Pulmonary Medicine

Idiopathic Interstitial Pneumonias

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What every physician needs to know:

The idiopathic interstitial pneumonias are a heterogeneous group of conditions that are unknown in their etiology and are characterized radiographically by diffuse interstitial infiltrates and distinctive pathologic changes. The prognoses for these conditions range from very poor (AIP) to favorable (DIP/RB-ILD). The most common of these conditions is IPF, which carries a poor prognosis (~median survival 2.5-5 years).

Classification

1) Idiopathic pulmonary fibrosis (IPF)

2) Non-specific interstitial pneumonia (NSIP)

3) Cryptogenic organizing pneumonia (COP), formerly referred to as bronchiolitis obliterans organizing pneumonia (BOOP)

4) Acute interstitial pneumonia (AIP), formerly referred to as "Hamman-Rich" syndrome

5) Desquamative interstitial pneumonia (DIP)

6) Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)

7) Lymphocytic interstitial pneumonia (LIP)

IPF: Epidemiology and Outcomes

IPF is the most common of the IIPs and is also the one which, aside from AIP, carries the worst prognosis. The estimated incidence in the USA is ≈30,000 new cases per year, with an overall prevalence of ≈80,000. It is a disease of the elderly that has increasing prevalence with advancing age. It is also more common among males. IPF is characterized histologically by the usual interstitial pneumonia (UIP). The poor overall prognosis is a median survival of ≈3-4 years from the time of diagnosis. The course of the disease can vary, and it is difficult to predict outcomes, although there are some physiological, radiographic, and other predictors that portend a worse outcome. Options for therapy are limited.

ATS/ERS recommendations for therapy in IPF

There are no proven effective medical therapies, despite many prospective clinical trials over the past decade. The most recent consensus statement by the ATS/ERS strongly recommends against the use of steroids and/or cytotoxic agents like azathioprine or cyclophosphamide. No drug is endorsed as a therapy in the consensus statement. It is recommended that patients be enrolled in clinical trials of therapy and/or be evaluated for lung transplantation.

NSIP: Epidemiology and outcomes

NSIP is the newest of the IIPs, so its incidence and prevalence has not been well established. In most case series of the IIPs, IPF predominates in a ≈3-4:1 fashion over NSIP. It tends to occur in younger individuals (median age of onset 40-50) and has a slight female predominance. It is frequently seen in association with a connective tissue disorder and sometimes predates the clinical onset of other systemic manifestations of the disease.

One school of thinking is that most cases of idiopathic NSIP are a manifestation of an undifferentiated CTD. The clinical course of NSIP is more protracted than that of IPF and is associated with distinctly better outcomes with five- and ten-year survivals reported at over 80 percent and over 70 percent, respectively.

COP: Epidemiology and outcomes

The initial description of COP was that of bronchiolitis obliterans with organizing pneumonia ("BOOP"). However, it is not an airway disease since it is characterized pathologically by organizing pneumonia within the alveolar ducts and alveoli. The same pathologic pattern may be seen in the context of a number of diseases, including connective tissue disorders and post-infectious, drug-related, and post-lung transplantation. The idiopathic form has no specific gender distribution and has a mean age of onset of ~55 years. Onset is usually recent (<3 months) and may be accompanied by flu-like or constitutional symptoms in conjunction with cough and shortness of breath.

AIP: Epidemiology and outcomes

AIP is a rapidly progressive disease that occurs over a wide age range (~mean 50 years) and that has no gender predominance or association with cigarette smoking. Patients often present with apparent viral respiratory tract infection and associated constitutional symptoms followed by severe, progressive shortness of breath.

RB-ILD/DIP: Epidemiology and outcomes

RB-ILD/DIP usually affects current smokers in the fourth or fifth decade of life, and men are affected more often than women (~2:1). Most patients have mild symptoms. Many patients improve upon cessation of smoking, and few patients develop progressive, disabling disease.

LIP: Epidemiology and outcomes

LIP is usually seen in the context of collagen vascular diseases (especially Sjogren's Syndrome) and HIV. More common in women, LIP typically develops in the fifth decade of life, although it may also be seen in children, where it tends to be associated with HIV or hypogammaglobulinemia.

