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Re: idiopathic Lung fibrosis

Hi, read this article. I think it will be very beneficial for you as far as management issues are concerned.

INTRODUCTION — Idiopathic pulmonary fibrosis (IPF, also called cryptogenic fibrosing alveolitis) is characterized by progressive parenchymal scarring and loss of pulmonary function. Treatment is aimed at minimizing the progression from inflammation to fibrosis. However, the underlying lesion in IPF may be more fibrotic than inflammatory, explaining why few patients respond to antiinflammatory therapies and the prognosis remains poor [1,2]. (See "Pathogenesis of idiopathic pulmonary fibrosis".
Although there have been no randomized, placebo-controlled trials to prove that treatment is beneficial, the dismal prognosis of the disease and reports of a beneficial response in some patients generally justify therapy. However, considerable uncertainty remains about the following therapeutic questions [3-5]:
• Which patients should be treated?
• When should therapy be started?
• What is the best therapy?
• How should the disease course and the response to treatment be monitored?
INDICATIONS FOR THERAPY — A careful risk benefit analysis for each patient is necessary when making decisions about who to treat since no therapies have been proven to change outcomes in patients with IPF and because the available treatments are potentially toxic. Although there are not strict criteria for initiating or withholding therapy, a number of clinical factors may help stratify patients into groups with different likelihoods of treatment failure.
Patients with one or more of the following are at higher risk for treatment failure [6,7]:
• Male gender
• Moderate to severe dyspnea with exertion
• Extensive smoking history (the greater the number of pack-years, the worse the prognosis)
• Moderate to severe loss of lung function at presentation (assessed by FVC, DLCO and gas exchange with exercise)
• Neutrophilia or eosinophilia on cellular analysis of bronchoalveolar lavage (BAL) fluid at presentation
• A predominance of honeycomb changes on a high resolution computed tomography (HRCT) scan
Reciprocally, patients with one or more of the following appear to have a more favorable survival that would encourage aggressive therapy:
• Younger (age 50 years)
• Shorter symptomatic period ( 1 year) before initiation of therapy [8].
• An earlier stage of disease, suggested by less dyspnea, more normal lung function, absence of oxygen desaturation (defined as <88 percent) on a 6-minute walk test [9-11].
• Less parenchymal disease on chest radiograph or HRCT [1,4,12-15].
Another factor that may influence the decision to treat is the patient's other comorbidities.
A frequent question is how to approach the patient whose disease has already progressed to a later, more fibrotic stage. Current therapy cannot reverse established fibrotic disease; as a result, the magnitude of the potential response for any patient is inversely related to the extent and severity of the fibrotic response. As the potential benefit diminishes in later disease, it becomes increasingly difficult to accept the side effects of therapy.
TIMING OF THERAPY — Because the rate of disease progression is variable, some clinicians have suggested that disease progression should be documented prior to initiating therapy. We disagree with this approach for several reasons:
• Historically patients with untreated IPF progress [15-17].
• Disease progression is often insidious and may be difficult to detect with commonly used parameters, such as symptoms, chest radiographic findings, or pulmonary function as measured by spirometry. These parameters are insensitive for documenting change in IPF.
• Patients in this age group (the majority are >55 years old) often have difficulty discerning whether their functional limitations are the result of disease progression, deconditioning, or simply the aging process.
• There is evidence that the disease is more likely to be responsive to treatment at an earlier stage than later in its course [18]. Thus, waiting for the disease to progress might decrease the likelihood of a response.
We initiate treatment in IPF as early as possible with the hope of slowing progression of the disease. The patient's pulmonary function may already be so compromised that it is critical to prevent any further decrement, if possible. We monitor the patients carefully to detect any benefit of therapy. Treatment is generally discontinued after an adequate clinical trial (usually three to six months) if there is no clear improvement or if serious side effects have developed.
GENERAL APPROACH — The 1999 American Thoracic Society and European Respiratory Society International Consensus Statement recommends combined therapy (corticosteroid and either azathioprine or cyclophosphamide) for initial treatment of those patients with IPF who have been given adequate information regarding the merits and pitfalls of treatment and who possess features consistent with a more likely favorable outcome [19].
