Pulmonary Medicine

Idiopathic Interstitial Pneumonias

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What every physician needs to know:

Revised ATS/ERS Classification of Idiopathic Interstitial Pneumonias:

Major idiopathic interstitial pneumonias:

1) Idiopathic pulmonary fibrosis (IPF)

2) Nonspecific interstitial pneumonia (NSIP)

3) Respiratory bronchiolitis–interstitial lung disease (RB-ILD)

4) Desquamative interstitial pneumonia (DIP)

5) Cryptogenic organizing pneumonia (COP)

6) Acute interstitial pneumonia (AIP)

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

Rare idiopathic interstitial pneumonias

7) Idiopathic lymphoid interstitial pneumonia (LIP)

8) Idiopathic pleuroparenchymal fibroelastosis (PPFE)

Unclassifiable idiopathic interstitial pneumonias

The idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of conditions that can be characterized by specific radiographic and histologic features. Radiographically, they are described as diffuse parenchymal lung diseases (DPLDs) with distinct patterns of injury. The prognoses for different types of IIPs range from very poor (AIP) to favorable (DIP/RB-ILD). The most common IIP is IPF, which carries a poor prognosis (median survival 2.5 years). Though smoking can compound the symptoms of all IIPs, only DIP and RB-ILD have a clear causal association with smoking.

Major IIPs

IPF: Epidemiology and Outcomes

IPF is the most common IIP and, aside from AIP, carries the worst prognosis. The estimated incidence in the US is ~30,000 new cases per year, with an overall prevalence of ~80,000. It is a disease of the elderly with increasing prevalence with advancing age. IPF is more common among males and is characterized histologically as usual interstitial pneumonia (UIP). The overall prognosis is poor with a median survival of 2.5 years from the time of diagnosis. The course of the disease can vary, and it is difficult to predict outcomes, although there are physiological, radiographic, and other predictors that portend a worse outcome.

ATS/ERS recommendations for therapy in IPF

There are no curative medical therapies. The most recent consensus statement by the ATS/ERS recommends the use of nintedanib or pirfenidone to slow the rate of decline in FVC and improve patient-reported outcomes. There is also a strong recommendation against the use of steroids, cytotoxic agents such as azathioprine or cyclophosphamide, empiric anticoagulation, imatinib, or selective endothelin receptor antagonists. It is recommended that all patients receive treatment with anti-acid therapy. Pulmonary rehabilitation may improve functional status, dyspnea, and quality of life for patients with IPF. Patients should also be enrolled in clinical trials of therapy, and be evaluated for lung transplantation if they are candidates.

NSIP: Epidemiology and outcomes

The true incidence and prevalence of NSIP has not been well established. In most case series of IIPs, IPF predominates in a 2-4:1 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 autoimmune disease.

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% and 70%, respectively.

COP: Epidemiology and outcomes

The initial name of COP was bronchiolitis obliterans with organizing pneumonia ("BOOP"). However, COP is not an airway disease as it is histologically characterized by organizing pneumonia within alveolar ducts and alveoli. This pathologic pattern may be seen in other diseases, including connective tissue disorders, post-infectious changes, post-radiation injury, drug-related lung damage, 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 acute to subacute (less than 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), with no gender predominance. Patients often present with apparent viral respiratory tract infection and constitutional symptoms followed by severe, progressive shortness of breath. Overall mortality is greater than 80%.

RB-ILD/DIP: Epidemiology and outcomes

RB-ILD/DIP usually affects current smokers 40-50 years of age, 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.

Rare IIPs

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.

PPFE: Epidemiology and outcomes

PPFE consists of fibrosing of both pleura and lung parenchyma. This is a disease of predominately the upper lobes. There is no gender predilection and typical age of onset is 50-60 years of age. This is often a progressive disease with an overall ~40% mortality rate.

Unclassifiable IIPs

There are pathological patterns of injury that don't fit within the histopathological framework of the IIPs. This classification acknowledges that a diagnosis may not be reached despite a multidisciplinary team approach.

Are you sure your patient has one of the IIPs? What should you expect to find?

Patients with one of the IIPs typically present with insidious onset of progressive dyspnea 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 chest x-ray, CT scan, or physical examination. Those with IPF have a family history in ~2-20% of cases. On physical examination, clubbing of the digits may be seen in some patients, and the chest examination is typically accompanied by coarse inspiratory ("Velcro-like") crackles at the lung bases.

Beware: there are other diseases that can mimic the IIPs.

