Idiopathic interstitial pneumonia medical therapy: Difference between revisions

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As IIPs are heterogenous group of unknown interstitial lung disease with different natural history and clinical course, their management should be based on the clinical subtype. Optimal therapy for IPF is controversial as all currently available medications for IPF are severely limited by the lack of clear understanding of the natural history of IPF, the presence of various forms of study designs; heterogeneous patient groups, disputable diagnostic certainty; variable study duration; differences in medication formulation, dosage, route of administration, and duration of treatment; lack of placebo controls; variable intervals between evaluations and differing types of non quantitative assessment criteria. To date, most of treatment strategies have been based on eliminating or suppressing the inflammatory component. As no pharmacological therapy has been proven a clinical efficacy in altering or reversing the inflammatory process of IPF. The clinical trials over the past decades are hopefully held to clear the controversial dilemmas regarding which patients should be treated? When should therapy be started? What is the best treatment and how it should delivered and maintained? and how can be the treatment monitored especially that majority of patients are suffering comorbidities related functional limitations.
As IIPs are heterogenous group of unknown interstitial lung disease with different natural history and clinical course, their management should be based on the clinical subtype. Optimal therapy for IPF is controversial as all currently available medications for IPF are severely limited by the lack of clear understanding of the natural history of IPF, the presence of various forms of study designs; heterogeneous patient groups, disputable diagnostic certainty; variable study duration; differences in medication formulation, dosage, route of administration, and duration of treatment; lack of placebo controls; variable intervals between evaluations and differing types of non quantitative assessment criteria. To date, most of treatment strategies have been based on eliminating or suppressing the inflammatory component. As no pharmacological therapy has been proven a clinical efficacy in altering or reversing the inflammatory process of IPF. The clinical trials over the past decades are hopefully held to clear the controversial dilemmas regarding which patients should be treated? When should therapy be started? What is the best treatment and how it should delivered and maintained? and how can be the treatment monitored especially that majority of patients are suffering comorbidities related functional limitations.


==Medical Therapy==
==Medical Response of Clinical Subtypes==
 
The following points are a general summary for the responsiveness of each subtype of IIPs:
The following points are a general summary for the responsiveness of each subtype of IIPs  
 
====Chronic Fibrosing IIPs====
====Chronic Fibrosing IIPs====
: '''[[Idiopathic Pulmonary Fibrosis]]'''
: '''[[Idiopathic Pulmonary Fibrosis]]'''
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::* good response to smoking cessation but unknown response to corticosteroids
::* good response to smoking cessation but unknown response to corticosteroids


==General outline of chronic fibrosing IIPs==
==Outline of Medical Therapy in Acute IIPs==
:The main treatment for acute interstitial pneumonia (AIP) is supportive care and corticosteroids.Supportive care with Noninvasive or invasive mechanical ventilation is usually required, since most patients develop respiratory failure also the prevention of complications as venous thromboembolism, gastrointestinal bleeding and nosocomial pneumonia. The optimum dosing of glucocorticoids and its clinical benefit remains unclear, However these are widely used.
*'''Glucocorticoids''': Once the diagnosis of AIP is made, high dose systemic glucocorticoids ( methylprednisolone 2 gm per day intravenously in divided doses) are given.<ref>{{Cite journal  | last1 = Vourlekis | first1 = JS. | title = Acute interstitial pneumonia. | journal = Clin Chest Med | volume = 25 | issue = 4 | pages = 739-47, vii | month = Dec | year = 2004 | doi = 10.1016/j.ccm.2004.07.001 | PMID = 15564019 }}</ref> High dose glucocorticoid therapy are just supported by small case series with widely varying results.<ref name="Olson-1990">{{Cite journal  | last1 = Olson | first1 = J. | last2 = Colby | first2 = TV. | last3 = Elliott| first3 = CG. | title = Hamman-Rich syndrome revisited. | journal = Mayo Clin Proc | volume = 65 | issue = 12 | pages = 1538-48 | month = Dec |year = 1990| doi =  | PMID = 2255216 }}</ref><ref name="Vourlekis-2000">{{Cite journal  | last1 = Vourlekis | first1 = JS. | last2 = Brown | first2 = KK. |last3 = Cool| first3 = CD. | last4 = Young | first4 = DA. | last5 = Cherniack | first5 = RM. | last6 = King | first6 = TE. | last7 = Schwarz | first7 = MI.| title = Acute interstitial pneumonitis. Case series and review of the literature. | journal = Medicine (Baltimore) | volume = 79 | issue = 6 | pages = 369-78 | month = Nov | year = 2000 | doi =  | PMID = 11144035 }}</ref><ref name="Suh-2006">{{Cite journal  | last1 = Suh | first1 = GY. | last2 = Kang |first2 = EH. |last3 = Chung | first3 = MP. | last4 = Lee | first4 = KS. | last5 = Han | first5 = J. | last6 = Kitaichi | first6 = M. | last7 = Kwon |first7 = OJ. | title = Early intervention can improve clinical outcome of acute interstitial pneumonia. | journal = Chest | volume = 129 | issue = 3 |pages = 753-61 | month = Mar | year = 2006 | doi = 10.1378/chest.129.3.753 | PMID = 16537878 }}</ref><ref name="Avnon-2009">{{Cite journal  | last1 = Avnon| first1 = LS. | last2 = Pikovsky | first2 = O. | last3 = Sion-Vardy | first3 = N. | last4 = Almog | first4 = Y. | title = Acute interstitial pneumonia-Hamman-Rich syndrome: clinical characteristics and diagnostic and therapeutic considerations. | journal = Anesth Analg | volume = 108 | issue = 1 | pages = 232-7 | month = Jan | year = 2009 | doi = 10.1213/ane.0b013e318188af7a | PMID = 19095855 }}</ref><ref name="Quefatieh-2003">{{Cite journal  | last1 = Quefatieh | first1 = A. | last2 = Stone | first2 = CH. | last3 = DiGiovine | first3 = B. | last4 = Toews | first4 = GB. | last5 = Hyzy | first5 = RC. |title = Low hospital mortality in patients with acute interstitial pneumonia. | journal = Chest | volume = 124 | issue = 2 | pages = 554-9 | month = Aug |year = 2003 | doi =  | PMID = 12907542 }}</ref>
*'''Antibiotics''': Empiric broad-spectrum antibiotics are given to cover any infections.
 
