Fibrosing alveolitis therapy Prepared By:Marwa Mamoon AbbassMedical Hawler University /Pharmacy College 5th Stage 2011-2012
Fibrosing alveolitis Synonyms: Idiopathic Pulmonary Fibrosis ,cryptogenic fibrosing alveolitis. is a chronic lung disease characterized initially by the presence of inflammatory cells within the alveoli. This is followed by thickening and fibrosis of the alveolar walls. The etiology and pathogenesis are as yet unknown. A form called the Hamman-Rich syndrome has a particularly poor prognosis. This is an acute interstitial pneumonia which presents with cough, fever and breathlessness. Histology shows bilateral diffuse alveolar damage. The condition usually progresses rapidly to acute respiratory distress and is often fatal (100% of patients between 5-26 days from admission).(2)
The condition is part of a spectrum of conditions known as interstitial lung disease. The term cryptogenic fibrosing alveolitis should be reserved for those patients in whom lung histology has shown to demonstrate the pathological changes termed usual interstitial pneumonitis (UIP). This is characterized by patchy interstitial changes, a honeycomb appearance to the lung tissue and eosinophilic infiltration.(3)
Pathogenesis(1)• Theories about the underlying pathological process are changing. It used to be thought that the initial trigger factor for fibrosis was a generalized inflammatory condition of interstitial lung tissue with subsequent scarring. Lack of response to steroids and immune modulators suggested this was unlikely. It is now considered that changes occur at endothelial cell level due to a response to some irritant, such as cigarette smoke, gastro-oesophageal reflux, environmental pollution.• the repair mechanism which subsequently comes into play is impaired, leading to excessive production of myofibroblasts and accumulation of extracellular matrix. 20% of patients have a positive family history, suggesting a genetic cause. Proposed mechanisms are mutations affecting surfactant C production and dysfunction of epithelial regeneration.
Risk factors•The condition is common in certainoccupations - for example, in peoplewho work with silica, asbestos, heavymetals or mouldy foliage.•Environmental factors include pigeonbreeding and contaminated ventilationsystems.•It can be an adverse effectof amiodarone.
Signs (1)These may include:•Exertional dyspnoea progressing tobreathlessness at rest.•Tachypnoea.•Cough.•Clubbing (50%).•Cyanosis.•Fine bilateral basal crepitationsparticularly at the end of expiration(Velcro rales).•Signs of cor pulmonale and right heartfailure in the later stages.
Symptoms (1)•The most common symptoms are progressively increasingshortness of breath and dry cough.•5% of patients diagnosed opportunistically have no initialsymptoms.•50% of patients are systemically unwell and may have a flulike illness, fatigue or weight loss.•Spontaneous remissions do not occur (in contrast tosarcoidosis).•Extrapulmonary features may include arthralgia, musclepains and skin rashes.•Obstructive sleep apnoea may be a common presentingfeature.
Differential diagnosis (1,8)Due to the nonspecific nature of the presenting symptoms andsigns, there are many other diagnoses which must be considered,ranging from very common disorders such as heart failurethrough to much rarer diseases.- Diagnoses to be considered include:•Heart failure.•Chronic obstructive pulmonary disease (COPD).•Sarcoidosis.•Pulmonary embolism.•Lymphangitis carcinomatosis.•Extrinsic allergic alveolitis.•Pneumonia.•Asbestosis.
heart disease cancercerebrovascular diseases chronic lower respiratory diseasesaccidents diabetesalzheimers kidney diseasessepticemia other causes 1.30% 20.20% * death may occur 1.50% 30.30% When there is 1.90% fibrosing alveolitis 2.90% in combination with 4.10% other diseases (16) . 5.20% 7% 23% Top ten causes of dea
Investigations (1) Laboratory tests•FBC may show mild anemia or may be normal.•ESR and CRP may be raised in 50% of patients.•Antinuclear factor and rheumatoid factor may be raised in up to a third ofall patients. Radio-imaging•CXR will show abnormalities in 95% of patients. The most common findingis bilateral basal and peripheral infiltrates. The fibrosis may also produce ahoneycombing effect.•High-resolution CT (HRCT) scanning. The specificity of this has beenquestioned in recent years but it is still a useful screening tool to decidewhether or not to proceed to lung histology tests. Typically, a ground glassappearance is indicative of fibrosing alveolitis, whereas a reticular patternis more predominant in other types of interstitial lung disease.(3,9)
Lung function testsThese may show:• A restrictive defect (forced expiratory volume in onesecond (FEV1) is usually less than 80% of predictedvalue, forced vital capacity (FVC) is usually less than 3liters, FEV1/FVC ratio is normal, because both arereduced).• Reduced gas transfer.• Reduced lung volumes.Bronchiolar lavageThis is not vital for the diagnosis of fibrosing alveolitisbut is sometimes used to exclude other diseases. (10)
HistologyLung biopsy is the definitive method of arriving at the diagnosisbut, as the lesions need to be separated both in time andspace, a large biopsy, e.g. open lung biopsy or several smallerbiopsies, may be required. Associated diseasesFibrosing alveolitis may be found in association with severalautoimmune disorders such as:•Thyroid disease.•Systemic sclerosis.•Rheumatoid arthritis.•Autoimmune liver disease.•Systemic lupus erythematosis.
