A clinician's guide to the diagnosis and treatment of interstitial lung diseases.
Abstract: Interstitial lung disease Interstitial lung disease
About 180 diseases fall into this category of breathing disorders. Injury or foreign substances in the lungs (such as asbestos fibers) as well as infections, cancers, or inherited disorders may cause the diseases. (ILD (Inter Layer Dielectric) The insulation used between layers of aluminum or copper wire that interconnect the transistors in a chip. There are three to four layers in a memory chip and five to seven in a logic chip with hundreds of meters of wiring. ) is a final common pathway for a large number of lung insults. It is characterized by progressive scarring of the lung leading to restriction and diminished oxygen transfer. Clinically, the presenting symptoms of ILD are nonspecific (cough and progressive dyspnea on exertion dyspnea on exertion Cardiology Shortness of breath which occurs with effort, often a sign of heart failure or ischemia ) and are often attributed to other diseases, thus delaying diagnosis and timely therapy. ILD occurs most commonly in older individuals and is increasingly encountered by internists. Both the diagnosis and treatment can be daunting daunt
tr.v. daunt·ed, daunt·ing, daunts
To abate the courage of; discourage. See Synonyms at dismay.
[Middle English daunten, from Old French danter, from Latin : patients frequently have irreversibly impaired lung function at diagnosis, and therapeutic modalities are limited and associated with significant adverse effects. This review will assist internists in the recognition and management of ILD, provide a benchmark for pulmonary referrals, and offer guidance in advising patients with this life-threatening disorder.
Key Words: interstitial lung disease, ILD, pulmonary fibrosis, dyspnea, cough, lung transplantation
The term interstitial lung disease (ILD) refers to a diverse collection of disorders in which pulmonary inflammation and/or fibrosis are the final common pathways of lung damage. Hence, the ILDs are often referred to collectively as "pulmonary fibrosis." The ILDs are distinguished from diseases predominantly affecting the airways and blood vessels and are also referred to as "diffuse parenchymal pa·ren·chy·ma
1. Anatomy The tissue characteristic of an organ, as distinguished from associated connective or supporting tissues.
2. lung diseases." The term parenchymal derives from the primary site of injury, namely the parenchyma Parenchyma
A ground tissue of plants chiefly concerned with the manufacture and storage of food. The primary functions of plants, such as photosynthesis, assimilation, respiration, storage, secretion, and excretion—those associated with living or interstitium. This is the potential space between the air-containing alveolus alveolus (ălvē`ələs): see lungs. and the vessels channeling red blood cells Red blood cells
Cells that carry hemoglobin (the molecule that transports oxygen) and help remove wastes from tissues throughout the body.
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red blood cells (Fig. 1). In a normal lung, this space is occupied by a single cell layer, only 10 [micro]m in width, allowing passive diffusion of oxygen between the alveolus and blood. As a group, the ILDs result from the accumulation of cells or fibrotic tissue in this space causing a barrier to oxygen diffusion.
There are more than 150 conditions/exposures known to be associated with ILD, including silicosis silicosis (sĭlĭkō`sĭs), occupational disease of the lungs caused by inhalation of free silica (quartz) dust over a prolonged period of time. , drug reactions, infections and collagen vascular diseases collagen vascular diseases Connective tissue diseases, see there such as rheumatoid arthritis and systemic sclerosis. The conditions/exposures known to be associated with ILD can be categorized into eight groups (1): collagen vascular disease collagen vascular disease
See collagen disease. (CVD CVD Cardiovascular disease, see there ), (2) hypersensitivity pneumonitis, (3) toxins, (4) infections, (5) inherited, (6) malignancy, (7) pneumoconiosis pneumoconiosis (n'məkō'nēō`sĭs), chronic disease of the lungs. and (8) idiopathic (Fig. 2). Unfortunately, the etiology of a given ILD more often falls into the idiopathic category. Even in cases of ILD with a defined etiology, the mechanisms of lung injury and fibrosis are largely undefined.
In an effort to simplify the classification of this heterogeneous group of disorders, the American Thoracic Society American Thoracic Society (ATS ), established in 1905, is an independently incorporated, international, educational and scientific society, serving its 18,000 members world-wide who are dedicated in respiratory and critical care medicine. and European Respiratory Society proposed a classification scheme of the interstitial lung diseases. (1) This classification (Fig. 3) separates ILDs of known etiology from the larger group of "idiopathic interstitial pneumonias." The idiopathic interstitial pneumonias (IIPs) are further divided into seven groups based on pathologic findings: usual interstitial pneumonitis pneumonitis /pneu·mo·ni·tis/ (noo?mo-ni´tis) inflammation of the lung; see also pneumonia.
hypersensitivity pneumonitis (UIP UIP Usual interstitial pneumonia, see there ), nonspecific interstitial pneumonitis (NSIP NSIP NASA Student Involvement Program
NSIP nonspecific interstitial pneumonia
NSIP National Sheep Improvement Program
NSIP NATO Security Investment Program
NSIP Network Security Improvement Program
NSIP Nutrition Service Incentive Program ), desquamative interstitial pneumonitis desquamative interstitial pneumonitis A nonspecific interstitial pulmonary reaction of adults; DIP is often idiopathic but may be associated with inhalation of inorganic particles Radiology Bilateral ground-glass opacifications Treatment Corticosteroids. (DIP), respiratory bronchiolitis-ILD (RB-ILD), acute interstitial pneumonitis (AIP AIP acute intermittent porphyria.
