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Definition
Epidemiology
Classification
Pathogenesis
Diagnosis
Treatment Final comments
1935 and 1944) four patients who died of rapidly progressive lung disease characterized by diffuse interstitial pneumonia and fibrosis.
decreased diffusing capacity (DLco) and abnormal alveolararterial oxygen gradient (PAO2 PaO2) at rest or with exertion.
4. Histopathology
with
varing
degrees
of
fibrosis
and
inflammation with or without evidence of granulomatous or secondary vascular changes in the pulmonary parenchyma.
It is more frequent than previously recognized. Incidence ranges from 3 to 26 per 100.000 per year. The prevalence of preclinical and undiagnosed ILD
Desquamative interstitial pneumonia Acute interstitial pneumonia Nonspecific interstitial pneumonia (provisional)
Respiratory bronchiolitis interstitial lung disease Cryptogenic organizing pneumonia Lymphocytic interstitial pneumonia
Histologic Pattern
Usual interstitial pneumonia Nonspecific interstitial pneumonia Organizing pneumonia Diffuse alveolar damage Respiratory bronchiolitis
Clinical/Radiologic/Pathologic Diagnosis
Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis Nonspecific interstitial pneumonia Cryptogenic organizing pneumonia Acute interstitial pneumonia Respiratory bronchiolitis interstitial lung disease Desquamative interstitial pneumonia Lymphoid interstitial pneumonia
Radiology
Fibrosis, HC GGO +/- fibrosis GGO, nodules, consolidation
Distribution
Basilar, peripheral Basilar, peripheral Patchy upper lungs, small airways, alveolar
Pathology
Temporal heterog., FF, fibrotic and normal lung, microscopic HC Diffuse interstitial inflammation +/- fibrosis Granulation tissue plugs in alveolar ducts and alveoli Hyaline membranes, immature fibroblasts in alveolar spaces and interstitium to variable degree Respiratory bronchiolitis surrounded by Ms in alveoli Alveolar Ms in air spaces diffusely in the biopsy Lymphoid hyperplasia
COP
AIP
GGO, consolidation
Bronchiectasis, GGO GGO, consolidation GGO, nodules, cysts
Diffuse, random
Upper lungs, bronchocentric Basilar, peripheral, alveolar Patchy
RB-ILD
DIP
LIP
HC, honeycombing; GGO, ground glass opacity; FF, fibrotic foci; M, macrophage
Four proposed mechanisms and potential variations in lung responses to inhaled agents Inhaled environmental agents
Immunologic Fibrotic
Normal
Pulmonary fibrosis
Inflammatory hypothesis
Epithelial Cell Apoptosis Angiogenesis
LUNG INJURY
Histopathologic Pattern
DIP RB-ILD LIP COP NSIP AIP UIP
Inflammation
Fibrosis
Pulmonologists
Radiologists
Pathologists
History
The patient's age, cigarette-smoking status and sex may provide useful clues. Thorough medical history that must include a review of environmental factors, occupations, exposures, medication, and drug usage and family medical history.
After age 50: IPF 1 in 500 people over the age of 75 yrs.
pulmonary fibrosis: Men tend to present later in the disease, whereas women tend to present earlier.
Women : Collagen vascular disease- associated ILD LAM Tuberous sclerosis Men: Pneumoconiosis IPF Hypersensitivity pnuemonitis
Smoking related ILD : 1. Desquamative interstitial pneumonia. 2. RBILD. 3. Pulmonary Langerhans cell histiocytosis. 4. IPF. 5. Rheumatoid arthritis associated ILD. 6. Acute eosinophilic pneumonia.
(especially SLE) COP Drugs DAH Eosinophilic lung disease Hypersensitivity pneumonitis
History (cont.)
Farming
or exposure to known causes of hypersensitivity pneumonitis including birds, drugs, humidifiers. History of aspiration, dysphagia, arthritis, recurrent sinusitis, pneumothorax, muscle and skin symptoms, dry and gritty eyes, dry mouth and hemoptysis.
occur not only in most patients with IPF but also in many other interstitial lung diseases. late inspiratory rhonchi inspiratory squeks found in some cases of ILD like RB-ILD.
The scaterred
patients with IPF and 50% of patients with DIP and 75% of patients with ILD from rheumatoid arthritis.
and
hepatosplenomegally
are
commonly
CREST syndrome.
