Alphabet Soup
A Primary Care Physician’s Guide to
Idiopathic Interstitial Pneumonitis
Matt Mundy MS3
Idiopathic Interstitial Pneumonitis :
The Dilemma
Identification of this class of diseases is notoriously difficult.
Uncertain etiologies, discrepancies in the descriptions of the
clinical, radiographic and pathologic characteristics of the
disease processes and the necessity for multidisciplinary
communication and cooperation in the clinical investigation all
add to the challenge of making an accurate diagnosis.
Combined with a seemingly endless string of acronyms used
to refer to specific disease subtypes, these factors can make
Idiopathic Interstitial Pneumonitis a seemingly insurmountable
challenge to clinicians.
So………
1. For a Primary Care Physician, what are the most important
questions to ask about Idiopathic Interstitial Pneumonitis?
2. What are the major subtypes of Idiopathic Interstitial
Pneumonitis?
3. What are the important Clinical, Pathologic, and
Radiographic findings in each of these subtypes?
4. What therapies are available when a diagnosis is ultimately
made?
What are the most important
questions to ask?
•By understanding the acronyms and answering just a few questions, a
primary care doctor can have good insight into a patients’ disease and
its prognosis. This understanding can then be used to guide future
therapy and clinical decision making.
Welcome to IIP 101
An quick and easy guide to the
basics of Idiopathic Interstitial
Pneumonitis
A, B, C, D, E, F, G………..
Question #1
What do all the acronyms mean?
Clinical Diagnosis
Pathologic Diagnosis
Idiopathic Pulmonary Fibrosis (IPF)……………………..……..Usual Interstitial Pneumonia (UIP)
Desquamative Interstitial Pneumonia (DIP)……………….……………………………….…….….same (DIP)
Respiratory Bronchiolitis Interstial Lung Disease (RBILD)…….…………….same (RBILD)
Acute Interstitial Pneumonia (AIP)…………………………..…Diffuse Alveolar Damage (DAD)
Nonspecific Interstitial Pneumonia (NSIP)………………………………………………………same (NSIP)
*adapted from: The American Thoracic Society / European Respiratory Society International
Multidisciplinary Consensus Classification 2002
Important clarifications about the acronyms
1. Each pathologic diagnoses has a distinct pattern
2. Each of the pathologic patterns has unique and consistent
radiographic findings
3. The pathologic and radiographic patterns can have multiple
etiologies
4. A clinical diagnosis of a corresponding Idiopathic Interstitial
Pneumonitis can only be made when no cause for the
pathology can be identified
ILD Vs. DLD: What, more acronyms?
•Interstitial Lung Disease (ILD), a term used by pathologists
refers to the same set of diseases that radiologists call Diffuse
Lung disease(DLD).
•There are over 150 identified processes that fall under this
description
•All of them can lead to lung scarring and respiratory failure
•Examples include: occupational, exposure related and drug
induced diseases, eosinophilic pneumonias, sarcoidosis, collagen
vascular related ILD, granulomatous disease and finally
Idiopathic Interstitial Pneumonitis
So………
IIP
is a subset of
ILD
And………..
IPF, DIP, RB-ILD,
AIP and NSIP
Are all subtypes of
IIP
See. It’s not so scary after all.
Question #2
What is the most important distinction
to make?
UIP
Vs.
Everything
Else
Why?
Complete recovery is possible
with all types of Idiopathic
Interstitial Pneumonitis
Except UIP/IPF!!!
• Because of its poor prognosis and refractoriness to
treatment, it is essential to identify cases of usual
interstitial pneumonia / idiopathic pulmonary fibrosis
• Things to remember:
1. Immunosuppression or smoking cessation will
improve survival all types of IIP
EXCEPT UIP/IPF
2. The median survival after diagnosis for
UIP/IPF is 2.5-3.5 years
3. No therapy has been shown to reduce the
severity of pathologic findings or improve the
prognosis of UIP/IPF
The diagnosis of UIP/IPF does
not require pathologic confirmation
•With a high clinical suspicion, the characteristic
radiographic findings of UIP are specific enough to be
sufficient for diagnosis
•Studies show that combining clinical history, including
pulmonary function tests, and CT findings alleviates the
need for biopsy in up to 89% of patients
•When conflicting or inconclusive findings arise, a biopsy
specimen can solidify the diagnosis
Again…….
