Ø Interstitial lung disease, or diffuse parenchymal lung disease, comprises a heterogeneous group of disorders that share a common response of the lung to injury: alveolitis, or inflammation, and fibrosis of the interalveolar septum (see later).
Ø The term "interstitial" is misleading since the pathologic process usually begins with injury to the alveolar epithelial or capillary endothelial cells. Persistent alveolitis à obliteration of alveolar capillaries and reorganization of the lung parenchyma + irreversible fibrosis.
Ø Now, new name for IPF is "idiopathic fibrosing interstitial pneumonia"; Today the clinical label "idiopathic pulmonary fibrosis" should be reserved for patients with a specific form of fibrosing interstitial pneumonia referred to as usual interstitial pneumonia.
Ø The process does not affect the airways proximal to the respiratory bronchioles.
Ø In most patients, no specific cause can be identified. In the remainder, drugs & a variety of organic & inorganic dusts are the principal causes.
Ø It's a progressive fibrosing inflammatory disease of the lung of unknown etiology characterized by sequential acute lung injury with subsequent scarring and end stage lung disease.
Ø It's one of a family of idiopathic pneumonias sharing the clinical features of shortness of breath, radiographically evident diffuse pulmonary infiltrates, and varying degrees of inflammation, fibrosis, or both on biopsy.
Ø The younger the patient à the more acute the history à the better the response to treatment.
-Classification of idiopathic fibrosing interstitial pneumonia:
· ATS Classification:
-Youngest age group (35-45 yrs)
-current smoking increase possibility
-The macrophages are uniformly distributed,
predominantly in the alveoli, non-pigmented
-and associated with minimal fibrosis in the alveolar septa.
-Reticulo-nodular infiltrates with no honey combing.
-Steroid good response with returned lung functions to normal
-Usually occurs in conjunction with .dysproteinemia (either a monoclonal or polyclonal gammopathy), .Sjögren's syndrome, .or AIDS.
-LIP is rarely seen as a primary disorder.
-Diffuse homogenous interstitial infiltration of T- lymphocytes which may be grouped into germinal centers.
-Reticular opacities, nodules.
-Steroid response is good.
*Unclassifiable Pathologic Findings
Even when ample tissue is available for histologic examination, there are subsets of patients whose pathologic characteristics are not classifiable into any of the seven specific entities. The ATS/ERS classification proposes that these patients be given the diagnosis of unclassifiable interstitial pneumonia and acknowledges that, at least in a subset of patients with interstitial pneumonia, it may be impossible to make a specific pathologic and clinical diagnosis
-Differential diagnosis of Interstitial Lung Disease:
-Clinical Picture of IPF:
Ø ATS criteria for diagnosis w/o surgical lung biopsy:
Major Criteria (4)
-Exclusion of other known causes of ILD (certain drug toxicities, environmental exposures, and connective tissue diseases)
-Abnormal pulmonary function à restrictive pattern (reduced VC, often with an increased FEV1/FVC ratio) and impaired gas exchange [increased P(A-a) O2, decreased PaO2 with rest or exercise or decreased DLCO]
-Bibasilar reticular abnormalities with minimal ground glass opacities on HRCT scans
-Trans-bronchial lung biopsy or BAL showing no features to support an alternative diagnosis
Minor Criteria (3 of 4)
-Age > 50 yr
-Insidious onset of otherwise unexplained dyspnea on exertion
-Duration of illness > 3 months
-Bibasilar, inspiratory crackles (dry or "Velcro"-type in quality)
-Radiological: (ATS classification)
Usual Radiographic Features
Typical Distribution on CT
Typical CT Findings
CT Differential Diagnosis
Basal-predominant reticular abnormality with volume loss
.Reticular, honey combing
.Traction bronchiectasis / bronchiolectasis; architecture distorted
.Focal ground glass or not found
.Asbestosis .Collagen vascular disease
Ground glass and reticular opacity
Peripheral, sub-pleural, basal, symmetric, peri-bronchovascular predominance
.Ground glass attenuation
Honey comb only in fibrotic type.