Unclassifiable IIPs

There are pathological patterns of injury that don't fit within the pathological framework of the IIPs. More recently described specific pathological patterns that are yet to be defined as specific IIP subsets include pleuroparenchymal fibroelastosis, acute fibrinous organizing pneumonia, and bronchiolocentric fibrosis.

Are you sure your patient has one of the idiopathic interstitial pneumonias? What should you expect to find?

Patients with one of the IIPs typically present with insidious onset and progressive dypsnea on exertion, often accompanied by a recalcitrant dry cough. In some cases the presenting symptom is cough alone, and a small minority of patients are asymptomatic with the diagnosis suggested by an incidental finding on CXR, CT scan, or physical examination. Those with IPF have a family history in ≈2-20 percent of cases. Other conditions that may mimic the IIPs should be excluded. On physical examination, clubbing of the digits may be seen in some patients, and the chest examination is typically accompanied by coarse inspiratory ("Velcro") crackles at the lung bases.

Beware: there are other diseases that can mimic the idiopathic interstitial pneumonias.

The IIPs are a diagnosis of exclusion, so other interstitial lung disorders (ILD) known to mimic or cause a similar constellation of symptoms, signs, and radiographic changes should be excluded. Most other ILD can be excluded with a comprehensive history and serologic studies. A useful mnemonic for other ILDs is five "I", "C," and "N."

Mnemonic for the ILDs

I = Infectious causes of ILD should always be considered first since they are the most treatable. Infections that can present with diffuse ILD changes radiographically include viral infections like influenza and CMV, fungal infections (Pneumocystic carinii), and--rarely--bacterial infections.

I = Inhalational injury from occupational exposures like asbestosis, silicosis, and coal miner pneumoconiosis.

I = Immunologic disorders--specifically, connective tissue diseases (CTD) and hypersensitivity pneumonitides. CTD most commonly associated with ILD include rheumatoid arthritis, scleroderma, SLE, mixed connective tissue disease, Sjogren's syndrome, and polymyositis/dermatomyositis. Not infrequently, the respiratory symptoms and ILD may antedate other manifestations of the CTD.

I = Iatrogenic causes. These include chemotherapeutic agents like bleomycin, antibiotics like nitrofurantoin, and radiation therapy.

I = idiopathic. Aside from the IIPs, many other conditions can result in diffuse ILD like sarcoidosis, lymphangioleiomyomatosis (LAM), pulmonary Langerhan's histiocytosis, and amyloidosis.

C= Cardiovascular causes. These include chronic congestive heart failure.

N = Neoplastic causes. These include bronchoalveolar carcinoma and lymphangitic carcinomatosis.

How and/or why did the patient develop idiopathic interstitial pneumonia?

The prototype IIP and the one condition that should always be excluded is IPF. It is the most common of the IIPs, and aside from AIP, it carries the worst prognosis. The cause is unknown, although there are a number of exposure associations. The most common risk factor is a current or prior history of cigarette smoking, but chronic exposure to any type of environment with airborne particulate matter like wood dust or metal is associated with a higher risk for developing IPF.

IPF is a disease of the elderly and is uncommon before age fifty. There is a greater incidence and prevalence with advancing age and there is a male predominance but no apparent ethnic predisposition. A small percentage (≈2-20%) of patients have a familial form of IPF. DIP and RB-ILD are invariably associated with cigarette smoking, and LIP is commonly seen in association with underlying disorders like Sjogren's syndrome, HIV, and hypogammaglobulinemia (especially in children). Causative factors in other forms of IIP--specifically COP, NSIP, and AIP--are less well understood.

Risk factors for IIP other than IPF

There is a strong association between RB-ILD and cigarette smoking. Almost all patients with this variant of IIP are current smokers. Abstaining from cigarette smoking tends to result in regression of disease in most cases.

Risk factors for NSIP are less well understood. This entity tends to occur in individuals who are younger than those with IPF, and predominates in females. NSIP can be the harbinger of an underlying connective tissue disorder (CTD), including undifferentiated CTD. When histopathology confirms NSIP, suspicion for an underlying CTD should be raised.