It has not been established whether one of these drugs is superior to the other and little data exist to support that combination therapy is effective [20,21]. Nevertheless, the dismal prognosis of the disease and reports of a beneficial response in some patients generally justify therapy. Because the side effects of azathioprine are potentially less severe than those of cyclophosphamide, it has become the agent of choice by most clinicians. (See "ATS guidelines: Idiopathic pulmonary fibrosis: Diagnosis and treatment".
Assessing the response to therapy — The response to therapy should be assessed three to six months after its initiation. A favorable response to therapy is often defined by [22]:
• A decrease in symptoms, especially dyspnea and cough
• A reduction in or clearing of radiographic abnormalities
• Physiologic improvement, assessed by FVC, TLC, DLCO, and both resting and exercise gas exchange. Physiologic improvement is defined as a 25 percent increase in TLC or FVC, a 40 percent increase in single breath DLCO, or a reduction in or normalization of oxygen desaturation during exercise
• Stabilization of lung function, radiographic abnormalities, and symptoms
Frequently, some parameters improve while others decline or are unchanged. As an example, changes in the chest radiograph and lung function tests are often divergent. In other patients, the DLCO may improve considerably while lung volumes do not, but the opposite can also occur.
Subjective improvement can occur in some patients who have no objective signs of improvement. The subjective response should not be the lone factor in determining whether to continue treatment.
The following findings are considered to represent failure of therapy and are an indication to modify the treatment regimen [23]:
• A fall in FVC or TLC of 10 percent or more
• Worsening of radiographic opacities, especially with development of honeycombing or signs of pulmonary hypertension
• Decreased gas exchange at rest or with exercise
Clinical deterioration is most frequently due to disease progression. However, disease-associated complications and adverse effects of therapy should also be considered (show table 1) [24]. Patients with IPF admitted to intensive care units are at greater risk of mortality than expected based on their severity of illness, as assessed by the APACHE score [25].
A favorable long-term clinical response to therapy is rare in patients with IPF [4,5,16,26-30]. However, many patients may have a positive initial response (within the first six weeks) but fail to sustain the improvement after several more months of therapy.
Duration of therapy — The proper duration of therapy is unknown. We usually continue treatment for at least one year, although some clinicians suggest that two years of treatment might be more effective in maintaining prolonged remission in responders. Lifelong low dose therapy is required in a small number of patients who respond to treatment. Discontinuing treatment prematurely is a relatively frequent cause of relapse.
CORTICOSTEROIDS — Corticosteroids are general immunosuppressants aimed at minimizing the progression from inflammation to fibrosis. They are the agents most commonly used for treatment although there have been no controlled trials using corticosteroids alone for the treatment of IPF. Currently, most experts believe that corticosteroid monotherapy is not indicated in the treatment of IPF [31]. It is clear that a substantial percentage of patients with IPF will not respond to corticosteroid treatment and overall there is no survival advantage for patients treated with corticosteroids alone or in combination with other agents.
Dosage and administration — The optimal dose of corticosteroids in IPF is unknown.
Chronic progressive disease — When used in conjunction with azathioprine, the typical starting dose of prednisone (or an equivalent dose of prednisolone) is 0.5 mg/kg per day given as a single daily oral dose (based upon the patient's ideal body weight and not exceeding 100 mg/day). This dose is continued for approximately 8 weeks, at which time the patient is reevaluated. If the patient's condition is felt to be stable or improved, the dose is tapered to 0.4 mg/kg per day and then 0.3 mg/kg per day one month later. If the patient continues to remain stable or improved, the dose is progressively reduced over months four through six to 10 mg per day. This dose is maintained for as long as the treatment appears indicated [32].
Acute or rapidly progressive disease — Some patients have acute or rapidly progressive disease, generally characterized by severe dyspnea, cough, occasionally systemic symptoms (fatigue, weight loss), and definite progression over the six to eight weeks prior to presentation. For these patients, we have sometimes used three to five days of an intravenous pulse corticosteroid regimen, (eg, methylprednisolone at a dose of 250 mg intravenously every six hours). Therapy as outlined above for chronic disease is instituted once the course is stabilized. We have only rarely found this approach to be effective in improving patients' symptoms.
Intermittent pulse therapy — Intermittent pulse therapy has also been used, especially in patients with severe and aggressive disease [33]. This regimen consists of the administration of intravenous methylprednisolone (2 g once a week) plus oral prednisone (0.25 mg/kg per day); however, this approach has not clearly been shown to improve the lung disease.
