IDIOPATHIC INTERSTITIAL PNEUMONIAS
The idiopathic interstitial pneumonias (IIPs) are a subset of the acute and chronic lung disorders collectively referred to as interstitial lung diseases (ILDs) or diffuse parenchymal lung diseases. In 2002, the American Thoracic Society/European Respiratory Society consensus classiﬁcation separated the IIPs into seven clinical-radiologic-pathologic entities: idiopathic pulmonary ﬁbrosis (IPF), idiopathic nonspeciﬁc interstitial pneumonia (NSIP), respiratory bronchiolitis–associated ILD/desquamative interstitial pneumonia (RB-ILD/DIP), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP), and lymphoid interstitial pneumonia (LIP). The various sub-groups of the IIPs are often clinically indistinguishable (with the exception of COP and AIP).
IDIOPATHIC PULMONARY FIBROSIS
IPF is a speciﬁc form of chronic ﬁbrosing interstitial
pneumonia limited to the lung and associated with the histologic appearance of
usual interstitial pneumonia (UIP) on surgical lung biopsy. IPF mainly affects
people older than 50 years of age. The incidence of IPF is estimated at 6.8
cases per 100,000, and the prevalence is estimated to be 14.0 per 100,000.
Cigarette smoking has been identiﬁed as a risk factor for developing IPF. The clinical
manifestations of IPF include dyspnea on exertion, nonproductive cough, and
inspiratory crackles on physical examination. Digital clubbing and signs of cor
pulmonale may be present in advanced disease.
The chest radiographs typically reveal diffuse
bibasilar reticular opacities. However, the chest radiograph lacks diagnostic
speciﬁcity. High-resolution computed tomography (HRCT) scanning is more
sensitive and speciﬁc for the diagnosis of IPF. The characteristic HRCT
features of IPF include patchy, predominantly basilar, subpleural reticular
opacities; traction bronchiectasis and bronchiolectasis; and subpleural
honeycombing. The presence of extensive ground-glass opacities, nodules, upper
lobe or mid-zone predominance of ﬁndings, and signiﬁcant hilar or mediastinal
lymphadenopathy should question the radiographic diagnosis of IPF.
Pulmonary function tests often reveal restrictive
impairment (decreased static lung volumes), reduced diffusing capacity for
carbon monoxide (DLCO), and arterial hypoxemia exaggerated or elicited by
exercise. The histologic appearance of the UIP pattern is essential to conﬁrm
this diagnosis. UIP is characterized by a heterogeneous, predominantly
subpleural distribution of involvement (often distinguishable even on low- power
magniﬁcation). There is temporal heterogeneity, with areas of end-stage ﬁbrosis
and “honeycombing” (thickened collagenous septa surrounding airspaces lined by
bronchial epithelium) abutting areas of active proliferation of ﬁbroblasts and
myoﬁbroblasts (termed ﬁbroblastic foci). There is generally minimal
interstitial inﬂammation, and if this is present in signiﬁcant amounts, the
histopathologic diagnosis should be reconsidered.
IPF patients have a distinctly poor prognosis with
only a 20% to 30% survival at 5 years after the time of diagnosis. Acute
deterioration in IPF—“acute exacerbations” with an abrupt and unexpected
worsening of the underlying lung
disease in the absence of any identiﬁable cause may occur and portends a poor prognosis (mortality
rate, 20%-86%). Lung transplantation is the only measure shown to prolong
No speciﬁc drug treatment recommendations can be made.
Treatment of patients with IPF with corticosteroids alone or with cytotoxic
agents is of unproven beneﬁt and causes substantial morbidity. N-acetyl-cysteine,
pirfenidone, or bosentan show promise, but there is insufﬁcient evidence to
recommend their general use. Improved management of acute exacerbations may
improve survival in patients with IPF.
Pulmonary rehabilitation and oxygen therapy are useful
adjuncts in treatment. In addition, where available, lung transplant should be
recommended to qualiﬁed patients.
