Overview

Definition

• Interstitial lung disease (ILD) comprises a heterogeneous group of disorders that cause varying degrees ofinflammationInflammationInflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function.Inflammation andfibrosisFibrosisAny pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury.Bronchiolitis Obliterans of the lung interstitium, the space between the capillaryendotheliumEndotheliumA layer of epithelium that lines the heart, blood vessels (vascular endothelium), lymph vessels (lymphatic endothelium), and the serous cavities of the body.Arteries: Histology and the alveolarepitheliumEpitheliumThe epithelium is a complex of specialized cellular organizations arranged into sheets and lining cavities and covering the surfaces of the body. The cells exhibit polarity, having an apical and a basal pole. Structures important for the epithelial integrity and function involve the basement membrane, the semipermeable sheet on which the cells rest, and interdigitations, as well as cellular junctions.Surface Epithelium: Histology.
• Clinically, affectedpatientsPatientsIndividuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures.Clinician–Patient Relationship will show restrictive lung disease by pulmonary function studies.

Epidemiology

IdiopathicIdiopathicDermatomyositis pulmonaryfibrosisFibrosisAny pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury.Bronchiolitis Obliterans,sarcoidosisSarcoidosisSarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly.Sarcoidosis, and ILD associated withconnective tissueConnective tissueConnective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix.Connective Tissue: Histology diseases are the most common types of ILD.

Classification

It is useful to categorize ILDs into those with and without a known cause.

Diagnosis

History

Physical examination

• End-inspiratory fine crackles in lungbasesBasesUsually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines.Acid-Base Balance (common finding, especially in IPF)
• WheezingWheezingWheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways.Wheezing is uncommon (may be found in HP, Churg-Strauss disease,sarcoidosisSarcoidosisSarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly.Sarcoidosis)
• Severe disease findings:cyanosisCyanosisA bluish or purplish discoloration of the skin and mucous membranes due to an increase in the amount of deoxygenated hemoglobin in the blood or a structural defect in the hemoglobin molecule.Pulmonary Examination, digitalclubbingClubbingCardiovascular Examination,cor pulmonaleCor PulmonaleCor pulmonale is right ventricular (RV) dysfunction caused by lung disease that results in pulmonary artery hypertension. The most common cause of cor pulmonale is chronic obstructive pulmonary disease. Dyspnea is the usual presenting symptom.Cor Pulmonale

Laboratory studies

Autoantibody detection may help with the diagnosis of some CTDs.

Pulmonary function testingPulmonary Function TestingPulmonary Function Tests

• The diffusing capacity forcarbon monoxideCarbon monoxideCarbon monoxide (CO). A poisonous colorless, odorless, tasteless gas. It combines with hemoglobin to form carboxyhemoglobin, which has no oxygen carrying capacity. The resultant oxygen deprivation causes headache, dizziness, decreased pulse and respiratory rates, unconsciousness, and death.Carbon Monoxide Poisoning (DLCODLCOPulmonary Function Tests) shows reduction.
• Most show a restrictive pattern.

Imaging

• ChestX-rayX-rayPenetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source.Pulmonary Function Tests may be suggestive of a type of ILD:
  • Peripheral reticular pattern in lower lung zones and smallcysticCysticFibrocystic Change spaces suggests IPF.
  • Central nodular pattern in mid-to-upper lung zones and hilarlymphLymphThe interstitial fluid that is in the lymphatic system.Secondary Lymphatic Organs node enlargement suggestssarcoidosisSarcoidosisSarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly.Sarcoidosis.
• Chest computed tomographyChest Computed TomographyHemothorax (CT):
  • Standard initial test
  • May confirm the diagnosis of IPF in the right setting and obviate the need forlung biopsyLung BiopsyAntineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis
  • Better defines disease extent and features (e.g., honeycombing)
  • Helps excludecomorbiditiesComorbiditiesThe presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival.St. Louis Encephalitis Virus (e.g.,pneumothoraxPneumothoraxA pneumothorax is a life-threatening condition in which air collects in the pleural space, causing partial or full collapse of the lung. A pneumothorax can be traumatic or spontaneous. Patients present with a sudden onset of sharp chest pain, dyspnea, and diminished breath sounds on exam.Pneumothorax) or differential diagnosis (e.g.,malignancyMalignancyHemothorax)
  • Helps determine the best location forbiopsyBiopsyRemoval and pathologic examination of specimens from the living body.Ewing Sarcoma

