Cryptogenic Fibrosing Alveolitis

-Introduction:

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.

-Definition:

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:

Name and Clinical Presentation Histopathology Radiographic Pattern Response to Therapy and Prognosis Usual interstitial pneumonia (UIP) -Patchy, temporally and geographically nonuniform distribution of fibrosis, honeycomb change, and normal lung. -Type I pneumocytes are lost, and there is proliferation of alveolar type II cells. "Fibroblast foci" of actively proliferating fibroblasts and myofibroblasts. -Inflammation is generally mild and consists of small lymphocytes. -Intra-alveolar macrophage accumulation is present but is not a prominent feature. -Diminished lung volume. -Increased linear or reticular bibasilar and subpleural opacities.(Unilateral disease is rare). -High-resolution CT scanning shows minimal ground-glass and variable honeycomb change. -Areas of normal lung may be adjacent to areas of advanced fibrosis. -Between 2% and 10% have normal chest radiographs and high-resolution CT scans on diagnosis. -No randomized study has demonstrated improved survival compared with untreated patients. -Inexorably progressive. -Response to corticosteroids and cytotoxic agents at best 15%, and these probably represent misclassification of histopathology. -Median survival approximately 3 years, depending on stage at presentation. -Current interest in antifibrotic agents. -Age 55–60, -slight M>F, 3-5/ 100,000 in Egypt. -past smokers > -Insidious dry cough and dyspnea lasting months to years. -Clubbing present at diagnosis in 25–50%. -Diffuse fine late inspiratory crackles on lung auscultation. -Restrictive ventilatory defect and reduced diffusing capacity on pulmonary function tests. -ANA and RF positive in 25% in the absence of documented collagen-vascular disease. Respiratory bronchiolitis- associated interstitial lung disease (RB-ILD)1 -Increased numbers of macrophages evenly dispersed within the alveolar spaces. -Rare fibroblast foci, little fibrosis, minimal honeycomb change. -In RB-ILD the accumulation of macrophages is localized within the peribronchiolar air spaces; -In DIP1 it is diffuse. -Alveolar architecture is preserved. -May be indistinguishable from UIP. -More often presents with a nodular or reticulonodular pattern. -Honeycombing rare. -High-resolution CT more likely to reveal diffuse ground-glass opacities and upper lobe emphysema. -Spontaneous remission occurs in up to 20% of patients, so natural history unclear. -Smoking cessation is essential. -Prognosis clearly better than that of UIP: median survival greater than 10 years. -Corticosteroids thought to be effective, but there are no randomized clinical trials to support this view. -Age 40–45. -Presentation similar to that of UIP though in younger patients. -Similar results on pulmonary function tests, but less severe abnormalities. -Patients with respiratory bronchiolitis are invariably heavy smokers. Acute interstitial pneumonitis (AIP) -Pathologic changes reflect acute response to injury within days to weeks. -Resembles organizing phase of diffuse alveolar damage. -Fibrosis and minimal collagen deposition. May appear similar to UIP but more homogeneous and there is no honeycomb change—though this may appear if the process persists for more than a month in a patient on mechanical ventilation. -Diffuse bilateral airspace consolidation with areas of ground-glass attenuation on HR CT scan. -Supportive care (MV) critical but effect of specific therapies unclear. -High initial mortality: Fifty to 90 percent die within 2 months after diagnosis. -Not progressive if patient survives. -Lung function may return to normal or may be permanently impaired. -Clinically known as Hamman-Rich syndrome. -Wide age range, many young patients. -Acute onset of dyspnea followed by rapid development of respiratory failure. -Half of patients report a viral syndrome preceding lung disease. -Clinical course indistinguishable from that of idiopathic ARDS. Nonspecific interstitial pneumonitis (NSIP) -Nonspecific in that histopathology does not fit into better-established categories. -Varying degrees of inflammation and fibrosis, patchy in distribution but uniform in time, suggesting response to single injury. -Most have lymphocytic and plasma cell inflammation without fibrosis. -Honeycombing present but scant. -Some have advocated division into cellular and fibrotic subtypes. -May be indistinguishable from UIP. -Most typical picture is bilateral areas of ground-glass attenuation and fibrosis on high-resolution CT. -Honeycombing is rare. -Treatment thought to be effective, but no prospective clinical studies have been published. -Prognosis overall good but depends on the extent of fibrosis at diagnosis. -Median survival greater than 10 years. -Age 45–55. -Slight female predominance. -Similar to UIP but onset of cough and dyspnea over months, not years. Cryptogenic organizing pneumonitis (formerly bronchiolitis obliterans organizing pneumonia [BOOP]) -Included in the idiopathic interstitial pneumonias on clinical grounds. -Buds of loose connective tissue (Masson bodies) and inflammatory cells fill alveoli and distal bronchioles. -Lung volumes normal. -Chest radiograph typically shows interstitial and parenchymal disease with discrete, peripheral alveolar and ground-glass infiltrates. Nodular opacities common. -High-resolution CT shows subpleural consolidation and bronchial wall thickening and dilation. -Rapid response to corticosteroids in 2/3 of patients. -Long-term prognosis generally good for those who respond. -Relapses are common. - Typically age 50–60 but wide variation. -> non-smokers -Abrupt onset, frequently weeks to a few months following a flu-like illness. -Dyspnea and dry cough prominent, but constitutional symptoms are common: fatigue, fever, and weight loss. -Pulmonary function tests usually show restriction, but up to 25% show concomitant obstruction.
Desquamative IP -Youngest age group (35-45 yrs) -current smoking increase possibility -same c/p	-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.	-Smoking cessation -Steroid good response with returned lung functions to normal
LIP -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:

