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Acute exacerbations of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without a clear
etiology. Peripheral and basal predominant pulmonary fibrosis with histopathologic and/or
computed tomography findings consistent with usual interstitial pneumonia (UIP) are
diagnostic of the disease. Patients with IPF have a poor prognosis: median survival of two to
three years from diagnosis, the individual clinical course is quite variable; some individuals
have stable or slow progression, others demonstrate rapid progression, and still others
develop episodic acute declines in lung function, known as "acute exacerbations" of IPF

"acute exacerbation" (AE) of IPF included all of the following:●A previous or concurrent
diagnosis of IPF●Deterioration within 30 days●New bilateral ground glass opacities and/or
consolidation on a background of reticular or honeycomb pattern consistent with usual
interstitial pneumonia (UIP)●No evidence of pulmonary infection by endotracheal aspiration
or bronchoalveolar lavage ●Exclusion of alternative causes including left heart failure,
pulmonary embolism, or an identifiable cause of acute lung injury

AE as "an acute, clinically significant respiratory deterioration characterized by evidence of

new widespread alveolar abnormality," but does not set an exact 30 day limit for symptom
onset and does not require exclusion of infection. The following diagnostic criteria are
proposed:●A known diagnosis of IPF (diagnosis may be made at the time of acute respiratory
deterioration)●Acute worsening, "typically less than one month's duration"●Computed
tomography of the chest with new bilateral ground glass opacification and/or consolidation
superimposed on a background of findings consistent with usual interstitial pneumonia
(bibasilar reticular opacities associated with honeycomb changes and traction bronchiectasis)
●Heart failure or fluid overload does not fully explain the worsening.

events are further classified into "triggered" (ie, postprocedure, drug toxicity, infection,
aspiration) versus "idiopathic" (ie, no inciting event identified).

There are multiple examples of lung injury that subsequently develop into an AE-IPF
Microaspiration of gastric contents – Microaspiration of gastric contents is a proposed risk
factor for exacerbations and progression of IPF ●Surgery and thoracic procedures –
Thoracic procedures, such as surgical lung biopsy, lung cancer resection, and bronchoscopy,
have been associated with the development of IPF exacerbations . Nonthoracic surgical
procedures have also been implicated in development of exacerbations . Potential
mechanisms include administration of high concentrations of oxygen and volutrauma or
barotrauma during mechanical ventilation. ●Advanced lung disease – Clinical factors of
physiologically advanced IPF are associated with increased rates of AE, including: lower
FVC, diffusing capacity of the lung for carbon monoxide (DLCO), and six-minute walk
distance ●Other – A number of other potential contributors have been implicated, such as
evidence of pulmonary hypertension, higher body mass index, coronary artery disease, and
treatment with immunosuppressive therapy

CLINICAL MANIFESTATIONS — In patients with IPF, an acute exacerbation typically

presents with shortness of breath or worsening exercise tolerance that develop over days to
weeks, but generally less than one month. Cough (with or without sputum production) is
common; fever and flu-like symptoms may also be present.
On physical examination, the patient may be tachypneic and will typically have bibasilar
crackles consistent with the underlying diagnosis of IPF.
Patients typically demonstrate impaired gas exchange, as evidenced by 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 computed tomography (HRCT) reveals bilateral ground glass or consolidative
opacities superimposed on a background of typical HRCT features of IPF (eg, bibasilar
reticular opacities, honeycomb changes, traction bronchiectasis). (

DIAGNOSTIC EVALUATION — The presenting symptoms and signs of AE-IPF are not
specific, and the evaluation should exclude alternate diagnoses (eg, pneumothorax, heart
failure, venous thromboembolism) and identify potential triggers of AE-IPF, such as lung
infection or a recent lung procedure.

There are no laboratory studies specific to the diagnosis of AE in IPF. As identification and
management of comorbidities is fundamental to the management of these patients, careful
evaluation for potential contributing or alternate diagnoses is critical. We typically obtain
complete blood and differential cell counts, brain natriuretic peptide, serial troponin tests,
procalcitonin, and sensitive D-dimer. C-reactive protein (CRP) and erythrocyte sedimentation
rate (ESR) are nonspecific and have not proved helpful.