The IIPs are a diagnosis of exclusion, so other diffuse parenchymal lung diseases (DPLDs) known to mimic or cause a similar constellation of symptoms, signs, and radiographic changes should be excluded. Most other DPLDs can be excluded with a comprehensive history and serologic studies. DPLDs can be sub-categorized as

1) IIPs

2) Granulomatous DPLDs such as sarcoidosis

3) DPLDs related to drugs, collagen vascular disease, or an unknown cause

4) Miscellaneous causes such as infection, LAM, hypersensitivity pneumonitis, or lymphangitic carcinomatosis

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

The cause of IPF 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 the age of 50. 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.

Risk factors for IIPs other than IPF

DIP and RB-ILD are invariably associated with cigarette smoking, and 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; however, abnormalities may persist on PFTs and radiographic studies despite smoking cessation and/or corticosteroid therapy.

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.

NSIP specifically 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 COP do not appear to have specific risk factors based on the available evidence.

PPFE patients have a history of preceding recurrent infections in ~50% of cases. Other cases have been associated with complications after bone marrow transplant, lung transplant, radiation, or chemotherapy. A minority will have non-specific auto-antibodies.

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 associated with an increased risk of developing IPF and is causative in RB-ILD/DIP. 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 exposure is likely to increase the risk for IPF. A high incidence of gastroesophageal reflux disease has also been associated with IPF though given the commonality of this condition, it remains unclear if it represents a true risk factor for IPF. Lastly, a family history of IPF has been shown to increase the risk of IPF.

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 CTD. The same pathological pattern of injury of any of the IIPs can be seen in the context of other known causes of DPLDs, including CTD and hypersensitivity pneumonitis. Known causes of DPLDs 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, are all serologic tests for CTDs and may be appropriate for evaluating patients with DPLDs. 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 CTD, then a more comprehensive panel should be obtained (e.g., anti-synthetase syndrome or myositis-related ILD).

Pulmonary function testing in the IIPs

Pulmonary function testing (PFTs) helps to differentiate obstructive from restrictive lung disease. IIPs are restrictive lung diseases, while more common conditions such as COPD are obstructive. PFTs do not help differentiate the various IIPs, but they are necessary to assess the degree of restriction and can be used to follow patients’ lung function prospectively.

There is no accepted standardization of mild, moderate, or severe disease on PFTs for IIPs. FVC percent predicted greater than 80% may be regarded as mild disease, FVC 50-69% is moderate disease, and FVC less than 50% is severe disease. Diffusing capacity (DLco) is also reduced in IIPs, and a DLco less than 40% may indicate the presence of associated pulmonary hypertension.

Restrictive versus obstructive disease

IIPs will manifest with a restrictive pattern on PFTs, characterized by a proportionate reduction in both the FVC and FEV1 with a normal or increased FEV1/FVC ratio. An increased ratio is due to reduced compliance (stiffer) of 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 includes the six-minute walk test (6MWT). Oxygen needs and prognostic information can also be obtained from the 6MWT. 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 due to deconditioning.

What imaging studies will be helpful in making or excluding the diagnosis of IIPs?

Chest x-ray is useful in suggesting the presence of DPLDs, but it rarely provides a diagnosis. The most important study to obtain is a high-resolution CT (HRCT) scan of the chest with inspiratory and expiratory phases. Abnormalities on HRCT can be so typical for IPF that no further diagnostic procedure is indicated, provided other causes of DPLDs have been ruled out on physical examination or serologic testing. HRCT can also be highly suggestive of other causes of DPLDs, 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. When all of these changes are present, there is typically 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% 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 lobes.

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 have reticulonodular infiltrates. The lower lobes tend to be more frequently involved. COP has the most variability and least predictability of IIPs on HRCT imaging.

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, usually located in the lower lobes and typically peripheral. The ground-glass infiltrates may 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 as ground-glass infiltrates, but it can also present with scattered thin-walled cysts. Linear reticulation, lung nodules and consolidation may also be seen.

HRCT of PPFE

The typical radiographic features for PPFE include pleural and parenchymal fibrosis with upper lobe predominance. Subpleural consolidations with traction bronchiectasis and volume loss can also be seen. Pneumothorax is seen in ~30% of cases.

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

Aside from the HRCT, there are no other specific non-invasive tests that are useful in making the diagnosis and differentiating the IIPs. Standard bronchoscopy with bronchoalveolar lavage (BAL) rarely provides a definitive diagnosis, but it can provide suggestive evidence for one of the DPLDs that can mimic an IIP, such as infection or sarcoidosis. Although they do not provide specific diagnostic information, PFTs and 6MWTs 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?

