered in various clinical contexts have yet to be determined (as there is a relatively long list of autoantibody tests that could be ordered).

7. MANAGEMENT & TREATMENT

Medical treatments range from immune modulators to antifibrotic medications, whereas lung transplantation remains the standard of care for patients with advanced and rapidly progressive ILDs. In some cases, medical therapy that is felt to be effective for some ILDs has been proven to be harmful for others.

7.1 Idiopathic Pulmonary Fibrosis (IPF)

Treatment: Historically, IPF was felt to be refractory to medical therapy, with lung transplantation the only viable therapeutic option. This dogma changed in 2014 with large clinical trials that demonstrated that antifibrotic therapy (pirfenidone and nintedanib) can slow the decline of lung function in IPF patients. Further meta-analyses have suggested that antifibrotic therapy may also improve survival. Occasionally subpleural sparing is noted, while peribronchiolar thickening and honeycombing are uncommon. More recent trials suggest that antifibrotic therapy may also be effective in other forms of progressive pulmonary fibrosis. In contrast, treatment with immunosuppression, which had been commonly prescribed to many IPF patients, has been shown to be associated with increased morbidity and mortality. Physical therapy and supplemental oxygen, when indicated, can improve exercise tolerance and reduce the likelihood of developing pulmonary hypertension. Lung transplantation can extend survival and improve the quality of life in a subset of IPF patients who meet the criteria to undergo transplant.

7.2 Nonspecific Interstitial Pneumonia (NSIP)

Treatment: Pulmonary fibrosis associated with CTD is commonly treated with immunosuppression despite the paucity of randomized clinical trials to demonstrate efficacy. Idiopathic NSIP is often treated with oral steroids (prednisone), cytotoxic agents (mycophenolate, azathioprine, and cyclophosphamide), or biologics (rituximab and tocilizumab). Recent trials suggest that NSIP patients with progressive pulmonary fibrosis may benefit from antifibrotic therapy. Oxygen therapy, pulmonary rehabilitation, and lung transplantation may be required in patients with progressive disease.

Treatment: Patients with smoking-related ILD should be counseled to discontinue smoking and/or encouraged to enroll in a formal smoking cessation program. Small studies have evaluated treatment with immunosuppressive (e.g., prednisone) and cytotoxic (e.g., azathioprine and cyclophosphamide) agents and, in some cases, bronchodilators. To date, there is no strong evidence that these therapies result in significant improvements in symptoms or measures of pulmonary function or prevent clinical deterioration.

7.4 Cryptogenic Organizing Pneumonia (COP)

Treatment: Corticosteroids can result in substantial clinical improvement in many patients but usually need to be continued for at least 6 months as relapse rates are high. Evidence is growing that alternate cytotoxic (e.g., mycophenolate, cyclophosphamide) or biologic (e.g., rituximab) therapies can be helpful in both treating the disease and reducing the need for steroids. In some patients with secondary forms of the disease, long-term therapy may be needed.

7.5 Systemic Sclerosis (SSc)

Treatment: Corticosteroids can result in substantial clinical improvement in many patients but usually need to be continued for at least 6 months as relapse rates are high. Evidence is growing that alternate cytotoxic (e.g., mycophenolate, cyclophosphamide) or biologic (e.g., rituximab) therapies can be helpful in both treating the disease and reducing the need for steroids. In some patients with secondary forms of the disease, long-term therapy may be needed.

7.6 Acute Interstitial Pneumonia (AIP)

Treatment: Overall, treatment is supportive. Mechanical ventilation, when not being used as a bridge to lung transplantation, is controversial as the survival rate in these patients tends to be poor. There is some evidence that drug therapy (e.g., nintedanib) may reduce the rate of acute exacerbations in patients with IPF. Drug therapy, in the context of an acute exacerbation, is also controversial. Immunosuppressive (e.g., prednisone) and cytotoxic (e.g., cyclophosphamide) therapies are commonly used without proven benefit.