Testing for potential lung infection typically includes blood cultures, urinary antigen assays
for Streptococcus pneumoniae and Legionella, rapid influenza antigen test on respiratory
secretions (in the appropriate season), and multiplex polymerase chain reaction (PCR) test for
respiratory viruses
Imaging — The first step is often a conventional chest radiograph to exclude a pneumothorax
or other abnormality that requires immediate attention. High-resolution computed
tomography (HRCT), with or without a rule-out pulmonary embolism protocol, is necessary
for appropriate classification of the parenchymal abnormalities .We have a very low
threshold to perform CT pulmonary angiogram to exclude pulmonary embolism due to the
significantly increased risk of venous thromboembolism in IPF . HRCT in patients with an
AE-IPF will demonstrate typical chronic background findings of a usual interstitial
pneumonia pattern (eg, reticulation, traction bronchiectasis, honeycomb changes) in
combination with more acute abnormalities of increased ground glass opacity and/or
consolidation. Three HRCT distribution patterns have been described: peripheral, multifocal,
and diffuse

For patients who are unable to undergo CT pulmonary angiography due to kidney disease, an
alternative approach is to obtain ventilation-perfusion (V/Q) scanning, possibly with lower
extremity compressive ultrasonography if the V/Q scan is indeterminate.

Flexible bronchoscopy — Flexible bronchoscopy with bronchoalveolar lavage (BAL) is part

of our standard evaluation of patients with AE-IPF, as long as the patient is clinically able to
tolerate the procedure. The main role is to identify and characterize any infection or
malignancy. When performing a BAL for this purpose, we select a subsegment that appears
to be involved based on the HRCT findings. BAL samples are sent for a broad spectrum of
microbiologic tests, including stains and cultures for bacteria, mycobacteria, and fungi, as
well as multiplex PCR testing for respiratory viruses. Transbronchial biopsies are generally
not helpful due to their small size and are not part of our standard work-up
Avoidance of surgical lung biopsy — Surgical lung biopsy is of minimal value in AE-IPF.
Given the high surgical risk in this patient population, we do not recommend it [

The differential diagnosis of AE-IPF includes venous thromboembolism, infection, and heart
failure. A pneumothorax can complicate IPF, but would usually be recognized on a
conventional chest radiograph. Pulmonary hypertension developing as a consequence of IPF
is also in the differential diagnosis of worsening dyspnea, but would not have the new
radiographic opacities associated with AE-IPF.

●Venous thromboembolism – IPF is associated with a significantly increased risk of venous

thromboembolism (VTE) ●Infection – For patients who can tolerate the procedure, our
standard practice is to perform a full investigation for potential lung infection and to initiate
empiric antibiotics for pneumonia while studies are pending ●Heart failure – Given the
average age of individuals with IPF, careful cardiac assessment for heart failure or
myocardial infarction is appropriate. We typically begin with serial troponin, brain natriuretic
peptide (BNP), and an electrocardiogram.- echocardiogram●Pulmonary hypertension –
Pulmonary hypertension (group 3), a well-known complication of IPF, also presents with
worsening dyspnea, but without increased radiographic opacities. The diagnosis is often
suspected in patients with worsening gas transfer without evidence of worsening interstitial
lung disease. Plasma BNP is often increased, and Doppler echocardiography can provide an
estimate of pulmonary artery systolic pressure
TREATMENT — Optimal therapy for AE-IPF has not been established. All patients require
supportive care to relieve hypoxemia and alleviate symptoms of shortness of breath and
cough. Most experts, including ourselves, administer systemic glucocorticoids

Supportive measures for all patients with AE-IPF include provision of supplemental oxygen
and relief of dyspnea. Standard measures for prevention of VTE and stress gastropathy are