Adverse effects — Side effects are almost universally encountered during prolonged corticosteroid therapy, most commonly insomnia, weight gain, skin changes, or irritability [15]. Other side effects include hypertension, a cushingoid appearance, hyperglycemia, cataracts, glaucoma, anxiety, depression, osteoporosis, myopathy, and infection. (See "Major side effects of systemic glucocorticoids".
Osteoporosis can be minimized by appropriate monitoring and preventive therapy beginning with calcium and vitamin D. (See "Prevention and treatment of glucocorticoid-induced osteoporosis". Myopathy can affect the muscles of respiration and may be difficult to differentiate from progressive parenchymal lung disease.
We apply a tuberculin skin test prior to initiating steroid therapy. Patients who are skin test positive and who will be receiving more than 15 mg of prednisone daily for more than three weeks are offered isoniazid preventive therapy.
CYTOTOXIC AND ANTIFIBROTIC AGENTS — Cytotoxic drugs, particularly azathioprine and cyclophosphamide , have been the most commonly employed second-line drugs in patients who fail therapy with corticosteroids [30,34]. Several newer agents are also being tried in an effort to identify better therapy [34,35].
Azathioprine — Azathioprine and low-dose corticosteroids have become a "standard of care" for IPF [32].
In a double-blind, controlled trial, 27 patients with previously untreated IPF were randomly assigned to receive prednisone plus azathioprine or prednisone plus placebo, then followed for nine years [20]. After one year, patients treated with azathioprine plus prednisone had better lung function as measured by the resting alveolar-arterial oxygen difference (P[A-a]O2), vital capacity, and single breath diffusing capacity for carbon monoxide (DLCO), although the differences were not statistically significant. In addition, there was a decrease in mortality in patients who received azathioprine (43 versus 77 percent), which also was not statistically significant (show figure 1).
Dosage and administration — We recommend a dose of 2 to 3 mg/kg per day given orally as a single dose. Dosing should begin at 25 to 50 mg/day and increase gradually, by 25 mg increments, every 7 to 14 days until the maximum dose is reached. As with cyclophosphamide, we do not exceed 150 mg/day.
Unlike with cyclophosphamide, the degree of leukopenia does not correlate with therapeutic efficacy. We therefore do not require the dose of azathioprine to be adjusted according to the WBC count, except for maintaining the count above 4000/µL. A discernible response to therapy may not be evident until the patient has received three to six months of treatment.
Adverse effects — Gastrointestinal side effects, including nausea, vomiting, and diarrhea, are the most common side effects of azathioprine. A small percentage of patients demonstrate abnormalities in liver function tests, but reports of severe hepatitis are rare. Hematologic side effects include depression of all cell lines. An increased risk of subsequent malignancy has been reported in renal transplant patients treated with azathioprine and prednisone. Azathioprine may be a teratogen and therefore should be used with caution in women of childbearing age. (See "Use of immunosuppressive drugs in pregnancy".
Cyclophosphamide — Cyclophosphamide (Cytoxan) is most often used as a second-line drug in patients whose condition is deteriorating despite corticosteroid and azathioprine therapy.
Several reports suggest that cyclophosphamide (usually given along with low doses of corticosteroids) may be beneficial in the treatment of IPF [21,23,36]. In one controlled trial, 43 patients with previously untreated IPF were randomly assigned to receive prednisolone plus cyclophosphamide or prednisolone alone [37]. After three years of treatment, the prednisolone plus cyclophosphamide group had more patients that were either improved or stable (38 versus 23 percent) and had fewer deaths (14 versus 45 percent), although the differences were not statistically significant (show figure 2).
Dosage and administration — Cyclophosphamide is usually administered orally at 2 mg/kg per day in one dose. We usually start at a dose of 25 to 50 mg/day; the dose is gradually increased by 25 mg increments every seven to 14 days, aiming to reduce and maintain the white blood cell (WBC) count between 4000 and 7000/µL. We usually measure the WBC count biweekly for the first six to 12 weeks and then at least monthly thereafter. Occasionally, the WBC count remains above 7000/µL despite increases in the cyclophosphamide dose. Because of our clinical impression that a beneficial response and low rate of side effects occur at doses less than 150 mg/day, we do not use doses higher than 150 mg/day even if the WBC count remains above 7000/µL.
