Treatment of Idiopathic Pulmonary Fibrosis

Treatment of idiopathic pulmonary fibrosis
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http://www.uptodate.com/contents/treatment-of-idiopathic-pulmonary-f...
Official reprint from UpToDate

www.uptodate.com 2015 UpToDate

Author
Talmadge E King, Jr, MD
Section Editor
Kevin R Flaherty, MD, MS
Deputy Editor
Helen Hollingsworth, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2015. | This topic last updated: Nov 21, 2014.
INTRODUCTION Idiopathic pulmonary fibrosis (IPF, also called cryptogenic fibrosing alveolitis) is specific
form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause, occurring in adults and limited to
the lungs. It is associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP).
In the past, treatment was aimed at minimizing inflammation and slowing the progression from inflammation to
fibrosis. However, the underlying lesion in IPF may be more fibrotic than inflammatory, explaining why few
patients respond to anti-inflammatory therapies and the prognosis remains poor [1-3].
The following questions will be discussed in this topic review, although considerable uncertainty remains about
the answers [2,4,5]:
Which patients should be treated?
When should therapy be started?
What is the best therapy?
How should the disease course and the response to treatment be monitored?
The evaluation, diagnosis, and pathogenesis of IPF are presented separately. (See "Idiopathic interstitial
pneumonias: Clinical manifestations and pathology", section on 'Usual interstitial pneumonia' and "Pathogenesis
of idiopathic pulmonary fibrosis".)
NATURAL HISTORY The following observations about the natural history of IPF may be helpful in guiding
therapy.
Historically, untreated IPF progresses, although disease progression is usually insidious, at least initially
[6-8]. Data from the placebo arm of clinical trials suggest that the rate of decline in forced vital capacity
(FVC) among untreated patients is 150 to 200 mL per year [9].
The course of the disease may be unpredictable, as some patients develop an acute deterioration after a
period of apparent stability.
Patients in the age group affected by IPF (the majority are >55 years old) may have difficulty discerning
whether their functional limitations are the result of disease progression, deconditioning, or simply the aging
process.
Comorbid conditions (eg, chronic obstructive pulmonary disease [COPD], heart failure) may also contribute
to symptoms such as cough and reduced exercise tolerance.
GENERAL APPROACH
Overview The most important first step is to establish the diagnosis since misdiagnosis can lead to
inappropriate initial therapy (algorithm 1). The diagnosis of IPF may be established with a high degree of
confidence in patients with a compatible clinical presentation, typical HRCT findings (eg, subpleural, bibasilar
predominance of reticular markings, honeycombing, and the absence of features inconsistent with UIP pattern,
eg, ground glass opacities, micronodules, cysts, or mosaic attenuation) and no evidence of another contributing
process (eg, asbestos exposure, hypersensitivity pneumonitis, systemic sclerosis, rheumatoid arthritis) [2].
Family history may identify cohorts at risk for familial usual interstitial pneumonia or other fibrosing lung
diseases. The diagnosis of IPF is discussed separately. (See "Idiopathic interstitial pneumonias: Clinical
manifestations and pathology", section on 'Usual interstitial pneumonia' and "Approach to the adult with
interstitial lung disease: Diagnostic testing".)
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When the results of HRCT are not classic for IPF, a video-assisted thoracoscopic or open lung biopsy is often
necessary. (See "Idiopathic interstitial pneumonias: Clinical manifestations and pathology", section on 'Usual
interstitial pneumonia' and "Role of lung biopsy in the diagnosis of interstitial lung disease".)
The next step is to stage the patient's severity of disease as this will help to guide treatment choices. Finally, a
disease management plan is tailored to the disease severity and desires of the individual patient. As no
FDA-approved therapy has been shown to be efficacious in this disease, management generally includes some
combination of supportive care, consideration for participation in clinical trials or use of selected medications (eg,
pirfenidone, nintedanib, phosphodiesterase inhibitors), referral for lung transplant evaluation (when appropriate),
and identification and treatment of comorbidities [2,10].
Education and various components of supportive care (eg, supplemental oxygen, pulmonary rehabilitation,
vaccination, palliative care) should be offered to all patients with IPF. (See 'Supportive care' below.)
Prevention of gastroesophageal reflux and recurrent microaspiration may slow disease progression. (See 'Future
directions' below.)
A number of other agents (eg, anticoagulation, azathioprine/prednisone/N-acetyl cysteine combination therapy,
colchicine, cyclophosphamide, cyclosporine, endothelin receptor antagonists, interferon gamma, methotrexate,
N-acetylcysteine, penicillamine) have been used in the past either in case series or clinical trials. The agents of
doubtful benefit or intolerable toxicity are described below with the evidence against their routine use. (See
'Agents without clear benefit' below.)
Ongoing assessment is needed to refine these choices as the disease progresses.
Assessing disease severity No definitive staging system exists for assessing the severity of IPF, although
patients usually progress from mild to moderate to severe respiratory limitation. Disease severity is assessed on
the basis of symptoms, HRCT, and pulmonary function testing.
Patients with mild or early disease are often asymptomatic or may have a mild, nonproductive cough and
dyspnea with substantial exertion. Radiographic changes of reticular opacities and areas of honeycombing are
limited to subpleural and basilar areas, involving less than 10 percent of the lung parenchyma. Pulmonary
function tests may be normal or may show mild reductions in forced vital capacity (FVC), diffusing capacity
(DLCO), and/or distance walked on the six-minute walk test. The alveolar to arterial oxygen gradient (P[A-a]O2)
is normal or mildly elevated (<20 mmHg).
Moderate disease is characterized by dyspnea on moderate exertion, nonproductive cough, and mild-tomoderate pulmonary function abnormalities. The latter may include a reduced FVC (eg, 50 to 70 percent of
predicted), a reduced DLCO (eg, 45 to 65 percent of predicted) and/or P(A-a)O2 (eg, 21 to 30 mmHg).
Discordance in the degree of impairment of FVC and DLCO may be noted. Supplemental oxygen may be
needed with exertion. Radiographic changes are more extensive with reticular opacities involving 20 to 30
percent of the lung and honeycombing involving of <5 percent of the parenchyma [11]. One way of assessing the
extent of radiographic changes is to quantitate these radiographic abnormalities on HRCT slices taken at three
levels (eg, tracheal carina, inferior pulmonary veins, and 1 cm above the dome of the diaphragm) [1].
Advanced disease is characterized clinically by dyspnea on mild exertion (eg, walking <300 feet or climbing more
than one flight of stairs) and requirement for supplemental oxygen at rest and/or with exertion. Extensive
honeycombing is noted on HRCT (>5 percent of the parenchyma in three or more zones) [11]. Pulmonary
function testing typically reveals moderate to severe reductions in the FVC (<50 percent of predicted), DLCO
(<50 percent of predicted), and oxygen desaturation (4 percent) during a six-minute walk test [12]. Gas
exchange is also impaired with room air oxygen saturation below 88 percent and P(A-a)O2 difference elevated
(>30 mmHg).
Ongoing monitoring Ongoing monitoring is used to evaluate the clinical course and identify patients who
develop accelerated deterioration. The response to therapy is usually assessed at three- to six-month intervals.
We monitor symptoms (eg, dyspnea, exercise tolerance), forced vital capacity (FVC), total lung capacity (TLC),
DLCO, and oxygenation at rest and with exercise (eg, oximetry, six-minute walk test) [12-16]. (See 'Acute
exacerbations' below and "Overview of pulmonary function testing in adults".)
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In patients with advanced or progressive disease, careful evaluation for the development of hypoxemia,
pulmonary hypertension, thromboembolic disease, or other comorbid conditions (eg, chronic obstructive
pulmonary disease [COPD], heart failure, obstructive sleep apnea, depression) may yield additional treatment
options [2,17]. (See 'Supplemental oxygen' below and "Pulmonary hypertension associated with interstitial lung
disease" and "Overview of acute pulmonary embolism in adults" and "Clinical presentation and diagnosis of
obstructive sleep apnea in adults" and 'Transplantation' below.)
Prognosis The prognosis of IPF is poor, with only 20 to 30 percent of subjects alive five years after diagnosis
[4,5,7,18-22]. Several factors have been associated with shortened survival time: older age at presentation,
extensive cigarette smoking, lower body mass index (BMI), more severe physiologic impairment, greater
radiologic extent of disease, and the development of other complications or conditions (eg, pulmonary
hypertension, emphysema, and bronchogenic cancer) [13,23-29]. Comorbid diseases and adverse effects of
therapy also contribute (table 1) [25,30]. Clinical deterioration is most frequently due to disease progression.
Data from the placebo arms of randomized clinical trials show that the mean rate of decline in forced vital
capacity (FVC) is approximately 150 to 200 mL/yr [25]. Hospitalizations for respiratory problems are common
events and are frequently associated with death [9,31]. Patients with IPF admitted to intensive care units are at
greater risk of mortality than expected based on their severity of illness, as assessed by the APACHE score
[25,32]. (See "Predictive scoring systems in the intensive care unit", section on 'Acute Physiologic and Chronic
Health Evaluation (APACHE)'.)
SUPPORTIVE CARE The most important components of supportive care for patients with IPF are provision of
supplemental oxygen (when needed), education, pulmonary rehabilitation, and vaccination against
Streptococcus pneumoniae and influenza [2,33]. Affective disorders are common during the course of IPF and
may need attention [34,35]. (See "Comorbid anxiety and depression: Epidemiology, clinical manifestations, and
diagnosis".)
Supplemental oxygen Virtually all patients with IPF will eventually require supplemental oxygen, initially just
with exertion and then continuously. Oxygen therapy should be prescribed to enable maintenance of normal
activity and possibly to prevent or delay the onset of secondary pulmonary hypertension in hypoxemic patients.
The indications, benefits, and prescription of supplemental oxygen are discussed in detail elsewhere. (See
"Long-term supplemental oxygen therapy".)
Education Results from a survey regarding patients' experience with IPF suggest that improved education
and communication about the diagnosis and management of IPF are needed [36]. For patients with progressive
IPF, part of the education should include a discussion of end-of-life issues and advanced directives.
Understanding a patient's individual preferences, beliefs, and values is a key step towards achieving an
appropriate management plan [37]. Introduction of principles of palliative care for patients with IPF should be
undertaken in patients with progressive IPF. (See "Palliative care: Benefits, services, and models of care" and
"Assessment and management of dyspnea in palliative care" and "Hospice: Philosophy of care and appropriate
utilization in the United States".)
Pulmonary rehabilitation Most of the data that supports the use of pulmonary rehabilitation in the
management of patients with chronic respiratory disease come from the study of chronic obstructive pulmonary
disease (COPD). Several studies also support the use of pulmonary rehabilitation in interstitial lung disease
[38-45]. As an example, in a series of 113 patients with interstitial lung disease, a significant reduction in
dyspnea and improvement in six-minute walk distance were found following participation in a pulmonary
rehabilitation program [39]. (See "Pulmonary rehabilitation in COPD".)
Vaccination Influenza and pneumococcal polysaccharide vaccine should be offered to patients with IPF, as
these infections are poorly tolerated in patients with interstitial lung disease (figure 1). (See "Seasonal influenza
vaccination in adults" and "Pneumococcal vaccination in adults".)
Palliative care Palliative care aims to relieve suffering at all stages of disease and is not limited to end of life
care [46]. Palliative measures (eg, facial cooling with a fan, opioids, anxiolytics) may be helpful for patients with
refractory dyspnea or cough. Patients with advanced IPF may benefit from hospice care (table 2 and table 3).
(See "Assessment and management of dyspnea in palliative care" and "Palliative care: Overview of cough,
stridor, and hemoptysis".)
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CLINICAL TRIALS The best hope for patients with IPF is that carefully performed clinical trials will confirm
the efficacy and safety of agents that are identified based on animal models of IPF. We encourage appropriate
patients to participate in clinical trials of emerging therapies for IPF. Specific trials and registries are available for
patients with a familial history of IPF. Inclusion and exclusion criteria for clinical trials vary, so we provide all
patients with information regarding participation in randomized clinical trials whenever appropriate trials are
available. Patients with mild-to-moderate disease are frequently ideal candidates for clinical trials as many trials
limit participation to patients with early disease.
Clinical trial information is available at Clinicaltrials.gov. Information about research into the genetic factors that
may contribute to the development of familial IPF is available at Clinical trials.gov: Genetics of IPF.
MEDICAL THERAPIES No medication has been found to cure IPF, but two medications, nintedanib and
pirfenidone, appear to slow disease progression. In addition, pirfenidone may have a mortality benefit.
Our approach For patients with mild or moderate IPF based on pulmonary function tests who do not have
underlying liver disease and who live in an area where either pirfenidone or nintedanib is available, we
recommend initiating therapy with the available agent. Current data are insufficient to direct a firm choice
between pirfenidone and nintedanib, if both are available, and further study is needed to guide this choice. When
choosing between the agents, patient preference and tolerances should be considered, particularly regarding
potential adverse effects, such as diarrhea and liver function test abnormalities with nintedanib versus nausea
and rash with pirfenidone (described further below).
For patients with more advanced IPF, a diffusing capacity (DLCO) <35 percent of predicted, echocardiographic
evidence of right ventricular dysfunction, and no contraindications to sildenafil, a trial of sildenafil may be a
reasonable option.
The following sections describe the individual agents and the evidence supporting their use in IPF. As none of
these agents is curative, we also provide patients with information about clinical trials. (See 'Clinical trials'
above.)
Nintedanib Nintedanib, a receptor blocker for multiple tyrosine kinases that mediate elaboration of fibrogenic
growth factors (eg, platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor),
appears to slow the rate of disease progression in IPF. Nintedanib has been approved by the US Food and Drug
Administration and is under review by regulatory agencies in other countries.
In clinical trials, the main benefit of nintedanib is a reduction in the rate of decline in lung function. One study
demonstrated a longer time to first exacerbation.
Nintedanib (BIBF 1120) showed promising results in a phase 2 trial (To Improve Pulmonary Fibrosis with
BIBF 1120) [47]. A total of 432 patients were randomly assigned to one of four oral doses of BIBF 1120 or
placebo. The group taking the highest dose of BIBF 1120, 150 mg twice daily, showed a trend towards a
slower decline in lung function and fewer exacerbations compared with placebo.
In two subsequent trials (INPULSIS-1 and INPULSIS-2), a total of 1066 patients with IPF were randomly
assigned to nintedanib 150 mg or placebo twice daily for 52 weeks [48]. In INPULSIS-1, the annual rate of
decline in forced vital capacity (FVC) was lower in the nintedanib group than the placebo group with a
difference of 125.3 mL/year (95% CI 77.7-172.8). The results were similar in INPULSIS-2 where the
difference in FVC decline was 93.7 mL/year (95% CI 44.8-142.7). In INPULSIS-1, no difference between
nintedanib and placebo was noted in the time to first exacerbation, but in INPULSIS-2, an increase in the
time to first exacerbation was noted (hazard ratio 0.38, 95% CI 0.19-0.77).
The tyrosine kinase inhibitor, imatinib, inhibits a narrower spectrum of growth factors and had no effect on
survival or lung function in IPF, when compared with placebo. (See 'Imatinib' below.)
Dose and administration The dose of nintedanib is 150 mg twice daily. Liver function tests (alanine
aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin) should be assessed prior to initiation of
nintedanib, then monthly for three months, every three months thereafter, and as clinically indicated [49]. Dose
modification or interruption may be necessary for liver enzyme elevations [49].
Nintedanib interacts with P-glycoprotein and CYP3A4 inhibitors and inducers and may also increase the risk of
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bleeding among patients on full anticoagulation.