Diagnosing an IIP can be difficult. HRCT is essential in the initial work-up of any patient with suspected IIP. In some cases, lung tissue may be needed. Traditionally, bronchoscopy with transbronchial biopsies has had limited diagnostic utility for IIPs. However, there is now growing evidence to support transbronchial cryobiopsy as a valid method for obtaining sufficient lung tissue for a diagnosis. Studies have shown that cryobiopsy can provide a definitive diagnosis in many patients undergoing workup for IIP, eliminating the need for surgical lung biopsy. Though the emerging data are encouraging for cryobiopsy, the current ATS/ERS guidelines for IIP diagnosis recommend surgical lung biopsy (SLB) as the gold standard. Usually, video-assisted thoracoscopic surgery (VATS) biopsy is chosen over open lung biopsy. To ensure the safest and most efficacious approach is taken, a multidisciplinary discussion for individual cases should precede any of the aforementioned procedures.

There are no other specific tests that are useful in diagnosing or differentiating the various IIPs.

Histopathologic features of the IIPs

Histopathology differentiates the various IIPs as UIP/IPF, NSIP, COP, AIP, DIP, and RB-ILD, as all have distinctive pathologic patterns. Some of these histopathologic patterns may co-exist within the same lung specimen or biopsies taken from different lobes of the lung. DIP and RB-ILD are often regarded as a spectrum of the same disease process, although their clinical presentation, characteristics on imaging studies, and efficacy of treatment may differ such that DIP and RB-ILD are still classified separately.

Histopathology of IPF

The pathological correlate of IPF is a pattern of injury termed usual interstitial pneumonia (UIP). UIP is characterized by anatomic and temporal heterogeneous changes, including areas of microscopic honeycombing, minimal or no inflammation, fibroblastic 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 are 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 CTD. 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, with 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 DIP

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

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 the 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.

Histopathology of PPFE:

Pathology typically demonstrates dense subpleural bands of fibroelastosis with abundant elastic fibers. There is often an abrupt interface between diseased and un-involved parenchyma.

If you decide the patient has an IIP, how should the patient be managed?

IIPs have varying responses to therapy. With the exception of IPF, therapies for IIPs are usually directed at an inflammatory component of the disease if one exists and usually consist of steroids with or without other immunosuppressive agents. For some diseases, such as RB-ILD, smoking cessation with observation may suffice to achieve spontaneous resolution of the disease.

The most 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-ILD and DIP.

Beyond urgent lung transplant, there is no known effective therapy for AIP although steroids are often trialed given the severity of the disease.

For patients with an IIP for which a specific diagnosis is uncertain, the management and consideration of immunosuppressive medications or other treatments can be individualized to the patient’s clinical circumstances. 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% at rest, at night, or with activity, and pulmonary rehabilitation may be recommended. For patients with worsening symptoms, disproportionately low DLco, or increased pulmonary artery diameter on CT scan, a workup for coexistent pulmonary hypertension should be considered. Palliative care 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 2015 ATS/ERS guidelines provided a conditional recommendation for the use of nintedanib or pirfenidone in patients with IPF. There is a strong recommendation against the use of combination prednisone, azathioprine and N-acetylcysteine. Likewise, there are strong recommendations against the use of the tyrosine kinase inhibitor imatinib and against empiric anticoagulation treatment with warfarin. For patients with pulmonary hypertension, there are also recommendations against the use of endothelin receptor antagonists (ambrisentan, macitentan, bosentan) and phosphodiesterase-5 inhibitors (sildenafil).

Indications for lung transplantation

Lung transplantation is indicated for patients with advanced IIP whose disease progresses despite maximal medical therapy. Patients should be evaluated at a lung transplant center early to determine their candidacy for transplant. IPF is one of the most common indications for lung transplantation.

Guidelines for transplantation include DLco less than 40% predicted, a decrease of more than 10% in FVC over six months, a SpO2 less than 89% during 6MWT, and extensive fibrosis and honeycombing on HRCT. Pulmonary hypertension associated with IPF is associated with a low DLco, hypoxemia, and worse clinical outcomes.

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

Absolute contraindications to lung transplant include:

1) Malignancy in the last two years, with the exception of skin cancers (excluding melanoma.) Five year disease-free survival is required for some cancers, such as lung and breast cancer.

2) Advanced comorbidities such as severe congestive heart failure, liver disease, and advanced kidney disease.