We do not generally expect to achieve a favorable response to cyclophosphamide therapy (either with or without low doses of corticosteroids) for at least three to six months after initiating treatment.
• Intravenous therapy — Intravenous cyclophosphamide therapy has been used occasionally in patients with rapidly progressive disease. We give a dose of 2 mg/kg ideal body weight over 30 to 60 minutes, once daily for three to five days. Following this, oral daily therapy is initiated as detailed above.
• Long-term intermittent ("pulse" intravenous therapy — There is little experience with the use of long-term intermittent ("pulse" intravenous cyclophosphamide therapy, as has been used in lupus and some other rheumatic diseases [23,36]. Intermittent therapy is of potential value because it is better tolerated, has less toxicity, and has a lower risk for malignancy (essentially abolishing the risk of bladder cancer) than daily therapy [36]. (See "The use of cyclophosphamide in rheumatic and renal disease: General principles".
An escalating regimen of cyclophosphamide is used, beginning with a dose of 500 mg intravenously. The dose is increased by 100 to 200 mg every two weeks, provided that the total white blood cell count remains greater than 3000/mm3. The maximum single administered dose is 1000 to 1800 mg of cyclophosphamide, depending upon body size. The patient is monitored for adverse side effects as noted below.
Adverse effects — Reductions in all hematologic cell lines can be seen and require dose adjustment. As discussed above, we monitor the WBC count frequently and adjust the cyclophosphamide dose in order to maintain WBC count between 4000 and 7000/µL. As with most immunosuppressive therapies, patients on cyclophosphamide are at increased risk of infection.
Hemorrhagic cystitis and carcinoma of the bladder have been associated with cyclophosphamide, especially when used in higher doses for cancer chemotherapy. These side effects are less common in the lower doses we use for IPF. Nevertheless, forced diuresis, with at least eight glasses (eight ounces each) of water daily, and monthly monitoring of the urine for red blood cells or other abnormalities are recommended in an attempt to prevent clinically significant hemorrhagic cystitis. (See "Mechanism of action and general toxicity of cyclophosphamide and chlorambucil in inflammatory diseases".
Additional adverse effects that can be seen:
• Infertility in both men and women
• Teratogenesis (thus caution should be used when prescribing it for women of child-bearing age)
• Gastrointestinal side effects (including stomatitis, nausea, diarrhea, and rarely hepatotoxicity)
• Severe generalized fatigue
• Risk of future cancer may be increased
Interferon gamma-1b — The rationale for the use of interferon gamma (interferon gamma-1b) in IPF comes, in part, from the hypothesis that an acquired deficiency of interferon gamma exists and may be necessary for the exaggerated wound healing process characteristic of this disease. Interferon-gamma is found in high levels in granulomatous diseases that rarely progress to end stage fibrosis (ie, sarcoidosis) and is diminished in the lung tissue from patients with IPF. Animal models suggest that interferon gamma can inhibit the proliferation of fibroblasts and reduce collagen synthesis [38].
An initial small randomized trial of 18 patients with IPF who were unresponsive to glucocorticoids found that patients treated with interferon (IFN) gamma-1b plus prednisolone manifested significantly better total lung capacity and oxygenation after 12 months of treatment compared with prednisolone alone [39,40]. However, several other studies of IFN gamma-1b treatment have suggested that the drug is not effective in patients with severe disease who had deteriorated on previous treatment [18,41-43]. This was best illustrated in a double-blind multi-national trial of 330 patients with steroid-unresponsive IPF who were randomly assigned to receive interferon gamma-1b or placebo and followed for over one year (median duration of follow-up 58 weeks) [18]. Patients treated with IFN gamma-1b had similar survival to those treated with placebo. Constitutional symptoms and pneumonia were more common among patients receiving IFN gamma-1b, but the incidence of severe or life-threatening respiratory infection was similar between groups.
Thus, IFN gamma-1b does not appear to modify the progression of IPF in patients who have not responded to steroid therapy. A large, multinational clinical trial is underway to examine the role of interferon gamma 1b in IPF patients with less advanced disease.
Dosage and administration — Interferon gamma-1b is administered via subcutaneous injection three times per week (200 micrograms). The appropriate duration of therapy remains unknown.