Epilepsy, mental retardation in tuberous sclerosis. Diabetes insipidus in Langerhans cell granulomatosis
allows the clinician to ascertain the onset, progression, chronicity and stability of patient's disease. A rare patient with ILD will present with a normal chest radiograph. When radiographic abnormalities are noted, their distribution and appearance are useful in narrowing the differential diagnosis of ILD.
disease.
Kerley
adenopathy:
sarcoidosis
(bilateral
and
LAM.
Thin
histiocytosis X, LAM.
CT and HRCT scans are more sensitive and have a greater ability to
HRCT helps in
inflammation"
(ground
irreversible
fibrotic
manifestations
(traction
disease with limited potential for both invasive diagnostic and therapeutic approaches which could be
toxic.
Tuberous
sclerosis
and
Langerhans
cell
granulomatosis
In LAM and Tuberous sclerosis, the cysts are numerous,
show multifocal diffuse ground glass attenuation despite a normal chest radiograph. Smokers with symptomatic RBILD typically have patchy ground glass attenuation on HRCT. IPF is characterized by patchy subpleural and basilar fibrosis. A normal HRCT does not exclude the presence of microscopic ILD in a patient with a high pretest probability of the disorder.
and decreased diffusing capacity (DLco) are the predominant physiological abnormalities seen in ILD.
Decreased FEV1, FVC, TLC The (PAO2 PaO2) difference, at rest or with
include; Churg-Strauss syndrome, ABPA, Sarcoidosis (endobronchial) and tropical pulmonary eosinophilia.
Resting pulmonary function tests:
interstitial
Document the existence, gauge the severity and provide clues that are useful in the differential diagnosis of ILD. Also they are useful in the monitoring of clinical progression of the disease or response to therapy.
Include:
Complete blood count, leucocytic differential ESR Chemistry profile (calcium, liver function tests, electrolytes,
appropriate,
creatinine
kinase,
aldolase,
and
abnormalities tend to be distributed in peribronchiovascular areas e.g. Sarcoidosis, LAM and Lymphangitic carcinomatosis and eosinophilic pnuemonia.
Tight, uniform, well formed non caseating granulomas of sarcoidosis. Smooth muscle proliferation of LAM. Lymphatic metastasis of malignant cells. Giant cell granulomas are suggestive of hard metal pneumoconiosis.
It is diagnostic if an infectious agent or malignancy
is detected.
"Bronchoalveolar lavage"
for diagnosis. It is, however, by no means always definitive: the size of specimens, site of biopsy, expertise of pathologists and interobserver differences among pathologists are factors that may preclude a conclusive diagnosis. The site of the biopsy should be chosen on the basis of HRCT findings and ideally be at the interface of involved and less involved lung tissue. A biopsy of more than one site in the lung is more helpful.
the final diagnostic step. Which patient are suitable candidates for these procedures? Unexplained dyspnea on exertion or abnormal results on pulmonary function testing favor such interventions (normal chest radiographs or HRCT scans do not negate the need for tissue diagnosis). On the other hand, not all patients with typical clinical features compatible with IPF require surgical lung biopsy for definitive diagnosis.
Major Criteria Exclusion of other known causes of ILD Evidence of restriction and/or impaired gas exchange HRCT: bibasilar reticular abnormalities with minimal ground glass opacities TBB or BAL that does not support an alternative diagnosis
Minor Criteria Age > 50 years Insidious onset of otherwise unexplained dyspnea on exertion
All major criteria and at least 3 minor criteria must be present to increase the likelihood of an IPF diagnosis
ATS/ERS. Am J Respir Crit Care Med. 2000;161:646-664.
ILD needs to be tailored to the patient and the disease process (disease-specific intervention). Avoidance of the offending agent or its environment. The use of corticosteroids, alone or in combination with immunosuppressives (azathioprine, cyclophosphamide) is currently recommended for most patients with chronic fibrotic lung disorders. However the clinical response is variable and unpredictable, some ILDs generally have a better prognosis and response more favorably than do others.
symptomatic ILD patients with eosinophilic pneumonias, COP, CTD, sarcoidosis, hypersensitivity pneumonitis, acute inorganic dust exposures, acute radiation pneumonitis, DAH, and drug-induced ILD. A common starting dose is prednisone, 0.51 mg/kg in a once-daily oral dose . This dose is continued for 412 weeks, at which time the patient is reevaluated. If the patient is stable or improved, the dose is tapered to 0.250.5 mg/kg and is maintained at this level for an additional 412 weeks, depending on the course.