AIP Acute intermittent porphyria ), lymphocytic interstitial pneumonitis (LIP) and bronchiolitis obliterans organizing pneumonia Bronchiolitis obliterans organizing pneumonia (BOOP) is an inflammation of the bronchioles and surrounding tissue in the lungs. BOOP is often caused by a pre-existing chronic inflammatory disease like rheumatoid arthritis. (BOOP BOOP Bronchiolitis obliterans organizing pneumonia A disease once considered a form of interstitial pneumonia Etiology Obscure; ? associated with toxic fumes, infection, connective tissue disease Clinical Cough, dyspnea, 'flu' symptoms, 50% recovery, 12% BOOPs ). (2) Each of these pathologic findings is associated with distinct clinical presentations, etiologies and prognoses (Table 1). The nomenclature associated with ILD presents its own challenges. For the purposes of this review, we will focus on the idiopathic interstitial pneumonias. In discussing the IIPs, we will adopt the commonly used term "interstitial lung disease (ILD)". We will distinguish this from the more narrowly defined disorder of idiopathic pulmonary fibrosis idiopathic pulmonary fibrosis Idiopathic interstitial fibrosis of lung Pulmonology An idiopathic condition characterized by scarring and fibrosis of alveolar septae more common in middle-aged men, possibly related to collagen vascular disease, with positive (IPF (Itanium Processor Family) See Itanium. ), the most common subset of the IIPs.
[FIGURE 1 OMITTED]
The incidence and prevalence of interstitial lung disease (ILD) is unclear, as it is often found incidentally and can be the result of innumerable insults. Idiopathic pulmonary fibrosis (IPF), the most common and best studied ILD, is a progressive lung disorder of unknown etiology that leads to death in the majority of patients within 3 to 5 years of diagnosis, regardless of treatment. (3-7) The prevalence of this disease was studied in Bernalillo County, New Mexico Bernalillo County is a county located in the U.S. state of New Mexico. As of 2000, the population was 556,678. The county seat is Albuquerque6. It is part of the Albuquerque, New Mexico Metropolitan Statistical Area. , and was estimated to be 13.2 to 20.2 per 100,000, with an annual incidence of 7.4 to 10.7 per 100,000 cases/yr. (8) Since IPF accounts for 60% of the ILD cases, one can estimate the true incidence of ILD in the general population is much greater. (8) Furthermore, the prevalence of IPF in individuals older than 75 years of age has been estimated to be as high as 175 per 100,000. (8) This is of importance given that two-thirds of patients with IPF are over 60 years of age at diagnosis. (1,9) This also suggests that as the US population ages, ILD will be encountered with increasing frequency.
Although the pathogenesis of ILD remains unknown, it appears to be an inappropriate response to a real or perceived lung injury. (10-12) Thus, normal mechanisms of wound repair proceed unchecked to the point of fibrosis. Triggering events can be diverse and include autoimmune disorders, drugs, allergic lergic reactions, infections, toxic inhalations and even inherited disorders (Fig. 2). More often, the trigger is unknown, leading to the diagnosis of "idiopathic interstitial pneumonia." Because the fibrotic process is likely a final common pathway for many insults, there is heterogeneity in the clinical course. Some patients present fulminantly with ILD due to hypersensitivity pneumonitis, eosinophilic pneumonia or of unknown cause labeled "acute interstitial pneumonia" (AIP), while others have a slowly progressive indolent indolent /in·do·lent/ (in´dah-lint)
1. causing little pain.
2. slow growing.
1. Disinclined to exert oneself; habitually lazy.
2. course (Table 1). Overall, the morbidity and mortality Morbidity and Mortality can refer to:
[FIGURE 2 OMITTED]
[FIGURE 3 OMITTED]
The clinical signs and symptoms of ILD vary depending on the cause, but are generally not specific to a diagnosis of ILD. Rather, the clinical presentation is common to a multitude of cardiopulmonary diseases. Individuals present with progressive dyspnea on exertion and cough with abnormal breath sounds (crackles) and interstitial infiltrates on x-ray. Patients complain of progressive breathlessness on exertion that may be exacerbated by climbing stairs or carrying groceries. Dry, paroxysmal paroxysmal (per´ksiz´ml),
adj recurring in paroxysms. cough is frequently present. Since two-thirds of patients with ILD are over 60 years of age at diagnosis, the initial symptoms may be attributed to cardiac disease, deconditioning or advancing age, thus delaying the ultimate diagnosis and treatment. (9) Occasionally, additional symptoms, such as muscle weakness or inflammatory arthritis, may suggest a potential etiology for the ILD. Collagen vascular disease-associated ILD often presents in previously diagnosed rheumatologic patients, although ILD may predate other manifestations of the rheumatologic disease. In these patients, symptoms of the rheumatologic disorder provide a critical clue to the etiology of the lung disease.