Lung biopsyLung BiopsyAntineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis

• Establishes the diagnosis
• Performed via fiberopticbronchoscopyBronchoscopyEndoscopic examination, therapy or surgery of the bronchi.Laryngomalacia and Tracheomalacia or surgery
• BiopsyBiopsyRemoval and pathologic examination of specimens from the living body.Ewing Sarcoma is not needed if:
  • High-resolution CTHigh-resolution CTImaging of the Lungs and Pleura (HRCTHRCTPulmonary Function Tests) shows classic usual interstitialpneumoniaPneumoniaPneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy.Pneumonia and the patient has no systemic diseases suggestive of an another disorder.
  • Patient has minimal signs or symptoms and a stable/nonprogressive disease.
• Indicated in cases ofcomorbiditiesComorbiditiesThe presence of co-existing or additional diseases with reference to an initial diagnosis or with reference to the index condition that is the subject of study. Comorbidity may affect the ability of affected individuals to function and also their survival; it may be used as a prognostic indicator for length of hospital stay, cost factors, and outcome or survival.St. Louis Encephalitis Virus or rapidly progressive symptoms

Individual Forms

IdiopathicIdiopathicDermatomyositis pulmonaryfibrosisFibrosisAny pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury.Bronchiolitis Obliterans

• Most common ILD of unknown cause
• Commonly diagnosed in 5th or 6th decade
• Affects men more than women
• Frequently associated with smoking
• 3–5-year survival rate is 50%.
• May be associated with acute exacerbations
• LungHRCTHRCTPulmonary Function Tests shows a pattern of UIP: subpleural reticular pattern with posterior-basal predominance with more advanced fibrotic features such as honeycombing and tractionbronchiectasisBronchiectasisBronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections.Bronchiectasis.
• Histopathology shows a pattern of UIP:subpleural reticulationSubpleural reticulationPulmonary Fibrosis, honeycombing,fibroblastsFibroblastsConnective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.Sarcoidosis, skipped lesions with preserved architecture (temporal and spatial heterogeneity).
• Treatment:physical therapyPhysical TherapyBecker Muscular Dystrophy andsupplemental oxygenSupplemental OxygenRespiratory Failure, antifibrotic therapy (pirfenidonePirfenidonePulmonary Fibrosis), andlung transplantationLung transplantationThe transference of either one or both of the lungs from one human or animal to another.Organ Transplantation if patient meets criteria

Non-specific interstitialpneumoniaPneumoniaPneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy.Pneumonia

• May beidiopathicIdiopathicDermatomyositis or commonly associated with CTDs
• Commonly diagnosed in non-smoking women in their 5th decade
• 5-year survival rate is 80%.
• LungHRCTHRCTPulmonary Function Tests shows diffuse and symmetric subpleural ground-glass and reticular opacities; tractionbronchiectasisBronchiectasisBronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections.Bronchiectasis may be seen; honeycombing and peribronchial thickening is uncommon.
• Histopathology shows uniform interstitialinflammationInflammationInflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function.Inflammation andfibrosisFibrosisAny pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury.Bronchiolitis Obliterans without honeycombing.
• Treatment:physical therapyPhysical TherapyBecker Muscular Dystrophy,supplemental oxygenSupplemental OxygenRespiratory Failure,steroidsSteroidsA group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus.Benign Liver Tumors, immunosuppressive therapy, andlung transplantationLung transplantationThe transference of either one or both of the lungs from one human or animal to another.Organ Transplantation if patient meets criteria

Cryptogenic organizing pneumoniaCryptogenic organizing pneumoniaAn interstitial lung disease of unknown etiology, occurring between 21-80 years of age. It is characterized by a dramatic onset of a ‘pneumonia-like’ illness with cough, fever, malaise, fatigue, and weight loss. Pathological features include prominent interstitial inflammation without collagen fibrosis, diffuse fibroblastic foci, and no microscopic honeycomb change. There is excessive proliferation of granulation tissue within small airways and alveolar ducts.Bronchiolitis Obliterans