AIP and BOOP have no specific risk factors.

Familial IPF

Genetic alterations of telomerases, surfactant protein A2 ,and protein C have been associated with the familial variant of IPF. The mode of inheritance is thought to be autosomal-dominant with variable penetrance.

Which individuals are at greatest risk of developing an idiopathic interstitial pneumonia?

Cigarette smoking is a risk factor for both IPF and RB-ILD, and exposures to various ambient particles are also associated with a greater risk for IPF. For example, farmers, wood workers ,and metal workers have a higher incidence of IPF, but any type of occupational inhalational exposure and the duration or intensity of that expoure is likely to increase the risk for IPF. A family history of IPF increases the risk of IPF and any of the IIPs.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Serologic testing is necessary to rule out an underlying connective tissue disorder (CTD). The same pathological pattern of injury of any of the IIPs can be seen in the context of other known causes of ILD, including CTDs. Known causes of ILD should be excluded before the diagnosis of an IIP can be made.

Blood tests for connective tissue disorders

ANA, RF, anti-CCP, anti-DS DNA, anti-SSA/Ro, anti-SSB/La, anti-Sm, anti-Scl 70, anti-centromere, aldolase, CPK, anti-Jo 1, anti-RNP, anti-phospholipid antibody. Not all of these need to be performed in every patient, but at least a screening ANA, RF or anti-CCP should be checked. If the index of suspicion is high for an underlying connective tissue disorder, then a more comprehensive panel should be obtained.

Pulmonary function testing in the IIPs

Pulmonary function testing (PFT) helps to differentiate obstructive lung disease from restrictive lung disease. The IIPs will invariably manifest as a restrictive ventilatory deficit, while more common conditions, such as COPD, will manifest with obstruction. PFTs do not help to differentiate the various IIPs, but they are necessary to assess the degree of impairment.

There is no accepted standardization of mild, moderate, or severe disease. An FVC predicted greater than 70 percent may be regarded as mild disease, an FVC of 55-69 percent may be regarded as moderate disease, and an FVC less than 55 percent may be regarded as severe disease. The diffusing capacity (DLco) is also reduced in the IIPs, and a DLco less than 35 percent may indicate the presence of associated pulmonary hypertension.

Restrictive versus obstructive disease

The IIPs will manifest with a restrictive ventilatory deficit, which is characterized by a proportionate reduction in both the FVC and the FEV1 with the result that the FEV1/FVC ratio is normal or increased. An increased ratio is due to reduced compliance (stiffer) in the lungs. Obstructive disease is associated with an FEV1 that is disproportionately reduced in comparison to the FVC, with the result that the FEV1/FVC ratio is reduced (typically <70%).

Functional studies

Objective testing to assess patients' functional status usually includes the six-minute walk test. Oxygen needs and prognostic information can also be obtained from this test. Less commonly, cardiopulmonary exercise testing can be helpful when it is uncertain whether the patient's shortness of breath is cardiac, pulmonary, or pulmonary vascular in origin or is due to deconditioning.

What imaging studies will be helpful in making or excluding the diagnosis of idiopathic interstitial pneumonias?

Chest X-ray is useful in suggesting the presence of interstitial lung disease, but it rarely provides a diagnosis. The pivotal study to obtain is a high-resolution CT (HRCT) scan of the chest. Changes on HRCT can be so typical for IPF that no further diagnostic procedure is indicated, provided other causes of ILD have been ruled out on physical examination or serologic testing. HRCT can also be highly suggestive of other causes of ILD, including sarcoidosis, LAM, and PLCH.

HRCT changes of IPF

Typical HRCT changes for IPF include subpleural (mostly basilar) reticulation, honeycombing, traction bronchiectasis, and a lack of significant ground-glass opacification. The case in which all of these changes are present might provide sufficient evidence to make the diagnosis.

HRCT changes of NSIP

The HRCT changes in NSIP are variable, and a definitive diagnosis cannot be made on CT alone. Reticular opacities with a basilar predominance are common. A peripheral predilection is common, but a rim of subpleural sparing, which tends to be specific for the disease, may be seen in ~20 percent of cases. Variable ground-glass opacities, which tend to correlate with the more cellular form of the disease, may also be present. Associated traction bronchiectasis and loss of lung volumes can be seen. Honeycombing is rare (~5%) and may suggest an alternate diagnosis (IPF).