●Oxygenation – Patients with AE-IPF often have a high oxygen requirement to maintain a
pulse oxygen saturation above 88 percent and their high inspiratory flow rate may make
oxygenation with standard low-flow nasal cannula difficult. High-flow oxygen therapy by
nasal cannula may be a reasonable alternative for patients with acute hypoxemic respiratory
failure without hypercapnia who are not able to achieve an adequate SpO2 with low-flow
oxygen. ●Relief of dyspnea – For some patients, treating hypoxemia with supplemental
oxygen is sufficient to treat dyspnea, but dyspnea due to IPF may be refractory. Palliative
care strategies may help alleviate dyspnea, as described below. ●Prevention of venous
thromboembolism ●Anti-acid therapy

Mechanical ventilation — The role and efficacy of noninvasive positive pressure ventilation
and low tidal volume mechanical ventilation have not been formally studied in AE-IPF. We
believe that mechanical ventilation is of limited value in the IPF patient with an acute
deterioration without a defined treatable trigger, based on high mortality rates and the poor
outcomes reported for mechanical ventilation in IPF. Thus, we make every effort to
communicate the limitations of mechanical ventilation to the patient and their family.
Multiple cohorts demonstrate poor short-term prognosis for patients with AE-IPF admitted to
the ICU and/or mechanically ventilated. Among those with a primary diagnosis of IPF, the
mortality rate was 49 percent regardless of the type of ventilatory support.
Glucocorticoids — The international evidence-based guidelines for AE-IPF suggest
administering systemic glucocorticoids in the majority of patients with AE-IPF. No clinical
trials have been performed, so the guidelines put a high value on anecdotal reports of benefit.
We typically treat AE-IPF with glucocorticoids in the range of prednisone 1 mg/kg per day
orally to methylprednisolone 1 gram per day intravenously for three days followed by a taper,
based on severity of disease and response to therapy. For those individuals who appear to a
have a clinical response to glucocorticoids, we will typically taper them slowly over the
course of weeks to months ensuring there is no recurrence with close follow up.

Antibiotics — Broad-spectrum antibiotics are typically initiated upon presentation as the

radiographic findings overlap with pneumonia. Given the severity of disease and poor
prognosis, many experts complete a seven day course even if all cultures are negative. Our
approach is to cover broadly at presentation, including atypical coverage. If cultures/testing
identify a specific pathogen, we narrow the coverage appropriately. For those without a
pathogen, we limit the antibiotics to a seven-day course.

Nintedanib and pirfenidone — Current data suggest that the antifibrotic agent, nintedanib,
may help prevent AEs . Unfortunately, the value of adding or continuing nintedanib or
pirfenidone during an AE remains unknown. Our practice is to continue the patient on their
established therapy. For patients not on one of these agents, it may be reasonable to initiate
one of the antifibrotic agents after resolution of the AE.
Lung transplantation — Lung transplantation provides a survival benefit for selected patients
who have IPF, but are not in the midst of an AE. For those with an acute deterioration,
perioperative risks of transplantation are clearly greater. For individuals transplanted in the
context of mechanical ventilation or ICU stay, both one- and five-year survivals after lung
transplantation are decreased compared with stable patients undergoing elective
transplantation The best recommendation remains that patients with IPF who may be
candidates for lung transplantation be referred for evaluation early in the course of their
disease, so that full assessments may be made while the patient is stable.
Palliative care — Given the poor prognosis of patients with AE-IPF, palliative care
consultation to provide relief from symptoms and stress for the patient and family is vital.
Palliation of dyspnea is an important component of end-of-life care. Palliative strategies to
reduce dyspnea in an individual patient may include relaxation techniques, facial cooling
with a fan, opiates, benzodiazepines, and sometimes noninvasive ventilation. A few studies
have suggested a role for noninvasive ventilation to reduce dyspnea, although this requires a
clear discussion of goals of care, especially in patients who prefer not to pursue life-
prolonging treatments.

PROGNOSIS — AE-IPF portends a poor prognosis for patients with this progressive fibrotic
lung disease. AE precedes approximately 40 percent of IPF deaths , and the median survival
following an AE is approximately three to four months. More severe disease (lower baseline
forced vital capacity and diffusing capacity of the lung for carbon monoxide) as well as more
extensive computerized tomography findings and worse oxygenation at presentation are
associated with worse outcome Respiratory failure resulting in the need for mechanical
ventilation or noninvasive ventilation has an extremely poor prognosis