==Outline of Medical Therapy in Chronic Fibrosing IIPs==
:Establishment of the diagnosis is the first critical step in management as misdiagnosis can lead to inappropriate initial therapy. The second step is severity stage to guide treatment choices. Finally, a disease management plan is tailored to the disease severity and patient’s preferences. Follow up assessment is needed to refine treatment options with the disease progression. As no therapy has been proven to be efficacious in this disease, management generally includes some combination of supportive care such as supplemental oxygen and pulmonary rehabilitation, consideration for participation in clinical trials, referral for lung transplant evaluation if possible and early detection and management of comorbidities.<ref name="Raghu-2011">{{Cite journal  | last1 = Raghu | first1 = G. | last2 = Collard | first2 = HR. | last3 = Egan | first3 = JJ. | last4 = Martinez | first4 = FJ. | last5 = Behr | first5 = J. | last6 = Brown | first6 = KK. | last7 = Colby | first7 = TV. | last8 = Cordier | first8 = JF. | last9 = Flaherty | first9 = KR. | title = An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. | journal = Am J Respir Crit Care Med | volume = 183 | issue = 6 | pages = 788-824 | month = Mar | year = 2011 | doi = 10.1164/rccm.2009-040GL | PMID = 21471066 }}</ref><ref name="Walter-2006">{{Cite journal  | last1 = Walter | first1 = N. | last2 = Collard | first2 = HR. | last3 = King | first3 = TE. | title = Current perspectives on the treatment of idiopathic pulmonary fibrosis. | journal = Proc Am Thorac Soc | volume = 3 | issue = 4 | pages = 330-8 | month = Jun | year = 2006 | doi = 10.1513/pats.200602-016TK | PMID = 16738197 }}</ref>
:Establishment of the diagnosis is the first critical step in management as misdiagnosis can lead to inappropriate initial therapy. The second step is severity stage to guide treatment choices. Finally, a disease management plan is tailored to the disease severity and patient’s preferences. Follow up assessment is needed to refine treatment options with the disease progression. As no therapy has been proven to be efficacious in this disease, management generally includes some combination of supportive care such as supplemental oxygen and pulmonary rehabilitation, consideration for participation in clinical trials, referral for lung transplant evaluation if possible and early detection and management of comorbidities.<ref name="Raghu-2011">{{Cite journal  | last1 = Raghu | first1 = G. | last2 = Collard | first2 = HR. | last3 = Egan | first3 = JJ. | last4 = Martinez | first4 = FJ. | last5 = Behr | first5 = J. | last6 = Brown | first6 = KK. | last7 = Colby | first7 = TV. | last8 = Cordier | first8 = JF. | last9 = Flaherty | first9 = KR. | title = An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. | journal = Am J Respir Crit Care Med | volume = 183 | issue = 6 | pages = 788-824 | month = Mar | year = 2011 | doi = 10.1164/rccm.2009-040GL | PMID = 21471066 }}</ref><ref name="Walter-2006">{{Cite journal  | last1 = Walter | first1 = N. | last2 = Collard | first2 = HR. | last3 = King | first3 = TE. | title = Current perspectives on the treatment of idiopathic pulmonary fibrosis. | journal = Proc Am Thorac Soc | volume = 3 | issue = 4 | pages = 330-8 | month = Jun | year = 2006 | doi = 10.1513/pats.200602-016TK | PMID = 16738197 }}</ref>
'''General Approach'''
----
'''Supportive Care''': The most important components of supportive care for patients with IPF are provision of supplemental oxygen (when needed), education, pulmonary rehabilitation, and vaccination against Streptococcus pneumoniae and influenza.
'''Supplemental oxygen''': All IPF patients will at the end require supplemental oxygen, initially with exertion and then continuously. Oxygen therapy should be prescribed to enable the patients to maintain normal activity and possibly to prevent or delay the onset of secondary pulmonary hypertension in hypoxemic patients.
'''Education''': Improved education and communication about the diagnosis, management of IPF, end of life issues and advanced directives are needed to optimize the plan of care.<ref name="Collard-2007">{{Cite journal  | last1 = Collard | first1 = HR. | last2 = Tino | first2 = G. | last3 = Noble | first3 = PW. | last4 = Shreve | first4 = MA. | last5 = Michaels | first5 = M. | last6 = Carlson | first6 = B. | last7 = Schwarz | first7 = MI. | title = Patient experiences with pulmonary fibrosis. | journal = Respir Med | volume = 101 | issue = 6 | pages = 1350-4 | month = Jun | year = 2007 | doi = 10.1016/j.rmed.2006.10.002 | PMID = 17107778 }}</ref><ref name="Daniels-2006">{{Cite journal  | last1 = Daniels | first1 = CE. | last2 = Ryu | first2 = JH. | title = Treatment of idiopathic pulmonary fibrosis. | journal = Semin Respir Crit Care Med | volume = 27 | issue = 6 | pages = 668-76 | month = Dec | year = 2006 | doi = 10.1055/s-2006-957338 | PMID = 17195143 }}</ref>
'''Pulmonary rehabilitation''': Significant reduction in dyspnea and improvement in six-minute walk distance were reported after a pulmonary rehabilitation program<ref name="Holland-2008">{{Cite journal  | last1 = Holland | first1 = AE. | last2 = Hill | first2 = CJ. | last3 = Conron | first3 = M. | last4 = Munro | first4 = P. | last5 = McDonald | first5 = CF. | title = Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease. | journal = Thorax | volume = 63 | issue = 6 | pages = 549-54 | month = Jun | year = 2008 | doi = 10.1136/thx.2007.088070 | PMID = 18245143 }}</ref><ref name="Ferreira-2009">{{Cite journal  | last1 = Ferreira | first1 = A. | last2 = Garvey | first2 = C. | last3 = Connors | first3 = GL. | last4 = Hilling | first4 = L. | last5 = Rigler | first5 = J. | last6 = Farrell | first6 = S. | last7 = Cayou | first7 = C. | last8 = Shariat | first8 = C. | last9 = Collard | first9 = HR. | title = Pulmonary rehabilitation in interstitial lung disease: benefits and predictors of response. | journal = Chest | volume = 135 | issue = 2 | pages = 442-7 | month = Feb | year = 2009 | doi = 10.1378/chest.08-1458 | PMID = 18849399 }}</ref><ref name="Nishiyama-2008">{{Cite journal  | last1 = Nishiyama | first1 = O. | last2 = Kondoh | first2 = Y. | last3 = Kimura | first3 = T. | last4 = Kato | first4 = K. | last5 = Kataoka | first5 = K. | last6 = Ogawa | first6 = T. | last7 = Watanabe | first7 = F. | last8 = Arizono | first8 = S. | last9 = Nishimura | first9 = K. | title = Effects of pulmonary rehabilitation in patients with idiopathic pulmonary fibrosis. | journal = Respirology | volume = 13 | issue = 3 | pages = 394-9 | month = May | year = 2008 | doi = 10.1111/j.1440-1843.2007.01205.x | PMID = 18399862 }}</ref><ref name="Salhi-2010">{{Cite journal  | last1 = Salhi | first1 = B. | last2 = Troosters | first2 = T. | last3 = Behaegel | first3 = M. | last4 = Joos | first4 = G. | last5 = Derom | first5 = E. | title = Effects of pulmonary rehabilitation in patients with restrictive lung diseases. | journal = Chest | volume = 137 | issue = 2 | pages = 273-9 | month = Feb | year = 2010 | doi = 10.1378/chest.09-0241 | PMID = 19858229 }}</ref><ref name="Kozu-2011">{{Cite journal  | last1 = Kozu | first1 = R. | last2 = Senjyu | first2 = H. | last3 = Jenkins | first3 = SC. | last4 = Mukae | first4 = H. | last5 = Sakamoto | first5 = N. | last6 = Kohno | first6 = S. | title = Differences in response to pulmonary rehabilitation in idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. | journal = Respiration | volume = 81 | issue = 3 | pages = 196-205 | month =  | year = 2011 | doi = 10.1159/000315475 | PMID = 20516666 }}</ref><ref name="Huppmann-2013">{{Cite journal  | last1 = Huppmann | first1 = P. | last2 = Sczepanski | first2 = B. | last3 = Boensch | first3 = M. | last4 = Winterkamp | first4 = S. | last5 = Schönheit-Kenn | first5 = U. | last6 = Neurohr | first6 = C. | last7 = Behr | first7 = J. | last8 = Kenn | first8 = K. | title = Effects of inpatient pulmonary rehabilitation in patients with interstitial lung disease. | journal = Eur Respir J | volume = 42 | issue = 2 | pages = 444-53 | month = Aug | year = 2013 | doi = 10.1183/09031936.00081512 | PMID = 23100507 }}</ref>