7.7 Acute Exacerbations (COPD Context)

Bronchodilators: Typically, patients are treated with inhaled beta agonists and muscarinic antagonists. These may be administered separately or together, and the frequency of administration depends on the severity of the exacerbation. Patients are often treated initially with nebulized therapy, as such treatment is often easier to administer in those in respiratory distress. It has been shown, however, that conversion to metered-dose inhalers is effective when accompanied by education and training of patients and staff. This approach has significant economic benefits and also allows an easier transition to outpatient care.

Antibiotics: Patients with COPD are frequently colonized with potential respiratory pathogens, and it is often difficult to identify conclusively a specific species of bacteria responsible for a particular clinical event. Bacteria frequently implicated in COPD exacerbations include Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Chlamydia pneumoniae; viral pathogens are also common etiologies of exacerbations. The choice of antibiotic should be based on local patterns of antibiotic susceptibility of the above bacterial pathogens as well as the patient's clinical condition. Patients with moderate or severe exacerbations are usually treated with 5–7 days of antibiotics, even in the absence of data implicating a specific pathogen.

Glucocorticoids: In patients admitted to the hospital, the use of systemic glucocorticoids reduces the length of stay, hastens recovery, and reduces the chance of subsequent exacerbation or relapse. Current recommendations suggest 40 mg of oral prednisone or its equivalent typically for a period of 5 days. Hyperglycemia, particularly in patients with preexisting diagnosis of diabetes, is the most frequently reported acute complication of glucocorticoid treatment.

Oxygen: Supplemental O2 should be supplied with a target oxygen saturation of 88–92%. Studies have demonstrated that in patients with both acute and chronic hypercarbia, the administration of supplemental O2 does not reduce minute ventilation. It does, in some patients, result in modest increases in arterial Pco2, chiefly by altering ventilation-perfusion relationships within the lung. This should not deter practitioners from providing the oxygen needed to correct hypoxemia.

Mechanical Ventilatory Support: The initiation of noninvasive positive-pressure ventilation (NIPPV) in patients with acute respiratory acidosis, defined as Paco2 >45 mmHg and pH ≤7.35, results in a significant reduction in mortality rate, need for intubation, complications of therapy, and hospital length of stay. Contraindications to NIPPV include cardiovascular instability, impaired mental status, inability to cooperate, copious secretions or the inability to clear secretions, or craniofacial abnormalities or trauma precluding effective fitting of the mask. Invasive (conventional) mechanical ventilation via an endotracheal tube is indicated for patients with severe respiratory distress, hypoxemia, severe hypercarbia and/or acidosis despite noninvasive ventilation, markedly impaired mental status, respiratory arrest, hemodynamic instability, or other complications. The goal of mechanical ventilation is to correct the aforementioned conditions. Factors to consider during mechanical ventilatory support include the need to provide sufficient expiratory time in patients with severe airflow obstruction and the presence of auto-PEEP (positive end-expiratory pressure), which can result in patients having to be generate significant respiratory effort to trigger a breath during a demand mode of ventilation. The mortality rate of patients requiring mechanical ventilatory support for a COPD exacerbation is 17–49% for that particular hospitalization. Owing to the high mortality of invasive mechanical ventilation in COPD exacerbations, patient preferences for advanced directives (e.g., do not resuscitate) should be discussed.

8. PROGNOSIS & COMPLICATIONS

IPF is a variably progressive disease that carries a poor prognosis with an estimated 50% 3- to 5-year survival. NSIP has a relatively good prognosis, with a 5-year survival of >80%; patients with a predominant cellular NSIP pattern have a more favorable prognosis than those with a fibrosing NSIP pattern. RB-ILD and death secondary to progressive ILD is felt to be rare. The mortality rate of patients requiring mechanical ventilatory support for a COPD exacerbation is 17–49% for that particular hospitalization. Following a hospitalization for COPD, ~20% of patients are rehospitalized in the next 30 days and 45% in the next year. Mortality is ~20% in the year following hospital discharge.

8.1 Survival Rates

IPF: 50% 3- to 5-year mortality. NSIP: 18% 5-year mortality. RB-ILD: 25% 7-year mortality. Sarcoidosis: 20–30% 10-year mortality.