An increased incidence of ILD has been noted in certain families. These cases of "familial idiopathic pulmonary fibrosis" are thought to account for less than 3% of all cases and may be associated with a defect in surfactant protein C Surfactant protein C is a membrane protein. See also
gastroesophageal reflux disease
GERD (90% in patients with IPF). (17-20)
Given the nonspecific clinical presentation, the diagnosis of ILD must be actively considered by the examining physician (Fig. 4). Since most patients do not seek care until their symptoms are interfering with their daily functioning, time is of the essence A phrase in a contract that means that performance by one party at or within the period specified in the contract is necessary to enable that party to require performance by the other party.
Failure to act within the time required constitutes a breach of the contract. in making the correct diagnosis and beginning therapy. Once end stage lung disease, characterized by honeycombing, is present, the lost lung function cannot be reversed and patients may be left with significant deficits.
While presenting symptoms are frequently nonspecific, a careful history can provide important clues regarding the etiology of ILD (Fig. 2). A thoughtful assessment of the tempo of the illness (weeks, months, years) provides some suggestions regarding etiology (Table 1). A history of prior chest x-rays demonstrating progressive fibrosis over many years is a good hint for idiopathic pulmonary fibrosis. A patient with a much more fulminant ful·mi·nant
Occurring suddenly, rapidly, and with great severity or intensity, usually of pain.
ful presentation might lead one to consider BOOP or AIP.
A thorough history for toxic, environmental (birds, mold, etc.) and occupational (asbestos, ground stone, metal dust) exposures or infectious agents is of paramount importance in detecting hypersensitivity pneumonitis, or chronic infections. These diagnoses may be further supported by additional laboratory studies, including sputum cultures and hypersensitivity serologies. The presence of a previously undiagnosed collagen vascular disease can be suggested by a history of arthralgias, myalgias, arthritis, muscle weakness or skin rashes. Family history may reveal other family members with unexplained lung disease or with collagen vascular disease. Reviewing the patient's past and present medications and herbal or over-the-counter drugs may suggest a relevant drug exposure. (18)
Physical examination provides important initial clues to this disease. Characteristic findings include "velcro crackles" on lung examination, digital clubbing, as well as evidence of elevated right heart pressures. Particular attention should be paid to evidence of autoimmune disorder (skin rashes, inflamed joints) and evidence of neuromuscular dysfunction (proximal muscle weakness).
[FIGURE 4 OMITTED]
High resolution CT scans demonstrating reticulonodular interstitial infiltrates, variable amounts of ground glass infiltrates and, in advanced cases, honeycombing, are strongly suggestive of ILD (21) (Fig. 5). The location of the infiltrates depends on the underlying cause: sarcoid sarcoid /sar·coid/ (sahr´koid)
2. a sarcoma-like tumor.
Of or resembling flesh.
1. , hypersensitivity, smoking-related ILD (RB-ILD/DIP) and infectious processes tend to occur in the upper lobes; whereas scleroderma scleroderma
or progressive systemic sclerosis
Chronic disease that hardens the skin and fixes it to underlying structures. Swelling and collagen buildup lead to loss of elasticity. The cause is unknown. and IPF favor the bases. The CT findings of basilar basilar /bas·i·lar/ (bas´i-lar) pertaining to a base or basal part.
Of, relating to, or located at or near the base, especially the base of the skull. honeycombing and subpleural distribution of involvement are classically associated with IPF, but may occur with other forms of ILD (Fig. 5C). (21,22)
[FIGURE 5 OMITTED]
Pulmonary function tests reveal restrictive physiology with simultaneous decrease in all lung volumes and a markedly diminished diffusing capacity for carbon monoxide. Occasionally, when ILD develops with pre-existing COPD/emphysema, lung volumes may appear normal, but obstruction is present and there is a greater deficit in the diffusing capacity than would normally be attributed to the fibrosis alone. Recently, a modified 6-minute walk monitoring oxygen desaturation desaturation /de·sat·u·ra·tion/ (de-sach?ah-ra´shun) the process of converting a saturated compound to one that is unsaturated, such as the introduction of a double bond between carbon atoms of a fatty acid. time has shown promise as a marker of disease severity and progression. (23)
Screening laboratories, including a complete blood count with differential (CBC (1) (Cell Broadcast Center) See cell broadcast.
(2) (Cipher Block Chaining) In cryptography, a mode of operation that combines the ciphertext of one block with the plaintext of the next block. ) and comprehensive metabolic profile, are useful in the initial evaluation. The CBC may show eosinophilia eosinophilia /eo·sin·o·phil·ia/ (e?o-sin?o-fil´e-ah) abnormally increased eosinophils in the blood.
An increase in the number of eosinophils in the blood. in cases of eosinophilic eosinophilic /eo·sin·o·phil·ic/ (-fil´ik)
1. readily stainable with eosin.
