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An Approach to the Treatment of Pulmonary Sarcoidosis With Corticosteroids^*

The Six Phases of Treatment

^* From the Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC.

	Abstract

TOP Abstract Introduction Natural History of Pulmonary... Corticosteroid Therapy: The... Treatment of Acute Pulmonary... Treatment of Chronic Pulmonary... Alternative Therapy Conclusions References

 
Corticosteroid therapy for pulmonary sarcoidosis is not standardized. There is no consensus on which patients should receive treatment, how patients should be monitored, and the dose of corticosteroids once the decision to treat has been made. These issues are important for several reasons. First, inappropriate use of corticosteroids may result in unnecessary toxic reactions. Second, inadequate use of corticosteroids might result in permanent pulmonary and extrapulmonary organ dysfunction from sarcoidosis. Third, patients who are inappropriately labeled as "corticosteroid failures" may be subjected to other potentially toxic drugs or even lung transplantation. Corticosteroid dosing involves six phases: (1) initial high doses to control inflammation; (2) tapering to a maintenance dose that will continue to suppress the inflammation but lessen the risk of corticosteroid toxic reactions; (3) continuing to receive the maintenance dose until a decision to taper off corticosteroids is made; (4) tapering off corticosteroid therapy; (5) observation for relapse; and (6) treatment if relapse occurs. Although these phases of treatment have been alluded to in the literature, few of them have been studied rigorously. This article describes the use of corticosteroids for pulmonary sarcoidosis in terms of the above six phases. The proposed dosing schedules are based on the natural history of the disease and the results from published treatment studies.

Key Words: corticosteroid • natural history • pulmonary sarcoidosis • therapy

	Introduction

TOP Abstract Introduction Natural History of Pulmonary... Corticosteroid Therapy: The... Treatment of Acute Pulmonary... Treatment of Chronic Pulmonary... Alternative Therapy Conclusions References

 
The decision to treat a medical condition depends on several factors that include the natural history of the disease, the expected response to treatment, and the toxicity of therapy. Pulmonary sarcoidosis poses unique treatment dilemmas because, unlike most interstitial lung diseases, the disease may remit or stabilize without therapy. Therefore, it is important to understand the natural course of pulmonary sarcoidosis when making therapeutic decisions, especially since therapy may produce significant toxic reactions.

Corticosteroids are used most commonly to treat pulmonary sarcoidosis, although the dose, duration of therapy, and method by which one can assess effectiveness have not been standardized. This article proposes an approach to the use of corticosteroids for pulmonary sarcoidosis, based on the natural history of the disease and the results from published treatment studies. This approach partitions the treatment of sarcoidosis into six phases.

	Natural History of Pulmonary Sarcoidosis

TOP Abstract Introduction Natural History of Pulmonary... Corticosteroid Therapy: The... Treatment of Acute Pulmonary... Treatment of Chronic Pulmonary... Alternative Therapy Conclusions References

 
Sarcoidosis is a systemic disease. A portion of the information about the natural history of pulmonary sarcoidosis is extracted from studies examining the clinical course of systemic sarcoidosis. Therefore, our understanding of the natural history of pulmonary sarcoidosis is not completely derived from patients who had only pulmonary involvement. In addition, most of these studies reported the outcome of patients comparing those who received corticosteroids with those who were untreated; usually the corticosteroid-treated group had more severe disease. Given these caveats, the natural history of pulmonary sarcoidosis is described below.

Pulmonary sarcoidosis usually follows one of two clinical courses. Acute pulmonary sarcoidosis is synonomous with the initial presentation and early course of the disease. Acute pulmonary sarcoidosis may present with or without symptoms, chest radiograph abnormalities, and pulmonary dysfunction. Chronic pulmonary sarcoidosis is defined as disease in which symptoms persist beyond 2 years.¹ Patients with chronic pulmonary sarcoidosis often have progressive pulmonary disease or persistent disease that requires therapy.