Table 1 — Table 304-1 Common Interstitial Lung Disease (ILD) Findings

Condition Clinical symptoms Physical exam findings Exposures HRCT findings Histopathology Clinical course
IPF Gradual onset of SOB, dry cough. More common in older adults. Frequent rales at lung bases; digital clubbing is common. Idiopathic but many exposed to smoke. Genetic findings may explain more than one-third of the risk of the disease. Bilateral subpleural reticular changes most prominent in lower, posterior lung zones. Traction bronchiectasis and honeycombing common. Classic usual interstitial pneumonia (UIP) pattern is considered diagnostic. UIP pattern including fibroblastic foci, temporal and spatial heterogeneity, honeycombing. 50% 3- to 5-year mortality.
Nonspecific Interstitial Pneumonia Subacute onset of SOB, dry cough. Frequently associated with other conditions. Frequent rales. Clubbing is less common. Can be idiopathic but should prompt consideration for associated conditions. Peripheral subpleural ground-glass and reticular patterns. Traction bronchiectasis is common, but honeycombing is rare. HRCT not diagnostic. Cellular or fibrotic pattern of NSIP. More uniform than a UIP pattern. 18% 5-year mortality.
Respiratory Bronchiolitis–Associated ILD Can be asymptomatic, or have SOB and cough. Rales common. Clubbing is rare. Strong association with smoking. Diffuse patchy centrilobular ground glass nodules. Respiratory bronchiolitis with adjacent inflammatory and fibrosing changes. Pigment-laden macrophages. 25% 7-year mortality.
Systemic Sclerosis–Associated ILD Gradual onset of SOB, dry cough. Fatigue, tightening of skin, exaggerated cold response, reflux, and difficulty swallowing. Can have rales in isolation. Also skin thickening, joint swelling, and telangiectasias. Mostly unknown; some debate about solvent and silicate exposures. Can have UIP or nonspecific interstitial pneumonia (NSIP) patterns, also dilated esophagus, occasional mediastinal calcifications, and pulmonary vascular enlargement. Both UIP or NSIP patterns can occur. 20–30% 10-year mortality.
Sarcoidosis Can be asymptomatic, or have SOB and cough. Can also have fatigue, palpitations, and eye, skin, and joint findings. Can be normal; rales may be present. Can have skin findings, joint pain, and enlarged lymph nodes. Mostly unknown, although silicate dusts thought to play a role in some cases. Can have mediastinal and hilar lymphadenopathy. Noncaseating granulomas. Generally low but varies by state.

8.2 Complications

Physical therapy and supplemental oxygen, when indicated, can improve exercise tolerance and reduce the likelihood of developing pulmonary hypertension. Lung transplantation can extend survival and improve the quality of life in a subset of IPF patients who meet the criteria to undergo transplant. In contrast, treatment with immunosuppression, which had been commonly prescribed to many IPF patients, has been shown to be associated with increased morbidity and mortality.

9. SPECIAL CONSIDERATIONS

Diagnosis is based on combined information obtained from a patient's clinical presentation, measures of pulmonary function, imaging, immune serologies, and histopathology. It is important to remember that prognosis and treatment vary widely by disorder (and disease extent). In some cases, medical therapy that is felt to be effective for some ILDs has been proven to be harmful for others. Medical treatments range from immune modulators to antifibrotic medications, whereas lung transplantation remains the standard of care for patients with advanced and rapidly progressive ILDs.

9.1 Genetic Factors

Genetic studies demonstrate that a significant portion of familial and sporadic pulmonary fibrosis or IPF may be explained, in part, by genetic factors. The most well-replicated genetic factors for pulmonary fibrosis include a promoter variant of a mucin gene [MUC5B] and various genetic determinants known to influence telomere length (e.g., variants in the telomerase reverse transcriptase gene [TERT]).

9.2 Smoking

A history of smoking is nearly always present in some forms of ILD (e.g., respiratory bronchiolitis and DIP—sometimes not referred to by pathologists jointly as smoking-related ILD) where it is felt to be causative. A history of smoking is also noted in approximately three-quarters of IPF patients. Occupational and environmental exposure histories are also important to obtain as they might identify exposures known to cause pulmonary fibrosis (e.g., significant asbestos exposure) or HP (pigeon breeder's lung).