.Drug-related Antiarrhythmic agents (amiodarone) Antibacterial agents (nitrofurantoin, sulfonamides) Antineoplastic agents (bleomycin, cyclophosphamide, methotrexate, nitrosoureas) Antirheumatic agents (gold salts, penicillamine) Phenytoin .Environmental and occupational (inhalation exposures) Dust, inorganic (asbestos, silica, hard metals, beryllium) Dust, organic (thermophilic actinomycetes, avian antigens, Aspergillus species) Gases, fumes, and vapors (chlorine, isocyanates, paraquat, sulfur dioxide) Ionizing radiation Talc (injection drug users) .Infections Fungus, disseminated (Coccidioides immitis, Blastomyces dermatitidis, Histoplasma capsulatum) Mycobacteria, disseminated Pneumocystis jiroveci Viruses .Primary pulmonary disorders Cryptogenic organizing pneumonitis (COP) Idiopathic fibrosing interstitial pneumonia: Acute interstitial pneumonitis, desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, usual interstitial pneumonitis, respiratory bronchiolitis-associated interstitial lung disease Pulmonary alveolar proteinosis .Systemic disorders Acute respiratory distress syndrome Amyloidosis Ankylosing spondylitis Autoimmune disease: Dermatomyositis, polymyositis, rheumatoid arthritis, systemic sclerosis (scleroderma), SLE Chronic eosinophilic pneumonia Goodpasture's syndrome Idiopathic pulmonary hemosiderosis Inflammatory bowel disease Langerhans cell histiocytosis (eosinophilic granuloma) Lymphangitic spread of cancer (lymphangitic carcinomatosis) Lymphangioleiomyomatosis Pulmonary edema Pulmonary venous hypertension, chronic Sarcoidosis Wegener's granulomatosis

-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)

Clinical Diagnosis	Histologic Pattern	Usual Radiographic Features	Typical Distribution on CT	Typical CT Findings	CT Differential Diagnosis
IPF/ CFA	UIP	Basal-predominant reticular abnormality with volume loss	Peripheral, subpleural, basal	.Reticular, honey combing .Traction bronchiectasis / bronchiolectasis; architecture distorted .Focal ground glass or not found	.Asbestosis .Collagen vascular disease .HP .Sarcoidosis
NSIP	NSIP	Ground glass and reticular opacity	Peripheral, sub-pleural, basal, symmetric, peri-bronchovascular predominance	.Ground glass attenuation Honey comb only in fibrotic type. .Irregular lines .Consolidation	UIP, DIP, COP, HP
COP	OP	Patchy bilateral consolidation	Subpleural/ peribronchial	Patchy consolidation and/or nodules	.Infection, .vasculitis, .sarcoidosis .alveolar carcinoma, .lymphoma .eosinophilic pn., .NSIP
AIP	DAD	Progressive diffuse ground glass density/ consolidation	Diffuse	.Consolidation and ground glass opacity, often with lobular sparing. .Traction bronchiectasis later	.Hydrostatic edema .Pneumonia .Acute eosinophilic pneumonia
DIP	DIP	Ground glass opacity	Lower zone, peripheral >	.Ground glass attenuation .Reticular lines	RB-ILD, HP, Sarcoidosis, PCP
RB-ILD	RB	Bronchial wall thickening; ground glass opacity	Diffuse	.Bronchial wall thickening .Centrilobular nodules .Patchy ground glass opacity	DIP, NSIP, HP
LIP	LIP	Reticular opacities, nodules	Diffuse	.Centrilobular nodules, .ground glass attenuation, .septal& bronchovascular thickening, .thin-walled cysts	.Sarcoidosis, .lymphangitic carcinoma.Langerhans' cell histiocytosis

*DAD is diffuse alveolar damage, PCP is Pneumocystis carinii pneumonia

-Treatment:

A. Anti-inflammatory agents:

§ Steroids:

-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 PO as single dose; not to > 150 mg/d

.Cyclophosphamide: 25-50 mg/d PO initially; increase dose gradually in 25-mg increments q7-14d, not to > 150 mg/d, with goal of reducing and maintaining WBC count at 4000-7000/µL

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).

D. Anti-oxidants:

-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.

E. Others:

§ Medical Care: Oxygen therapy should be prescribed for patients with documented hypoxemia; this may improve exercise tolerance.

§ Diet: Maintaining adequate nutritional intake and immunizations (i.e., pneumonia vaccine, influenza vaccine) in patients with IPF is important for quality of life.

§ 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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