'''Vaccination''': Pulmonary infections are poorly tolerated in patients with interstitial lung disease, so Influenza and pneumococcal polysaccharide vaccine should be offered to patients with IPF.
'''Comorbidities''': Prevention of gastroesophageal reflux and recurrent microaspiration and cotrolling other comorbidities may slow the progression and have an additional treatment benefit<ref name="Raghu-2011">{{Cite journal  | last1 = Raghu | first1 = G. | last2 = Collard | first2 = HR. | last3 = Egan |first3 = JJ. | last4 = Martinez | first4 = FJ. | last5 = Behr | first5 = J. | last6 = Brown | first6 = KK. | last7 = Colby | first7 = TV. | last8 = Cordier| first8 = JF. | last9 = Flaherty | first9 = KR. | title = An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. | journal = Am J Respir Crit Care Med | volume = 183 | issue = 6 | pages = 788-824 | month = Mar | year = 2011 | doi = 10.1164/rccm.2009-040GL | PMID = 21471066 }}</ref><ref name="Lancaster-2009">{{Cite journal  | last1 = Lancaster | first1 = LH. | last2 = Mason | first2 = WR. | last3 = Parnell | first3 = JA. | last4 = Rice | first4 = TW. | last5 = Loyd | first5 = JE. | last6 = Milstone | first6 = AP. | last7 = Collard |first7 = HR. | last8 = Malow | first8 = BA. | title = Obstructive sleep apnea is common in idiopathic pulmonary fibrosis. | journal = Chest | volume = 136| issue = 3 | pages = 772-8 | month = Sep | year = 2009 | doi = 10.1378/chest.08-2776 | PMID = 19567497 }}</ref>
'''Gastroesophageal reflux and chronic microaspiration''': GERD is an important risk factor for the development and progression of IPF,<ref name="Schachter-2003">{{Cite journal  | last1 = Schachter | first1 = LM. | last2 = Dixon | first2 = J. | last3 = Pierce | first3 = RJ. | last4 = O'Brien | first4 = P. | title = Severe gastroesophageal reflux is associated with reduced carbon monoxide diffusing capacity. | journal = Chest | volume = 123 | issue = 6 | pages = 1932-8 | month = Jun | year = 2003 | doi =  | PMID = 12796170 }}</ref><ref name="Lee-2010">{{Cite journal  | last1 = Lee | first1 = JS. | last2 = Collard | first2 = HR. | last3 = Raghu | first3 = G. | last4 = Sweet | first4 = MP. | last5 = Hays | first5 = SR. | last6 = Campos | first6 = GM. | last7 = Golden | first7 = JA. | last8 = King | first8 = TE. | title = Does chronic microaspiration cause idiopathic pulmonary fibrosis? | journal = Am J Med | volume = 123 | issue = 4 | pages = 304-11 | month = Apr | year = 2010 | doi = 10.1016/j.amjmed.2009.07.033 | PMID = 20362747 }}</ref><ref name="Pashinsky-2009">{{Cite journal  | last1 = Pashinsky | first1 = YY. | last2 = Jaffin | first2 = BW. | last3 = Litle | first3 = VR. | title = Gastroesophageal reflux disease and idiopathic pulmonary fibrosis. | journal = Mt Sinai J Med | volume = 76 | issue = 1 | pages = 24-9 | month = Feb | year = 2009 | doi = 10.1002/msj.20088 | PMID = 19170215 }}</ref><ref name="Raghu-2006">{{Cite journal  | last1 = Raghu | first1 = G. | last2 = Yang | first2 = ST. | last3 = Spada | first3 = C. | last4 = Hayes | first4 = J. | last5 = Pellegrini | first5 = CA. | title = Sole treatment of acid gastroesophageal reflux in idiopathic pulmonary fibrosis: a case series. | journal = Chest | volume = 129 | issue = 3 | pages = 794-800 | month = Mar | year = 2006 | doi = 10.1378/chest.129.3.794 | PMID = 16537884 }}</ref> especially that 90% of IPF patients have GERD. <ref name="Sweet-2006">{{Cite journal  | last1 = Sweet | first1 = MP. | last2 = Hoopes | first2 = C. | last3 = Golden | first3 = J. | last4 = Hays | first4 = S. | last5 = Leard | first5 = L. | last6 = Patti | first6 = M. | title = Prevalence of delayed gastric emptying and gastroesophageal reflux in patients with end-stage lung disease. | journal = Ann Thorac Surg | volume = 82 | issue = 4 | pages = 1570; author reply 1570-1 | month = Oct | year = 2006 | doi = 10.1016/j.athoracsur.2005.11.018 | PMID = 16996990 }}</ref> Studies reported that use of anti-GERD medications were associated with decreased radiographic fibrosis scores on HRCT and was related to a longer survival time.<ref>{{Cite journal  | last1 = Lee | first1 = JS. | last2 = Ryu | first2 = JH. | last3 = Elicker | first3 = BM. | last4 = Lydell | first4 = CP. | last5 = Jones | first5 = KD. | last6 = Wolters | first6 = PJ. | last7 = King | first7 = TE. | last8 = Collard | first8 = HR. | title = Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. | journal = Am J Respir Crit Care Med | volume = 184 | issue = 12 | pages = 1390-4 | month = Dec | year = 2011 | doi = 10.1164/rccm.201101-0138OC | PMID = 21700909 }}</ref> Those reports show that abnormal acid gastroesophageal reflux is directly linked to disease progression. However, controlled clinical trials of acid reflux treatments in IPF are needed.
'''Medical agents''' such as pirfenidone show promise, but there is insufficient evidence to recommend their general use at this time. In the past colchicine, cyclophosphamide, endothelin receptor antagonists, interferon gamma, methotrexate,cyclosporine, penicillamine) have been in case series or clinical trials. Recently there is an evidence against their routine use due to their doubtful benefit and intolerable toxicity.
:*'''Corticosteroids''': Current evidence is against Corticosteroids as monotherapy in IPFs. Historically, corticosteroids were accepted as the last effective treatment for IPFs with transient clinical response on small population of patients, however no survival benefit was reported. Even those transient responses were doubted, as most of the old studies were of bad quality retrospective studies. Also the old studies have defined IPF with less clear criteria as defined nowadays and probably the reported population may had NSIP or DIP other than IPF by nowadays definition. <ref name="Walter-2006">{{Cite journal  | last1 = Walter | first1 = N. | last2 = Collard | first2 = HR. | last3 = King | first3 = TE. | title = Current perspectives on the treatment of idiopathic pulmonary fibrosis. | journal = Proc Am Thorac Soc | volume = 3 | issue = 4 | pages = 330-8 | month = Jun | year = 2006 | doi = 10.1513/pats.200602-016TK | PMID = 16738197 }}</ref>. Cortisone responders in the old studies were more young with less fibrosis and more cellular infiltration in histopahtological analysis, which make justify the response to cortisone as anti inflammatory but not an antifibrotic agent.
:*'''Pirfenidone''': Antifibrotic agent