Abnormalities seen in the chest radiograph of patients with untreated acute pulmonary sarcoidosis clear, improve, or stabilize in 60 to 90%.² The radiographic response is better and complete resolution occurs more frequently in patients with hilar adenopathy alone on the initial chest radiograph (radiographic stage I) than in those with varying degrees of parenchymal infiltration (radiographic stages II and III).¹

The prognosis of acute pulmonary sarcoidosis correlates with several extrapulmonary factors. The presence of erythema nodosum, arthritis, or fever at presentation is associated with a good prognosis, while disfiguring cutaneous lesions (lupus pernio), splenomegaly, or bone involvement are associated with a poor prognosis.^{2 ,3} The disease has a worse prognosis in black patients⁴ and patients with disease onset after age 40 years.³

Spontaneous remissions occur in nearly two thirds of patients with acute pulmonary sarcoidosis, while 10 to 30% develop a chronic course. Remissions often occur within the first 6 months after diagnosis, although it may take 2 to 5 years.³

Chronic pulmonary sarcoidosis is a persistent and progressive disease with destruction of the alveolar architecture and progressive pulmonary dysfunction.⁵ The hallmark of chronic pulmonary sarcoidosis is the development of pulmonary fibrosis. Chest radiographs demonstrate fibrocystic changes (radiographic stage IV) with lung distortion, volume loss, and end-stage honeycombed lung. Fatalities ascribed to sarcoidosis occur in 1 to 6% of patients, and three fourths of these deaths are related to chronic progressive pulmonary disease,⁶ including complications from aspergilloma.⁷

The fibrosis of chronic pulmonary sarcoidosis may be related to granulomatous inflammation from sarcoidosis, and may depend on susceptibility factors in certain individuals. These two conjectures are consistent with our knowledge of the natural course of pulmonary sarcoidosis but remain unproved. Both the early T-cell alveolitis⁸ and granulomatous inflammation⁹ of acute sarcoidosis are amenable to steroid therapy, whereas pulmonary fibrosis is probably minimally responsive or unresponsive. However, if granulomatous inflammation does cause the fibrosis of chronic pulmonary sarcoidosis, it is intuitive to treat such patients with corticosteroids. Corticosteroid treatment regimens will differ depending on whether the disease takes an acute or chronic course.

	Corticosteroid Therapy: The Decision To Treat Acute Pulmonary Sarcoidosis

TOP Abstract Introduction Natural History of Pulmonary... Corticosteroid Therapy: The... Treatment of Acute Pulmonary... Treatment of Chronic Pulmonary... Alternative Therapy Conclusions References

 
The future course of acute pulmonary sarcoidosis cannot be predicted for an individual patient. Thus, the decision to prescribe corticosteroids for a patient whose disease may remit spontaneously is difficult. The clinical factors described above that are associated with disease prognosis (eg, erythema nodosum at presentation suggests a mild course, lupus pernio a severe course) can be used to guide this decision. Table 1 outlines general guidelines concerning corticosteroid treatment decisions for sarcoidosis.

Many patients with pulmonary sarcoidosis will have spontaneous improvement or remission within 6 months of diagnosis.¹⁰ Therefore, it is recommended that patients with mild-to-moderate pulmonary sarcoidosis be observed for 2 to 6 months, if possible.^{10 ,11} Patients whose conditions improve will have avoided the toxicity of corticosteroids, while patients whose conditions deteriorate over this period should be treated. Patients with pulmonary dysfunction whose conditions neither improve nor deteriorate during the observation period are often given a corticosteroid trial¹⁰ or are otherwise observed further.

Patients with severe pulmonary dysfunction or pulmonary symptoms causing significant impairment should be treated with corticosteroids. Patients with chronic pulmonary sarcoidosis are often treated for prolonged periods; sometimes therapy is life-long. These patients need long-term monitoring of their pulmonary status if corticosteroid therapy is discontinued, as disease exacerbation can occur years later.

Some authors¹² have recommended incorporating findings on the presenting chest radiograph into the decision to initiate treatment for sarcoidosis. Most studies^{13 ,14 ,15} that have evaluated corticosteroid therapy based on the initial radiographic stage of sarcoidosis failed to stratify patients in terms of symptoms or pulmonary function. These studies failed to demonstrate a long-term benefit of corticosteroids based on the initial radiographic stage. Asymptomatic patients with pulmonary sarcoidosis have been shown not to receive a long-term benefit from corticosteroid therapy, regardless of their presenting radiographic stage.¹⁶

Based on these data, asymptomatic pulmonary sarcoidosis patients with normal pulmonary function should not be treated because of radiographic abnormalities alone. Patients with stage III radiographs will usually have symptoms and pulmonary function abnormalities,¹² but the rare asymptomatic patient with normal pulmonary function should be followed up closely without treatment.