2. pertaining to eosinophils.
3. pertaining to or characterized by eosinophilia. lung disease. Elevated liver functions or renal impairment can suggest a systemic or multi-organ process and are also important in later considerations of therapy. Laboratory measurements, including ESR ESR - Eric S. Raymond , ANA, RF, aldolase aldolase /al·do·lase/ (al´do-las)
2. an enzyme that acts as a catalyst in the production of dihydroxyacetone phosphate and glyceraldehyde phosphate from fructose 1,6-bisphosphate. , CPK CPK creatine kinase.
creatine phosphokinase. , and SCL-70, often help to identify collagen vascular diseases as an etiology for the ILD. Low titers of ANA and RF have been reported in patients with IPF and, thus, the significance of these is unclear. (24) In appropriate settings, sputum cultures should be sent for fungi and non-TB mycobacterium. In a patient with a history suggestive of hypersensitivity, specific or general hypersensitivity panels may point to an exact etiology.
Occasionally, bronchoalveolar lavage and transbronchial biopsy are revealing, especially with sarcoid, pulmonary alveolar proteinosis Pulmonary Alveolar Proteinosis Definition
Pulmonary alveolar proteinosis (PAP) is a rare disease of the lungs.
In this disease, also called alveolar proteinosis or phospholipidosis, gas exchange in the lungs is progressively or to confirm active alveolitis alveolitis /al·ve·o·li·tis/ (al-ve?o-li´tis) inflammation of a dental or pulmonary alveolus.
allergic alveolitis , extrinsic allergic alveolitis hypersensitivity pneumonitis. in collagen vascular diseases. However, a definitive diagnosis can only be made from a surgical lung biopsy (open or video-assisted thoracoscopic surgery--VATS). Biopsies should ideally be obtained from 3 separate lobes, avoiding areas of severely scarred or honeycombed lung. The decision to obtain an invasive biopsy is tempered by clinical history, radiographic radiographic (rā´dēōgraf´ik),
adj relating to the process of radiography, the finished product, or its use. findings and the patient's individual risk/benefit profile. Using ATS criteria for the diagnosis of IPF, clinical and radiographic diagnosis alone has a sensitivity of 62% and 79% and a specificity of 97% and 90%, respectively. (25) However, for non-IPF ILDs, while the sensitivity is similar (89% and 59%), the specificity declines markedly to 40% for both clinical and radiographic diagnosis. (25) Surgical biopsy is most useful when there is a discrepancy between clinical and radiographic features of IPF or if a non-IPF ILD is suspected. Biopsy findings can be divided based on Katzenstein criteria into seven pathologic groups summarized in Table 1. (2,26) These pathologies are associated with distinct, albeit overlapping, clinical presentations.
In retrospect, the symptoms and radiographic abnormalities of ILD often precede presentation, evaluation and diagnosis by several years, thus delaying diagnosis, treatment and perhaps limiting efficacy of treatments. Effective treatment options for ILD are limited and traditionally are not successful, especially in the case of IPF. Establishing a clear diagnosis of ILD and identifying a potential etiology is critical in determining appropriate therapeutic interventions. Given lack of demonstrated efficacy of most therapeutic regimens and the significant side effect profiles, patients with some forms of ILD should be given the option of no pharmacologic treatment with close follow-up. This is most pertinent in the case of IPF where only 10 to 15% of patients with biopsy-proven UIP respond to current therapies. (22,27) Even for patients with more responsive forms of ILD, therapeutic interventions are still associated with significant adverse side effects. Thus, if a patient chooses to be treated, objective measures of efficacy need to be followed and surveillance for adverse effects carried out. We recommend follow-up visits and complete PFTs every 3 months with HRCT HRCT high-resolution computed tomography. and every 6 to 12 months while undergoing therapy. In addition, depending on the agent used, CBC with differential, LFTs and urinalysis may need to be followed. If no objective improvement (increased FVC FVC forced vital capacity.
forced vital capacity
n See forced vital capacity.
forced vital capacity. or DLCO DLco
diffusing capacity of the lung for carbon monoxide. by > 10%) occurs within 6 to 9 months of starting therapy, the drug should be stopped and potentially changed to a different agent.
A common conundrum arises when a patient's objective parameters remain stable on therapy. Does this indicate a response to the therapy or is the patient simply in an inactive phase of the disease and might have remained stable regardless of therapy? This is less of an issue if the patient was objectively declining before starting the drug, but often therapy is initiated without waiting for decline. We recommend evaluating each patient at a subjective and objective level and minimizing therapy in those patients for whom benefit is not apparent. Choosing initial therapy involves balancing side effect profile against potential benefits to the individual patient. The commonly recommended agents are summarized in Figure 6.