The most frequent adverse effects associated with nintedanib are diarrhea (62 percent), nausea (24 percent),
vomiting (12 percent), and elevation in liver function tests (14 percent), which were greater than five times
normal in 6 percent [48,49]. Diarrhea led to permanent dose reduction in 11 percent of patients and to
discontinuation in 5 percent. In clinical trials, diarrhea was treated with hydration and antidiarrheal medication
(eg, loperamide), and sometime reduction in the dose to 100 mg twice daily. If the lower dose was not tolerated,
treatment was interrupted.
Pirfenidone The predominant pathological findings in IPF are fibroblast foci, collagen deposition, and minimal
inflammatory cell infiltration, raising the possibility that antifibrotic agents might slow the rate of disease
progression [50,51]. Pirfenidone is an antifibrotic agent that inhibits transforming growth factor beta (TGF-b)stimulated collagen synthesis, decreases the extracellular matrix, and blocks fibroblast proliferation in vitro. (See
"Pathogenesis of idiopathic pulmonary fibrosis".)
For patients with mild-to-moderate disease based on pulmonary function tests who are not interested in
participating in a clinical trial and live in an area where pirfenidone is available, we recommend initiation of
pirfenidone. This recommendation is based upon data from randomized trials and case series that have shown a
beneficial effect of pirfenidone in slowing the progression of IPF when administered to patients with mild-tomoderate disease and a possible mortality benefit in a pooled analysis [52-57]. As examples:
In the ASsessment of pirfenidone to Confirm Efficacy aND safety in idiopathic pulmonary fibrosis
(ASCEND) trial, 555 patients with IPF were randomly assigned to receive oral pirfenidone (2403 mg per
day) or placebo for 52 weeks [58]. Pirfenidone resulted in a significant reduction in the one-year rate of
decline in forced vital capacity (FVC); the proportion of patients in the pirfenidone group who had a decline
of 10 percentage points or more in the percent of predicted FVC or died was reduced by 48 percent
compared with the placebo group (46 patients [16.5 percent] versus 88 patients [31.8 percent]),
respectively. Nearly 23 percent of the pirfenidone group had no decline in percent of predicted FVC at week
52, compared with 10 percent of the placebo group, representing a more than 133 percent increase in the
proportion of patients with no evidence of FVC decline. As secondary end-points, pirfenidone reduced the
rate of decline in the six-minute walk difference and improved progression-free survival compared with
placebo, but did not reduce dyspnea. In a prespecified analysis that pooled results of the ASCEND trial with
two prior trials (CAPACITY 004 and 006; 1247 total patients) [55], pirfenidone decreased death from any
cause relative to placebo (22 [3.5 percent] in the pirfenidone group as compared with 42 [6.7 percent] in the
placebo group; hazard ratio, 0.52; 95% CI, 0.31-0.87). As the ASCEND trial was 52 weeks in duration, the
pooled survival analysis only considered data from the first 52 weeks of the CAPACITY trials (which were
72 weeks in duration). A separate pooled analysis considering all available data on all cause mortality
showed a trend favoring pirfenidone but was not statistically significant (Kaplan-Meier Estimate 0.75 (95%
CI 0.51-1.11) [59].
Two concurrent, multicenter trials (Clinical studies Assessing Pirfenidone in idiopathic pulmonary fibrosis,
CAPACITY 004 and 006) assessed the change in percentage forced vital capacity (FVC) at week 72 [55].
Patients with mild-to-moderate IPF (ie, FVC 50 percent predicted and diffusing capacity [DLCO] 35
percent predicted) were randomly assigned to oral pirfenidone 2403 mg/day, 1197 mg/day, or placebo in
the 004 trial and oral pirfenidone 2403 mg/day or placebo in the 006 trial. The higher dose of pirfenidone
significantly decreased the percent fall in FVC in the 004 trial (difference between groups, 4.4 percent, p =
0.001), but not the 006 trial (difference between groups, 0.6 percent, p = 0.51). The higher dose of
pirfenidone significantly reduced the decline in the 6MWTD, a secondary endpoint, in the 006 (absolute
difference 32 meters, p = 0.0009), but not the 004 trial.
A randomized trial of pirfenidone (1800 mg/day) versus placebo was carried out in 107 patients with IPF
[53]. The change in the lowest oxygen saturation by pulse oximetry (SpO2) during a six-minute exercise
test, the primary endpoint, was not significantly different between the two groups from baseline to six
months (+0.6 versus -0.5 percent) and nine months (+0.5 versus -0.9 percent). In a prespecified subset of
patients who maintained the SpO2 >80 percent during a six-minute exercise test at baseline, a significant
improvement was noted in the pirfenidone group in the lowest SpO2 that occurred during a six-minute
exercise test at six months (+0.5 versus -1.9 percent) and nine months (+0.5 versus -1.6 percent),
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suggesting there may be greater benefit in patients whose disease is less severe.
In the same trial, a positive treatment effect was demonstrated in secondary endpoints including an
increase in vital capacity measurements at nine months (-0.03 versus -0.13 liters) and fewer episodes of
acute exacerbation of IPF (14 percent versus none). The trial was aborted in favor of pirfenidone treatment
due to the decreased number of acute exacerbations in the pirfenidone group.
In a separate multicenter trial, 275 patients were randomly assigned to one of three groups: pirfenidone
1800 mg per day, 1200 mg per day, or placebo [54]. The primary endpoint, change in vital capacity (VC),
was assessed at 52 weeks; the secondary endpoint was progression free survival. The decline in VC was
only slightly less in the high-dose pirfenidone group compared with placebo, but the difference was
statistically significant. The progression-free survival time was slightly longer in the high-dose pirfenidone
group compared with placebo.
Pirfenidone is approved for marketing in a number of countries, including (among others) Germany, France, the
United Kingdom, Canada, and Japan. Pirfenidone has been approved by the US Food and Drug Administration
for use in patients with mild or moderate IPF and is available. Pirfenidone has not been formally studied in
patients with more advanced disease.
Pirfenidone appears to slow the progression of lung impairment in patients with pulmonary fibrosis due to
Hermansky-Pudlak syndrome [60].
Dose and administration The dose of pirfenidone ranges up to 40 mg/kg per day (to maximum of 2403
mg per day) in three divided doses. Pirfenidone is initiated at a dose of 267 mg (1 capsule) three times a day.
After one week, the dose is increased to 534 mg (two capsules) three times a day, and after the second week to
the full dose of 801 mg (three capsules) three times a day. Pirfenidone should always be taken with food. Liver
function tests (LFTs; alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin) should be
obtained prior to initiation of therapy, then monthly for the first six months and every three months thereafter [59].
The most common side effects include rash (30 percent), photosensitivity (9 percent), nausea (36 percent),
diarrhea (26 percent), abdominal discomfort (24 percent), dyspepsia (19 percent), anorexia (13 percent), and
fatigue (26 percent) [59]. Dose reduction or interruption for gastrointestinal events was required in 18 percent of
patients in the 2403 mg/day group, and 2 percent discontinued study medication. Taking the medication after
meals may ameliorate the gastrointestinal side effects [61]. Other potential side effects include diarrhea,
constipation, itching, dry skin, hyperpigmentation, headache, and weakness.
Elevations in LFTs three times the upper limit of normal or higher occurred in 4 percent of patients [59]. All LFT
elevations resolved with dose modification or treatment discontinuation. Elevations in the ALT and/or AST may
require a reduction or interruption in dose.
The dose of pirfenidone should be reduced in the presence of strong or moderate CYP1A2 inhibitors (eg,
fluvoxamine, ciprofloxacin) [59] .
Phosphodiesterase inhibitors As IPF progresses, a substantial portion of patients develop pulmonary
hypertension (PH). This has led to the hypothesis that treating IPF-related pulmonary hypertension with a
phosphodiesterase inhibitor might improve exercise tolerance, as in idiopathic pulmonary hypertension [62-64].
(See "Treatment of pulmonary hypertension in adults", section on 'PDE5 inhibitors'.)
In a randomized trial, 180 patients with advanced IPF (defined as a diffusing capacity less than 35 percent of
predicted) were assigned to sildenafil 20 mg three times daily or placebo for 12 weeks [64]. Exclusion criteria
included a six-minute walk distance (6MWD) less than 50 m (164 feet), treatment with medications containing
nitrates, and presence of aortic stenosis or hypertrophic subaortic stenosis. No difference was found in the
primary end-point of at least a 20 percent improvement in the six-minute walk distance compared with baseline.
Small differences were noted between the groups in dyspnea and quality of life, favoring sildenafil. In a substudy
of this trial that looked at subjects with pretreatment echocardiograms, sildenafil treatment of 22 subjects with
right ventricular systolic dysfunction was associated with a smaller decrement in 6MWD and a greater
improvement in quality of life measures than placebo [65].
Two smaller studies found mixed results with sildenafil. An open-label observational study of 14 patients with IPF
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and PH found that treatment with the phosphodiesterase inhibitor sildenafil resulted in a modest improvement in
six-minute walk with a mean increase in distance walked of 49 meters, which is lower than the usual standard of
54 m for a clinically important increase [62]. However, a subsequent randomized trial of 29 subjects found no
significant difference in the six-minute walk with sildenafil compared with placebo [63].
Further trials of longer duration are needed to determine the safety and efficacy of sildenafil in the treatment of
IPF. However, given the paucity of treatment options for advanced IPF, a trial of sildenafil may be a reasonable
option in patients with a DLCO <35 percent, echocardiographic evidence of right ventricular dysfunction, and no
contraindications to sildenafil (eg, unstable angina, use of nitrates). The initial dose of sildenafil (20 mg) is given
while monitoring symptoms, blood pressure, and pulse oxygen saturation for 60 minutes. If tolerated, sildenafil is
continued at a dose of 20 mg three times daily.
ACUTE EXACERBATIONS Patients with IPF may suffer acute deterioration secondary to infections,
pulmonary embolism, pneumothorax, or heart failure [10,66]. In addition, the clinical course of IPF is often
complicated by "acute exacerbations" or an "accelerated phase of rapid clinical decline" without an identifiable
cause [9,66-70]. These processes are associated with a poor prognosis.
The incidence of these acute exacerbations ranges from 10 to 57 percent, apparently depending on the length of
follow-up [66,70]. The risk factors for acute exacerbations of IPF are unknown. Acute viral infection is unlikely to
be a common etiology [71]. When lung biopsies have been performed during an episode, the histopathologic
pattern of acute lung injury (diffuse alveolar damage) is often found on the background of usual interstitial
pneumonia (UIP).
Definition The following criteria for an acute exacerbation of IPF have been proposed [66]:
Previous or concurrent diagnosis of idiopathic pulmonary fibrosis