Management (1,10)There is no consensus regarding management.(11) Nondrug management:•Supportive therapy with oxygen and physiotherapy may behelpful.•Regular exercise and weight control should be encouraged.•Vaccinate against influenza and pneumococcus.•Encourage the patient to stop smoking if he or she continuesto do so.
Drug managementIt has been acknowledged for some time that the effectiveness of currentmedical therapies has been disappointing and recent research highlightingthe likely etiology of fibrosing alveolitis explains why. The search is thereforeon for more targeted treatment but standard drug regimes should be offereduntil these avenues of research come to fruition. Medication should beinitiated under specialist supervision.•The risks and benefits of all options should be discussed with patients andsome may prefer not to have any treatment for their Fibrosing alveolitis in theearly stages, particularly if they have significant comorbidities.•Current British Thoracic Society (BTS) guidelines do not recommendsteroids as monotherapy. Systematic reviews suggest that the optimal first-line treatment is a combination of prednisolone and azathioprine (the lattersubstituted by colchicine if it cannot be tolerated).
•Pirfenidone - a growth factor inhibitor - has shown promisingresults in trials and has been approved for use in the UK; theintended launch date is mid-2012.(12)•The use of N-acetylcysteine - an antioxidant - is currentlybeing investigated as a therapy, either in combination withprednisolone and azathioprine or as monotherapy.•Bosentan, imatinib and interferon-γ, all once thought to bepromising treatments, have proved disappointing in Phase IIIstudies.(6)•Opiates are useful to control cough in end-stage disease.•Proton pump inhibitors should be trialed due to the highassociated incidence of gastro-oesophageal disease.
References1.Godfrey A et al; Pulmonary Fibrosis, Idiopathic, Medscape, Aug 20102.Avnon LS, Pikovsky O, Sion-Vardy N, et al; Acute interstitial pneumonia-Hamman-Rich syndrome: clinical characteristics andAnesth Analg. 2009 Jan;108(1):232-7.3.Katzenstein AL, Myers JL; Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med.1998 Apr;157(4 Pt 1):1301-15.; Am J Respir Crit Care Med. 1998 Apr;157(4 Pt 1):1301-15.4.Gribbin J, Hubbard RB, Le Jeune I, et al; The incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK.Thorax. 2006 Jul 14;.; Thorax. 2006 Jul 14.5.Gustafson T, Dahlman-Hoglund A, Nilsson K, et al; Occupational exposure and severe pulmonary fibrosis. Respir Med. 2007Oct;101(10):2207-12. Epub 2007 Jul 12.6.Guenther A; The European IPF Network: towards better care for a dreadful disease Eur Respir J. 2011 Apr;37(4):747-7487.Olson AL, Swigris JJ, Lezotte DC, et al; Mortality from pulmonary fibrosis increased in the United States from 1992 to 2003. Am JRespir Crit Care Med. 2007 Aug 1;176(3):277-84. Epub 2007 May 3.8.Michaelson JE, Aguayo SM, Roman J; Idiopathic pulmonary fibrosis: a practical approach for diagnosis and management. Chest.2000 Sep;118(3):788-94.; Chest. 2000 Sep;118(3):788-94.9.Gulati M; Diagnostic assessment of patients with interstitial lung disease. Prim Care Respir J. 2011 Apr 20. pii: pcrj-2010-07-0078.doi.10.Interstitial lung disease guideline, British Thoracic Society (September 2008)11.Collard HR, Loyd JE, King TE Jr, et al; Current diagnosis and management of idiopathic pulmonary fibrosis: a survey ofacademic physicians. Respir Med. 2007 Sep;101(9):2011-6. Epub 2007 May 16.12.Pirfenidone, New Drugs Online, 2011.13.Le Jeune I, Gribbin J, West J, et al; The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in theUK. Respir Med. 2007 Dec;101(12):2534-40. Epub 2007 Sep 17.14.Mejia M, Carrillo G, Rojas-Serrano J, et al; Idiopathic pulmonary fibrosis and emphysema: decreased survival associated withChest. 2009 Jul;136(1):10-5. Epub 2009 Feb 18.15.Noth I, Martinez FJ; Recent advances in idiopathic pulmonary fibrosis. Chest. 2007 Aug;132(2):637-50.16.http://www.rightdiagnosis.com/death/overview.htm