The diagnosis of UIP/IPF
implies many things, including:
1. There is probably no need for a biopsy
2. Treatment of any sort is likely to have little, if any
effect
3. MOST IMPORTANTLY: UIP/IPF implies a
very poor prognosis for the patient no matter what
their age, gender or extent of disease
Question #3
What is “ground glass” anyway?
*many of the radiographic patterns of IIP involve ground glass
opacities, therefore, the ability to identify ground glass on a
CXR and CT is essential
Ground Glass Opacity:
“focal or diffuse areas of ill-defined, hazy, increased lung
attenuation, which cause pulmonary vascular indistinctness,
yet through which vessels can still be identified.”*
*Nowers et al
Ground Glass Opacity:
The ground glass pattern can be identified on both CT
and conventional radiographs
Ground Glass Opacity:
Ground glass falls on a spectrum of increasing opacification
that culminates in consolidation
consolidation
Ground glass
What are the major subtypes of IIP?
and
What are the most pertinent clinical,
radiographic and pathologic findings?
*remember that IIP is a multidisciplinary diagnosis
Important subtypes of IIP
1. UIP/IPF (usual interstitial pneumonia/idiopathic pulmonary fibrosis)
2. NSIP (nonspecific interstitial pneumonia)
3. AIP/DAD (acute interstitial pneumonia/diffuse alveolar damage)
4. RB-ILD (respiratory bronchiolitis interstitial lung disease)
5. DIP (desquamative interstitial pneumonia)
*RB-ILD and DIP are strongly associated with smoking and respond well to smoking
cessation. Therefore, arguments have been made against classifying them as idiopathic.
UIP
IPF
UIP / IPF
(Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis)
Clinical Presentation -History
•age: usually greater than 50
•male to female ratio: between 1:1 and 2:1
•75% have a smoking history
•insidious exertional dyspnea which is disabling over time
•nonproductive cough - refractory to antitussive medication
•fever, malaise and arthralgia reported in 50%
UIP / IPF
(Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis)
Clinical Presentation - Physical Exam
•tachypnea
•bibasilar inspiratory crackles
•75% have digital clubbing
•PFTs show restrictive physiology (
VC and TLC,
FEV1 to FVC ratio)
•reduced diffusion capacity (DL )
CO
•symptoms usually start >6 months before clinical presentation
UIP / IPF
(Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis)
Digital Clubbing
UIP / IPF
(Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis)
Differential Diagnosis (etiologies that can cause a UIP pattern)
•asbestosis
•collagen vascular disease induced interstitial lung disease
•drug toxicity
•chronic extrinsic allergic alveolitis
UIP / IPF
(Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis)
Radiographic Findings – Chest Radiograph
•Peripheral, lace-like areas of fine reticular opacity
•Concentrated posteriorly in the bases
•Visible fibrosis in costophrenic recesses on lateral CXR
•Ground glass opacification of lower lobes
UIP/IPF
Peripheral reticular opacity
more predominant in the
bases
UIP / IPF
(Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis)
Radiographic Findings – CT
•Similar to CXR
•Fibrosis
•Traction bronchiectasis
•Architectural distortion
•+- honeycombing
•Variable ground glass opacity
•Concentrated in lower lobes
UIP/IPF
Peripheral
ground
glass
No evidence of honeycombing
Area of consolidation
UIP/IPF
Peripheral traction bronchiectasis
and honeycombing
More predominant in lung base
UIP/IPF
Bilateral peripheral honeycomb cysts
UIP/IPF
marked honeycombing – end stage disease
UIP / IPF
(Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis)
If the clinical and radiographic
findings are consistent and suggest
UIP/IPF a diagnosis can be made
without a biopsy. Pathologic
evidence is only necessary in cases
where the diagnosis is uncertain
*all other forms of IIP require pathologic confirmation for diagnosis
UIP / IPF
(Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis)
Pathologic Findings
•Video Assisted Thoroscopic Biopsy (VATS) required
because of the peripheral distribution of disease
•Patchy, dense subpleural collagenous fibrosis +/Honeycombing
•Fibroblastic foci of acute injury
•Very little inflammation
•Areas of interspersed normal lung
•The hallmark is spatial and temporal heterogeneity of disease
UIP/IPF – gross specimen
Small, firm, fibrosed lung seen in advanced disease
UIP/IPF – gross specimen
White tissue represents interstitial fibrosis
UIP/IPF – histologic section
Spatial heterogeneity: fibrosis with interspersed normal lung
UIP/IPF – histologic section
Area of acute lung injury: fibroblastic foci
UIP/IPF – histologic section
Honeycombing: the final stage of UIP/IPF
UIP / IPF
(Usual Interstitial Pneumonia/Idiopathic Pulmonary Fibrosis)
Treatment and Prognosis
•no response to steroids or other immunosuppressive drugs
•smoking cessation does not change course of disease
•course marked by periods of rapid clinical deterioration
•5 year survival rate: 10%-50%
•median survival after diagnosis: 2.5-3.5 years
•prognosis worse in men
NSIP
NSIP
Nonspecific Interstitial Pneumonia
Clinical Presentation - History and Physical
•less chronic than UIP with a duration of months to years
•age: 39-50 years
•male to female ratio: 2:1
•68% with smoking history
•dyspnea, cough and occasional fever
•tachypnea, crackles, no digital clubbing
•PFT’s: restrictive
NSIP
Nonspecific Interstitial Pneumonia
Differential Diagnosis (etiologies that can cause an NSIP pattern)
•collagen vascular disease induced interstitial lung disease
•extrinsic allergic alveolitis
•resolving acute lung injury
•drug induced pneumonitis
•infection (HIV)
NSIP
Nonspecific Interstitial Pneumonia
•NSIP is further divided into subtypes
•Cellular NSIP is the less severe form that occurs in
younger people
•Fibrotic NSIP shares many of the features of UIP and
has a worse prognosis than the cellular subtype
•These distinctions become important for both the
radiographic and pathologic investigation of the disease
•Although distinctions have been made, it is clear that the
two subtypes lie on a continuum and overlap does exist
NSIP
Nonspecific Interstitial Pneumonia
Radiographic Findings – cellular subtype
•Relative predominance of ground glass opacity with fewer
areas of fibrosis
•Can be distributed diffusely or in a basilar predominant
pattern
•Peribronchovascular thickening and areas of consolidation
•Occasional traction bronchiectasis secondary to chronic
inflammation
NSIP
Nonspecific Interstitial Pneumonia
Radiographic Findings – fibrotic subtype
•Relative predominance of fibrosis with areas of ground
glass opacity
•Reticular opacities and traction bronchiectasis can be
seen
•Severe form can be indistinguishable from UIP
•Decreased occurrence and severity of honeycombing in
the face of severe fibrosis suggests NSIP
NSIP
Reticular
opacity
Ground glass
Bilateral basal ground glass and reticular
opacities with peripheral distribution
NSIP
Ground glass
Reticular
opacity
Traction bronchiectasis
NSIP
Nonspecific Interstitial Pneumonia
Pathologic Findings
•Diffuse pattern of inflammation
•Relatively more fibrosis in fibrotic subtype