The American Thoracic Society has published therapeutic guidelines for specific subtypes of ILD. (1) Although no therapy has ever been shown to be effective for IPF (60% of ILD cases), corticosteroids plus a steroid-sparing agent are often used as initial therapy if the patient desires treatment (Fig. 6). (1) However, early referral to a pulmonary specialist, tertiary care center tertiary care center Hospital care A hospital or medical center for Pts often referred from secondary care centers, which provides subspecialty expertise
Tertiary care center
Surgery and/or lung transplant center is strongly advised in all patients with IPF who may benefit from clinical trials or lung transplantation. While on steroids, prophylaxis for gastric ulcers, bone loss and pneumocystic pneumonia is recommended. Close monitoring for additional side effects, such as bone marrow suppression Bone marrow suppression
A decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting.
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bone marrow suppression , hepatotoxicity hepatotoxicity (hepˑ··tō·t (azathioprine azathioprine: see metabolite. ), and hemorrhagic cystitis (cyclophosphamide cyclophosphamide /cy·clo·phos·pha·mide/ (-fos´fah-mid) a cytotoxic alkylating agent of the nitrogen mustard group; used as an antineoplastic, as an immunosuppressant to prevent transplant rejection, and to treat some diseases ), is also necessary. In addition, it is advisable to check a PPD (1) (Parallel Presence Detect) The method used by earlier SIMM memory modules to communicate their capacity to the computer. A binary number coming from a parallel set of pins was read by the system, with each pin representing one bit. Contrast with SPD. before beginning immunosuppressant immunosuppressant /im·mu·no·sup·pres·sant/ (-sah-pres´ant) an agent capable of suppressing immune responses.
An agent that suppresses the body's immune response. therapy.
Importantly, patients may experience acute exacerbations of ILD that present as cough, fever, leukocytosis Leukocytosis Definition
Leukocytosis is a condition characterized by an elevated number of white cells in the blood.
Leukocytosis is a condition that affects all types of white blood cells. and flu-like symptoms in the absence of overt infection. HRCT often shows new ground glass attenuation Loss of signal power in a transmission.
The reduction in level of a transmitted quantity as a function of a parameter, usually distance. It is applied mainly to acoustic or electromagnetic waves and is expressed as the ratio of power densities. on top of the underlying honeycomb fibrosis. Lung histology demonstrates diffuse alveolar damage diffuse alveolar damage DAD The histologic findings in ARDS, which is characterized by an acute onset of diffuse pulmonary infiltrates Etiology AIDS, air embolism, cardiopulmonary bypass, connective tissue disease–SLE, rheumatoid arthritis, scleroderma, superimposed on the existing fibrotic lung. Although not well studied, a case series of patients with acute exacerbations of IPF demonstrated a favorable response to high-dose pulse steroids during the exacerbation. (27,28) In addition, there is a significant decrease in survival in patients experiencing acute exacerbations compared with patients without exacerbations. (27) These acute exacerbations suggest that the scarring in pulmonary fibrosis may not occur as a continuous progressive process, but instead as the result of an accumulation of episodic exacerbations. (27)
Treatment of CVD-associated ILD is similar to that of IPF. While response to therapy has been considered better in CVD-ILD than IPF, this has recently come into question. (29) In general, therapy for CVD-ILD is initiated with a steroid and steroid-sparing agent. Several specific disorders merit comment. A systematic evaluation of therapy for scleroderma-associated alveolitis demonstrated a modest benefit to cyclophosphamide over patients treated with steroids alone. (30,31) Because of the association of scleroderma renal crisis with pulse steroids, treatment of pulmonary crises in this group of patients should not include pulse steroids. Polymyositis/dermatomyositis and antisynthetase-associated pulmonary fibrosis (pulmonary fibrosis with clinical or subclinical subclinical /sub·clin·i·cal/ (sub-klin´i-k'l) without clinical manifestations.
Not manifesting characteristic clinical symptoms. Used of a disease or condition. myositis myositis
Inflammation of muscle tissue, often from bacterial, viral, or parasitic infection but sometimes of unknown origin. Most types destroy muscle and surrounding tissue. Bacteria may directly infect muscle (usually after injury) or produce substances toxic to it. ) sometimes show differential response in the affected organ. It may be necessary to pursue multiple agents to control the myositis even after the lung inflammation responds.
Drug-related ILD (amiodarone, methotrexate methotrexate, drug used in halting the growth of actively proliferating tissues. Introduced in the 1950s, it is used in the treatment of leukemia, psoriasis, and non-Hodgkin's lymphoma. ) is typically responsive to stopping the offending agent. Although steroid therapy is often initiated, there is little evidence for long-term benefit. (32,33) The management of both hypersensitivity pneumonitis and smoking-related ILD is dependent on avoidance of the triggering substance. (34)
In addition to the standard therapies described, a number of agents are currently in or just finished clinical trials for the treatment of IPF. These include interferon-gamma, pirfenidone, N-acetylcysteine and tumor necrosis factor tumor necrosis factor
n. Abbr. TNF
A protein that is produced in the presence of an endotoxin, especially by monocytes and macrophages, is able to attack and destroy tumor cells, and exacerbates chronic inflammatory diseases. inhibitors. N-acetylcysteine has recently been demonstrated to slow the progression of IPF in a randomized clinical trial randomized clinical trial,
n a clinical study where volunteer participants with comparable characteristics are randomly assigned to different test groups to compare the efficacy of therapies. combining N-acetylcysteine 600 mg p.o. t.i.d. with standard of care (prednisone prednisone (prĕd`nĭsōn): see corticosteroid drug. and azathioprine). (35) In addition, although demonstrating promising results in a small phase II trial, interferon-gamma has recently been shown to be ineffective in altering disease progression or mortality in a large multinational clinical trial. (36,37) However, subgroup analysis from that trial did suggest a potential benefit of the drug in certain patients with IPF with preserved lung function, thus a second phase III trial is currently underway to determine if these findings are indeed true. Several other agents, such as colchicine colchicine (kŏl`chəsēn'), alkaloid extracted from plants of the genus Colchicum and especially from the corms of the autumn crocus, Colchicum autumnale (see meadow saffron). , have been reported to have efficacy in ILD, but have not been tested in prospective, randomized clinical trials. Until further data is available regarding these agents, it is difficult to recommend any of them as other than second or third-line therapy.