	Treatment of Acute Pulmonary Sarcoidosis With Corticosteroids: The Six Phases of Treatment

TOP Abstract Introduction Natural History of Pulmonary... Corticosteroid Therapy: The... Treatment of Acute Pulmonary... Treatment of Chronic Pulmonary... Alternative Therapy Conclusions References

 
Corticosteroids are the primary form of treatment for acute pulmonary sarcoidosis,¹¹ that is, the initial episode of pulmonary sarcoidosis or relapse as opposed to maintenance therapy for chronic pulmonary sarcoidosis, defined as disease in which symptoms persist beyond 2 years.¹ Corticosteroids have been shown to be superior to placebo for acute pulmonary sarcoidosis as measured by improved radiographic findings and spirometry in short-term (3 to 7 month) randomized trials.^{14 ,17} However, most randomized trials^{14 ,15 ,17 ,18} do not demonstrate a long-term benefit (5 years after therapy). A recent study¹⁹ suggested that corticosteroids may promote relapse of sarcoidosis, although this study was retrospective and the untreated and corticosteroid groups were not matched.

The granulomatous inflammation from sarcoidosis usually lasts from several months to years. The initial intent of anti-inflammatory therapy is suppression of the acute inflammation, which is composed of a T-cell alveolitis and granulomatous inflammation. Subsequently, anti-inflammatory therapy is required to avoid recrudescence of a clinically significant inflammatory response. At some point, a decision to withdraw anti-inflammatory therapy is made and the patient is monitored for relapse. Ideally corticosteroid therapy should be withdrawn when there is no potential for recurrence of the T-cell alveolitis and granulomatous inflammation. However, effective anti-inflammatory therapy suppresses all aspects of the sarcoidosis inflammatory response so that it is impossible to determine when there is no further potential for recurrence. Therefore, treatment of pulmonary sarcoidosis with corticosteroids can be categorized into six different phases (Fig 1 and Table 2 ): initial dosing, taper to maintenance, maintenance dosing, corticosteroid taper, monitoring while not receiving therapy, and treatment of relapse. Neither the doses nor the time period of these six phases has been standardized. It is likely that the six phases need to be individualized based on the severity of disease and response to therapy. Nevertheless, doses and time periods for the six phases have been suggested in the medical literature, and they should be viewed as general therapeutic guidelines.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 1. The six phases of corticosteroid treatment of acute pulmonary sarcoidosis. Initial dosing (phase 1) is with high-dose corticosteroids and then is tapered to a maintenance dose (phase 2). Maintenance dosing is continued (phase 3) until a decision is made to taper off corticosteroid therapy (phase 4). Patients must be monitored once therapy has been discontinued (phase 5). Therapy must be reinstituted if relapse occurs (phase 6).

Taper to Maintenance
Symptomatic improvement usually occurs within a month, and tapering from these corticosteroid doses is usually begun within 2 to 6 weeks.^{11 ,20} It has been suggested that failure to improve within 1 month implies that either the disease is steroid resistant or pulmonary sarcoidosis is not responsible for the pulmonary dysfunction.¹¹ It is unusual for longer trials at these high doses to be successful. Tapering to a maintenance dose is usually completed in 1 to 3 months,^{6 ,12 ,20} although a slower taper to maintenance over 6 months has also been suggested.²¹

The decision to taper corticosteroid therapy is based on stabilization or improvement in pulmonary symptoms and pulmonary function.^{11 ,20} Spirometry is adequate to assess pulmonary function in most cases. Measurement of diffusing capacity rarely adds additional information, since spirometry and diffusing capacity have a concordant response in two thirds of cases, and they move in opposite directions only 5% of the time.²²

Some authors^{10 ,23} have used the chest radiograph to monitor the clinical status of pulmonary sarcoidosis patients. Pulmonary function tests and the chest radiograph should be regarded as complementary tests. The chest radiograph detects the presence and extent of parenchymal involvement, whereas pulmonary function tests assess the physiologic consequences of the disease.