Unexplained development or worsening of dyspnea within 30 days
High-resolution computed tomography with new bilateral ground-glass abnormality and/or consolidation
superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia
No evidence of pulmonary infection by endotracheal aspirate or bronchoalveolar lavage
Exclusion of alternative causes, including left heart failure, pulmonary embolism, and other identifiable
causes of acute lung injury
Patients who do not meet all five criteria should be termed "suspected acute exacerbation."
Clinical manifestations The key clinical feature is acute or subacute worsening of dyspnea over days to
weeks, but generally in less than 30 days [66,72]. Cough, fever, and flu-like symptoms may also be present.
Respiratory insufficiency can be severe and requires noninvasive support or mechanical ventilation. The most
common criteria for impaired gas exchange are an arterial oxygen tension to fraction of inspired oxygen ratio
(PaO2/FIO2) of less than 225 mmHg or a decrease in the PaO2 of 10 mmHg or more from baseline.
High-resolution CT scans (HRCT) obtained during an acute exacerbation of IPF typically show the underlying
fibrotic changes of IPF with new, superimposed alveolar opacities that may be peripheral, multifocal, or diffuse
[72-74]. Among these patterns, prognosis appears to vary; the peripheral pattern may have a better prognosis,
multifocal an intermediate prognosis, and diffuse a worse outcome.
Implications for practice After excluding other potential causes of worsening dyspnea and hypoxemia, we
typically treat patients who have an acute exacerbation with broad-spectrum antibiotics and high dose
glucocorticoids (eg, prednisone 1 mg/kg per day orally or methylprednisolone 1 to 2 g per day intravenously),
although scientific evidence for this is lacking [2,66,75]. Some practitioners add a cytotoxic agent such as
azathioprine or, rarely, cyclophosphamide [70,72]. Better understanding and management of these episodes will
be critical to reducing the death rate in IPF [10].
Mechanical ventilation is often required but is not usually successful; the hospital mortality rate was 78 percent in
one study [76]. In patients who survive, a recurrence of acute exacerbation is common and usually results in
death [32].
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TRANSPLANTATION IPF is the most common interstitial lung disease among referrals for lung
transplantation and the second most frequent disease for which lung transplantation is performed [77,78].
Indications and choice of procedure Patients with IPF have the highest death rate among the diagnostic
groups on the transplant waiting list [79]. For this reason, early referral for transplant evaluation should be
considered, even before the response to initial medical therapy has been determined [80]. Under the current
United Network for Organ Sharing (UNOS) system, priority for transplantation is determined by medical urgency
and expected outcome using a lung allocation score (LAS) (table 4). Scores are normalized to a continuous
scale from 1 to 100, with higher scores representing higher urgency and greater potential transplant benefit. (See
"Lung transplantation: An overview", section on 'Lung allocation' and "Lung transplantation: Disease-based
choice of procedure".)
General guidelines for transplantation include histologic or radiographic evidence of usual interstitial pneumonia
(UIP) and any of the following [81]:
A diffusing capacity (DLCO) <39 percent of predicted
A decrement in forced vital capacity (FVC) >10 percent during six months of follow-up
A decrease in pulse oximetry below 88 percent saturation during a six-minute walk test
Honeycombing on high resolution chest tomography (HRCT) (fibrosis score >2 [82])
Among 1256 patients transplanted between May 2005 and December 2007, the one-year survival rate was 74
percent among those with scores in the highest lung allocation quartile (LAS 52.0 to 94.1) and 84 percent among
those in the lowest lung allocation score quartile (LAS 31.1 to 37.8) [83]. Evaluation of the LAS factors predicting
mortality revealed that IPF patients being ventilated before transplantation had an increased risk of mortality at
one year (HR, 3.78; 95% CI, 2.32 to 6.17) [83]. The five-year survival rate for lung transplantation in IPF is 40 to
50 percent, compared with a five-year survival rate of 53 percent for all lung transplant recipients [84-86].
Although single lung transplantation (SLT) has been the standard procedure for IPF, bilateral lung transplant
(BLT) may prove to have better long-term survival [78,84,87-92]. Mild-to-moderate secondary pulmonary
hypertension preoperatively increased the risk of reperfusion injury in one study but did not appear to affect
survival in two retrospective studies [93,94].
Following SLT, the low lung compliance and high vascular resistance of the remaining native lung preferentially
direct both ventilation and perfusion to the transplanted lung. Cysts, bullae, and bronchiectasis that occasionally
develop in the later stages of IPF can act as a nidus for infectious complications after SLT; when these are
identified, BLT may be preferred.
Early experience suggests that living donor lobar lung transplantation (LDLLT) may be an option for patients with
IPF who are likely to die while waiting for SLT. In a report of nine such patients, eight of whom were dependent
on systemic glucocorticoids (up to 50 mg/day), only one early death occurred after transplant of two lower lobes
donated by two healthy relatives [95]. Eight patients were still alive after 10 to 48 months of follow-up.
Physiologic changes After SLT or BLT, spirometric parameters, lung volumes, diffusing capacity, and
oxygenation improve significantly, and these improvements have been sustained in long-term follow-up of
recipients without complications [87-90]. In a series that compared SLT and BLT recipients with IPF, the mean
FEV1 was higher in BLT recipients than SLT recipients one year after transplantation (2.25 versus 2.00 liters)
[90].
After SLT, most lung function is contributed by the allograft. As a result, the vital capacity (VC) of the recipient
correlates closely with the predicted vital capacity of the donor organ [96]. Improvements in cardiopulmonary
function continue for up to one year following transplantation. As an example, in one study of SLT recipients, the
mean VC increased from 43 percent of the predicted normal value preoperatively to 65 percent three months
and 69 percent one year after transplantation. None of the eight recipients tested one year after transplantation
required supplemental oxygen at rest or during exercise, and their treadmill exercise tolerance was much
improved [89].
Prior treatment The effect of prior glucocorticoid therapy on the outcome of lung transplantation is uncertain.
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Most studies suggest that low-dose glucocorticoid therapy has no adverse effect on outcome [97-99]. However,
high-dose glucocorticoid therapy may be associated with decreased survival after lung transplantation [99]. The
International Guidelines for the Selection of Lung Transplant Candidates lists prednisone use >20 mg/day as a
relative contraindication for lung transplantation [81]. (See "Lung transplantation: General guidelines for recipient
selection", section on 'Glucocorticoid use'.)
AGENTS WITHOUT CLEAR BENEFIT A number of agents have been evaluated for use in IPF but are not
currently used for this indication. The following agents are mentioned here to provide clinicians with an overview
of the evidence for and against their use.
Anticoagulation It has been proposed that a prothrombotic state exists in patients with IPF that may
contribute to mortality [100,101]. The hypothesis that anticoagulation might reduce mortality in IPF was initially
tested in a nonblinded trial of 56 IPF patients who were hospitalized due to worsening dyspnea; subjects were
randomly assigned to prednisolone PLUS long-term anticoagulation or prednisolone alone [102]. A significant
improvement in survival was found at three years in the anticoagulant group (63 versus 35 percent).
However, due to methodologic concerns with the above study, the Anticoagulant Effectiveness in Idiopathic
Pulmonary Fibrosis trial (ACE-IPF; NCT00957242) was performed [10,103,104]. In the ACE-IPF trial, 145
subjects with IPF but without other indications for anticoagulation were randomly assigned to warfarin
anticoagulation (to an International Normalized Ratio [INR] of 2.0 to 3.0) or placebo [104]. After a mean follow-up
of 28 weeks, the study was stopped due to an increase in mortality in the subjects randomized to warfarin (14
warfarin versus 3 placebo deaths; p = 0.005) and a low probability of benefit. None of the deaths was attributed
to bleeding complications.
Anticoagulation with warfarin is not indicated in patients with IPF who lack other indications for anticoagulation,
due to the increased risk of mortality. However, anticoagulation should not be withheld from patients with IPF
based on this trial, if the patient does have other indications for anticoagulation.
Azathioprine-prednisone-N-acetylcysteine Combination therapy with systemic glucocorticoid and
azathioprine has been used for IPF for many years, although supportive clinical trial data were limited [105,106].
However, the multicenter PANTHER trial (Prednisone, Azathioprine, and N-acetylcysteine [NAC]: A Study That
Evaluates Response in IPF) found that combination therapy (prednisone-azathioprine-NAC) was associated with
greater mortality (eight versus one deaths), more hospitalizations (23 versus 7), and more serious adverse
events (24 versus 8) than placebo (78 patients) [107]. Based on data from the PANTHER trial, we suggest not
initiating combination therapy (azathioprine, prednisone, NAC) in patients with IPF.
The combination of systemic glucocorticoid, azathioprine, and the antioxidant NAC was previously assessed in
the IFIGENIA (Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual) trial
[108,109]. However, the IFIGENIA trial examined the addition of NAC or placebo to a baseline regimen of
prednisone and azathioprine, rather than comparing the combination regimen to placebo. (See 'N-Acetylcysteine'
below.)
Colchicine We suggest not using colchicine in the treatment of IPF, because evidence of efficacy is lacking.
There have been numerous in vitro and animal model studies suggesting that colchicine may slow the fibrotic
process [110-113]. However, several clinical studies, including retrospective studies [23,114], a randomized trial
[24], and a nonrandomized prospective study [115], failed to show a significant difference in the rate of decline of
lung function when patients were treated with colchicine or glucocorticoids.
Cyclophosphamide We do not use cyclophosphamide (Cytoxan) in IPF because of its toxicity and lack of
proven benefit. Although several small series suggested that cyclophosphamide (usually given along with low
doses of glucocorticoids) might be beneficial in the treatment of IPF [116-118], one of the largest retrospective
series found no survival benefit among 82 patients on the combination of prednisone and oral cyclophosphamide
compared with 82 on prednisone alone [119].
Rarely, cyclophosphamide may be used to treat an acute exacerbation episode in a patient with IPF. However,
no sound evidence supports its use in this setting.
Dosing and treatment considerations for the use of cyclophosphamide are discussed in detail separately. (See
"General principles of the use of cyclophosphamide in rheumatic and renal disease" and "General toxicity of
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cyclophosphamide in inflammatory diseases".)