NONSPECIFIC INTERSTITIAL PNEUMONIA
NSIP is a histopathologic pattern commonly found in
the context of another disorder, such as a connective tissue disease, chronic
hypersensitivity pneumonitis, or drug-induced ILD. Idiopathic NSIP is a
distinct clinical entity that occurs mostly in middle-aged women who have never
smoked. It has been suggested that idiopathic NSIP may be the lung manifestation of
“undifferentiated connective tissue disease.”
Dyspnea and cough are the most common symptoms.
Serologic abnormalities (i.e., positive antinuclear anti-bodies or rheumatoid
factor) are common. A restrictive pattern of pulmonary function abnormality is
common. Chest radiographic ﬁndings show primarily lower-zone reticular or hazy
opacities. HRCT shows bilateral symmetric ground-glass opacities or bilateral
airspace consolidation. A reticular pattern with traction bronchiectasis and
volume loss is also common. Honey-combing is uncommon and when present should suggest another diagnosis.
Surgical lung biopsy is required to conﬁrm the
diagnosis of NSIP. The main histologic feature of NSIP is the homogeneous
appearance of either inﬂammation or ﬁbrosis. The lung injury pattern is
characterized by varying degrees of inﬂammation and ﬁbrosis (“ﬁbrotic NSIP”).
There is less temporal and spatial heterogeneity than in UIP and little
Patients with NSIP have a good prognosis, with most
showing improvement after treatment with corticosteroids (often with a
cytotoxic agent such as azathioprine). The 5-year mortality rate is estimated
at 10% to 20%.
RESPIRATORY BRONCHIOLITIS–ASSOCIATED INTERSTITIAL LUNG
RB-ILD is a clinical syndrome found in young adults
(30-40 years old). Most are current or former cigarette smokers with a history
of more than 30 pack-years of smoking. The clinical presentation is with cough
and breathlessness on exertion, and crackles are found on chest examination.
Routine laboratory studies are not helpful. A mixed
obstructive-restrictive pattern is found on lung function testing, and arterial
hypoxemia is common.
The chest radiograph shows diffuse, ﬁne reticular or
nodular interstitial opacities, usually with normalappearing lung volumes. HRCT
scanning often reveals centrilobular nodules, ground-glass opacity, thickening
of central and peripheral airways with associated centrilobular emphysema, and
Pathologic criteria for the diagnosis of RB-ILD
include the accumulation of pigmented alveolar macrophages within the lumina of
respiratory bronchioles and alveolar ducts accompanied by chronic inﬂammation
of the respiratory bronchiolar walls and both bronchiolar and peribronchiolar
alveolar ﬁbrosis causing architectural distortion. These features, at low
magniﬁcation, are commonly patchy and conﬁned to the peribronchiolar region.
Prolonged survival is common in patients with RB-ILD.
However, symptomatic and physiologic improvement occurs in only a minority of
patients (28% and 11% of cases, respectively). Neither smoking cessation nor
immunosuppressive therapy is regularly associated with clinically signiﬁcant
LYMPHOID INTERSTITIAL PNEUMONITIS
LIP is common in children but uncommon in adults. LIP
is frequently associated with infection (HIV, Epstein-Barr virus, and human
T-cell leukemia virus type 1), a serum protein abnormality (variable
immunodeﬁciency and dysproteinemia), or autoimmune disorders (Sjögren syndrome,
rheumatoid arthritis, systemic lupus erythematosus, polymyositis). LIP may
occur before or after the diagnosis of the underlying process. LIP is part of a
spectrum of pulmonary lymphoid proliferations that includes follicular
bronchiolitis, nodular lymphoid hyperplasia, and low-grade malignant lymphoma.
In fact, idiopathic LIP is rare, and many experts question if this entity
should be a part of the IIPs.