UIP, DIP, COP, HP
Patchy bilateral consolidation
Patchy consolidation and/or nodules
.Infection, .vasculitis, .sarcoidosis .alveolar carcinoma, .lymphoma .eosinophilic pn.,
Progressive diffuse ground glass density/ consolidation
.Consolidation and ground glass opacity, often with lobular sparing.
.Traction bronchiectasis later
.Pneumonia .Acute eosinophilic pneumonia
Ground glass opacity
.Ground glass attenuation
RB-ILD, HP, Sarcoidosis, PCP
Bronchial wall thickening; ground glass opacity
.Bronchial wall thickening
.Patchy ground glass opacity
DIP, NSIP, HP
Reticular opacities, nodules
.ground glass attenuation, .septal& bronchovascular thickening,
.Sarcoidosis, .lymphangitic carcinoma.Langerhans' cell histiocytosis
*DAD is diffuse alveolar damage, PCP is Pneumocystis carinii pneumonia
A. Anti-inflammatory agents:
-Action: reduce so-called ground glass opacities seen on HR-CT in some patients with idiopathic interstitial pneumonias, and this reduction parallels improvement in pulmonary function but the progression to irreversible honeycomb fibrosis is not altered.
-Indicated: in selected patients particularly those patients for whom the diagnosis of IPF is not certain (As when anti inflammatory agents were given only to patients with a secure diagnosis of IPF, there was no evidence of a meaningful response) (e.g., those with atypical HRCT scan features who decline surgical lung biopsy or atypical HRCT scan features with UIP in lung biopsy specimens), with rigorous assessment for objective improvement in physiological measures, radiographic findings, and clinical symptoms.
N.B. Latent tuberculosis should be excluded before patients begin corticosteroid therapy.
-Longer trials of prednisone or the prolonged use of cytotoxic agents remains controversial (for high side effect liability).
-Dosing: .Initial response usually occurs within 3 Ms of high dose of steroids. Objective parameters (chest radiograph, CT scan, PFT, dyspnea scores) and non-subjective improvement should be used for subsequent steroid therapy because of placebo effects or mood-enhancement effects of steroids.
.Most pulmonologists continue low-dose prednisone (approximately 15-20 mg) as maintenance therapy in steroid-responsive patients for 1-2 yrs and occasionally indefinitely à detected good response with PFT and radiological improvement with increased lymphocytic count in BAL > 11% (non improvement is detected by the contrary with increased neutrophil and eosinophil levels à discontinue treatment).
.Relapse or progression of disease after an initial response suggests need for prolonging treatment or addition of an immunosuppressive agent.
§ Cytotoxic drugs:
-Used in: .patients in which corticosteroid therapy fails.
.patients experiencing serious adverse effects from steroids;
.patients at high risk: such as elderly patients, for serious adverse effects of steroid complications; or patients with poorly controlled diabetes, hypertension, severe osteoporosis, or peptic ulcer disease.
-Action: Cytotoxic drugs suppress B- and T-lymphocyte function.
Azathioprine (imuran): Inhibits mitosis and cellular metabolism by antagonizing purine metabolism and inhibiting synthesis of DNA, RNA, and proteins. Effects may decrease proliferation of immune cells and result in lower autoimmune activity.
Cyclophosphamide (cytoxan): Alkylating agent of the nitrogen mustard group. Metabolite inhibits the cross linking of DNA strands, leading to cell death. Has anti-inflammatory effect.
-Doses:.Azathioprine: 2-3 mg/kg/d
.Cyclophosphamide: 25-50 mg/d
B. Anti-fibrotic agents:
-Useful agents might interfere with matrix synthesis, fibroblast proliferation, or profibrotic cell–cell signaling, like:
a. Colchicine interferes with intracellular pro-collagen processing, increases the expression of collagen- degrading enzymes, and suppresses release of fibroblast growth factors by macrophages. Because of its safety, colchicine has been tried in patients with IPF à Initial studies seemed promising, but follow up studies that incorporated strict diagnostic criteria for IPF have failed to show any benefit of colchicine over no therapy at all.
b. Penicillamine (collagen cross-link inhibitor) also showed no beneficial effect.