Lung transplantation, which has been used effectively in a number of chronic lung disorders, offers hope in a selected group of patients with ILD. The survival of patients with ILD is lower than average with 73.6%, 60.8% and 37.4% patient survival at 1, 3 and 5 years, respectively. (38,39) Based on recently developed international guidelines, patients with ILD should be referred for transplant evaluation if the patient is judged to have less than a 50% 2- to 3-year predicted survival or NYHA NYHA New York Heart Association class III or IV level of function. (38,39) In general, we suggest referring patients under 65 years of age who have forced vital capacity forced vital capacity
n. Abbr. FVC
Vital capacity measured with subject exhaling as rapidly as possible.
forced vital capacity,
n a measure of the maximum rate of exhalation. or diffusing capacity less than 40% predicted. Most transplant centers do not consider patients over the age of 65, thus eliminating many patients with IPF. Furthermore, some younger patients with collagen vascular-associated ILD may be excluded from transplant consideration because of their coexisting CVD. Nevertheless, this remains an important option for selected patients.
Perhaps the most beneficial treatment for progressive ILD is to ensure adequate oxygenation oxygenation /ox·y·gen·a·tion/ (ok?si-je-na´shun)
1. the act or process of adding oxygen.
2. the result of having oxygen added. . Unless the fibrosis is severe, resting room air oxygen levels are usually within the normal range. However, even minimal exertion can lead to significant exertional hypoxemia hypoxemia /hy·pox·emia/ (hi?pok-sem´e-ah) deficient oxygenation of the blood.
Insufficient oxygenation of arterial blood. with moderate ILD. Thus, informal oxygen desaturation testing (in-office 600 yard walk with pulse oximetry) or modified 6 minute walk testing is beneficial. (23) Most patients will need a home oxygen concentrator, as well as portable cylinders for use outside the home. In cases of mild to moderate exertional hypoxemia, patients may be able to achieve adequate oxygenation with a pulse-demand system of oxygen that delivers oxygen only when the patient inhales. Unfortunately, many patients still perceive a stigma with oxygen use and, in our experience, are often reluctant to use it.
Additional therapeutic interventions such as pulmonary rehabilitation provide subjective improvement to the patient and counteract the deconditioning which occurs as a result of limited exertional capacity. As the ILD progresses, patients may become severely limited by exertional hypoxemia and unable to perform activities of daily living or even leave the house. In many cases, mobility can be helped with the use of motorized mo·tor·ize
tr.v. mo·tor·ized, mo·tor·iz·ing, mo·tor·iz·es
1. To equip with a motor.
2. To supply with motor-driven vehicles.
3. To provide with automobiles. wheelchairs. In addition, for help with activities of daily living, we find that occupational and physical therapy consults are beneficial.
Although nearly all patients will develop pulmonary hypertension as the ILD progresses, the impact this has on their disease course is unclear. The pulmonary hypertension has been thought to be the result of hypoxia-induced vasoconstriction vasoconstriction /vaso·con·stric·tion/ (-kon-strik´shun) decrease in the caliber of blood vessels.vasoconstric´tive
n. leading to remodeling of the pulmonary vasculature vasculature /vas·cu·la·ture/ (vas´ku-lah-chur)
1. circulatory system.
2. any part of the circulatory system.
n. that may be prevented or ameliorated by adequate oxygen. However, the exact mechanism producing pulmonary hypertension remains under investigation. Of note, patients with ILD due to collagen vascular diseases, particularly scleroderma, may develop pulmonary hypertension that is independent of hypoxia, but rather intrinsic to the rheumatologic disease itself. In these cases, medications targeting pulmonary arterial hypertension may have a beneficial role.
Because of the complexity of decisions involving treatment and the importance of clinical trials in identifying potential new therapies for ILD, we recommend referral of patients with suspected or known ILD for whom therapy is planned to a center with experience in this area. Furthermore, any patient for whom a diagnosis is in question or in whom a diagnosis other than IPF is being considered may benefit from an evaluation by a pulmonologist pul·mo·nol·o·gist
A physician who specializes in the diagnosis and treatment of respiratory disorders. . The NIH "Not invented here." See digispeak.
