A clinician's guide to the diagnosis and treatment of interstitial lung diseases.

Abstract: Interstitial lung disease (ILD) 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) 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: 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

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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 lung diseases." The term parenchymal derives from the primary site of injury, namely the parenchyma or interstitium. This is the potential space between the air-containing alveolus and the vessels channeling 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, drug reactions, infections and collagen vascular diseases 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 (CVD), (2) hypersensitivity pneumonitis, (3) toxins, (4) infections, (5) inherited, (6) malignancy, (7) pneumoconiosis 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 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 (UIP), nonspecific interstitial pneumonitis (NSIP), desquamative interstitial pneumonitis (DIP), respiratory bronchiolitis-ILD (RB-ILD), acute interstitial pneumonitis (AIP), lymphocytic interstitial pneumonitis (LIP) and bronchiolitis obliterans organizing pneumonia (BOOP). (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 (IPF), 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, 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 course (Table 1). Overall, the morbidity and mortality of ILD depends upon the etiology but can be as high as a 50% 2-year mortality rate in idiopathic pulmonary fibrosis (6,13,14) on par with that of lung cancer. (14)

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Clinical Presentation

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 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. (15,16) As ongoing studies looking for links between "familial idiopathic pulmonary fibrosis" and specific genes are completed, there may be additional cases that may be attributed to a genetic cause. Other factors associated with an increased incidence of ILD include tobacco use, certain medications (tricyclic antidepressants) and occult GERD (90% in patients with IPF). (17-20)

Diagnostic Evaluation

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 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.

History

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 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

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, hypersensitivity, smoking-related ILD (RB-ILD/DIP) and infectious processes tend to occur in the upper lobes; whereas scleroderma and IPF favor the bases. The CT findings of basilar 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 time has shown promise as a marker of disease severity and progression. (23)

Screening laboratories, including a complete blood count with differential (CBC) and comprehensive metabolic profile, are useful in the initial evaluation. The CBC may show eosinophilia in cases of eosinophilic 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, ANA, RF, aldolase, CPK, 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 or to confirm active alveolitis 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 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.

Treatment

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 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 or DLCO 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 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, hepatotoxicity (azathioprine), and hemorrhagic cystitis (cyclophosphamide), is also necessary. In addition, it is advisable to check a PPD before beginning immunosuppressant therapy.

Importantly, patients may experience acute exacerbations of ILD that present as cough, fever, leukocytosis and flu-like symptoms in the absence of overt infection. HRCT often shows new ground glass attenuation on top of the underlying honeycomb fibrosis. Lung histology demonstrates diffuse alveolar damage 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 myositis) 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) 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 inhibitors. N-acetylcysteine has recently been demonstrated to slow the progression of IPF in a randomized clinical trial combining N-acetylcysteine 600 mg p.o. t.i.d. with standard of care (prednisone 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, 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 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 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. 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 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 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 leading to remodeling of the pulmonary vasculature 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. The NIH 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.

Prognosis

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. (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 <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 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)

Summary

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 with lavage 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, 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.

References

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What we do in life echoes in eternity.
--Maximus Decimus Meridias, from "Gladiator"

Sonye K. Danoff, MD, PhD, FCCP, Peter B. Terry, MD, and Maureen R. Horton, MD

From the Department of Medicine, Johns Hopkins University School of Medicine, 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: [e-mail]

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.