• May beidiopathicIdiopathicDermatomyositis or secondary topolymyositisPolymyositisPolymyositis (PM) is an autoimmune inflammatory myopathy caused by T cell-mediated muscle injury. The etiology of PM is unclear, but there are several genetic and environmental associations. Polymyositis is most common in middle-aged women and rarely affects children.Polymyositis, medications, ormalignancyMalignancyHemothorax
• Commonly diagnosed in 6th or 7th decade
• LungHRCTHRCTPulmonary Function Tests shows migratory, patchy, subpleural consolidations and ground-glass opacities with or without a rim of subpleural sparing known as thehalo signHalo signAspergillus/Aspergillosis (characteristic).
• Treatment:steroidsSteroidsA group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus.Benign Liver Tumors and immunosuppressives

Smoking-related ILD

• Occurs in heavy smokers in the 5th or 6th decade
• Honeycombing is typically absent
• BiopsyBiopsyRemoval and pathologic examination of specimens from the living body.Ewing Sarcoma confirms diagnosis
• Treatment includes smoking cessation and immunosuppressive therapy

Connective tissueConnective tissueConnective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix.Connective Tissue: Histology disease–associated ILD and granulomatous ILD

Complications

• Acute exacerbations of IIPs:
  • Accelerated phaseAccelerated phaseThe phase of chronic myeloid leukemia following the chronic phase, where there are increased systemic symptoms, worsening cytopenias, and refractory leukocytosis.Chronic Myeloid Leukemia of lung injury in a patient with an underlying ILD
  • Acute onset (< 30 days) of respiratory distress andhypoxemiaHypoxemiaNeonatal Respiratory Distress Syndrome more severe than what was previously experienced by the underlying ILD and not explained by other causes (e.g.,pneumoniaPneumoniaPneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy.Pneumonia,heart failureHeart FailureA heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction.Total Anomalous Pulmonary Venous Return (TAPVR))
  • Most commonly described in IPF
  • LungHRCTHRCTPulmonary Function Tests shows a change in the pattern previously observed due to the underlying ILD with patchy bilateral ground-glass opacities andconsolidationConsolidationPulmonary Function Tests in dependent regions.
  • Histopathology shows diffuse alveolar damage.
  • Treatment is supportive as no proven therapy exists;lung transplantationLung transplantationThe transference of either one or both of the lungs from one human or animal to another.Organ Transplantation may provide cure.
  • MortalityMortalityAll deaths reported in a given population.Measures of Health Status rate > 85%
• Pulmonary hypertensionPulmonary HypertensionPulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies.Pulmonary Hypertension
• PneumoniaPneumoniaPneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy.Pneumonia
• Ischemic heart diseaseIschemic heart diseaseCoronary heart disease (CHD), or ischemic heart disease, describes a situation in which an inadequate supply of blood to the myocardium exists due to a stenosis of the coronary arteries, typically from atherosclerosis.Coronary Heart Disease
• Thromboembolic disease
• Lung cancerLung cancerLung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort.Lung Cancer

Differential Diagnosis

• Cardiovascular disease (e.g.,heart failureHeart FailureA heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction.Total Anomalous Pulmonary Venous Return (TAPVR))
• DiffuseinfectionsInfectionsInvasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases.Chronic Granulomatous Disease (e.g., pneumocystispneumoniaPneumoniaPneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy.Pneumonia)
• MalignancyMalignancyHemothorax (e.g., bronchoalveolar cell carcinoma):
  • Note that ILDs such as COP may occur secondary todermatomyositisDermatomyositisA subacute or chronic inflammatory disease of muscle and skin, marked by proximal muscle weakness and a characteristic skin rash. The illness occurs with approximately equal frequency in children and adults. The skin lesions usually take the form of a purplish rash (or less often an exfoliative dermatitis) involving the nose, cheeks, forehead, upper trunk, and arms. The disease is associated with a complement mediated intramuscular microangiopathy, leading to loss of capillaries, muscle ischemia, muscle-fiber necrosis, and perifascicular atrophy. The childhood form of this disease tends to evolve into a systemic vasculitis. Dermatomyositis may occur in association with malignant neoplasms.Paraneoplastic Syndromes andmalignancyMalignancyHemothorax; however, lung malignancies such as bronchoalveolar cell carcinoma can mimic the symptoms and signs of ILD.

References

1. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill Education; 2018.
2. King TE, Raj R. Role of lung biopsy in the diagnosis of interstitial lung disease, in UpToDate Evidence-Based Medicine. Retrieved on August 18, 2020, fromhttps://www.uptodate.com/contents/role-of-lung-biopsy-in-the-diagnosis-of-interstitial-lung-disease?search=interstitial-lung-disease&topicRef=4310&source=see_link#H4256910517