Adverse effects — The most frequent side effects associated with interferon gamma-1b therapy include flu-like symptoms such as fever, headache, muscle soreness, malaise, fatigue, and chills. Acetaminophen (>500 mg) or ibuprofen (>400 mg with food) is to be taken at the time of injection to lessen these side effects. Other side effects reported include diarrhea, vomiting, nausea, abdominal pain, injection site erythema or tenderness, and depression.
The use of interferon gamma-1b in patients with advanced interstitial lung disease may be complicated by acute respiratory failure and diffuse alveolar damage. A concerning report from a single center described four patients with severe IPF who developed rapidly progressive acute respiratory distress syndrome (ARDS) following the initiation of interferon gamma-1b therapy [44]. It is unclear if interferon gamma-1b caused lung damage, or was only temporally related to the accelerated phase of late IPF.
Acetylcysteine — Acetylcysteine is a precursor of the antioxidant, glutathione, and has been shown to restore depleted glutathione levels in the lung [45-48]. Interest in acetylcysteine as a potential therapy has increased because an oxidant-antioxidant imbalance may contribute to the pathogenesis of IPF [45-50]. In one small, observational cohort study, treatment with acetylcysteine was associated with increased pulmonary function [47].
A double-blind, controlled, multi-national trial, randomly assigned 155 IPF patients to add either acetylcysteine or placebo to their baseline regimen of prednisone and azathioprine for one year [32]. Acetylcysteine slowed the deterioration of vital capacity (-60 versus -190 mL) and single-breath carbon monoxide diffusing capacity (DLCO) (-0.11 versus -0.70 mmol/min per kPa). Mortality was not significantly changed (9 versus 11 percent). There were no significant differences in the type or severity of adverse effects.
Dosage and administration — The dose of acetylcysteine for the treatment of IPF is 600 mg administered as effervescent tablets orally three times per day (1800 mg/day).
Adverse effects — Oral administration of acetylcysteine is generally well tolerated. The most common adverse effects include nausea, vomiting, and other gastrointestinal complaints. Rarely, rash with or without fever may occur.
Pirfenidone — Pirfenidone (5-methyl-1-phenyl-2-(1H)-pyridone) is an agent that inhibits transforming growth factor beta (TGF-b)-stimulated collagen synthesis, decreases the extracellular matrix, and blocks fibroblast proliferation in vitro. One open label phase II trial of the drug in 54 patients with IPF suggested that it may help to stabilize lung function [51]. Pirfenidone may slow the progression of lung impairment in patients with pulmonary fibrosis due to Hermansky-Pudlak syndrome [52].
A multicenter, randomized, double blind placebo-controlled study of pirfenidone (1800 mg/day) versus placebo was carried out in 107 Japanese patients with IPF [53]. The change in the lowest oxygen saturation by pulse oximetry (SpO2) during a six-minute exercise test, the primary endpoint, was not significantly different between the two groups from baseline to six months (+0.6 versus -0.5 percent) and nine months (+0.5 versus -0.9 percent). In a prespecified subset of patients who maintained SpO2 >80 percent during a six-minute exercise test at baseline, the lowest SpO2 improved during a six-minute exercise test in the pirfenidone group at six months (+0.5 versus -1.9 percent) and nine months (+0.5 versus -1.6 percent), suggesting there may be greater benefit in patients whose disease is less severe.
Positive treatment effect was demonstrated in secondary endpoints including an increase in vital capacity measurements at nine months (-0.03 versus -0.13 liters) and fewer episodes of acute exacerbation of IPF (14 percent versus none). The study was aborted in favor of pirfenidone treatment due to an increased number of acute exacerbations. Significant adverse events were associated with pirfenidone; however, adherence to treatment regimen was similar between pirfenidone and placebo groups. A follow-up multicenter clinical trial is underway in Japan.
Dosage and administration — The dose of pirfenidone ranges up to 40 mg/kg/day (to maximum of 3600 mg/d) in divided doses.
Adverse effects — The most common side effects include rash (photosensitivity), abdominal discomfort, dyspepsia, anorexia, nausea, fatigue, and lethargy. Other potential side effects include: diarrhea, constipation, itching, dry skin, hyperpigmentation, headache, and weakness.