HRCT changes of AIP

Diffuse ground-glass infiltrates are usually seen early in AIP, and they may progress to dense consolidation. The distribution tends to be basilar in its distribution, but it may be diffuse; it is rarely predominant in the upper lobe.

HRCT changes of COP

COP may show scattered areas of airspace consolidation, sometimes with an ill-defined nodular appearance. Air bronchograms are commonly seen within the areas of consolidation and are usually bilateral, but they may be unilateral. A minority of patients can manifest with a reticulonodular infiltrates. The lower lobes tend to be more frequently involved.

HRCT changes of RB-ILD

Centrilobular nodules, patchy ground-glass attenuation, and thickening of the airways may all be seen in RB-ILD. Evidence of upper lobe emphysema is common, as are areas of hypoattenuation consistent with air trapping.

HRCT changes of DIP

Most commonly seen in DIP are ground-glass infiltrates, which are usually located in the lower lobe and tend to be peripheral. They may also be patchy and diffuse in their distribution. Linear reticulation may also be seen, but it is usually limited to the lower lung zones.

HRCT changes of LIP

LIP usually manifests with ground-glass infiltrates, but it can also present with scattered thin-walled cysts. Linear reticulation, lung nodules and consolidation may also be seen.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of the idiopathic interstitial pneumonias?

Aside from the HRCT, there are no other specific non-invasive tests that are useful in making the diagnosis and differentiating the IIPs. Bronchoscopy rarely provides a definitive diagnosis, but it can provide suggestive evidence for one of the IIPs. Bronchoscopy can be useful in providing a diagnosis of other conditions that can mimic an IIP, such as sarcoidosis. Although they do not provide specific diagnostic information, pulmonary function studies and a functional test like the six-minute walk test provide important information about the severity of the disease and its functional impact.

What diagnostic procedures will be helpful in making or excluding the diagnosis of an IIP?

HRCT is usually essential in the work-up of a patient with suspected IIP, and lung biopsy is helpful in many cases. Bronchoscopy with transbronchial biopsies does not usually provide sufficient tissue to attain a specific diagnosis of one of the IIPs, so a surgical lung biopsy--usually a video-assisted thoracoscopic surgery (VATS) biopsy--is indicated in most patients in whom a tissue diagnosis is required.

There are no other specific tests that are useful in diagnosing or differentiating the various IIPs. Gallium scanning is of no specific utility and should not be used to distinguish an inflammatory component upon which treatment decisions are made, and PET scanning, which is of no proven utility, requires further study.

Histopathologic features of the IIPs

Histopathology is what differentiates the various IIPs, as UIP/IPF, NSIP, COP, AIP, DIP, and RB-ILD all have distinctive pathologic patterns. Some of these patterns may co-exist within the same lung specimen or biopsies taken from different lobes of the lung. DIP and RB-ILD are now regarded as part of the spectrum of the same disease process.

Histopathology of DIP

DIP features intra-alveolar accumulation of macrophages that is uniform and diffuse. They may be accompanied by alveolar wall thickening and mild fibrosis, but there is usually no chronic scarring or remodeling.

Histopathology of IPF

The pathological correlate of IPF is a pattern of injury described as usual interstitial pneumonias (UIP). UIP is characterized by heterogeneous changes, including areas of microscopic honeycombing, no or minimal inflammation, fibrosis with remodeling, fibroblasic foci, and areas of normal lung.

Histopathology of NSIP

NSIP features a homogenous pattern characterized by a predominance of fibrosis (fibrotic NSIP) or cellular (mostly lymphocytic) infiltrates (cellular NSIP) or a mixed pattern of cellular/fibrotic NSIP. There is minimal or no fibroblastic foci, and there is usually no microscopic honeycombing.