10. KEY PEARLS & CLINICAL TRAPS

A generally accepted central tenet of ILD diagnosis is that the combined weight of clinical data, laboratory studies, pulmonary function testing, imaging findings, and histopathology (if obtained) are jointly required to make a confident diagnosis. No single piece of data confers a diagnosis alone. For example, a lung biopsy demonstrating the usual interstitial pneumonia (UIP) pattern is helpful in diagnosing a patient with idiopathic pulmonary fibrosis (IPF) but is also present in some connective tissue diseases (CTDs) (e.g., RA-associated ILD). In light of this challenge, most ILD centers recommend a multidisciplinary approach to the diagnosis (and, in some cases, the management) of ILDs. An example of a multidisciplinary approach is a conference attended by pulmonologists, rheumatologists, radiologists, and pathologists where all of the data generated on a patient can be discussed and reviewed jointly by those with unique sets of expertise in the care of patients with ILD.

10.1 Diagnostic Clues

End-inspiratory fine crackles, or rales, noted at the lung bases are found in most patients with IPF and may be one of the earliest signs of the disease. However, rales are nonspecific and can be found in many forms of ILD and other disorders. Wheezing is uncommon in most forms of ILD but can be present in some disorders, such as sarcoidosis, HP, and eosinophilic GPA. Signs of advanced disease include cyanosis, digital clubbing, and cor pulmonale. The presence of extensive ground-glass opacities, bronchovascular changes, micronodules, mosaic attenuation, or an upper lung predominance should raise suspicion for an alternative diagnosis in IPF. Honeycombing is generally felt to be rare in RB-ILD and indicates a worse prognosis. Caseating granulomas are rare in sarcoid and should prompt additional evaluation for an underlying infection.

10.2 Exclusion Criteria

A reduced FEV1/FVC ratio, which is diagnostic of airway obstruction, is unusual in many forms of ILD but can be present as an isolated finding or in conjunction with an additional restrictive deficit in ILDs involving the airways such as sarcoidosis, HP, and LAM. With a few exceptions, CXRs alone rarely lead to a specific diagnosis. Bronchoscopically obtained tissue samples are often felt to be insufficient to diagnose most of the IIPs. To date, studies have been mixed on whether bronchoscopically obtained cryobiopsies, which can result in yields larger than those obtained by transbronchial forceps biopsies, could improve the diagnostic yield of bronchoscopy; however, the precise role of cryobiopsies in the diagnostic workup of ILD has yet to be determined.

Flowcharts & Algorithms

Reproduced from Harrison's 22nd Edition.

Flowchart 1

Classification of interstitial lung disease

Caption: FIGURE 304-1 Classification of interstitial lung disease. This algorithm represents a the interstitial lung diseases into those of known and unknown causes (although it is and idiopathic pulmonary fibrosis [classically described as diseases of unknown cause] were more precisely defined by a 2002 study as described in Am J Respir Crit Care Med

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

Chest CT imaging and interstitial lung disease

Caption: FIGURE 304-2 Chest CT imaging and interstitial lung disease. A. Idiopathic pulmonary basilar predominance of subpleural reticular markings and more advanced features constellation of findings is often referred to as a usual interstitial pneumonia (UIP) overlap with those of a UIP pattern but tend to include a bilateral, symmetric pattern that a UIP pattern. Additional unique findings include more diffuse imaging abnormalities the subpleural regions, and thickening of the bronchovascular bundles (as is apparent Chest CT findings include patchy, sometimes migratory, subpleural consolidative Peribronchiolar or perilobar opacities can be present, and sometimes a rim of can help to aid in the diagnosis. D. Sarcoidosis: Sarcoidosis can present with varied a pattern of reticular-nodular opacities involving the bronchovascular bundles (apparent nodules in a miliary pattern, larger nodular opacities, extensive ground-glass infiltrates, advanced cases, signs of pulmonary fibrosis. — Figure 304-1: Classification of interstitial lung disease into known causes (occupational, medications, systemic disease) and unknown causes (idiopathic interstitial pneumonias, sarcoidosis, etc.).