glucocorticoids but need a glucocorticoid-sparing agent, have an incomplete response, or have not responded, but are not rapidly progressing. AZA is usually started at 50 mg/day and increased by 25 mg increments every 7 to 14 days up to 1.5 to 2.0 mg/kg per day, but not exceeding a maximum total dose of 200 mg/day.
pneumonia. IPF has a distinctly poor response to therapy and a bad prognosis. Patients with IPF and coexisting emphysema [combined pulmonary fibrosis and emphysema (CPFE)] are more likely to require long-term oxygen therapy and develop pulmonary hypertension and may have a more dismal outcome than those without emphysema.
consistent finding. The extent of fibroblastic proliferation is predictive of disease progression. There is no effective therapy for IPF. Chronic microaspiration secondary to gastroesophageal reflux may play a role in the pathogenesis and natural history of IPF.
ground-glass abnormality, nodular opacities, upper or midzone predominance, and prominent hilar or mediastinal lymphadenopathy
secondary to infections, pulmonary embolism, or pneumothorax. Heart failure and ischemic heart disease are common problems in patients with IPF, accounting for nearly one-third of deaths. These acute exacerbations are defined by worsening of dyspnea within a few days to 4 weeks; newly developing diffuse ground-glass abnormality and/or consolidation superimposed on a background reticular or honeycomb pattern consistent with the UIP pattern; worsening hypoxemia; and absence of infectious pneumonia, heart failure, and sepsis.
inhibitor).
that inhibits the synthesis of TGF-beta. The typical starting dose is 200mg, taken 3 times a day. Gastrointestinal (GI) events (nausea, dyspepsia, vomiting, and anorexia), skin disorders (rash, photosensitivity reaction), and dizziness are most common side effects of the perfenidone.
NSIP
is a subacute restrictive process with a presentation similar to that of IPF but usually at a younger age, most commonly in women who have never smoked. It is often associated with a febrile illness.
The key histopathologic feature of NSIP is the
uniformity of interstitial involvement across the biopsy section and little or no honeycombing .
opacities, often associated with lower lobe volume loss. Patchy areas of airspace consolidation and reticular abnormalities may be present, but honeycombing is unusual.
prognosis (5-year mortality rate estimated at <15%), with most showing improvement after treatment with glucocorticoids, often used in combination with azathioprine.
cough, fever, malaise, fatigue, and weight loss. The roentgenographic manifestations are distinctive, revealing bilateral, patchy, or diffuse alveolar opacities in the presence of normal lung volume. Glucocorticoid therapy induces clinical recovery in two-thirds of patients. A few patients have rapidly progressive courses with fatal outcomes despite glucocorticoids.
glass opacities, small nodular opacities, and bronchial wall thickening and dilation. These changes occur more frequently in the periphery of the lung and in the lower lung zone.
presentation are cough, dyspnea, chest pain, weight loss, and fever.
Pneumothorax occurs in ~25% of patients. Hemoptysis
10 mm in diameter), reticular or nodular opacities, bizarre-shaped upper zone cysts, preservation of lung volume, and sparing of the costophrenic angles are characteristics of PLCH.
walled cysts is virtually diagnostic of PLCH. The nodular lesions are poorly defined and are distributed in a bronchiolocentric fashion with intervening normal lung parenchyma.
resulting in clinical improvement in one-third of patients. Most patients with PLCH experience persistent or progressive disease. Death due to respiratory failure occurs in ~10% of patients.
Hydroxychloroquine:
is effective for control of cutaneous sarcoid and has been successfully used to treat sarcoid-associated hypercalcemia, arthritis, neurological disease, and pulmonary disease. Infliximab and etanercept (TNF-alpha inhibitor). Pentoxifyllin and Thalidomide (TNF-alpha antagonists). Methotrexate (10-25mg / week).
Infliximab.
Bosentan.
(GM-CSF):
A cytokine that stimulates the granulocytes, macrophages, dendritic cells, and bone marrow precursors of platelets. Administered by either S.C injection or aerosolized form. It has recently been demonstrated to effectively control disease course and provide a very useful alternative to traditional therapy of whole lung lavage
Estrogen-containing
medications
should
be
discontinued. Oophorectomy, progesterone, Tamoxifen and luteinizing hormone-releasing hormone analogs have been used with limited success. Lung transplantation offers the only hope for cure despite reports of recurrent disease in the transplanted lung.
Other measures
Plasmapheresis is indicated in intractable and severe cases of
saturation.
Unless
contraindicated,
all
patients
should
receive
in appropriate patients.
Lung transplantation is a viable surgical option for selected