NIH - The United States National Institutes of Health. has recently funded a number of centers to develop a coordinated network for the investigation of IPF (https://www.ipfnet.org/). In addition to the IPFnet, many academic medical centers serve as local sites for research and clinical trials. Furthermore, patients for whom lung transplantation is a consideration should be referred early to a lung transplantation center.
It is unclear how many ILD patients actually die of their lung disease. A study conducted a decade ago found that only one third of patients with IPF will die of progressive fibrosis. (8) In this study, the majority of IPF patients died due to heart disease, infections, cancer or pulmonary emboli emboli /em·bo·li/ (em´bo-li) plural of embolus.
Plural of embolus. An embolus is something that blocks the blood flow in a blood vessel. . (8) More recent studies suggest that progressive IPF results in death in 56% of patients. (40) Given the advanced age of many with ILD, patients are at risk for other age-related diseases and need close follow-up with their internists. Regardless, with appropriate diagnosis and therapeutic intervention, the quality of ILD patients' lives can be markedly improved.
Survival for ILD is worse if at time of diagnosis there is advanced age (>50), male gender, moderate/severe dyspnea on exertion, history of tobacco use, moderate loss of lung function (TLC TLC total lung capacity; thin-layer chromatography.
1. thin-layer chromatography
2. <45%, DLCo <40%), neutrophilia/eosinophilia on bronchoalveolar lavage, honeycombing on HRCT, lack of a response to corticosteroids, or moderate/severe fibrosis and fibroblastic foci on histology. (6,7,13,41) Prognosis and response to therapy is improved if there is increased ground glass infiltrates on HRCT or lymphocytosis lymphocytosis /lym·pho·cy·to·sis/ (-si-to´sis) an excess of normal lymphocytes in the blood or an effusion.
n. on bronchoalveolar lavage. (21,41) This improved prognosis may be related to the fact that ground glass and lymphocytosis is usually found in ILD due to collagen vascular disease and not IPF.
We recommend that early in the disease, discussions are initiated regarding advanced directives. Given the relentless progression and paucity of effective treatments for many forms of ILD, patients and their physicians should have end-of-life discussions. These are especially important in IPF, as there are currently no effective treatments and numerous studies have demonstrated poor prognosis if patients are intubated or even admitted to an ICU--61% acute mortality and 92% 2-month post-ICU mortality. (42)
Interstitial lung disease encompasses a heterogeneous group of diseases with multiple etiologies (Fig. 2, Table 1). The presenting symptoms, cough and dyspnea, are nonspecific and the diagnosis is often delayed unless the examining physician has a high level of suspicion. Diagnosis comes from a thoughtful history/physical, specific laboratories and x-rays. The etiology may be further clarified by lung biopsy or bronchoscopy Bronchoscopy Definition
Bronchoscopy is a procedure in which a cylindrical fiberoptic scope is inserted into the airways. This scope contains a viewing device that allows the visual examination of the lower airways. with lavage lavage /la·vage/ (lah-vahzh´)
1. the irrigation or washing out of an organ, as of the stomach or bowel.
2. to wash out, or irrigate.
n. and transbronchial biopsy. However, the diagnosis of the subcategory of idiopathic pulmonary fibrosis cannot be made by transbronchial biopsy. Depending on the etiology, therapy may include immunosuppression immunosuppression
Suppression of immunity with drugs, usually to prevent rejection of an organ transplant. Its aim is to allow the recipient to accept the organ permanently with no unpleasant side effects. , trigger avoidance or observation. The prognosis is closely tied to the etiology. Overall, patient well-being can be profoundly impacted by sensitivity to progressive physical limitations and difficult end-of-life decisions. Early diagnosis is critical for best patient outcomes and is dependent on physician awareness of this often deadly disease.
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Of obscure or unknown origin. Used of diseases. fibrosing alveolitis. Thorax 1983;38:349-355.
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1. A rigid military disciplinarian.
2. One who demands absolute adherence to forms and rules.
[After Jean Martinet (died 1672), French army officer. Y, Rom WN, Grotendorst GR, et al. Exaggerated spontaneous release of platelet-derived growth factor platelet-derived growth factor
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A watery or thin mucous discharge from the eyes or nose.
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What we do in life echoes in eternity. --Maximus Decimus Meridias, from "Gladiator"
Sonye K. Danoff, MD, PhD, FCCP FCCP Fellow of the American College of Chest Physicians
FCCP Fellow of the American College of Clinical Pharmacy
FCCP Feeder Calf Certification Program
FCCP Family-Controlled Corporation Program (The Wharton School) , Peter B. Terry, MD, and Maureen R. Horton, MD
From the Department of Medicine, Johns Hopkins University School of Medicine The Johns Hopkins University School of Medicine, located in Baltimore, Maryland, USA, is a highly regarded medical school and biomedical research institute in the United States. , Baltimore, MD.
Reprint requests to Dr. Maureen R. Horton, Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, 5th floor, Baltimore, MD 21205. Email: firstname.lastname@example.org
The authors have no financial disclosures to declare.