•Underlying parenchyma is intact
•Fibrosis, when present, is temporally homogenous
•Mature hypocellular collagen
•Little or no honeycombing
•Inflammation predominantly lymphocytes
NSIP
Widened alveolar walls (arrows) with increased numbers of
lymphocytes adjacent to an area of normal lung
NSIP
Pattern of mixed inflammation and fibrosis
inflammation
Fibrosis
*note the absence of honeycombing
NSIP
Nonspecific Interstitial Pneumonia
Treatment and Prognosis
•the two subtypes are treated the same but their outcomes
are very different
•glucocorticoids are the mainstay of therapy
•prognosis highly dependent on amount of fibrosis present
•cellular: 5 year survival - 100%, 10 year survival - 100%
•fibrotic: 5 year survival - 90%, 10 year survival - 35%
AIP
DAD
AIP/DAD
Acute interstitial Pneumonia/Diffuse Alveolar Damage
Clinical Presentation - History and Physical
•Acute onset of respiratory distress
•Mainly affects current smokers
•Usually presents in 4th or 5th decade – mean age is 49
•Male to female ratio: 2:1
•Cough and dyspnea lasting weeks to months
•50% have fever
•50% have digital clubbing
AIP/DAD
Acute interstitial Pneumonia/Diffuse Alveolar Damage
Differential Diagnosis – (etiologies that can cause DAD pattern)
•ARDS
•Shock
•Sepsis
•Radiation
•Chemotherapy
•Toxic inhalants
•Viruses
AIP/DAD
Acute interstitial Pneumonia/Diffuse Alveolar Damage
Radiographic Findings
•Initial patchy ground glass opacity
•Evolves into more confluent ground glass
•Scattered areas of consolidation
•Traction bronchiectasis and architectural distortion may
be seen on CT
AIP/DAD
Diffuse symmetric
ground glass
opacities with
slightly peripheral
predominance
AIP/DAD
Bilateral ground glass
AIP/DAD
Bilateral ground glass opacity
Air bronchogram
AIP/DAD
Acute interstitial Pneumonia/Diffuse Alveolar Damage
Pathologic Findings
•Divided into acute, organizing and fibrotic stages
•Acute stage: (peak at 4 days) interstitial and air space
edema, hyaline membranes, hemorrhage, fibrinous exudate
•Organizing stage: (peak at 2-3 weeks) proliferation of
fibroblasts, loose granulation tissue involving septa,
thickened vessels
•Fibrotic stage: (after 3-4 weeks) extensive, dense fibrotic
remodeling, possible honeycombing
AIP/DAD
Organizing stage : Interstitial thickening with collapsed alveolar septa
Alveolar Ducts
AIP/DAD
Acute Stage : fibrinous exudate
Hyaline membranes
AIP/DAD
Acute interstitial Pneumonia/Diffuse Alveolar Damage
Treatment and Prognosis
•Supportive care is mainstay of treatment – mechanical
ventilation is often required
•Steroids and antibiotics have shown little benefit
•>60% mortality
•Most deaths occur within the first 6 months
•People who survive usually do not have recurrence of
disease
RB-ILD
RB-ILD
Respiratory Bronchiolitis Associated Interstitial Lung Disease
Clinical Presentation – history and physical
•Usually asymptomatic
•May have cough or mild dyspnea
•Age: usually 4th or 5th decade
•Male to female ratio: 1:1
•History of heavy smoking
•Bibasilar end inspiratory crepitations
•Coarse rales
RB-ILD
Respiratory Bronchiolitis Associated Interstitial Lung Disease
Radiographic findings
•Ill-defined ground glass centrilobular nodules
•Confluent patchy areas of ground glass may also be seen
•mid to upper lung zone predominant
•Fibrosis not seen on CXR or CT
•Progressive decrease in lung volumes
•CXR is often normal
RB-ILD
Diffuse centrilobular opacities
predominantly in lower lung zones
RB-ILD
Diffuse centrilobular
ground glass opacities
RB-ILD
Respiratory Bronchiolitis Associated Interstitial Lung Disease
Pathologic Findings