Colchicine — Colchicine has been suggested as a treatment for a variety of fibrotic disorders, including IPF. There have been numerous in vitro and animal model studies suggesting that colchicine may slow the fibrotic process [18,54-56]. However, several clinical studies, including retrospective studies [57,58], a randomized trial [59], and a nonrandomized prospective study [60], failed to show a significant difference in the rate of decline of lung function when patients were treated with colchicine or corticosteroids. The side effects of colchicine were less frequent and less serious than prednisone.
Dosage and administration — Colchicine is administered at a dose of 0.6 mg orally once or twice daily as tolerated.
Adverse effects — Colchicine is generally well tolerated at the doses given for IPF. Side effects that may be encountered include nausea, vomiting, abdominal pain, and diarrhea.
Methotrexate — Methotrexate is used clinically for both its antineoplastic and immunosuppressive effects. Clinical experience with methotrexate for the treatment of interstitial lung disease is limited. There have been several descriptions of its use in sarcoidosis [61-64], but very little has been written regarding its effectiveness in IPF. One study described three patients with IPF associated with connective tissue disease who appeared to respond favorably to methotrexate [65].
Dosage and administration — Methotrexate may be administered orally or intramuscularly. We recommend starting with a dose of 7.5 mg once weekly. The dose is then gradually increased (eg, at increments of 2.5 mg every two weeks) until a dose of 15 mg per week is achieved.
A trial of methotrexate therapy should last at least four to six months to assess effectiveness.
Adverse effects — When methotrexate is used in immunosuppressive doses as described above, the most serious side effects are hepatic fibrosis (in up to ten percent of cases when the total dose exceeds five grams) and interstitial pneumonitis resulting in pulmonary fibrosis.
Liver function tests and WBC count should be monitored monthly to assess for toxicity. Because hepatic toxicity may initially be clinically occult, some clinicians have advocated liver biopsy when the total dose exceeds one gram or after 18 to 24 months of therapy, even in the absence of signs of hepatic injury. (See "Methotrexate-induced hepatotoxicity".
In a patient with IPF treated with methotrexate, it may be difficult to distinguish pulmonary drug toxicity from progression of the underlying disease. Other toxicities include bone marrow suppression, nausea, alopecia, and skin rash. Methotrexate is known to be teratogenic and may transiently suppress gonadal function. The oncogenic potential of methotrexate remains controversial. (See "Major side effects of methotrexate" and see "Methotrexate-induced lung injury".
Penicillamine — Several animal studies suggest a possible role for penicillamine in the treatment of fibrotic lung disorders [66-69]. In addition, two retrospective studies of patients with fibrosing alveolitis associated with scleroderma reported that penicillamine therapy was associated with an improvement in DLCO (but not in other pulmonary function test parameters) [70,71].
Experience with penicillamine in patients with IPF is limited [60,72,73]. In one study, penicillamine was given to 12 patients with "end stage" fibrosis [73]. All patients improved clinically and functionally during the first year of treatment, and overall survival rates were felt to compare favorably with those in historical controls. A nonrandomized prospective study in patients with IPF compared prednisone (n =19), D-penicillamine/prednisone (n = 11), D-penicillamine/colchicine/prednisone (n = 11), and prednisone alone (n =15). No significant differences in survival or in lung function relative to the baseline measurement were found in any group [60].
Dosage and administration — The dosage we recommend is the same used for the management of rheumatoid arthritis. The initial dose is 125 or 250 mg given orally as a single daily dose. After four to eight weeks, the dose is increased weekly to a final dose of 500 mg/day. Daily doses as high as 1000 mg may be utilized if tolerated. A determination of effectiveness cannot be made before three to six months.
Adverse effects — Reported side effects include nausea, vomiting, diarrhea, dyspepsia, anorexia, transient loss of taste for sweet and salt, cutaneous lesions, hematologic toxicity (leukopenia, aplastic anemia, granulocytopenia), renal toxicity (reversible proteinuria and hematuria, nephrotic syndrome), myasthenia gravis, and bronchoalveolitis. In the past, preparations of penicillamine contained trace amounts of penicillin. While this is no longer the case, some of the reactions which occur may be explained by cross-reactivity with penicillin.
Most side effects are experienced during the first 18 months of therapy. Concomitant drug therapy should be closely monitored, since adverse reactions may occur.
Cyclosporine — Experience with cyclosporine for the treatment of IPF is limited. The few published reports have been anecdotal and less than encouraging [74-76]. A specific role for cyclosporine in patients with IPF awaiting lung transplantation has been suggested [75]. In these patients, the addition of cyclosporine may allow reduction in the dose of corticosteroids without precipitating clinical deterioration.