Cyclosporine Experience with cyclosporine for the treatment of IPF is limited; we do not prescribe
cyclosporine in patients with IPF because of the high toxicity and absence of proven benefit. The few published
reports have been anecdotal and less than encouraging [120-123].
Endothelin receptor antagonists Several trials examining the efficacy of endothelin receptor antagonists in
IPF failed to meet their primary objectives and are not being used in IPF treatment. Bosentan (Tracleer), a
nonselective endothelin receptor antagonist, was evaluated as a therapy for IPF because of its antifibrotic
properties [124]. In the multicenter trial BUILD 1 (Efficacy and Safety of Oral Bosentan in Patients With Idiopathic
Pulmonary Fibrosis), there was no significant difference in the primary endpoint of exercise capacity, as
measured by a six-minute walk, or in the secondary endpoints of dyspnea and quality of life [125,126]. A
follow-up study, the multinational BUILD 3 trial (Bosentan Use in Interstitial Lung Disease 3), was designed to
examine the trend toward delayed time to death or disease progression observed in BUILD 1 [125,127].
However, it did not meet its primary end-point of time to IPF worsening or death.
A multinational trial examining the role of macitentan, a highly potent, tissue-targeting endothelin receptor
antagonist in early IPF, failed to meet the primary endpoint (Macitentan Use in an IPF Clinical Study or "MUSIC"
trial) [128].
The "ARTEMIS-IPF Trial" (Randomized, Placebo-Controlled Study to Evaluate Safety and Effectiveness of
Ambrisentan in IPF; clinical trials identifier: NCT00768300) comparing ambrisentan, a type A endothelin receptor
antagonist, was terminated due to lack of efficacy [129]. Of note, ambrisentan may be deleterious in IPF, not just
of no benefit. The risks of disease progression and respiratory hospitalization were higher in the ambrisentantreated group than placebo. A subset analysis of patients with pulmonary hypertension complicating IPF found
similar results, including a greater likelihood of disease progression.
Etanercept Animal models of pulmonary fibrosis have suggested that antagonists of tumor necrosis factor
(TNF)-alpha might be effective in treating IPF [130]. The efficacy and safety of the TNF-alpha receptor blocker,
etanercept, were evaluated in a trial that randomly assigned 88 patients to twice weekly subcutaneous
etanercept or placebo [131]. After 48 weeks, no significant difference was seen in the primary endpoints of
change in percent predicted FVC or DLCO, or in the arterial-alveolar oxygen gradient. Given the potential side
effects and lack of proven efficacy, we recommend that etanercept NOT be used to treat IPF [2].
Interferon gamma-1b The rationale for the use of subcutaneous interferon gamma (interferon gamma-1b) in
IPF came, in part, from the hypothesis that an acquired deficiency of interferon gamma exists in IPF and may
contribute to the exaggerated wound healing process characteristic of this disease [132-134]. A placebocontrolled, randomized trial suggested a possible mortality benefit [110], but a subsequent large multinational
trial was halted when the primary end point of a mortality benefit was not achieved [135]. We recommend not
using subcutaneous interferon gamma-1b to treat IPF.
Methotrexate Methotrexate, an analogue of the vitamin folic acid, inhibits cellular proliferation by inducing an
acute intracellular deficiency of certain folate coenzymes. It has both antineoplastic and immunosuppressive
effects. There have been several descriptions of using methotrexate in sarcoidosis, but very little has been
written regarding its effectiveness in IPF [136-139].
In general, we do not use methotrexate to treat patients with IPF because of the lack of data demonstrating
benefit and concern about methotrexate-induced pneumonitis. In patients with IPF, it may be difficult to
distinguish pulmonary drug toxicity from progression of the underlying disease.
Interstitial lung disease in the context of autoimmune disease (eg, rheumatoid arthritis) may have a significant
component of usual interstitial pneumonitis based on radiographic and histologic assessment. In this situation,
methotrexate may be of benefit. As an example, one study described three patients with IPF associated with
connective tissue disease who appeared to respond favorably to methotrexate [140].
The use of low dose methotrexate is described separately. (See "Use of methotrexate in the treatment of
rheumatoid arthritis" and "Major side effects of low-dose methotrexate" and "Methotrexate-induced lung injury".)
N-Acetylcysteine Lung injury from excess production of oxidants is thought to be a contributing factor in IPF
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[108,141-146]. N-Acetylcysteine (NAC), a precursor of the antioxidant glutathione, restores depleted glutathione
levels in the lung but does not ameliorate the course of IPF [143-147]. (See "Pathogenesis of idiopathic
pulmonary fibrosis".)
Initial evidence from the IFIGENIA (Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine
I Annual) trial appeared to suggest a benefit to using NAC to treat IPF [141]. However, in the PANTHER trial
(Prednisone, Azathioprine, and N-acetylcysteine [NAC]: A Study That Evaluates Response in IPF), NAC (1800
mg orally per day) did not slow the decline in forced vital capacity (FVC) over 60 weeks compared with placebo
[107,148]. Furthermore, NAC did not reduce deaths or acute exacerbations but appeared to increase the rate of
serious adverse events for cardiac disorders, which occurred in 6.8 percent in the NAC group and 1.5 percent in
the placebo group (p = 0.03). Serious gastrointestinal disorders occurred in no patients in the NAC group and in
4.6 percent of the placebo group (p = 0.01).
Penicillamine We suggest not using d-penicillamine, an agent that affects collagen biosynthesis and the
immune system, as a treatment for IPF because evidence of efficacy is lacking.
Several animal studies and two retrospective studies of patients with pulmonary fibrosis associated with
scleroderma suggested a possible role for penicillamine in the treatment of fibrotic lung disorders [149-154]. In
addition, two retrospective studies of patients with fibrosing alveolitis associated with scleroderma reported that
penicillamine therapy was associated with an improvement in DLCO (but not in other pulmonary function test
parameters) [153,154]. However, experience with penicillamine in patients with IPF, while limited, is not
encouraging [115,155,156]. A nonrandomized prospective study in patients with IPF compared
colchicine/prednisone (n = 19), D-penicillamine/prednisone (n = 11), D-penicillamine/colchicine/prednisone (n =
11), and prednisone alone (n = 15). No significant differences in survival or in lung function relative to the
baseline measurement were found in any group [115].
FUTURE DIRECTIONS The agents currently available for the treatment of IPF are inadequate. Therapeutic
response is obtained in only a subset of patients, and survival is poor even for those who respond. In addition,
these agents all carry significant side effects and toxicity. For these reasons, there is much interest in developing
more effective, less toxic pharmacologic therapy [157,158]. Some examples of potential future therapies, of
which nintedanib and prevention of acid reflux are two of the most promising, are described below.
Imatinib Imatinib mesylate is a tyrosine kinase inhibitor with activity against the platelet-derived growth factor
receptors (PDGFRs), c-kit, and c-Abl. As PDGF has been implicated in the pathogenesis of IPF, imatinib was
evaluated as a possible therapy. In a 96-week trial, 119 patients with mild-to-moderate IPF were randomly
assigned to receive imatinib or placebo 600 mg once daily [159]. Imatinib had no effect on survival or lung
function when compared with placebo. In contrast, the tyrosine kinase inhibitor nintedanib shows promise. (See
'Nintedanib' above.)
Thalidomide Thalidomide is an immune modulator and antifibrotic agent that ameliorates bleomycin-induced
pulmonary fibrosis in mice [160]. The effect of thalidomide on cough, a debilitating symptom in IPF, was
assessed in 23 patients with IPF who were randomly assigned to thalidomide or placebo in a 24-week crossover
trial [161]. Twenty-two participants completed 12 weeks of the placebo regimen, and 20 completed 12 weeks of
thalidomide. The primary endpoint, improvement in the Cough Quality of Life Questionnaire (CQLQ), favored
thalidomide (mean difference versus placebo, -11.4 [95% CI, -15.7 to -7.0]). Cough severity measured on a
visual analog scale also improved. Adverse events attributed to thalidomide included constipation (36 percent),
dizziness (27 percent), malaise 14 percent, anorexia (5 percent) and asymptomatic bradycardia (5 percent). The
potential benefit of thalidomide in IPF will need validation in a larger and longer multicenter trial that assesses
additional endpoints, such as mortality and lung function.
Immunomodulation Although there is still much to be learned regarding the roles of various cytokines and
growth factors in the complex process of pulmonary fibrosis, it is clear that these agents are critical
[157,158,162]. Inhibitors of specific fibrogenic cytokines or growth factors (eg, tumor necrosis factor alpha
antagonists, interleukin 1 receptor antagonist [IL-1ra], anti-CD 11 antibody) may help to retard the fibrotic
process. Although these agents may appear to be effective in animal models of pulmonary fibrosis, it will be
important to evaluate them fully in randomized, placebo-controlled trials in humans. Another potential strategy
involves interfering with the process of leukocyte recruitment and retention in the lung by using agents that block
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the expression or function of adhesion molecules. (See "Pathogenesis of idiopathic pulmonary fibrosis", section
on 'Mechanisms of fibrosis'.)
Gastroesophageal reflux and chronic microaspiration Up to 90 percent of patients with IPF have
gastroesophageal reflux (GER) [163-165]. It has been hypothesized that GER is an important risk factor for the
development and/or progression of IPF [166-170]. In a systematic review, it was noted that 67 to 76 percent of
patients with IPF assessed with ambulatory pH probe monitoring had abnormal distal esophageal acid exposure
[171]. In addition, classic symptoms of GER (heartburn, acid regurgitation) were poor predictors of increased
esophageal acid exposure among patients with moderate to severe IPF. In a separate study, reflux in patients
with IPF was associated with a hypotensive lower esophageal sphincter and abnormal esophageal peristalsis,
and often extended into the proximal esophagus [172].
The effect of anti-GER treatment on IPF disease progression has also been examined. A retrospective study of
204 patients with IPF found that reported use of anti-GER medications was associated with decreased
radiographic fibrosis scores on chest computed tomography and was an independent predictor of longer survival
time [173]. An analysis of data from three randomized controlled trials identified patients with IPF assigned to
receive placebo and used prospectively obtained data about diagnosis and treatment of abnormal acid
gastroesophageal reflux [174]. Of the 242 patients randomly assigned to the placebo groups of the three trials,
124 (51 percent) were taking a proton-pump inhibitor (PPI) or H2 blocker at enrollment. After adjustment for sex,
baseline FVC as a percentage of predicted, and baseline diffusing capacity for carbon monoxide (DLCO) as a
percentage of predicted, patients taking a PPI or H2 blocker at baseline had a smaller decrease in FVC at 30
weeks (-0.06 L, 95% CI -0.11 to -0.01) than those not taking anti-acid treatment (-0.12 L, -0.17 to -0.08;
difference 007 L, 95% CI 0-0.14). These data suggest that anti-GER treatment could be beneficial in patients
with IPF and support the previous reports suggesting that abnormal acid gastroesophageal reflux contributes to
disease progression. However, controlled clinical trials of acid reflux treatments in IPF are needed.
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)
Basics topic (see "Patient information: Idiopathic pulmonary fibrosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
Sufficient clinical evidence that any treatment improves survival or quality of life for patients with idiopathic
pulmonary fibrosis (IPF) is lacking. (See 'General approach' above.)
We offer supportive care (eg, supplemental oxygen, pulmonary rehabilitation, seasonal influenza and
pneumococcal vaccination) and provide information regarding participation in randomized trials to all
patients. (See 'General approach' above and 'Supportive care' above and 'Clinical trials' above.)
For patients with mild-to-moderate IPF based on pulmonary function tests who live in an area where either
pirfenidone or nintedanib is available, we recommend initiating therapy with the available agent (Grade
1B). Current data are insufficient to direct a firm choice between nintedanib and pirfenidone. Patient
preference and tolerances should be considered, particularly regarding potential adverse effects. (See 'Our
approach' above and 'Assessing disease severity' above.)
The dose of nintedanib is 150 mg by mouth twice daily. Patients with known liver disease (Pugh B or
worse) or full anticoagulation are not candidates for nintedanib. Diarrhea, nausea, vomiting, and liver
function test elevation are common side effects of nintedanib. (See 'Nintedanib' above.)
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The dose of pirfenidone ranges up to 40 mg/kg per day (to maximum of 2403 mg per day) in three
divided oral doses. Rash, photosensitivity, nausea, and abdominal discomfort are common side
effects of pirfenidone. (See 'Pirfenidone' above.)
Neither nintedanib nor pirfenidone has been formally studied in patients with more advanced disease, so
the decision to try one of these medications depends on the values and preferences of the patient
regarding a choice of active (but unproven for advanced disease) therapy versus supportive care alone.
(See 'Medical therapies' above.)
Systemic glucocorticoid monotherapy, combination therapy with azathioprine, prednisone, and
N-acetylcysteine, and monotherapy with N-acetylcysteine are no longer part of the routine maintenance
care for patients with IPF, as there is no demonstrated efficacy and they may be potential harmful. (See
'Azathioprine-prednisone-N-acetylcysteine' above.)
A trial of sildenafil may be a reasonable option in patients with advanced IPF, a diffusing capacity (DLCO)
<35 percent of predicted, echocardiographic evidence of right ventricular dysfunction, and no
contraindications to sildenafil. (See 'Phosphodiesterase inhibitors' above.)
Therapy to prevent acid reflux may be beneficial in patients with IPF. (See 'Gastroesophageal reflux and
chronic microaspiration' above.)
Lung transplantation may be an option for patients with progressive disease and minimal comorbidities. For
appropriate patients (based on criteria from the United Network for Organ Sharing [UNOS]), we suggest
early referral for lung transplantation evaluation rather than waiting until the patient has developed
advanced disease (Grade 2C). (See 'Transplantation' above.)
For patients with an acute exacerbation of IPF, we suggest administering high dose glucocorticoids based
on the poor prognosis of exacerbations and anecdotal experience that some patients improve on this
therapy (Grade 2C). The usual dose is the equivalent of prednisone 1 mg/kg per day orally to
methylprednisolone 1 to 2 g per day, intravenously. Broad-spectrum antibiotics are typically initiated until
infection can be excluded. A cytotoxic agent such as azathioprine may be added for glucocorticoid sparing,
although data to support immunosuppressive therapy in this setting are lacking. (See 'Acute exacerbations'
above and 'Azathioprine-prednisone-N-acetylcysteine' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
Topic 4328 Version 42.0
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GRAPHICS
Interstitial lung disease
PFT: pulmonary function tests; HRCT: high resolution computed tomography; ILD:
interstitial lung disease; BAL: bronchoalveolar lavage; UIP: usual interstitial
pneumonia; IPF: idiopathic pulmonary fibrosis; NSIP: nonspecific interstitial
pneumonia; OP: organizing pneumonia; PLCH: pulmonary Langerhans cell
histiocytosis; TBB: transbronchial lung biopsy.
* Serology as indicated by clinical findings: rheumatoid factor, anti-cyclic
citrulinated peptide, antinuclear antibody, antisynthetase antibodies, creatine
kinase, aldolase, Sjgren's antibodies and scleroderma antibodies.
Classic HRCT features of UIP:
1. Reticular opacities in basal and peripheral distribution
2. Traction bronchiectasis
3. Honeycombing (clustered airspaces 3 to 10 mm diameter) in subpleural
location
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4. Ground glass opacities may be present but are less extensive than reticular
opacities
Adapted from: Raghu G. Am J Respir Crit Care Med 1995; 151:909.
Graphic 69044 Version 3.0
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Complications of idiopathic pulmonary fibrosis