::Most case series and randomized trials have shown a modest beneficial effect of pirfenidone in slowing the progression of IPF.<ref name="Raghu-1999">{{Cite journal  | last1 = Raghu | first1 = G. | last2 = Johnson | first2 = WC. | last3 = Lockhart | first3 = D. | last4 = Mageto | first4 = Y. | title = Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label Phase II study. | journal = Am J Respir Crit Care Med | volume = 159 | issue = 4 Pt 1 | pages = 1061-9 | month = Apr | year = 1999 | doi = 10.1164/ajrccm.159.4.9805017 | PMID = 10194146 }}</ref><ref name="Azuma-2005">{{Cite journal  | last1 = Azuma | first1 = A. | last2 = Nukiwa | first2 = T. | last3 = Tsuboi | first3 = E. | last4 = Suga | first4 = M. | last5 = Abe | first5 = S. | last6 = Nakata | first6 = K. | last7 = Taguchi | first7 = Y. | last8 = Nagai | first8 = S. | last9 = Itoh | first9 = H. | title = Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. | journal = Am J Respir Crit Care Med | volume = 171 | issue = 9 | pages = 1040-7 | month = May | year = 2005 | doi = 10.1164/rccm.200404-571OC | PMID = 15665326 }}</ref><ref name="Taniguchi-2010">{{Cite journal  | last1 = Taniguchi | first1 = H. | last2 = Ebina | first2 = M. | last3 = Kondoh | first3 = Y. | last4 = Ogura | first4 = T. | last5 = Azuma | first5 = A. | last6 = Suga | first6 = M. | last7 = Taguchi | first7 = Y. | last8 = Takahashi | first8 = H. | last9 = Nakata | first9 = K. | title = Pirfenidone in idiopathic pulmonary fibrosis. | journal = Eur Respir J | volume = 35 | issue = 4 | pages = 821-9 | month = Apr | year = 2010 | doi = 10.1183/09031936.00005209 | PMID = 19996196 }}</ref><ref name="Spagnolo-2010">{{Cite journal  | last1 = Spagnolo | first1 = P. | last2 = Del Giovane | first2 = C. | last3 = Luppi | first3 = F. | last4 = Cerri | first4 = S. | last5 = Balduzzi | first5 = S. | last6 = Walters |first6 = EH. | last7 = D'Amico | first7 = R. | last8 = Richeldi | first8 = L. | title = Non-steroid agents for idiopathic pulmonary fibrosis. | journal = Cochrane Database Syst Rev | volume =  | issue = 9 | pages = CD003134 | month =  | year = 2010 | doi = 10.1002/14651858.CD003134.pub2 | PMID = 20824834 }}</ref><ref name="Okuda-2013">{{Cite journal  | last1 = Okuda | first1 = R. | last2 = Hagiwara | first2 = E. | last3 = Baba | first3 = T. | last4 = Kitamura | first4 = H. | last5 = Kato | first5 = T. | last6 = Ogura | first6 = T. | title = Safety and efficacy of pirfenidone in idiopathic pulmonary fibrosis in clinical practice. | journal = Respir Med | volume = 107 | issue = 9 | pages = 1431-7 | month = Sep | year = 2013 | doi = 10.1016/j.rmed.2013.06.011 | PMID = 23849626 }}</ref>
:::*'''CAPACITY''' 004 and 006 trials ('''C'''linical studies '''A'''ssessing '''P'''irfenidone in idiopathic pulmonary fibrosis, showed that the higher dose of pirfenidone significantly reduced the decline in the 6 minutes walk test distance (MWTD).<ref name="Noble-2011">{{Cite journal  | last1 = Noble | first1 = PW. | last2 = Albera|first2 = C. | last3 = Bradford | first3 = WZ. | last4 = Costabel | first4 = U. | last5 = Glassberg | first5 = MK. | last6 = Kardatzke | first6 = D. |last7 = King |first7 = TE. | last8 = Lancaster | first8 = L. | last9 = Sahn | first9 = SA. | title = Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. | journal = Lancet | volume = 377 | issue = 9779 | pages = 1760-9 | month = May | year = 2011 | doi = 10.1016/S0140-6736(11)60405-4 | PMID = 21571362 }}</ref>
:::*A randomized trial of pirfenidone versus placebo.<ref>{{Cite journal  | last1 = Azuma | first1 = A. | last2 = Nukiwa | first2 = T. | last3 = Tsuboi | first3 = E. | last4 = Suga | first4 = M. | last5 = Abe | first5 = S. | last6 = Nakata | first6 = K. | last7 = Taguchi | first7 = Y. | last8 = Nagai | first8 = S. | last9 = Itoh | first9 = H. | title = Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. | journal = Am J Respir Crit Care Med | volume = 171 | issue = 9 | pages = 1040-7 | month = May | year = 2005 | doi = 10.1164/rccm.200404-571OC | PMID = 15665326 }}</ref> suggested that there may be greater benefit in patients whose disease is less severe.
:::*Dosage and administration : 40 mg/kg per day in three divided doses. It is approved for use in patients with mild-to-moderate IPF in Japan, Europe, and Canada, but not in the United States.
:*'''Phosphodiesterase Inhibitors''': The IPF-related pulmonary hypertension may be treated with a phosphodiesterase inhibitor that might improve exercise tolerance, as in idiopathic pulmonary hypertension.<ref name="Azuma-2005">{{Cite journal  | last1 = Azuma | first1 = A. | last2 = Nukiwa | first2 = T. | last3 = Tsuboi | first3 = E. | last4 = Suga | first4 = M. | last5 = Abe | first5 = S. | last6 = Nakata | first6 = K. | last7 = Taguchi | first7 = Y. | last8 = Nagai | first8 = S. | last9 = Itoh | first9 = H. | title = Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. | journal = Am J Respir Crit Care Med | volume = 171 | issue = 9 | pages = 1040-7 | month = May | year = 2005 | doi = 10.1164/rccm.200404-571OC | PMID = 15665326 }}</ref><ref name="Jackson-2010">{{Cite journal  | last1 = Jackson | first1 = RM. | last2 = Glassberg | first2 = MK. | last3 = Ramos | first3 = CF. | last4 = Bejarano | first4 = PA. | last5 = Butrous | first5 = G. | last6 = Gómez-Marín | first6 = O. | title = Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. | journal = Lung | volume = 188 | issue = 2 | pages = 115-23 | month = Apr | year = 2010 | doi = 10.1007/s00408-009-9209-8 | PMID = 20012639 }}</ref><ref name="Zisman-2010">{{Cite journal  | last1 = Zisman | first1 = DA. | last2 = Schwarz | first2 = M. | last3 = Anstrom | first3 = KJ. | last4 = Collard | first4 = HR. | last5 = Flaherty | first5 = KR. | last6 = Hunninghake | first6 = GW. | last7 = de Andrade | first7 = J. | last8 = Anstrom | first8 = KJ. | last9 = Collard | first9 = HR. | title = A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. | journal = N Engl J Med | volume = 363 | issue = 7 | pages = 620-8 | month = Aug | year = 2010 | doi = 10.1056/NEJMoa1002110 | PMID = 20484178 }}</ref> A trial of sildenafil may be a good option in patients with a DLCO <35 percent, echocardiographic evidence of right ventricular dysfunction, and no contraindications to sildenafil ( unstable angina, use of nitrates). Longer duration trials are needed to assess the safety and efficacy of sildenafil in the treatment of IPF.
:*'''Methotrexate''': is an antineoplastic and immunosuppressive agent, and not recommended for IPF due to lack of data of clinical benefit and the concerns about methotrexate-induced pneumonitis, which makes it difficult to distinguish pulmonary drug toxicity from progression of the IIPs. However, methotrexate can be effective in sarcoidosis induced IIPs.<ref name="Pesci-">{{Cite journal  | last1 = Pesci | first1 = A. | last2 = Bertorelli | first2 = G. | last3 = Manganelli | first3 = P. | last4 = Ambanelli | first4 = U. | title = Bronchoalveolar lavage analysis of interstitial lung disease in CREST syndrome. | journal = Clin Exp Rheumatol | volume = 4 | issue = 2 | pages = 121-4 | month =  | year =  | doi =  | PMID = 3731570 }}</ref><ref name="Lacher-1968">{{Cite journal  | last1 = Lacher | first1 = MJ. | title = Spontaneous remission or response to methotrexate in sarcoidosis. | journal = Ann Intern Med | volume = 69 | issue = 6 | pages = 1247-8 | month = Dec | year = 1968 | doi =  | PMID = 5725738 }}</ref><ref name="Lower-1990">{{Cite journal  | last1 = Lower | first1 = EE. | last2 = Baughman | first2 = RP. | title = The use of low dose methotrexate in refractory sarcoidosis. | journal = Am J Med Sci | volume = 299 | issue = 3 | pages = 153-7 | month = Mar | year = 1990 | doi =  | PMID = 2316559 }}</ref> Methotrexate may have a clinical benefit, as evidenced by radiographic and histologic assessment, in [[interstitial lung disease]] in the context of autoimmune disease as [[rheumatoid arthritis]].<ref name="Scott-1980">{{Cite journal  | last1 = Scott | first1 = DG. | last2 = Bacon | first2 = PA. | title = Response to methotrexate in fibrosing alveolitis associated with connective tissue disease. | journal = Thorax | volume = 35 | issue = 10 | pages = 725-31 | month = Oct | year = 1980 | doi =  | PMID = 7466720 }}</ref>