Dosage and administration — The optimal dose of cyclosporine is unknown. It is usually given in a once daily dose of 5 to 10 mg/kg for the first three to nine months of treatment. The dose may be adjusted to maintain a blood level of 100 to 200 ng/mL. Maintenance therapy should be continued at the lowest dose associated with stabilization of disease activity, usually 3 to 5 mg/kg per day.
Adverse effects — The major adverse reactions are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia. (See "Cyclosporine and tacrolimus nephrotoxicity".
TRANSPLANTATION — IPF is the most common interstitial lung disease among referrals for transplantation [77].
Indications and choice of procedure — Patients with IPF are often referred late in the course of their disease, and they have the highest death rate among the diagnostic groups on the transplant waiting list [78]. For this reason, early referral for transplant evaluation should be considered, even before the response to initial medical therapy has been determined [79]. Failure to respond to medical treatment, worsening exercise-induced desaturation, resting hypoxemia, and/or a sustained downward trend in vital capacity are harbingers of trouble and should prompt consideration of lung transplantation.
Single lung transplantation (SLT) has been the standard procedure for patients with IPF, and has produced good results [80-83]. A retrospective review of all 821 patients undergoing SLT (n = 636) or BLT (n = 185) for IPF in the United States between 1994 and 2000 noted that, for patients under 60 years of age, SLT was associated with improved survival compared to BLT [84].
Following SLT, the low lung compliance and high vascular resistance of the remaining native lung preferentially direct both ventilation and perfusion to the transplanted lung. However, cysts, bullae, and bronchiectasis occasionally develop in the later stages of IPF and other fibrotic lung diseases like sarcoidosis and can act as a nidus for infectious complications in the native lung after SLT; thus BLT remains necessary in some cases.
Early experience suggests that living donor lobar lung transplantation (LDLLT) may be an option for patients with IPF who are likely to die while waiting for SLT. In a report of nine such patients, eight of whom were dependent on systemic corticosteroids (up to 50 mg/day), only one early death occurred after transplant of two lower lobes donated by two healthy relatives [85]. Eight patients were still alive after 10 to 48 months of follow-up.
Physiologic changes — After SLT or BLT, spirometric parameters, lung volumes, diffusing capacity, and oxygenation improve significantly, and these improvements have been sustained in long-term follow-up of recipients without complications [80-83]. In a series that compared SLT and BLT recipients with IPF, the mean FEV1 was higher in BLT recipients than SLT recipients one year after transplantation (2.25 versus 2.00 liters) [83].
After SLT, most lung function is contributed by the allograft. As a result, the vital capacity (VC) of the recipient correlates closely with the predicted vital capacity of the donor organ [86]. Improvements in cardiopulmonary function continue for up to one year following transplantation. As an example, in one study of SLT recipients, the mean VC increased from 43 percent of the predicted normal value preoperatively to 65 percent three months and 69 percent one year after transplantation. None of the eight recipients tested one year after transplantation required supplemental oxygen at rest or during exercise, and their treadmill exercise tolerance was much improved [82].
Prior treatment — The effect of prior corticosteroid therapy on the outcome of lung transplantation is uncertain. Most studies suggest that low-dose corticosteroid therapy has no adverse effect on outcome [87-89]. However, high-dose corticosteroid therapy may be associated with decreased survival after lung transplantation [89]. The International Guidelines for the Selection of Lung Transplant Candidates lists prednisone use >20 mg/day as a relative contraindication for lung transplantation [90]. For this reason, we avoid immunosuppressive therapy in patients with IPF who are transplant candidates. (See "Indications; selection of recipients; and choice of procedure for lung transplantation", section on Use of immunosuppressive drugs).
FUTURE DIRECTIONS — The agents currently available for the treatment of IPF are clearly inadequate. Therapeutic response is obtained in only a subset of patients, and survival is poor even for those who respond. In addition, these agents all carry significant side effects and toxicity. For these reasons, there is much interest in developing more effective, less toxic pharmacologic therapy [91,92].
Immunomodulation — Although there is still much to be learned regarding the roles of various cytokines and growth factors in the complex process of pulmonary fibrosis, it is clear that these agents are critical [91,92]. Inhibitors of specific fibrogenic cytokines or growth factors may help to retard the fibrotic process [93-95].