Progressive respiratory failure
Mortality - 39 percent
Findings suggestive of disease progression are multiple and nonspecific
Bronchogenic carcinoma
Excess risk of 14:1 compared to general population; same histologic distribution as seen in
population
Cardiovascular disease
Right ventricular hypertrophy, cor pulmonale due to progressive, longstanding pulmonary
hypertension and right heart failure
Left ventricular heart failure usually due to concurrent ischemic heart disease
Pulmonary infection
Mortality - 2 to 4 percent
Increased incidence; glucocorticoid and cytotoxic therapy may further increase risk
Pneumothorax
Occurs less often than in other interstitial lung disease - <10 percent
Pulmonary embolism
Mortality 3 to 7 percent
Pulmonary angiography frequently required to make diagnosis
Complications of therapy
See text
Adapted from Panos, RJ, Mortenson, RL, Niccoli, SA, King TE Jr, Am J Med 1990; 88:396.
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Recommended adult immunization schedule, by vaccine and age group*

- United States, 2014
NOTE: These recommendations must be read with the footnotes that follow containing number of
doses, intervals between doses, and other important information. The recommendations in this
schedule were approved by the Centers for Disease Control and Prevention's (CDC) Advisory
Committee on Immunization Practices (ACIP), the American Academy of Family Physicians (AAFP),
the American College of Physicians (ACP), American College of Obstetricians and Gynecologists
(ACOG), and American College of Nurse-Midwives (ACNM).
* Additional information
Additional guidance for the use of the vaccines described in this supplement is available at
www.cdc.gov/vaccines/hcp/acip-recs/index.html.
Information on vaccination recommendations when vaccination status is unknown and other general
immunization information can be found in the General Recommendations on Immunization at
www.cdc.gov/mmwr/preview/mmwrhtml/rr6002a1.htm.
Information on travel vaccine requirements and recommendations (eg, for hepatitis A and B,
meningococcal, and other vaccines) is available at http://wwwnc.cdc.gov/travel/destinations/list.
Additional information and resources regarding vaccination of pregnant women can be found at
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http://www.cdc.gov/vaccines/adults/rec-vac/pregnant.html.
Report all clinically significant postvaccination reactions to the Vaccine Adverse Event Reporting
System (VAERS). Reporting forms and instructions on filing a VAERS report are available at
www.vaers.hhs.gov or by telephone, 800-822-7967.
Information on how to file a Vaccine Injury Compensation Program claim is available at
www.hrsa.gov/vaccinecompensation or by telephone, 800-338-2382. To file a claim for vaccine injury,
contact the US Court of Federal Claims, 717 Madison Place, NW, Washington, DC 20005; telephone,
202-357-6400.
Covered by the Vaccine Injury Compensation Program.
Influenza vaccination
Annual vaccination against influenza is recommended for all persons aged six months or older.
Persons aged six months or older, including pregnant women and persons with hives-only allergy to
eggs, can receive the inactivated influenza vaccine (IIV). An age-appropriate IIV formulation should
be used.
Adults aged 18 to 49 years can receive the recombinant influenza vaccine (RIV) (FluBlok). RIV does
not contain any egg protein.
Healthy, nonpregnant persons aged 2 to 49 years without high-risk medical conditions can receive
either intranasally administered live, attenuated influenza vaccine (LAIV) (FluMist), or IIV. Healthcare
personnel who care for severely immunocompromised persons (ie, those who require care in a
protected environment) should receive IIV or RIV rather than LAIV.
The intramuscularly or intradermally administered IIV are options for adults aged 18 to 64 years.
Adults aged 65 years or older can receive the standard-dose IIV or the high-dose IIV (Fluzone
High-Dose).
Tetanus, diphtheria, and acellular pertussis (Td/Tdap) vaccination
Administer one dose of Tdap vaccine to pregnant women during each pregnancy (preferred during 27
to 36 weeks' gestation) regardless of interval since prior Td or Tdap vaccination.
Persons aged 11 years or older who have not received Tdap vaccine or for whom vaccine status is
unknown should receive a dose of Tdap followed by tetanus and diphtheria toxoids (Td) booster doses
every 10 years thereafter. Tdap can be administered regardless of interval since the most recent
tetanus or diphtheria-toxoid containing vaccine.
Adults with an unknown or incomplete history of completing a three-dose primary vaccination series
with Td-containing vaccines should begin or complete a primary vaccination series including a Tdap
dose.
For unvaccinated adults, administer the first two doses at least four weeks apart and the third dose 6
to 12 months after the second.
For incompletely vaccinated (ie, less than three doses) adults, administer remaining doses.
Refer to the Advisory Committee on Immunization Practices (ACIP) statement for recommendations
for administering Td/Tdap as prophylaxis in wound management (see footnote *).
Varicella vaccination
All adults without evidence of immunity to varicella (as defined below) should receive two doses of
single-antigen varicella vaccine or a second dose if they have received only one dose.
Vaccination should be emphasized for those who have close contact with persons at high risk for
severe disease (eg, healthcare personnel and family contacts of persons with immunocompromising
conditions) or are at high risk for exposure or transmission (eg, teachers; child care employees;
residents and staff members of institutional settings, including correctional institutions; college
students; military personnel; adolescents and adults living in households with children; nonpregnant
women of childbearing age; and international travelers).
Pregnant women should be assessed for evidence of varicella immunity. Women who do not have
evidence of immunity should receive the first dose of varicella vaccine upon completion or termination
of pregnancy and before discharge from the healthcare facility. The second dose should be
administered four to eight weeks after the first dose.
Evidence of immunity to varicella in adults includes any of the following:
Documentation of two doses of varicella vaccine at least four weeks apart;
US-born before 1980, except healthcare personnel and pregnant women;
History of varicella based on diagnosis or verification of varicella disease by a healthcare provider;
History of herpes zoster based on diagnosis or verification of herpes zoster disease by a healthcare
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provider; or
Laboratory evidence of immunity or laboratory confirmation of disease.
Human papillomavirus (HPV) vaccination
Two vaccines are licensed for use in females, bivalent HPV vaccine (HPV2) and quadrivalent HPV
vaccine (HPV4), and one HPV vaccine for use in males (HPV4).
For females, either HPV4 or HPV2 is recommended in a three-dose series for routine vaccination at
age 11 or 12 years and for those aged 13 through 26 years, if not previously vaccinated.
For males, HPV4 is recommended in a three-dose series for routine vaccination at age 11 or 12 years
and for those aged 13 through 21 years, if not previously vaccinated. Males aged 22 through 26 years
may be vaccinated.
HPV4 is recommended for men who have sex with men through age 26 years for those who did not
get any or all doses when they were younger.
Vaccination is recommended for immunocompromised persons (including those with HIV infection)
through age 26 years for those who did not get any or all doses when they were younger.
A complete series for either HPV4 or HPV2 consists of three doses. The second dose should be
administered four to eight weeks (minimum interval of four weeks) after the first dose; the third dose
should be administered 24 weeks after the first dose and 16 weeks after the second dose (minimum
interval of at least 12 weeks).
HPV vaccines are not recommended for use in pregnant women. However, pregnancy testing is not
needed before vaccination. If a woman is found to be pregnant after initiating the vaccination series,
no intervention is needed; the remainder of the three-dose series should be delayed until completion
of pregnancy.
Zoster vaccination
A single dose of zoster vaccine is recommended for adults aged 60 years or older regardless of
whether they report a prior episode of herpes zoster. Although the vaccine is licensed by the US Food
and Drug Administration (FDA) for use among and can be administered to persons aged 50 years or
older, ACIP recommends that vaccination begin at age 60 years.
Persons aged 60 years or older with chronic medical conditions may be vaccinated unless their
condition constitutes a contraindication, such as pregnancy or severe immunodeficiency.
** Measles-mumps-rubella (MMR) vaccination
Adults born before 1957 are generally considered immune to measles and mumps. All adults born in 1957
or later should have documentation of one or more doses of MMR vaccine unless they have a medical
contraindication to the vaccine or laboratory evidence of immunity to each of the three diseases.
Documentation of provider-diagnosed disease is not considered acceptable evidence of immunity for
measles, mumps, or rubella.
Measles component:
A routine second dose of MMR vaccine, administered a minimum of 28 days after the first dose, is
recommended for adults who:
Are students in postsecondary educational institutions;
Work in a healthcare facility; or
Plan to travel internationally.
Persons who received inactivated (killed) measles vaccine or measles vaccine of unknown type
during 1963 to 1967 should be revaccinated with two doses of MMR vaccine.
Mumps component:
A routine second dose of MMR vaccine, administered a minimum of 28 days after the first dose, is
recommended for adults who:
Are students in a postsecondary educational institution;
Work in a healthcare facility; or
Plan to travel internationally.
Persons vaccinated before 1979 with either killed mumps vaccine or mumps vaccine of unknown type
who are at high risk for mumps infection (eg, persons who are working in a healthcare facility)
should be considered for revaccination with two doses of MMR vaccine.
Rubella component:
For women of childbearing age, regardless of birth year, rubella immunity should be determined. If
there is no evidence of immunity, women who are not pregnant should be vaccinated. Pregnant
women who do not have evidence of immunity should receive MMR vaccine upon completion or
termination of pregnancy and before discharge from the healthcare facility.
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Healthcare personnel born before 1957:

For unvaccinated healthcare personnel born before 1957 who lack laboratory evidence of measles,
mumps, and/or rubella immunity or laboratory confirmation of disease, healthcare facilities should
consider vaccinating personnel with two doses of MMR vaccine at the appropriate interval for measles
and mumps or one dose of MMR vaccine for rubella.
Pneumococcal conjugate (PCV13) vaccination
Adults aged 19 years or older with immunocompromising conditions (including chronic renal failure
and nephrotic syndrome), functional or anatomic asplenia, cerebrospinal fluid leaks, or cochlear
implants who have not previously received PCV13 or PPSV23 should receive a single dose of PCV13
followed by a dose of PPSV23 at least eight weeks later.
All adults 65 years of age should receive a single dose of PCV13 followed by PPSV23 6 to 12
months later.
Adults aged 19 years or older with the aforementioned conditions who have previously received one
or more doses of PPSV23 should receive a dose of PCV13 one or more years after the last PPSV23
dose was received. For adults who require additional doses of PPSV23, the first such dose should be
given no sooner than eight weeks after PCV13 and at least five years after the most recent dose of
PPSV23.
When indicated, PCV13 should be administered to patients who are uncertain of their vaccination
status history and have no record of previous vaccination.
Although PCV13 is licensed by the US Food and Drug Administration for use among and can be
administered to persons aged 50 years or older, ACIP recommends PCV13 for adults aged 19 years
or older with the specific medical conditions noted above.
Pneumococcal polysaccharide (PPSV23) vaccination
When PCV13 is also indicated, PCV13 should be given first (see footnote ).
Vaccinate all persons with the following indications:
All adults aged 65 years or older;
Adults younger than 65 years with chronic lung disease (including chronic obstructive pulmonary
disease, emphysema, and asthma), chronic cardiovascular diseases, diabetes mellitus, chronic
renal failure, nephrotic syndrome, chronic liver disease (including cirrhosis), alcoholism, cochlear
implants, cerebrospinal fluid leaks, immunocompromising conditions, and functional or anatomic
asplenia (eg, sickle cell disease and other hemoglobinopathies, congenital or acquired asplenia,
splenic dysfunction, or splenectomy [if elective splenectomy is planned, vaccinate at least two
weeks before surgery]);
Residents of nursing homes or long-term care facilities; and
Adults who smoke cigarettes.
Persons with immunocompromising conditions and other selected conditions are recommended to
receive PCV13 and PPSV23 vaccines. See footnote for information on timing of PCV13 and
PPSV23 vaccinations.
Persons with asymptomatic or symptomatic HIV infection should be vaccinated as soon as possible
after their diagnosis.
When cancer chemotherapy or other immunosuppressive therapy is being considered, the interval
between vaccination and initiation of immunosuppressive therapy should be at least two weeks.
Vaccination during chemotherapy or radiation therapy should be avoided.
Routine use of PPSV23 vaccine is not recommended for American Indians/Alaska Natives or other
persons younger than 65 years unless they have underlying medical conditions that are PPSV23
indications. However, public health authorities may consider recommending PPSV23 for American
Indians/Alaska Natives who are living in areas where the risk for invasive pneumococcal disease is
increased.
When indicated, PPSV23 vaccine should be administered to patients who are uncertain of their
vaccination status and have no record of vaccination.
Revaccination with PPSV23
One-time revaccination five years after the first dose of PPSV23 is recommended for persons aged
19 through 64 years with chronic renal failure or nephrotic syndrome, functional or anatomic
asplenia (eg, sickle cell disease or splenectomy), or immunocompromising conditions.
Persons who received one or two doses of PPSV23 before age 65 years for any indication should
receive another dose of the vaccine at age 65 years or later if at least five years have passed since
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their previous dose.