A chest radiograph should be obtained when a sarcoidosis patient develops worsening pulmonary symptoms or pulmonary function because it may suggest an unsuspected clinical problem. For example, a normal chest radiograph in the face of worsening pulmonary symptoms or function may suggest endobronchial sarcoidosis, a steroid myopathy, or pulmonary vascular disease from sarcoidosis. Cardiomegaly may suggest myocardial involvement with sarcoidosis. In addition, the chest radiograph may support pulmonary sarcoidosis as the cause of pulmonary dysfunction if new infiltrates are detected. New stage IV disease on chest radiograph may prompt more aggressive immunosuppressive therapy. Although some authors^{10 ,23} have used the chest radiograph to monitor the clinical status of sarcoidosis, the utility of serial chest radiographs in patients with stable or improving pulmonary function is controversial.

The adjustment of corticosteroid dose in asymptomatic patients with worsening pulmonary function or chest radiographs is also controversial. The corticosteroid dose is usually not modified in symptomatic patients¹⁹ unless there is a major deterioration in pulmonary function²⁰ because pulmonary sarcoidosis has a variable course with spontaneous remissions. Pulmonary infiltrates may appear on chest radiograph prior to the development of pulmonary symptoms or dysfunction.²³ However, it is not known how frequently these radiographic abnormalities resolve spontaneously or if therapy for new infiltrates in asymptomatic patients affects outcome. Therefore, modification of corticosteroid doses cannot be recommended for asymptomatic patients who develop new pulmonary infiltrates, although such patients should be followed up closely.

Since most patients with acute pulmonary sarcoidosis will have improved conditions with the initial high doses of corticosteroids, monitoring for relapse first becomes an issue during the "taper to maintenance" phase. In terms of monitoring, it is important to note that measurements of "active" granulomatous inflammation are not used routinely to guide treatment decisions. Active sarcoidosis suggests that the inflammatory process is occurring, resulting in the formation of "fresh granulomas." Active granulomatous inflammation mandates treatment in the case of tuberculosis. However, it is not clear that "active" disease carries the same mandate for sarcoidosis.

During the immunologic cascade of sarcoidosis, a huge number of measurable substances are elaborated, including CD4 lymphocytes, activated macrophages, receptors, and cytokines.²⁴ Studies have indicated that three clinical tests may reflect "active disease": (1) serum angiotensin-converting enzyme;^{25 ,26} (2) BAL cell count differentials;²⁷ and (3) gallium radionuclide scans (⁶⁷Ga).²⁸ However, conflicting data from other studies indicate that these tests do not accurately predict prognosis,²⁹ the response to treatment,^{30 ,31 ,32} or the presence or intensity of inflammation in sarcoidosis.^{33 ,34 ,35 ,36}

Even if the above tests did accurately reflect active inflammation in sarcoidosis, the question remains if such activity mandates treatment. Granulomatous inflammation often spontaneously resolves in sarcoidosis, although it may resolve more rapidly with therapy.^{15 ,18 ,21} Most permanent organ dysfunction in sarcoidosis relates to the development of fibrosis, and it is unclear if this is dependent solely on the presence or degree of the granulomatous inflammation or if other additional factors are required.^{24 ,37} To date, and to my knowledge, no data exist to support the contention that therapy based solely on the results of any of the indexes of activity will alter the eventual outcome of a patient with sarcoidosis. Therefore, sarcoidosis patients with stable pulmonary function should not have their treatment plan adjusted on the basis of laboratory evidence of "active disease."

Maintenance Dosing
The recommended maintenance corticosteroid doses is 10 to 15 mg daily,^{6 ,12} although 0.25 mg/kg/d has been suggested.²⁰ The duration of maintenance is controversial. Some have suggested that corticosteroid therapy can be discontinued as early as 6 months after starting therapy.¹¹ However, others have shown that when corticosteroid therapy is continued for at least 1 year, relapse is less common²⁰ and long-term pulmonary function is slightly improved.¹⁰ These benefits must be weighed against the increased risk of side effects from prolonged therapy,¹⁰ many of which are transient (eg, weight gain, GI disturbance, acne). Alternate-day dosing may reduce the prevalence of corticosteroid side effects, and such dosing has been shown to be as effective as daily dosing for acute pulmonary sarcoidosis.³⁸ An important concern is that patient compliance with this dosing schedule is often poor¹² and must be monitored carefully.