Another potential strategy involves interfering with the process of leukocyte retention in the lung [91]. Leukocyte adhesion molecules play an important role in this process, and antibodies to such adhesion molecules have been shown to prevent collagen deposition in an animal model of lung injury [96]. Agents that block the expression or function of adhesion molecules are rapidly becoming available and may someday prove clinically useful [92].
Antioxidant enzymes — Because epithelial injury in IPF may be mediated by oxygen radicals, one possible strategy might involve delivery of antioxidant enzymes to the lung parenchyma or even augmenting genetic expression of antioxidant enzymes [91,92]. (See "Pathogenesis of idiopathic pulmonary fibrosis".
Acid suppression — More than 90 percent of patients with IPF have increased gastroesophageal reflux (GER) [97]. As a result, it has been hypothesized that GER is an important risk factor for the development and/or progression of IPF. A case series of four patients reported that adequate suppression of GER (determined by 24-hour esophageal pH monitoring) was associated with disease stabilization [98]. These observations suggest that the treatment of GER may prove to be an important adjunct in the management of IPF.
SUMMARY AND RECOMMENDATIONS
• We lack sufficient clinical evidence that any treatment improves survival or the quality of life for patients with IPF. However, the dismal prognosis of the disease and reports of a beneficial response justify a trial of therapy in patients who do not have contraindications. (See "Indications for therapy" above).
• The 1999 American Thoracic Society and European Respiratory Society International Consensus Statement recommends combined therapy (corticosteroid and either azathioprine or cyclophosphamide) for initial treatment of those patients with IPF who have been given adequate information regarding the merits and pitfalls of treatment and who possess features consistent with a more likely favorable outcome [19] (See "ATS guidelines: Idiopathic pulmonary fibrosis: Diagnosis and treatment" and see "General approach" above).
• We suggest a trial of therapy in patients with the following characteristics: young age ( 50 years), mild loss of lung function, increased ground glass opacity and little fibrosis on high-resolution chest CT, and no contraindications to therapy (Grade 2B). We suggest that therapy not be offered to elderly patients with severe loss of lung function, little ground glass opacity and extensive fibrosis on high-resolution chest CT, and significant contraindications to therapy (Grade 2B). In all other patients, therapy should be considered on a case-by-case basis after carefully weighing the benefits versus the risks. (See "Indications for therapy" above).
• When the decision is made to treat, we suggest that therapy be initiated as soon as clinical or physiological evidence of impaired lung function is detected (Grade 2C). (See "Timing of therapy" above).
• We suggest that corticosteroid monotherapy not be administered as initial therapy (Grade 2B). (See "Corticosteroids" above).
• We suggest that combination therapy be initiated if there is ongoing deterioration and if the patient is not eligible for a controlled clinical trial or lung transplantation (Grade 2B). We typically use azathioprine (2 to 3 mg/kg per day) and low-dose corticosteroids (0.25 mg/kg per day, usually less than 20 mg per day). It appears that the addition of high-dose acetylcysteine to this regimen (600 mg administered as effervescent tablets orally three times per day) significantly reduces the side effects of azathioprine. Alternatively, cyclophosphamide (2 mg/kg per day) can be added while continuing low-dose corticosteroids. (See "General approach" above, see "Prior treatment" above, see "Azathioprine" above, see "Cyclophosphamide" above, and see "Acetylcysteine" above).
• A discernible response to corticosteroid and azathioprine (or cyclophosphamide) may not be evident until the patient has received three to six months of treatment. We reassess the patient's response to therapy every three months. (See "Assessing the response to therapy" above).
• We recommend that cyclosporine or colchicine not be used to treat IPF (Grade 1B). The role of novel agents, such as interferon gamma, pirfenidone, bosentan, or etanercept, remain to be defined.
• The proper duration of therapy is unknown. We usually continue treatment for at least one year, although some clinicians suggest that two years of treatment might be more effective. (See "Duration of therapy" above).
• We suggest early referral for lung transplantation evaluation, even before the outcome of medical therapy has been determined (Grade 2C). (See "Transplantation" above).

Posted by: yusmanPosts: 21 :: 27-03-2007 :: | Reply to this Message

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idiopathic Lung fibrosis

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