:*'''Cyclosporine''': is not recommended in IPF based on limited experience, high toxicity and absence of proven benefit. <ref name="Alton-1989">{{Cite journal  | last1 = Alton | first1 = EW. | last2 = Johnson | first2 = M. | last3 = Turner-Warwick | first3 = M. | title = Advanced cryptogenic fibrosing alveolitis: preliminary report on treatment with cyclosporin A. | journal = Respir Med | volume = 83 | issue = 4 | pages = 277-9 | month = Jul | year = 1989 | doi =  | PMID = 2692090 }}</ref><ref name="Venuta-">{{Cite journal  | last1 = Venuta | first1 = F. | last2 = Rendina | first2 = EA. | last3 = Ciriaco | first3 = P. | last4 = De Giacomo | first4 = T. | last5 = Pompeo | first5 = E. | last6 = Bachetoni | first6 = A. | last7 = Ricci | first7 = C. | title = Efficacy of cyclosporine to reduce steroids in patients with idiopathic pulmonary fibrosis before lung transplantation. | journal = J Heart Lung Transplant | volume = 12 | issue = 6 Pt 1 | pages = 909-14 | month =  | year =  | doi =  | PMID = 8312314 }}</ref><ref name="Moolman-1991">{{Cite journal  | last1 = Moolman | first1 = JA. | last2 = Bardin | first2 = PG. | last3 = Rossouw | first3 = DJ. | last4 = Joubert | first4 = JR. | title = Cyclosporin as a treatment for interstitial lung disease of unknown aetiology. | journal = Thorax | volume = 46 | issue = 8 | pages = 592-5 | month = Aug | year = 1991 | doi =  | PMID = 1926031 }}</ref><ref name="Grgic-2008">{{Cite journal  | last1 = Grgic | first1 = A. | last2 = Lausberg | first2 = H. | last3 = Heinrich | first3 = M. | last4 = Koenig | first4 = J. | last5 = Uder | first5 = M. | last6 = Sybrecht | first6 = GW. | last7 = Wilkens | first7 = H. | title = Progression of fibrosis in usual interstitial pneumonia: serial evaluation of the native lung after single lung transplantation. | journal = Respiration | volume = 76 | issue = 2 | pages = 139-45 | month =  | year = 2008 | doi = 10.1159/000108440 | PMID = 17851227 }}</ref>
:*'''Etanercept''': Antagonists of tumor necrosis factor (TNF)-alpha might be effective in IPF animal model.<ref>{{Cite journal  | last1 = Piguet | first1 = PF. | last2 = Vesin | first2 = C. | title = Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. | journal = Eur Respir J | volume = 7 | issue = 3 | pages = 515-8 | month = Mar | year = 1994 | doi =  | PMID = 7516893 }}</ref> However studies<ref name="Raghu-2008">{{Cite journal  | last1 = Raghu | first1 = G. | last2 = Brown | first2 = KK. | last3 = Costabel | first3 = U. | last4 = Cottin | first4 = V. | last5 = du Bois | first5 = RM. | last6 = Lasky | first6 = JA. | last7 = Thomeer | first7 = M. | last8 = Utz | first8 = JP. | last9 = Khandker | first9 = RK. | title = Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. | journal = Am J Respir Crit Care Med | volume = 178 | issue = 9 | pages = 948-55 | month = Nov | year = 2008 | doi = 10.1164/rccm.200709-1446OC | PMID = 18669816 }}</ref> failed to prove any improvement in FVC or DLCO, or in the arterial-alveolar oxygen gradient. Based on the potential side effects and lack of proven efficacy, etanercept not recommended to treat IPF. <ref>{{Cite journal  | last1 = Raghu | first1 = G. | last2 = Collard | first2 = HR. | last3 = Egan | first3 = JJ. | last4 = Martinez | first4 = FJ. | last5 = Behr | first5 = J. | last6 = Brown | first6 = KK. | last7 = Colby | first7 = TV. | last8 = Coardier | first8 = JF. | last9 = Flaherty | first9 = KR. | title = An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. | journal = Am J Respir Crit Care Med | volume = 183 | issue = 6 | pages = 788-824 | month = Mar | year = 2011 | doi = 10.1164/rccm.2009-040GL | PMID = 21471066 }}</ref>
:*'''Penicillamine''': impairs collagen biosynthesis and the immune system in anima models of fibrotic lung disorders.<ref name="Ward-1983">{{Cite journal  | last1 = Ward | first1 = WF. | last2 = Shih-Hoellwarth | first2 = A. | last3 = Tuttle | first3 = RD. | title = Collagen accumulation in irradiated rat lung: modification by D-penicillamine. | journal = Radiology | volume = 146 | issue = 2 | pages = 533-7 | month = Feb | year = 1983 | doi = 10.1148/radiology.146.2.6849102 | PMID = 6849102 }}</ref><ref name="Ekimoto-1985">{{Cite journal  | last1 = Ekimoto | first1 = H. | last2 = Aikawa | first2 = M. | last3 = Ohnuki | first3 = T. | last4 = Takahashi | first4 = K. | last5 = Matsuda | first5 = A. | last6 = Takita | first6 = T. | last7 = Umezawa | first7 = H. | title = Immunological involvement in pulmonary fibrosis induced by peplomycin. | journal = J Antibiot (Tokyo) | volume = 38 | issue = 1 | pages = 94-8 | month = Jan | year = 1985 | doi =  | PMID = 2579054 }}</ref><ref name="Molteni-1985">{{Cite journal  | last1 = Molteni | first1 = A. | last2 = Ward | first2 = WF. | last3 = Ts'ao | first3 = CH. | last4 = Solliday | first4 = NH. | last5 = Dunne | first5 = M. | title = Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine. | journal = Proc Soc Exp Biol Med | volume = 180 | issue = 1 | pages = 112-20 | month = Oct | year = 1985 | doi =  | PMID = 2994075 }}</ref><ref name="Geismar-1986">{{Cite journal  | last1 = Geismar | first1 = LS. | last2 = Hennessey | first2 = S. | last3 = Reiser | first3 = KM. | last4 = Last | first4 = JA. | title = D-penicillamine prevents collagen accumulation in lungs of rats given bleomycin. | journal = Chest | volume = 89 | issue = 3 Suppl | pages = 153S-154S | month = Mar | year = 1986 | doi =  | PMID = 2419048 }}</ref>  However experience with penicillamine in patients with IPF is limited, not encouraging and evidence of efficacy is lacking.<ref name="Selman-1998">{{Cite journal  | last1 = Selman | first1 = M. | last2 = Carrillo | first2 = G. | last3 = Salas | first3 = J. | last4 = Padilla | first4 = RP. | last5 = Pérez-Chavira | first5 = R. | last6 = Sansores | first6 = R. | last7 = Chapela | first7 = R. | title = Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial. | journal = Chest | volume = 114 | issue = 2 | pages = 507-12 | month = Aug | year = 1998 | doi =  | PMID = 9726738 }}</ref><ref name="Cegla-1977">{{Cite journal  | last1 = Cegla | first1 = UH. | title = [Treatment of idiopathic fibrosing alveolitis. Therapeutic experiences with azathioprine-prednisolone and D-penicillamine-prednisolone combination therapy]. | journal = Schweiz Med Wochenschr | volume = 107 | issue = 6 | pages = 184-7 | month = Feb | year = 1977 | doi =  | PMID = 834991 }}</ref><ref name="Chapela-1986">{{Cite journal  | last1 = Chapela | first1 = R. | last2 = Zúñiga | first2 = G. | last3 = Selman | first3 = M. | title = D-penicillamine in the therapy of fibrotic lung diseases. | journal = Int J Clin Pharmacol Ther Toxicol | volume = 24 | issue = 1 | pages = 16-7 | month = Jan | year = 1986 | doi =  | PMID = 3957484 }}</ref>Only improvement in DLCO in fibrosing alveolitits in scleroderma (but not in other pulmonary function test parameters).