Accepted January 3, 2007.
RELATED ARTICLE: Key Points
* Early recognition and diagnosis of interstitial lung disease is critical for optimal management.
* Recognition of interstitial lung disease by internists depends on identifying nonspecific symptoms in an appropriate clinical context and obtaining appropriate diagnostic studies.
* Optimal management of interstitial lung disease depends on the close collaboration between internists and pulmonologists to identify the etiology of the disease, select appropriate treatments and carefully monitor for objective response and side effects.
Table. Summary of idiopathic interstitial lung diseases (ILD) UIP NSIP DIP/RB-ILD Demographics 60s-80s; 40s-50s; 40s-50s; M = F Increased F > M Associated with risk with Associated smoking smoking with collagen vascular disease or with extrinsic allergic alveolitis History/course Long Subacute onset Subacute onset of asymptomatic of months to months to years period years (radiographic evidence); Several years progressive dyspnea Physical exam Velcro crackles Raynaud Crackles Clubbing sclerodactyly Clubbing Lab RF ANA, SCL-70 Jo-1 CK; aldolase Serum Ab to birds, organisms, etc Biopsy (3) Variable from Uniform pattern DIP: Uniform area to area of involvement intra-alveolar ("temporal of the lung in macrophages, heterogeneity" biopsies. mild-mod septal in biopsy) Cellular type: thickening, mild Subpleural, Mid-mod chronic septal, and chronic peribronchiolar intersitial inflammation Treatment Steroids Steroids Discontinue Cytotoxic agents Cytotoxic Tobacco agents (Steroids) Response to Poor Good Good tratment Prognosis Poor Good Good, if smoking stops Median-2.8 yr 55% Fibrosing: 90% DIP: 95.2%-100% (5 (2 yr) 20%-43% (5 yr) 35% (10 yr) 69.6%-100% (5 yr) (2,31) yr) Cellular: (10 yr) (31) 15% (10 yr) (31) 100% (5 yr) 100% (10 yr) (31) AIP (Hamman-Rich) BOOP (30) LIP Demographics No age limitation 20s-70s; 20s-70s; F > M (in F > M some Associated with reports) immunodeficiencies, Associated including HUV, and with collagen vascular collagen disease vascular disease, medications and infections. May occur in context of other in interstitial lung process History/course Rapidly Variable onset Slowly progressive progressive of months to over years over days to years; weeks with sometimes rapid waxing and progression to waning; flu- respiratory like failure symptoms including fever Physical exam Respiratory Fever Crackles Clubbing Crackles failure Lab ESR HIV Biopsy (3) Early AIP: Intraluminal Intersitial lymphoid hyaline fibromyxoid infiltrate with membranes tissue in lymphocytes, plasma lining alveoli. the terminal cells and Later, type II and histiocytes; pneumonocyte respiratory lymphoid follicles proliferation branches and then intersitial Treatment Steroids Steroids Steroids Cytotoxic Antiretrovirals agents Response to Poor Good Variable tratment Prognosis Extremly poor Good, except Fair, one-third will for rapidly progress to progressive diffuse fibrosis form Many cases diagnosed >95% (1 as LIP are really yr) (33) low grade lymphoma. Both LIP and low grade lung lymphoma may "transform" to a high grade lymphoma UIP, usual interstitial pneumonitis; NSIP, nonspecific interstitial pneumonitis; DIP, desquamative interstitial pneumonitis; RB-ILD, respiratory bronchiolitis-ILD; AIP, acute interstitial pneumonitis; BOOP, bronchiolitis obliterans organizing pneumonia; LIP, lymphocytic interstitial pneumonitis. Drug Dose Monitoring prednisone 0.5 mg/kg Glucose Bone density cyclophosphamide 2 mg/kg CBC monthly Urinanalysis azathioprine 2 mg/kg CBC and LFTs monthly colchicine 0.1 mg BID Interferon-1[beta] 200 mcg sc TIW CBC q month pirfenidone 600mg PO TOD ? N-acetylcysteine 600mg PO TID none Drug Adverse Effects Reference prednisone Diabetes, AJRCCM 161:646, 2000 osteoporosis Chest 114:507, 1998 cyclophosphamide Hemorrhagic Thorax 44:280, 1989 cystitis, cancer, Chest 125:2169, 2004 infections azathioprine Hepatitis, cancer ARRD 144:291, 1991 Infections colchicine Diarrhea Mayo Clin Proc 72:201, 1997 Chest 114:507, 1998 Interferon-1[beta] Flu-like symptoms NEJM 341:1264, 1999 Leukopenia Chest 127:171, 2005 pirfenidone Photosensitivity AJRCCM 159:1061, 1999 GI distress AJRCCM 171:1040, 2005 N-acetylcysteine none AJRCCM 156:1897, 1997 NEJM 353:2229, 2005 Fig. 6 Therapeutic options for interstitial lung disease. A number of medications have been tested for treatment of ILD or are in the process of clinical trials. Each medication is associated with side effects that must be carefully monitored.