In patients with a histologic diagnosis of NSIP, a diligent search should be performed for other associated conditions, such as an underlying occult connective tissue disorder. A similar histopathologic pattern can also be seen with resolving diffuse alveolar damage co-existing with UIP, with hypersensitivity pneumonitis, and with occupational exposures.

Histopathology of AIP

The AIP pattern is similar to that seen in patients with ARDS: diffuse alveolar damage with intra-alveolar hyaline membranes, acute inflammation, and edema. Varying degrees of loose organizing fibrosis may be seen as the disease evolves.

Histopathology of RB-ILD

RB-ILD is characterized by pigmented macrophages within respiratory bronchioles accompanied by submucosal and peribronchial cellular infiltrates (lymphocytes and histiocytes). Peribronchiolar fibrosis that extends into adjacent alveolar septa may also be seen.

Histopathology of COP

The histopathology of COP includes proliferation of granulation tissue in the small airways, alveolar ducts, and alveolar spaces with some surrounding chronic inflammation. COP is the condition formerly referred to as BOOP (bronchiolitis obliterans with organizing pneumonia).

If you decide the patient has an idiopathic interstitial pneumonia, how should the patient be managed?

IIPs have varying responses to therapy. Therapies are usually directed at the inflammatory component of the disease and usually consist of steroids with or without other immunosuppressive agents. For some of the diseases, such as RB-ILD, observation alone and smoking cessation may suffice to achieve spontaneous resolution of the disease.

The most broadly studied of the diseases is IPF, which is generally considered a steroid-resistant disease, but the other IIPs, including NSIP, COP, RB-ILD, DIP, and LIP, are largely regarded as being steroid-responsive. Treatment might not be indicated in all cases, especially RB-LD and DIP.

There is no known effective therapy for AIP.

For patients with an IIP for which a specific diagnosis is uncertain, the management can be individualized. A trial of steroids, usually with another agent, such as azathioprine or mycophenolate mofetil, might be reasonable. For patients with advanced disease of any sort, lung transplantation may be an option .

Other management considerations

Supplemental oxygen may be required if there is documented sustained desaturation to less than 88 percent at rest, at night, or with activity, and pulmonary rehabilitation may be recommended for patients who are limited by their dypsnea. Palliative care/hospice is recommended for patients with advanced disease, and patients may be referred to a tertiary care center for clinical trial evaluation. Lung transplant evaluation may be made in appropriate candidates.

Treatment of IPF

The current ATS/ERS guidelines, published in 2011, do not endorse any medical therapy for IPF. The only management options that are recommended are consideration for enrollment in a clinical trial or lung transplantation in appropriate cases. The strongest recommendation from these guidelines for any drug is a "weak no" for N-acetylcysteine and Pirfenidone. This recommendation does not preclude the use of these or other agents in select, well-informed patients. Pirfenidone is approved and available in Europe, India and Japan, but not in the US. N-acetylcysteine is available in a liquid form from pharmacies or in tablet form as a nutritional supplement.

Indications for lung transplantation

Because of the unpredictable nature of the disease's progression, patients with IPF who are candidates for lung transplant should be referred at the time of their diagnosis. Guidelines for transplantation include Dlco less than 39 percent predicted, a decrease of less than 10 percent in the FVC over six months, a SpO2 less than 88 percent during the six-minute walk test, and extensive fibrosis and honeycombing on HRCT. The presence of associated pulmonary hypertension also portends worse outcomes and is usually associated with a low Dlco and desaturation.

NSIP patients should be considered for transplantation when DLco is less than 35 percent and there is a decrease of more than 10 percent in the FVC or more than 15 percent in the DLco over six months.

Absolute contraindications to lung transplant are malignancy in the last two years (except cutaneous squamous and basal cell tumors, and some malignancies, such as breast and lung, require a disease-free interval of at least five years); advanced, irreversible organ dysfunction (heart, liver, kidney); non-curable chronic extrapulmonary infections (chronic active hepatitis B, active hepatitis C, and HIV); significant chest wall or spinal abnormalities; medical non-compliance; active smoker or other substance addiction; untreatable psychiatric or psychological conditions; and absence of adequate social support.