<ref name="Steen-1985">{{Cite journal  | last1 = Steen | first1 = VD. | last2 = Owens | first2 = GR. | last3 = Redmond | first3 = C. | last4 = Rodnan | first4 = GP. | last5 = Medsger | first5 = TA. | title = The effect of D-penicillamine on pulmonary findings in systemic sclerosis. | journal = Arthritis Rheum | volume = 28 | issue = 8 | pages = 882-8 | month = Aug | year = 1985 | doi =  | PMID = 4026885 }}</ref><ref name="de Clerck-1987">{{Cite journal  | last1 = de Clerck | first1 = LS. | last2 = Dequeker | first2 = J. | last3 = Francx | first3 = L. | last4 = Demedts | first4 = M. | title = D-penicillamine therapy and interstitial lung disease in scleroderma. A long-term followup study. | journal = Arthritis Rheum | volume = 30 | issue = 6 | pages = 643-50 | month = Jun | year = 1987 | doi =  | PMID = 3606683 }}</ref> A study comparing colchicine/prednisone versus penicillamine/prednisone versus D-penicillamine/colchicine/prednisone  versus prednisone alone showed no significant differences in survival or in lung function relative to the baseline measurement were found in any group.<ref>{{Cite journal  | last1 = Selman | first1 = M. | last2 = Carrillo | first2 = G. | last3 = Salas | first3 = J. | last4 = Padilla | first4 = RP. | last5 = Pérez-Chavira | first5 = R. | last6 = Sansores | first6 = R. | last7 = Chapela | first7 = R. | title = Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial. | journal = Chest | volume = 114 | issue = 2 | pages = 507-12 | month = Aug | year = 1998 | doi =  | PMID = 9726738 }}</ref>
:*'''Colchicine''': is not recommended for treatment of IPF because evidence of efficacy is lacking. Animal model studies suggesting that colchicine may slow the fibrotic process.<ref name="Raghu-2004">{{Cite journal  | last1 = Raghu | first1 = G. | last2 = Brown | first2 = KK. | last3 = Bradford | first3 = WZ. | last4 = Starko | first4 = K. | last5 = Noble | first5 = PW. | last6 = Schwartz | first6 = DA. | last7 = King | first7 = TE. | title = A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. | journal = N Engl J Med | volume = 350 | issue = 2 | pages = 125-33 | month = Jan | year = 2004 | doi = 10.1056/NEJMoa030511 | PMID = 14711911 }}</ref><ref name="Dubrawsky-1978">{{Cite journal  | last1 = Dubrawsky | first1 = C. | last2 = Dubravsky | first2 = NB. | last3 = Withers | first3 = HR. | title = The effect of colchicine on the accumulation of hydroxyproline and on lung compliance after irradiation. | journal = Radiat Res | volume = 73 | issue = 1 | pages = 111-20 | month = Jan | year = 1978 | doi =  | PMID = 622454 }}</ref><ref name="Zhang-1992">{{Cite journal  | last1 = Zhang | first1 = L. | last2 = Zhu | first2 = Y. | last3 = Luo | first3 = W. | last4 = Xi | first4 = P. | last5 = Yan | first5 = Y. | title = The protective effect of colchicine on bleomycin-induced pulmonary fibrosis in rats. | journal = Chin Med Sci J | volume = 7 | issue = 1 | pages = 58-60 | month = Mar | year = 1992 | doi =  | PMID = 1384784 }}</ref><ref name="Rennard-1988">{{Cite journal  | last1 = Rennard | first1 = SI. | last2 = Bitterman | first2 = PB. | last3 = Ozaki | first3 = T. | last4 = Rom | first4 = WN. | last5 = Crystal | first5 = RG. | title = Colchicine suppresses the release of fibroblast growth factors from alveolar macrophages in vitro. The basis of a possible therapeutic approach ot the fibrotic disorders. | journal = Am Rev Respir Dis | volume = 137 | issue = 1 | pages = 181-5 | month = Jan | year = 1988 | doi = 10.1164/ajrccm/137.1.181 | PMID = 3337460 }}</ref> However different clinical studies failed to show any clinical benefit.<ref name="Douglas-1997">{{Cite journal  | last1 = Douglas | first1 = WW. | last2 = Ryu | first2 = JH. | last3 = Bjoraker | first3 = JA. | last4 = Schroeder | first4 = DR. | last5 = Myers | first5 = JL. | last6 = Tazelaar | first6 = HD. | last7 = Swensen | first7 = SJ. | last8 = Scanlon | first8 = PD. | last9 = Peters | first9 = SG. | title = Colchicine versus prednisone as treatment of usual interstitial pneumonia. | journal = Mayo Clin Proc | volume = 72 | issue = 3 | pages = 201-9 | month = Mar | year = 1997 | doi = 10.1016/S0025-6196(11)64749-6 | PMID = 9070193 }}</ref><ref name="Douglas-2000">{{Cite journal  | last1 = Douglas | first1 = WW. | last2 = Ryu | first2 = JH. | last3 = Schroeder | first3 = DR. | title = Idiopathic pulmonary fibrosis: Impact of oxygen and colchicine, prednisone, or no therapy on survival. | journal = Am J Respir Crit Care Med | volume = 161 | issue = 4 Pt 1 | pages = 1172-8 | month = Apr | year = 2000 | doi = 10.1164/ajrccm.161.4.9907002 | PMID = 10764308 }}</ref> <ref name="Douglas-1998">{{Cite journal  | last1 = Douglas | first1 = WW. | last2 = Ryu | first2 = JH. | last3 = Swensen | first3 = SJ. | last4 = Offord | first4 = KP. | last5 = Schroeder | first5 = DR. | last6 = Caron | first6 = GM. | last7 = DeRemee | first7 = RA. | title = Colchicine versus prednisone in the treatment of idiopathic pulmonary fibrosis. A randomized prospective study. Members of the Lung Study Group. | journal = Am J Respir Crit Care Med | volume = 158 | issue = 1 | pages = 220-5 | month = Jul | year = 1998 | doi = 10.1164/ajrccm.158.1.9709089 | PMID = 9655733 }}</ref> <ref name="Selman-1998">{{Cite journal  | last1 = Selman | first1 = M. | last2 = Carrillo | first2 = G. | last3 = Salas | first3 = J. | last4 = Padilla | first4 = RP. | last5 = Pérez-Chavira | first5 = R. | last6 = Sansores | first6 = R. | last7 = Chapela | first7 = R. | title = Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial. | journal = Chest | volume = 114 | issue = 2 | pages = 507-12 | month = Aug | year = 1998 | doi =  | PMID = 9726738 }}</ref>
:*'''Cyclophosphamide''': is not recommended due its toxicity and lack of proven benefit. small showed that it might be beneficial in the treatment of IPF,<ref name="Kolb-1998">{{Cite journal  | last1 = Kolb | first1 = M. | last2 = Kirschner | first2 = J. | last3 = Riedel | first3 = W. | last4 = Wirtz | first4 = H. | last5 = Schmidt | first5 = M. | title = Cyclophosphamide pulse therapy in idiopathic pulmonary fibrosis. | journal = Eur Respir J | volume = 12 | issue = 6 | pages = 1409-14 | month = Dec | year = 1998 | doi =  | PMID = 9877500 }}</ref><ref name="Johnson-1989">{{Cite journal  | last1 = Johnson | first1 = MA. | last2 = Kwan | first2 = S. | last3 = Snell | first3 = NJ. | last4 = Nunn | first4 = AJ. | last5 = Darbyshire | first5 = JH. | last6 = Turner-Warwick | first6 = M. | title = Randomised controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisolone in combination in cryptogenic fibrosing alveolitis. | journal = Thorax | volume = 44 | issue = 4 | pages = 280-8 | month = Apr | year = 1989 | doi =  | PMID = 2669218 }}</ref><ref name="Baughman-1992">{{Cite journal  | last1 = Baughman | first1 = RP. | last2 = Lower | first2 = EE. | title = Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis. | journal = Chest | volume = 102 | issue = 4 | pages = 1090-4 | month = Oct | year = 1992 | doi =  | PMID = 1395749 }}</ref> however, one of the largest retrospective studies found no survival benefit on the combination of prednisone and oral cyclophosphamide compared prednisone alone.<ref name="Collard-2004">{{Cite journal  | last1 = Collard | first1 = HR. | last2 = Ryu | first2 = JH. | last3 = Douglas | first3 = WW. | last4 = Schwarz | first4 = MI. | last5 = Curran-Everett | first5 = D. | last6 = King | first6 = TE. | last7 = Brown | first7 = KK. | title = Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis. | journal = Chest | volume = 125 | issue = 6 | pages = 2169-74 | month = Jun | year = 2004 | doi =  | PMID = 15189938 }}</ref>