The insidious onset of cough and dyspnea are the most
common presenting symptoms of LIP. Weight loss, fevers, arthralgias, and
pleuritic chest pain are other common ﬁndings. Physical examination may reveal
crackles on chest examination.
Pulmonary function testing shows reduced lung volumes
and diffusing capacity with preserved airﬂow. Marked hypoxemia may occur. Bronchoalveola
lavage may reveal increased numbers of
LIP has a
varied and nonspeciﬁc radiographic appearance. HRCT scanning is characterized
by the presence of ground-glass attenuation, poorly deﬁned centrilobular
nodules, and thickening of the interstitium along the lymphatic vessels.
Thin-walled cystic lesions have been described. Lymph node enlargement is more
The natural history and prognosis of LIP are poorly
understood and highly variable. Corticosteroid therapy alone or in combination
with other agents has been used to treat symptomatic patients with LIP,
although its efﬁcacy has not been established in a controlled trial.
ACUTE INTERSTITIAL PNEUMONIA
AIP is an uncommon fulminant form of lung injury that
presents acutely (days to weeks from onset of symptoms). The clinicopathologic
term is synonymous with the histopathologic pattern of idiopathic diffuse
alveolar damage (DAD). Most patients have been previously healthy before the
onset of the illness. There is no gender predilection.
A high index of suspicion is required to make this
diagnosis. The onset is usually abrupt, although a prodromal illness lasting
usually 7 to 14 days before presentation is common. Fever, cough, and shortness
of breath are common clinical signs and symptoms. Tachypnea is present, and
chest examination reveals crackles on auscultation. Routine laboratory studies
are nonspeciﬁc and generally not helpful. Most patients have moderate to severe
hypoxemia and develop respiratory failure.
The chest radiograph shows diffuse, bilateral,
airspace opacities. CT scans show bilateral, patchy, symmetric areas of
ground-glass opacities or occasionally airspace consolidation. A predominantly
subpleural distribution may be seen.
Surgical lung biopsy is required to conﬁrm the
diagnosis, and the histologic presence of organizing DAD is usually present.
The mortality rate is high, with the majority of patients dying within 6 months
of presentation. If the patient recovers, substantial improvement in lung
function and radiographic clearing may be seen. It is not clear whether
corticosteroid therapy is effective in AIP. Mechanical ventilation is often
required. The main treatment is supportive care.
DESQUAMATIVE INTERSTITIAL PNEUMONIA
DIP is a rare process that affects cigarette smokers
in their fourth or ﬁfth decades of life. Many cases previously called DIP are
actually cases of RB-ILD. Clear evidence of cigarette smoke exposure is not
always present in patients with DIP.
Most patients present with dyspnea. Lung function
testing shows a restrictive pattern with reduced DLCO and hypoxemia on arterial
blood gas analysis.
The chest radiographs may be normal in up to 20% of
cases. HRCT commonly shows bilateral symmetric areas of ground-glass
opaciﬁcation involving mainly the lower lung zones. Reticular opacities can be
seen on CT in approximately 50% of patients.
The dominant histologic feature is intraalveolar
macrophage accumulation. At low magniﬁcation, the process typically seems to
affect the lung diffusely and appears uniform from ﬁeld to ﬁeld. There is often
interstitial ﬁbrosis present. Prussian blue staining for iron may reveal a
ﬁnely granular hemosiderin pigment. Alveolar pneumocyte proliferation may be
prominent along the thickened alveolar septa, but ﬁbroblastic foci do not
occur. Several histopathologic ﬁndings appear more often in patients with
DIP compared with RB extent of interstitial ﬁbrosis, presence of lymphoid
follicles, and eosinophilic inﬁltration.
Smoking cessation results in clinical improvement. The
5- and 10-year survival rates are 95% and 70%, respectively. Corticosteroid
therapy appears to be associated with modest clinical beneﬁt but usually not
with resolution of disease. Progressive disease with eventual death may occur
in subjects with DIP, especially
with continued cigarette smoking.