Relative contraindications to lung transplant are age greater than 65-70, critical or unstable condition, severe functional limitation, colonization with highly resistant organisms, severe obesity, severe or symptomatic osteoporosis, mechanical ventilation (unless for short periods and previously listed), and other conditions that have resulted or may result in end-organ damage.

Treatment of AIP

There are no known effective therapies for AIP. Attempts should be made to exclude entities that may complicate, cause, or mimic AIP, including congestive heart failure and an infectious etiology. A diagnostic bronchoscopy with BAL may not be feasible in non-intubated patients who require high-flow oxygen. Whether patients should be intubated for the purposes of performing a bronchoscopy is a judgment call. If the patient is already intubated, then bronchoscopy with BAL is usually indicated to rule out an underlying infection.

Viral pneumonias are also worth excluding with available serologies and bronchial cultures. It is reasonable to treat with broad spectrum antibiotics in the event there is an underlying precipitating infection. High-dose intravenous steroids are also commonly used, but there is no firm data to support this treatment, nor is there consensus on the appropriate dosing. Solumedrol at doses as high as 1 gram daily for three days or at lower doses, such as 40-60 mg q4-6 hourly initially, are all reasonable alternatives. Despite therapy, the prognosis of AIP remains poor, with a mortality exceeding 80 percent.

Treatment of NSIP

There have been no randomized, controlled studies of therapy in NSIP. However, it is generally agreed that therapy with steroids in conjunction with cytotoxic agents is useful. The cellular subtype is more likely to be treatment-responsive, although similar therapy is generally also recommended for the more fibrotic and mixed variants. Prednisone at doses of 20-40 milligrams per day, together with either azathioprine at 1-2 mg/kg./day or mycophenolate mofetil at 500-1,500 mg twice a day are reasonable regimens for consideration.

The duration of therapy has not been well characterized and should be individualized based on clinical circumstances and subsequent response. Life-long therapy may be necessary. For patients with progressive disease who are otherwise good candidates, consideration for lung transplantation may become necessary.

Treatment of COP

COP is generally regarded as a steroid-responsive condition, and most patients (~2/3rds) respond to therapy. Some patients (~1/3rd) can have recalcitrant or recurrent disease. There have been no randomized controlled trails of therapy, nor are there firm guidelines on the duration. Steroid therapy should be individualized and patients monitored closely for response and recurrence when the steroids are being weaned.

Treatment of RB-ILD

RB-ILD is invariably associated with cigarette smoking, and spontaneous resolution may occur with smoking cessation. Some patients may require steroid therapy to facilitate resolution.

Treatment of DIP

Cessation of cigarette smoking can result in improvement of the disease, and steroid therapy may be required in ongoing symptomatic, refractory or recurrent cases.

Treatment of LIP

LIP is generally a steroid-responsive condition with marked improvement and resolution commonly seen.

What is the prognosis for patients managed in the recommended ways?

The prognoses of the IIPs run the spectrum from very poor (AIP) to favorable (RB-ILD and DIP). The courses of these diseases can be highly variable.

Prognosis of AIP

The prognosis of AIP is generally very poor, with mortality rates exceeding 80 percent. The course is predictably a downhill one, with acute respiratory failure invariably supervening. Support with mechanical ventilation might be indicated in select patients, especially if there is a potentially reversible precipitating factor and/or the patient is deemed to be an appropriate transplant candidate. At specialized centers, extracorporeal support with ECMO has also been used as a bridge to transplantation for highly select patients.

Prognosis of IPF

IPF carries a poor prognosis, with a median survival from the time of diagnosis of 2.5-4 years. There does appear to be a subgroup of patients (~25%) who have a more protracted, indolent course. The course is highly variable and is typically punctuated by periods of stability and other periods of unpredictable deterioration.

Acute exacerbations that complicate the course in 10-20 percent of patients are frequently terminating events. Acute exacerbations, which are defined by increasing dypsnea, usually over a short period (typically four weeks or less), are associated with increased oxygen requirements and new ground-glass infiltrates on radiographic imaging. The diagnosis can be made only after other causes of acute deterioration, such as heart failure and pneumonia, have been excluded. The etiology is unknown, and if patients undergo a lung biopsy, the pattern of injury is typically that of diffuse alveolar damage, which is the same pattern as that seen in ARDS.