==References==
==References==

Latest revision as of 22:04, 23 November 2013

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2];

Overview

As IIPs are heterogenous group of unknown interstitial lung disease with different natural history and clinical course, their management should be based on the clinical subtype. Optimal therapy for IPF is controversial as all currently available medications for IPF are severely limited by the lack of clear understanding of the natural history of IPF, the presence of various forms of study designs; heterogeneous patient groups, disputable diagnostic certainty; variable study duration; differences in medication formulation, dosage, route of administration, and duration of treatment; lack of placebo controls; variable intervals between evaluations and differing types of non quantitative assessment criteria. To date, most of treatment strategies have been based on eliminating or suppressing the inflammatory component. As no pharmacological therapy has been proven a clinical efficacy in altering or reversing the inflammatory process of IPF. The clinical trials over the past decades are hopefully held to clear the controversial dilemmas regarding which patients should be treated? When should therapy be started? What is the best treatment and how it should delivered and maintained? and how can be the treatment monitored especially that majority of patients are suffering comorbidities related functional limitations.

Medical Response of Clinical Subtypes

The following points are a general summary for the responsiveness of each subtype of IIPs:

Chronic Fibrosing IIPs

Idiopathic Pulmonary Fibrosis
  • poor response to corticosteroids and cytotoxic drugs
Idiopathic Nonspecific Interstitial Pneumonia
  • good response to corticosteroids

Acute/Subacute IIPs

Cryptogenic Organizing Pneumonia
  • good response to corticosteroids
Acute Interstitial Pneumonia (Hamman-Rich Syndrome)]
  • unknown response to corticosteroids

Smoking-related IIPs

Respiratory Bronchiolitis-Interstitial Lung Disease
  • good response to smoking cessation but unknown response to corticosteroids
Desquamative Interstitial Pneumonia
  • good response to smoking cessation but unknown response to corticosteroids

Outline of Medical Therapy in Acute IIPs

The main treatment for acute interstitial pneumonia (AIP) is supportive care and corticosteroids.Supportive care with Noninvasive or invasive mechanical ventilation is usually required, since most patients develop respiratory failure also the prevention of complications as venous thromboembolism, gastrointestinal bleeding and nosocomial pneumonia. The optimum dosing of glucocorticoids and its clinical benefit remains unclear, However these are widely used.
  • Glucocorticoids: Once the diagnosis of AIP is made, high dose systemic glucocorticoids ( methylprednisolone 2 gm per day intravenously in divided doses) are given.[1] High dose glucocorticoid therapy are just supported by small case series with widely varying results.[2][3][4][5][6]
  • Antibiotics: Empiric broad-spectrum antibiotics are given to cover any infections.