3) Incurable chronic extrapulmonary infections, such as chronic active hepatitis B, active hepatitis C, and HIV

4) Severe chest wall or vertebral abnormalities

5) Psychosocial issues such as a history of medical non-adherence, active tobacco use, other substance abuse or 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 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 can be effective for NSIP. 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 mg per day, together with either azathioprine at 1-2 mg/kg/day or mycophenolate mofetil at 500-1500 mg twice a day are reasonable regimens for consideration for NSIP thought to be due to CTD.

The duration of therapy has not been well characterized and should be individualized based on clinical circumstances and response to treatment. Lifelong therapy may be necessary. For patients with progressive disease who are candidates, consideration for lung transplantation may become necessary.

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 infectious etiologies. 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 depends on an individual patient’s clinical circumstances. If the patient is already intubated, then bronchoscopy with BAL is usually indicated to rule out an underlying infection.

The presence of a viral pneumonia should be assessed with available serologies and BAL cultures. It is reasonable to treat with broad-spectrum antibiotics in the event there is an underlying precipitating infection. High-dose IV steroids are commonly used, but there is no firm data to support this treatment, nor is there consensus on the appropriate dosing. Methylprednisolone at doses as high as 1 gram daily for three days or at lower doses, such as 40-60mg q4-6 hrs initially, are all used in clinical practice. Despite therapy, the prognosis of AIP remains poor, with a mortality exceeding 80%.

Treatment of COP

COP is generally regarded as a steroid-responsive condition, and most patients (~60-70%) respond to therapy. Some patients (~30-40%) can have recalcitrant or recurrent disease. There have been no randomized controlled trials of therapy, nor are there firm guidelines on the duration. One suggested algorithm by King: prednisone 1-1.5 mg/kg/d of IBW (maximum 100 mg/d) for 4-8 weeks, then gradually tapering to 0.5-1 mg/kg/d for the ensuing 4-6 wks. If the patient continues to respond favorably, the corticosteroid therapy may be gradually tapered to zero over the next 3-6 months. If the patient does not respond to corticosteroid therapy alone, adding a cytotoxic agent is considered. Case reports suggest use of cyclophosphamide or mycophenolate mofetil may have some efficacy in steroid-refractory cases.

Steroid therapy should be individualized and patients monitored closely for response and recurrence when the steroids are being weaned. It has been suggested that therapy should be reinstituted aggressively when recurrence is suspected.

Treatment of DIP/RB-ILD

DIP/RB-ILD are invariably associated with cigarette smoking, and spontaneous resolution may occur with smoking cessation. Patients with refractory or recurrent cases may require steroid therapy to facilitate resolution.

Treatment of LIP

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

Treatment of PPFE

Aside from lung transplantation, no effective therapy has been identified for PPFE.

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

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

Prognosis of IPF

IPF carries a poor prognosis and patients will die without transplantation (median survival time from diagnosis, 2.5-3.5 years). Therefore, it is critically important to distinguish IPF from other DPLDs that have a more favorable prognosis.

There does appear to be a subgroup of patients (~25%) who have a more protracted, indolent course. The course is highly variable and typically punctuated by periods of stability and other periods of unpredictable deterioration. Median survival post-transplantation among IPF patients is estimated at 4.5 years. From the most recent Organ Procurement and Transplantation Network data, 1 year survival ranged from 75-81%; 3 year from 59-64%; and 5 year from 47-53%.

Acute exacerbations that complicate the course in 10-20% of patients can be terminal events. Acute exacerbations, which are defined by increasing dyspnea over a short period (typically four weeks or less), are associated with increased oxygen requirements and new ground glass infiltrates on 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 IPF, there is still a ~20% five-year mortality associated with NSIP. The ten-year survival is ~70%. 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 those with IPF and may warrant lung transplant evaluation.

Prognosis of AIP

The prognosis of AIP is very poor, with mortality rates exceeding 80%. The course is predictably rapidly progressive, resulting in acute respiratory failure. 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 been used as a bridge to transplantation for highly select patients.

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 DIP/RB-ILD

In DIP the prognosis is generally good, with ~30% twelve-year mortality reported in one study. 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 case reports, most of which have been favorable, with improvement or resolution in response to steroids. The course of LIP is frequently determined by the underlying disease (Sjogren's syndrome, HIV).

Prognosis of PPFE

Disease progression occurs in 60% of patients, with death from disease in ~40%

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

Patients with an IIP, especially IPF, are at high risk for various comorbidities especially co-existing GERD and silent aspiration. Consideration should be given to screening for these, as addressing them may impact outcomes. Oxygen supplementation should be instituted in all patients with significant desaturation (<89%), and consideration should be given to nocturnal oxygen saturation monitoring. Pulmonary rehabilitation is useful in improving functional capacity 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.

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