•VATS required for diagnosis because disease is
centered around terminal bronchioles
•Mild interstitial mononuclear infiltrates of terminal
bronchioles that extend into adjacent alveolar septa
•Mild interstitial thickening
•Little or no fibrosis
RB-ILD
•Alveolar macrophages in lumen of respiratory bronchiole
•mildly thickened bronchiolar wall
RB-ILD
Respiratory Bronchiolitis Associated Interstitial Lung Disease
Treatment and Prognosis
•Smoking cessation is mainstay of therapy
•Favorable but variable response to corticosteroids
•100% 10 year survival
DIP
DIP
Desquamative Interstitial Pneumonia
Clinical Presentation – history and physical
•>90% are smokers
•Age: 4th or 5th decade
•Subacute cough and dyspnea lasting weeks to months
•Male to female ratio: 2:1
•Restrictive PFT’s, Decreased DLCO, hypoxemia
•50% with digital clubbing
DIP
Desquamative Interstitial Pneumonia
Differential Diagnosis (etiologies that result in DIP pattern)
•Subacute extrinsic allergic alveolitis
•PCP
•Sarcoid
•Drug toxicity
•Asbestosis
•Eosinophilic granulomatosis
•UIP, NSIP
DIP
Desquamative Interstitial Pneumonia
Radiographic findings
•Diffuse ground glass opacities
•Similar to RB-ILD, but confluent patchy areas of
ground glass predominate
•More likely affects basilar and sub-pleural areas
•Fibrosis rarely seen on CXR or CT
•Progressive decrease in lung volumes
DIP
Diffuse Gound Glass Opacities on CXR and CT
DIP
Diffuse Gound Glass Opacities on CXR and CT
DIP
Desquamative Interstitial Pneumonia
Pathologic findings
•Diffuse intraalveolar pigmented macrophage accumulation
•Mild interstitial thickening
•Inflammation superimposed on normal lung architecture
•Fibrosis of septa
•Occasional honeycombing
•Hyperplasia of Type 2 pneumocytes
•Temporal Homogeneity
DIP
Macrophage accumulation with mild interstitial thickening
DIP
Diffuse intraalveolar macrophage accumulation
A quick recap……..
1. IIPs are a spectrum of interstitial lung diseases for which
no clear etiology can be determined
2. The primary responsibility, when confronted with a patient
with IIP is to differentiate whether they have a case of
UIP/IPF or a case of something else
3. Although different types of IIP can present similarly in the
clinic, radiographic and pathologic findings can clarify the
diagnosis - A multidisciplinary approach is essential
4. Whether it be smoking cessation, or corticosteroid
therapy, all types of IIP can be effectively treated and
even cured, except UIP/IPF
Most Importantly…………
Remember that behind the radiographs, chest CTs and
histological sections, somewhere lost in the sea of acronyms is a
person with a disease. Therefore, making an accurate
diagnosis is essential, as it will dramatically influence the way
your patient approaches the future.
References
1.
Myers J. Pathologic Classification of Idiopathic Interstitial Pneumonias.
Up To Date, 2004.
2.
Nowers K. Rasband JD. Berges G. Gosselin M. Approach to
Ground Glass Opacification of the Lung. Seminars in Ultrasound, CT
and MRI. 23(4): 302-323, August 2002.
3.
Pandit-Bhalla M. Diethelm L. Ovella T. Sloop GD. Valentine VG.
Idiopathic interstitial pneumonias: an update. Journal of Thoracic Imaging.
18(1):1-13, Jan uary 2003.
4.
Reynolds JH. Hansell DM. The interstitial pneumonias: understanding
the acronyms. Clinical Radiology. 55(4):249-60, April 2000.
5.
Sholand MB. Clinical Approach to Interstitial Lung Disease. Seminars
in Ultrasound, CT and MRI. 23(4): 269-274, August 2002.
6.
Szakacs JG. Pathologist’s Approach to Diffuse Lung Disease.
Seminars in Ultrasound, CT and MRI. 23(4): 275-287, August 2002.