Prognosis of NSIP

Although the prognosis of NSIP is better than that of IPF, there is still a ≈20 percent five-year mortality associated with NSIP. The ten-year survival is ≈70 percent. Cellular NSIP tends to have a better prognosis than the fibrotic form. There is a small subgroup of NSIP patients (Dlco<35%) who will have a course similar to that of those with IPF and who might be suitable lung transplant candidates.

Prognosis of COP

Approximately two-thirds of patients with COP will respond to therapy, while about a third of patients will have recalcitrant or recurrent disease. A few patients may die from a rapidly progressive form of the disease.

Prognosis of RB-ILD

While there have been no prospective studies of RB-ILD, the clinical course is generally regarded as favorable, with few deaths secondary to progressive disease reported.

Prognosis of LIP

While there have been no longitudinal studies, a varied course has been reported in the context of case reports, most of which have been favorable, with improvement or resolution in response to steroid therapy. The course of LIP is frequently determined by that of the underlying disease (Sjogren's syndrome, HIV).

Prognosis of DIP

The prognosis is generally good, with a 28 percent twelve-year mortality reported in one study.

What other considerations exist for patients with one of the IIPs?

Patients with an IIP, especially IPF, are at high risk for various comorbidities. Consideration should be given to screening for these, as addressing them where they occur may impact outcomes. Oxygen supplementation should be instituted in all patients with significant desaturation (<88%), and consideration should be given to nocturnal oxygen saturation monitoring. Pulmonary rehabilitation is useful in improving the functional ability and quality of life and should be considered in all symptomatic patients. End-of-life issues should be addressed with patients who have advanced disease and/or one of the more ominous IIPs, such as AIP or IPF.

IPF comorbidities

IPF comorbidities include pulmonary hypertension, coronary artery disease, obstructive sleep apnea, GERD, osteoporosis, hypogonadism, depression, diabetes, and deconditioning.

Table 1.

Summary of IPF studies
Trial N Age Physiological entry criteria Primary endpoint Duration Result
Interferon-beta 167 Progression-free survival time Negative
Interferon-gamma (GIPF-001) 330 20-79 FVC 50-90%, Dlco>25%, PaO2>55 mmHg Progression-free survival 58 weeks (median) Negative
Interferon-gamma (Inspire) 826 40-79 FVC 55-90%, Dlco 35-90%, 6MWD>150 meters Survival time 64 weeks (mean) Negative
Pirfenidone (Japanese multicenter) 275 20-75 Exercise SpO2 drop>5% with SpO2 low>85% change in FVC 52 weeks Positive
Pirfenidone (Capacity 1 study) 344 40-80 FVC 50-90%, DLco 35-90%, 6MWD>150 meters Change in FVC% 72 weeks (from last patient in) Positive
Pirfenidone (Capacity 2) 435 40-80 FVC 50-90%, DLco 35-90%, 6MWD>150 meters Change in FVC% 72 weeks (from last patient in) Negative
Etanercept 100 FVC>45%, Dlco>25%, PaO2>55 mmHg Change in DLco, FVC, P (A-a) O2 48 weeks Negative
Imatinib Mesylate 119 20-79 FVC>55%, Dlco>35%, PaO2<60mmHg Progression-free survival 96 weeks (from last patient in) Negative
Bosentan (Build 1) 132 FVC>50-90%, Dlco>30%, PaO2<55 mmHg, 6MWD 150-499 Change in 6MWD 12 months Negative
Bosentan (Build 3) 616 >18 FVC>50, Dlco>30% Progression-free survival Event-driven Negative
N-acetylcysteine 182 18-75 FVC<80%/TLC<90%+ Dlco<80% Change in FVC, DLco 12 months Positive
Anticoagulation 56 47-89 Survival Positive
Coumadin (ACE study) Survival Stopped early for lack of efficacy
Sildenafil (STEP study) 180 DLco<35%, 6MWD>50 meters 20% increase in 6MWD 12 weeks Negative
Ambrisentan (Artemis studies) Stopped early for lack of efficacy

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