c. Pirfenidone is a pyridone molecule reported to block in vitro growth factor–stimulated collagen synthesis, extracellular matrix secretion, and fibroblast proliferation + used in cyclophosphamide-induced pulmonary fibrosis à small trials detected stable PFT but larger studies are still not feasible due to unavailability of the agent for clinical use yet.
d. Relaxin is a peptide that circulates during the later phases of gestation and contributes to remodeling of the pubic ligaments; with the capacity to block fibrogenesis + decrease collagen production by cultured fibroblasts and alter the proteinase–antiproteinase balance to favor matrix breakdown à showed improved skin texture and pulmonary-function test results in patients with progressive systemic sclerosis when taken for 24 weeks.
e. Suramin is a synthetic compound that has been used to treat nematode infestations + it has been found to inhibit the effect of numerous profibrotic growth factors + it delays wound healing and prevents hypertrophic scarring after eye surgery (on animal models but still tried on IPF).
f. Endothelin-1 is a mitogenic and vasoactive peptide synthesized and secreted by vascular endothelium and airway epithelium. This mediator has been found in association with fibroblast foci in lung biopsies and can be recovered from the distal air space by BAL. In animal models, inhibition of endothelin-1 (like Bosentan) prevents pulmonary scarring after lung injury (also used in pulmonary hypertension).
g. Angiotensin II is another vasoactive peptide with fibroblast mitogenic effects. Angiotensin II– mediated fibroblast proliferation appears to be linked to autocrine production of transforming growth factorb1 (TGF). Given the availability of effective inhibitors of angiotensin II receptors, these agents will be evaluated for the treatment of IPF.
h. Tumor necrotic factor alpha antagonist: like Etanercept à stimulation of fibroblast proliferation and collagen gene upregulation & relatively resistant to bleomycin/silica-induced fibrosis à improvement of FVC after an average of 9 months of treatment (twice-weekly etanercept and 10 mg prednisolone).
C. Immune modulators:
-Interferon gamma, a Th1 cytokine, down-regulates the expression of transforming growth factor b1, a mediator strongly implicated in fibroblast proliferation and collagen deposition + may suppress established Th2-type inflammatory responses à small improvements in lung volumes, gas exchange, and symptoms + reduction in the expression of genes for TGF b1 and connective-tissue growth factor in lung tissue were seen (when taken 3 times/wk with prednisone low dose for 12 months) à patients can develop flu-like symptoms during the early phases, fatigue, and arthralgia.
-Other promising targets of the Th2 inflammatory response include the cytokines interleukin-4 and interleukin-13 and the pluripotent growth factor transforming growth factor b1 à inhibition of these profibrotic mediators has been demonstrated to decrease fibrosis (on animal models).
-N-Acetyl Cysteine: far from being a mucolytic, chelator to heavy metals and its use in paracetemol toxicity, it also acts as an antioxidant by its metabolism to glutathione rapidly in the body which aids the transfer of nutrients to lymphocytes and phagocytes à used in combination with steroids and cytotoxic drugs decreasing their myelotoxic effects and improving FVC and DLCo within 1 year of use by dose 1,800 mg/d (600 mg tds PO) à has few side effects: headache, nausea, and vomiting.
E. Lung Transplantation:
-Lung transplantation is a viable option for some patients with IPF.
-Many patients show improvement with single lung transplantation, a result that facilitates better utilization of this scarce resource.
-Patients under the age of 55 years without complicating medical illnesses are best served by early referral to regional transplantation centers, since the waiting period for transplantation is generally around two years.
-Unfortunately, most patients are not eligible, because of older age or complicating medical conditions.
§ Activity: Deconditioning is a common problem in patients with IPF and can exacerbate functional impairment and psychosocial aspects. Thus, participation in a pulmonary rehabilitation program should be encouraged.
§ Oral anti-coagulants: Used because: Pulmonary embolism is commonly implicated as a common cause of death in patients with IPF. Furthermore, microvascular injury is evident, with abnormal vascular phenotypes identified in patients with idiopathic pulmonary fibrosis and secondary pulmonary hypertension.
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