Figure 2

Histopathology of interstitial lung disease

Caption: FIGURE 304-3 Histopathology of interstitial lung disease. A. Idiopathic pulmonary honeycomb changes alternating with areas of preserved normal lung architecture above). Additional important diagnostic findings include fibroblast foci, which are powered inset of this image). Collectively, these pathologic findings are referred to as Histopathologic findings of NSIP include varying amounts of interstitial inflammation changes are usually absent and fibroblast foci are rare. NSIP is often referred to organizing pneumonia (COP): Histopathologic findings of COP include patchy regions small airways, alveolar ducts, and alveoli with surrounding inflammation that can histopathologic feature of sarcoidosis is presence of granulomas (as are apparent inset image). Typically, these are referred to as noncaseating, which suggests the additional evaluation for an underlying infection. Because malignancy can result in a granulomatous involvement for additional signs of malignancy. — Figure 304-2A: Chest CT of Idiopathic Pulmonary Fibrosis (IPF) showing posterior, basilar predominance of subpleural reticular markings, traction bronchiectasis, and honeycombing (UIP pattern).

Figure 3

Histopathology of interstitial lung disease

Caption: FIGURE 304-3 Histopathology of interstitial lung disease. A. Idiopathic pulmonary honeycomb changes alternating with areas of preserved normal lung architecture above). Additional important diagnostic findings include fibroblast foci, which are powered inset of this image). Collectively, these pathologic findings are referred to as Histopathologic findings of NSIP include varying amounts of interstitial inflammation changes are usually absent and fibroblast foci are rare. NSIP is often referred to organizing pneumonia (COP): Histopathologic findings of COP include patchy regions small airways, alveolar ducts, and alveoli with surrounding inflammation that can histopathologic feature of sarcoidosis is presence of granulomas (as are apparent inset image). Typically, these are referred to as noncaseating, which suggests the additional evaluation for an underlying infection. Because malignancy can result in a granulomatous involvement for additional signs of malignancy. — Figure 304-2B: Chest CT of Nonspecific Interstitial Pneumonia (NSIP) showing bilateral, symmetric ground-glass opacities and reticular patterns with sparing of subpleural regions.

Figure 4

Histopathology of interstitial lung disease

Caption: FIGURE 304-3 Histopathology of interstitial lung disease. A. Idiopathic pulmonary honeycomb changes alternating with areas of preserved normal lung architecture above). Additional important diagnostic findings include fibroblast foci, which are powered inset of this image). Collectively, these pathologic findings are referred to as Histopathologic findings of NSIP include varying amounts of interstitial inflammation changes are usually absent and fibroblast foci are rare. NSIP is often referred to organizing pneumonia (COP): Histopathologic findings of COP include patchy regions small airways, alveolar ducts, and alveoli with surrounding inflammation that can histopathologic feature of sarcoidosis is presence of granulomas (as are apparent inset image). Typically, these are referred to as noncaseating, which suggests the additional evaluation for an underlying infection. Because malignancy can result in a granulomatous involvement for additional signs of malignancy. — Figure 304-2C: Chest CT of Cryptogenic Organizing Pneumonia (COP) showing patchy, sometimes migratory, subpleural consolidative opacities with ground-glass opacities and a reversed halo sign.

Figure 5

Histopathology of interstitial lung disease

Caption: FIGURE 304-3 Histopathology of interstitial lung disease. A. Idiopathic pulmonary honeycomb changes alternating with areas of preserved normal lung architecture above). Additional important diagnostic findings include fibroblast foci, which are powered inset of this image). Collectively, these pathologic findings are referred to as Histopathologic findings of NSIP include varying amounts of interstitial inflammation changes are usually absent and fibroblast foci are rare. NSIP is often referred to organizing pneumonia (COP): Histopathologic findings of COP include patchy regions small airways, alveolar ducts, and alveoli with surrounding inflammation that can histopathologic feature of sarcoidosis is presence of granulomas (as are apparent inset image). Typically, these are referred to as noncaseating, which suggests the additional evaluation for an underlying infection. Because malignancy can result in a granulomatous involvement for additional signs of malignancy. — Figure 304-2D: Chest CT of Sarcoidosis showing mediastinal and hilar lymphadenopathy with reticular-nodular opacities involving bronchovascular bundles.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.