Outline of Medical Therapy in Chronic Fibrosing IIPs

Establishment of the diagnosis is the first critical step in management as misdiagnosis can lead to inappropriate initial therapy. The second step is severity stage to guide treatment choices. Finally, a disease management plan is tailored to the disease severity and patient’s preferences. Follow up assessment is needed to refine treatment options with the disease progression. As no therapy has been proven to be efficacious in this disease, management generally includes some combination of supportive care such as supplemental oxygen and pulmonary rehabilitation, consideration for participation in clinical trials, referral for lung transplant evaluation if possible and early detection and management of comorbidities.[7][8]

General Approach

Supportive Care: The most important components of supportive care for patients with IPF are provision of supplemental oxygen (when needed), education, pulmonary rehabilitation, and vaccination against Streptococcus pneumoniae and influenza.

Supplemental oxygen: All IPF patients will at the end require supplemental oxygen, initially with exertion and then continuously. Oxygen therapy should be prescribed to enable the patients to maintain normal activity and possibly to prevent or delay the onset of secondary pulmonary hypertension in hypoxemic patients.

Education: Improved education and communication about the diagnosis, management of IPF, end of life issues and advanced directives are needed to optimize the plan of care.[9][10]

Pulmonary rehabilitation: Significant reduction in dyspnea and improvement in six-minute walk distance were reported after a pulmonary rehabilitation program[11][12][13][14][15][16]

Vaccination: Pulmonary infections are poorly tolerated in patients with interstitial lung disease, so Influenza and pneumococcal polysaccharide vaccine should be offered to patients with IPF.

Comorbidities: Prevention of gastroesophageal reflux and recurrent microaspiration and cotrolling other comorbidities may slow the progression and have an additional treatment benefit[7][17]

Gastroesophageal reflux and chronic microaspiration: GERD is an important risk factor for the development and progression of IPF,[18][19][20][21] especially that 90% of IPF patients have GERD. [22] Studies reported that use of anti-GERD medications were associated with decreased radiographic fibrosis scores on HRCT and was related to a longer survival time.[23] Those reports show that abnormal acid gastroesophageal reflux is directly linked to disease progression. However, controlled clinical trials of acid reflux treatments in IPF are needed.

Medical agents such as pirfenidone show promise, but there is insufficient evidence to recommend their general use at this time. In the past colchicine, cyclophosphamide, endothelin receptor antagonists, interferon gamma, methotrexate,cyclosporine, penicillamine) have been in case series or clinical trials. Recently there is an evidence against their routine use due to their doubtful benefit and intolerable toxicity.

  • Corticosteroids: Current evidence is against Corticosteroids as monotherapy in IPFs. Historically, corticosteroids were accepted as the last effective treatment for IPFs with transient clinical response on small population of patients, however no survival benefit was reported. Even those transient responses were doubted, as most of the old studies were of bad quality retrospective studies. Also the old studies have defined IPF with less clear criteria as defined nowadays and probably the reported population may had NSIP or DIP other than IPF by nowadays definition. [8]. Cortisone responders in the old studies were more young with less fibrosis and more cellular infiltration in histopahtological analysis, which make justify the response to cortisone as anti inflammatory but not an antifibrotic agent.
  • Pirfenidone: Antifibrotic agent
Most case series and randomized trials have shown a modest beneficial effect of pirfenidone in slowing the progression of IPF.[24][25][26][27][28]
  • CAPACITY 004 and 006 trials (Clinical studies Assessing Pirfenidone in idiopathic pulmonary fibrosis, showed that the higher dose of pirfenidone significantly reduced the decline in the 6 minutes walk test distance (MWTD).[29]
  • A randomized trial of pirfenidone versus placebo.[30] suggested that there may be greater benefit in patients whose disease is less severe.
  • Dosage and administration : 40 mg/kg per day in three divided doses. It is approved for use in patients with mild-to-moderate IPF in Japan, Europe, and Canada, but not in the United States.
  • Phosphodiesterase Inhibitors: The IPF-related pulmonary hypertension may be treated with a phosphodiesterase inhibitor that might improve exercise tolerance, as in idiopathic pulmonary hypertension.[25][31][32] A trial of sildenafil may be a good option in patients with a DLCO <35 percent, echocardiographic evidence of right ventricular dysfunction, and no contraindications to sildenafil ( unstable angina, use of nitrates). Longer duration trials are needed to assess the safety and efficacy of sildenafil in the treatment of IPF.
  • Methotrexate: is an antineoplastic and immunosuppressive agent, and not recommended for IPF due to lack of data of clinical benefit and the concerns about methotrexate-induced pneumonitis, which makes it difficult to distinguish pulmonary drug toxicity from progression of the IIPs. However, methotrexate can be effective in sarcoidosis induced IIPs.[33][34][35] Methotrexate may have a clinical benefit, as evidenced by radiographic and histologic assessment, in interstitial lung disease in the context of autoimmune disease as rheumatoid arthritis.[36]
  • Cyclosporine: is not recommended in IPF based on limited experience, high toxicity and absence of proven benefit. [37][38][39][40]
  • Etanercept: Antagonists of tumor necrosis factor (TNF)-alpha might be effective in IPF animal model.[41] However studies[42] failed to prove any improvement in FVC or DLCO, or in the arterial-alveolar oxygen gradient. Based on the potential side effects and lack of proven efficacy, etanercept not recommended to treat IPF. [43]
  • Penicillamine: impairs collagen biosynthesis and the immune system in anima models of fibrotic lung disorders.[44][45][46][47] However experience with penicillamine in patients with IPF is limited, not encouraging and evidence of efficacy is lacking.[48][49][50]Only improvement in DLCO in fibrosing alveolitits in scleroderma (but not in other pulmonary function test parameters).[51][52] A study comparing colchicine/prednisone versus penicillamine/prednisone versus D-penicillamine/colchicine/prednisone versus prednisone alone showed no significant differences in survival or in lung function relative to the baseline measurement were found in any group.[53]
  • Colchicine: is not recommended for treatment of IPF because evidence of efficacy is lacking. Animal model studies suggesting that colchicine may slow the fibrotic process.[54][55][56][57] However different clinical studies failed to show any clinical benefit.[58][59] [60] [48]
  • Cyclophosphamide: is not recommended due its toxicity and lack of proven benefit. small showed that it might be beneficial in the treatment of IPF,[61][62][63] however, one of the largest retrospective studies found no survival benefit on the combination of prednisone and oral cyclophosphamide compared prednisone alone.[64]

References

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  48. ↑ 48.0 48.1 Selman, M.; Carrillo, G.; Salas, J.; Padilla, RP.; Pérez-Chavira, R.; Sansores, R.; Chapela, R. (1998). "Colchicine, D-penicillamine, and prednisone in the treatment of idiopathic pulmonary fibrosis: a controlled clinical trial". Chest. 114 (2): 507–12. PMID 9726738. Unknown parameter |month= ignored (help)
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  63. ↑ Baughman, RP.; Lower, EE. (1992). "Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis". Chest. 102 (4): 1090–4. PMID 1395749. Unknown parameter |month= ignored (help)
  64. ↑ Collard, HR.; Ryu, JH.; Douglas, WW.; Schwarz, MI.; Curran-Everett, D.; King, TE.; Brown, KK. (2004). "Combined corticosteroid and cyclophosphamide therapy does not alter survival in idiopathic pulmonary fibrosis". Chest. 125 (6): 2169–74. PMID 15189938. Unknown parameter |month= ignored (help)

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