No further doses of PPSV23 are needed for persons vaccinated with PPSV23 at or after age 65 years.
Meningococcal vaccination
Administer two doses of quadrivalent meningococcal conjugate vaccine (MenACWY [Menactra,
Menveo]) at least two months apart to adults of all ages with functional asplenia or persistent
complement component deficiencies. HIV infection is not an indication for routine vaccination with
MenACWY. If an HIV-infected person of any age is vaccinated, two doses of MenACWY should be
administered at least two months apart.
Administer a single dose of meningococcal vaccine to microbiologists routinely exposed to isolates of
Neisseria meningitidis, military recruits, persons at risk during an outbreak attributable to a vaccine
serogroup, and persons who travel to or live in countries in which meningococcal disease is
hyperendemic or epidemic.
First-year college students up through age 21 years who are living in residence halls should be
vaccinated if they have not received a dose on or after their 16th birthday. MenACWY is preferred for
adults with any of the preceding indications who are aged 55 years or younger as well as for adults
aged 56 years or older who (a) were vaccinated previously with MenACWY and are recommended for
revaccination, or (b) for whom multiple doses are anticipated. Meningococcal polysaccharide vaccine
(MPSV4 [Menomune]) is preferred for adults aged 56 years or older who have not received
MenACWY previously and who require a single dose only (eg, travelers).
Revaccination with MenACWY every five years is recommended for adults previously vaccinated with
MenACWY or MPSV4 who remain at increased risk for infection (eg, adults with anatomic or
functional asplenia, those with persistent complement component deficiencies, or microbiologists).
Hepatitis A vaccination
Vaccinate any person seeking protection from hepatitis A virus (HAV) infection and persons with any
of the following indications:
Men who have sex with men and persons who use injection or noninjection illicit drugs;
Persons working with HAV-infected primates or with HAV in a research laboratory setting;
Persons with chronic liver disease and persons who receive clotting factor concentrates;
Persons traveling to or working in countries that have high or intermediate endemicity of hepatitis
A; and
Unvaccinated persons who anticipate close personal contact (eg, household or regular
babysitting) with an international adoptee during the first 60 days after arrival in the United
States from a country with high or intermediate endemicity. (See footnote * for more information
on travel recommendations.) The first dose of the two-dose hepatitis A vaccine series should be
administered as soon as adoption is planned, ideally two or more weeks before the arrival of the
adoptee.
Single-antigen vaccine formulations should be administered in a two-dose schedule at either 0
and 6 to 12 months (Havrix), or 0 and 6 to 18 months (Vaqta). If the combined hepatitis A and
hepatitis B vaccine (Twinrix) is used, administer three doses at 0, 1, and 6 months; alternatively,
a four-dose schedule may be used, administered on days 0, 7, and 21 to 30 followed by a booster
dose at month 12.
Hepatitis B vaccination
Vaccinate persons with any of the following indications and any person seeking protection from
hepatitis B virus (HBV) infection:
Sexually active persons who are not in a long-term, mutually monogamous relationship (eg,
persons with more than one sex partner during the previous six months); persons seeking
evaluation or treatment for a sexually transmitted disease (STD); current or recent injection drug
users; and men who have sex with men;
Healthcare personnel and public safety workers who are potentially exposed to blood or other
infectious body fluids;
Persons with diabetes who are younger than age 60 years as soon as feasible after diagnosis;
persons with diabetes who are age 60 years or older at the discretion of the treating clinician
based on the likelihood of acquiring HBV infection, including the risk posed by an increased need
for assisted blood glucose monitoring in long-term care facilities, the likelihood of experiencing
chronic sequelae if infected with HBV, and the likelihood of immune response to vaccination;
Persons with end-stage renal disease, including patients receiving hemodialysis, persons with HIV
infection, and persons with chronic liver disease;
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Household contacts and sex partners of hepatitis B surface antigenpositive persons, clients and
staff members of institutions for persons with developmental disabilities, and international
travelers to countries with high or intermediate prevalence of chronic HBV infection; and
All adults in the following settings: STD treatment facilities, HIV testing and treatment facilities,
facilities providing drug abuse treatment and prevention services, healthcare settings targeting
services to injection drug users or men who have sex with men, correctional facilities, end-stage
renal disease programs and facilities for chronic hemodialysis patients, and institutions and
nonresidential day care facilities for persons with developmental disabilities.
Administer missing doses to complete a three-dose series of hepatitis B vaccine to those persons not
vaccinated or not completely vaccinated. The second dose should be administered one month after
the first dose; the third dose should be given at least two months after the second dose (and at least
four months after the first dose). If the combined hepatitis A and hepatitis B vaccine (Twinrix) is
used, give three doses at 0, 1, and 6 months; alternatively, a four-dose Twinrix schedule,
administered on days 0, 7, and 21 to 30 followed by a booster dose at month 12 may be used.
Adult patients receiving hemodialysis or with other immunocompromising conditions should receive
one dose of 40 mcg/mL (Recombivax HB) administered on a three-dose schedule at 0, 1, and 6
months or two doses of 20 mcg/mL (Engerix-B) administered simultaneously on a four-dose
schedule at 0, 1, 2, and 6 months.
*** Haemophilus influenzae type b (Hib) vaccination
One dose of Hib vaccine should be administered to persons who have functional or anatomic asplenia
or sickle cell disease or are undergoing elective splenectomy if they have not previously received Hib
vaccine. Hib vaccination 14 or more days before splenectomy is suggested.
Recipients of a hematopoietic stem cell transplant should be vaccinated with a three-dose regimen 6
to 12 months after a successful transplant, regardless of vaccination history; at least four weeks
should separate doses.
Hib vaccine is not recommended for adults with HIV infection since their risk for Hib infection is low.
Adapted from:
1. Advisory Committee on Immunization Practices (ACIP). Adult immunization schedules, United States
2014. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/vaccines
/schedules/hcp/adult.html (Accessed on February 11, 2014).
2. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13-valent pneumococcal conjugate vaccine and
23-valent pneumococcal polysaccharide vaccine among adults aged 65 years: Recommendations of
the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014;
63:822.
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Guide to discussing hospice care with patients

Identify other
"Is there anyone you rely on to help you make important decisions?"
decision
makers
"Who in the family should be there with us when we discuss the results?"
Assess
understanding
"What have your other doctors told you about your condition?"
of prognosis
"Have they talked to you about what this latest problem might mean for you?"
"From what you know, do you think that over the next month your cancer will
get better, worse, or stay the same?"
Define the
"What do you hope for most in the next few months?"
patient's goals
for care
"Is there anything that you're afraid of?"
Reframe goals
"I wish we could guarantee that we could keep you alive until your daughter's
graduation, but unfortunately we can't. Perhaps we can work together on a
letter for her to read on that day, so she will know you are there in spirit in
case you cannot be there."
Identify needs
"It can be very difficult to care for a family member at home, and no one can
for care
do it alone. Have you thought about what kinds of help you might need?"
"Would it help if we could find a way to deliver your medications to you?"
"Would it reassure you if we could send a nurse out to your home to check on
you?"
Summarize and
"So I think I understand that your main goal is to stay at home and spend
link goals with

care needs
time with your family. To do that, we will need to help you in several ways, for
instance, by sending a nurse out to your home and giving you both some help
around the house. Is that right?"
Introduce
hospice
"One of the best ways to give you the help that you will need to stay at home
with your family is a program called hospice. Have you heard of hospice?"
"Hospice is able to provide more services and support at home than most
other home care programs."
"The hospice team has a lot of experience caring for seriously ill patients at
home."
Respond to emotions elicited and provide closure

Acknowledge
response
"You seemed surprised to learn how sick you are."
Legitimize
reaction
"Many people are understandably upset when they learn how ill their loved
one is and that hospice is a possibility."
Empathize
"I can imagine how hard this is for both of you; you care about each other so
"I can see it's not easy for you to talk about hospice."
much."
Explore
"Tell me what's upsetting you the most."
concerns
Explain
"Hospice doesn't help people die sooner. Hospice helps people die naturally, in
hospice goals
their own time."

"Hospice helps people live as well as they can for as long as they can."
Reassure
"Hospice's goal is to improve your quality of life as much as possible for

whatever time you have left."
"Hospice can help you and your family make the most of the time you have
left."
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Reinforce
commitment to
"Let's think this over for a day or two; you know I will continue to care for
you whatever decision you make."
care
Recommend
hospice
"I think that hospice would be your best choice right now, but of course, the
final decision is yours."
"Hospice could be very helpful to you in the ways that we've talked about, but
I realize it's a big decision. I'd like to arrange for a hospice nurse to visit you
so you can decide for yourself whether hospice is right for you."
Reproduced with permission from: Casarett DJ, Quill TE. "I'm Not Ready for Hospice": Strategies for
Timely and Effective Hospice Discussions. Ann Intern Med 2007; 146:443. Copyright 2007 American
College of Physicians.
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Medical guidelines for determining appropriateness of hospice

referral: Disease specific guidelines
A patient will be considered to have a life expectancy of six months and be eligible for hospice
services if he/she meets criteria for the following disease specific baseline guidelines as well as
evidence of decline as outlined in non disease-specific baseline guidelines (shown on a separate
table):
Cancer diagnoses
Disease with metastases at presentation, OR
Progression from an earlier stage of disease to metastatic disease with either continued decline in
spite of therapy or patient declines further disease-directed therapy
Dementia
Severity level beyond Stage 7c of the Functional Assessment Staging (FAST): unable to walk,
dress, bathe, and toilet without assistance; urinary and fecal incontinence; no meaningful verbal
communication (stereotypical phrases only or the ability to speak is limited to six words or less);
AND
At least one medical complication within the past 12 months: aspiration pneumonia,
pyelonephritis or other urinary tract infection, septicemia, multiple stage 3-4 decubitus ulcers,
recurrent fever after antibiotics, inability to maintain sufficient fluid and calorie intake (>10
percent weight loss over 6 months or serum albumin <2.5 g/dL)
Heart disease
Symptomatic at rest despite optimal treatment with diuretics and vasodilators (preferably
ACE-inhibitors or ARBs)
Symptomatic supraventricular or ventricular arrhythmias resistant to antiarrhythmic medications
Elderly patients with intractable angina despite appropriate medical therapy who are not
candidates for coronary revascularization
HIV
CD4+ (T cell) count <25
Viral load >100,000 copies/mL
Decreased functional status with a Karnofsky performance score <50
At least one AIDS related illness
Central nervous system lymphoma
Poorly responsive systemic lymphoma
Weight loss of >30 percent lean body mass
Mycobacterium avium (MAC) bacteremia
Progressive multifocal leukoencephalopathy (PML)
Refractory visceral Kaposi sarcoma (KS)
Refractory cryptosporidium infection
Refractory toxoplasmosis
Liver disease
Prothrombin time more than five seconds over normal values or INR >1.5
Serum albumin <2.5 gm/dL
One or more medical conditions associated with advanced liver failure
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Ascites despite optimal diuretic regimen

Episodes of spontaneous bacterial peritonitis
Hepatorenal syndrome
Hepatic encephalopathy despite optimal medical treatment
Recurrent bleeding from esophageal varices after treatment
Pulmonary disease
Irreversible obstructive or restrictive disease
Disabling dyspnea at rest or with minimal exertion (FEV1 <30 percent predicted value is helpful
but not required)
Progressive disease documented as increasing Emergency Room visits or hospitalizations
Hypoxemia as defined as PaO2 55 mmHg or oxygen saturation 88 percent on room air
Hypercapnia as defined as PaCO2 50 mmHg
Cor pulmonale: right heart failure as a result of lung disease
Unintentional progressive weight loss of greater than 10 percent of body weight over the
preceding six months
Resting tachycardia >100 beats/min
Renal disease (acute and chronic)

No hemodialysis or renal transplant
Signs of uremia (confusion, nausea, pruritus, restlessness, pericarditis)
Intractable fluid overload
Oliguria
Intractable hyperkalemia >7.0 mg/dL
Creatinine clearance <10 cc/min (15 cc/min for diabetics)
Serum creatinine >8.0 mg/dL
Stroke or coma
Coma for greater than three days after a cerebrovascular accident (CVA)
Severe dysphagia in patients not receiving a feeding tube or parenteral nutrition
Chronic phase post-CVA with
Dementia Stage 7-C of the FAST scale
Karnofsky performance status <40
Weight loss of >10 percent in six months
Serum albumin <2.5 gm/dL
Coma with
Abnormal brain stem reflexes
No response to verbal stimuli
No withdrawal from painful stimuli
Serum creatinine >1.5 mg/dL
Karnofsky = 50: Requires considerable assistance and frequent medical care.

Karnofsky <50: Unable to care for self; requires equivalent of institutional or hospital care;
disease may be progressing rapidly.
FEV1: forced vital capacity in one second; PaO2: arterial oxygen tension; PaCO2: arterial carbon dioxide
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tension; FAST 7-C: Functional Assessment Staging 7-C; ARB: angiotensin receptor blocker;
ACE-inhibitor: angiotensin converting enzyme inhibitor; INR: international normalized ratio; ADL:
activities of daily living.
Sources:
1. The NHO medical guidelines for non-cancer disease and local medical review policy: hospice
access for patients with diseases other than cancer. Hosp J 1999.
2. Centers for Medicare & Medicaid Services. Local Coverage Determination (LCD) for Hospice
Determining Terminal Status (L32015) http://www.cms.gov (Accessed on July 16, 2013).
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Lung allocation score for candidates age 12 and older

Step 1: The transplant center enters the factors in part 1 below on the UNet web site. A Cox
proportional hazards model is used to derive an estimate of the number of days a recipient would
be expected to live during the first year post transplant. This is the post transplant survival
measure.
Step 2: The transplant center enters the factors in part 2 below on the UNet web site. A Cox
proportional hazards model is used to derive an estimate of the expected number of days a
candidate would live without a transplant during an additional year on the waitlist. This is the
waitlist survival measure.
Step 3: Using the values derived in steps 1 and 2, the transplant benefit measure is calculated:
Transplant benefit = post transplant survival (days) - waitlist survival (days).
Step 4: The raw allocation score = transplant benefit (days) - waitlist survival (days).
Step 5: The lung allocation score is derived by normalizing the raw allocation score to a range
of 0 to 100. The higher the score the higher the priority.
Part 1 Post transplant survival measure:

1. FVC (Group B, D)
2. PCW pressure 20 (Group D)
3. Continuous mechanical ventilation
4. Age
5. Serum creatinine
6. Functional Status (NYHA class)
7. Diagnosis
Part 2 Waiting list urgency measure:

1. Forced vital capacity (FVC)
2. Pulmonary artery systolic pressure (Group A, C, D)*
3. Pulmonary artery mean pressure
4. Pulmonary capillary wedge pressure
5. Supplemental O 2 required at rest (Group A, C, D)*
6. Age
7. Body mass index (BMI)
8. Diabetes
9. Functional status
10. Six-minute walk distance
11. Continuous mechanical ventilation
12. Diagnosis
13. pCO 2
*Group A: COPD, alpha-1-antitrypsin, emphysema, lymphangioleiomyomatosis, bronchiectasis,
sarcoidosis with a mean PA pressure 30 mmHg.
Group B: Pulmonary hypertension (IPAH, Eisenmenger's syndrome, etc).
Group C: Cystic fibrosis, immunodeficiency disorders (eg, Hypogammaglobulinemia).
Group D: IPF, other causes of pulmonary fibrosis, sarcoidosis with PA >30 mmHg, obliterative
bronchiolitis (non-retransplant).
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pCO2 may be taken from arterial, capillary or venous measurement. If venous, 6 mmHg will be
subtracted to produce an equivalent arterial value. This a adjusted for any change in value over time
that is greater than 15 percent.
Data from: http://optnpilot.unos.org/converge/resources/allocationcalculators.asp?index=88.
2/12/2015 02:54

Treatment of Idiopathic Pulmonary Fibrosis

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Treatment of idiopathic pulmonary fibrosis

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