Corticosteroid Taper
The maintenance dose is usually continued until the decision to taper the patient completely off corticosteroid therapy is made, which is usually done over a 6-week to 3-month period.²⁰ Although unsubstantiated, it is intuitive that doses should not be routinely tapered more rapidly than every 2 weeks, since this is usually the minimal amount of time for clinical relapse to occur if anti-inflammatory therapy is inadequate.

Monitoring Off Therapy
As mentioned previously, pulmonary symptoms and spirometry are the most useful parameters to monitor when deciding if corticosteroid therapy should be reinstituted. Also, as mentioned above, tests of active granulomatous inflammation such as serum angiotensin-converting enzyme, BAL, and gallium scans are not useful guides for therapy, relapse, or prognosis and should not be used for monitoring purposes.

Although it has been recommended that patients be monitored for 1 year without therapy until sarcoidosis is considered arrested,³⁹ 20% of relapses occur >1 year after cessation of corticosteroid therapy, and 10% beyond 2 years.¹⁹ In a retrospective review,¹⁹ chest radiographic stage and race did not correlate with the rate of relapse. Relapse was more frequent in patients who were treated with corticosteroids, although the corticosteroid group may have had more severe disease at baseline. Erythema nodosum at presentation was associated with a lower rate of relapse. Based on these data, it seems intuitive to observe patients who have been treated with corticosteroids for pulmonary sarcoidosis for at least 2 years. Spirometry and pulmonary symptoms should be monitored.

Relapse
Relapses occur in 20 to 50% of patients in whom corticosteroid therapy is discontinued.¹² Relapses are treated identically to initial treatment with reinstitution of high-dose corticosteroids for 2 to 6 weeks followed by an identical tapering scheme.²⁰ Some authors have recommended higher maintenance doses or prolonging the maintenance period in patients who experience relapse.¹² Alternative anti-inflammatory medications, either used alone or as steroid-sparing agents, should be considered if daily prednisone doses of 20 mg are required to avoid exacerbations of pulmonary sarcoidosis.

	Treatment of Chronic Pulmonary Sarcoidosis

TOP Abstract Introduction Natural History of Pulmonary... Corticosteroid Therapy: The... Treatment of Acute Pulmonary... Treatment of Chronic Pulmonary... Alternative Therapy Conclusions References

 
As mentioned, most deaths from sarcoidosis result from progressive pulmonary disease.⁴⁰ Three quarters of pulmonary sarcoidosis patients who require corticosteroids for 5 years will have a relapse when corticosteroid therapy is withdrawn.⁴¹ Almost all of these relapses occur within 1 to 2 months of corticosteroid therapy withdrawal.⁴¹ Over 90% of these patients can be maintained on a regimen of 15 mg of daily prednisone, and 65% on 10 mg.⁴¹ In general, complications from corticosteroids are neither frequent nor serious in nature (weight gain is most common).⁴¹

These data imply that corticosteroid management for chronic pulmonary sarcoidosis should be different than for acute sarcoidosis, and therefore the dose and schedule of the six phases of corticosteroid therapy must be modified in this group of patients. These patients have demonstrated their propensity for the development of pulmonary fibrosis, which is often progressive and is minimally or unresponsive to corticosteroids and other anti-inflammatory therapies. Since granulomatous inflammation probably leads to significant fibrosis in this subset of sarcoidosis patients, it makes sense to treat such patients with corticosteroids if there is evidence of active granulomatous inflammation.

These patients should have corticosteroid therapy weaned very slowly, with close monitoring of pulmonary symptoms, chest radiographs, and pulmonary function. Withdrawal of corticosteroid therapy will usually be unsuccessful.⁴¹ In this group of patients, even asymptomatic radiographic infiltrates or pulmonary dysfunction during a corticosteroid taper probably justifies increasing the corticosteroid dose to avoid further pulmonary fibrosis and possible permanent pulmonary dysfunction.⁴¹ Often a smaller corticosteroid burst may be used rather than the higher doses used for initial treatment or relapse for acute pulmonary sarcoidosis. If a patient cannot be completely weaned off corticosteroid therapy with relapsing, the lowest maintenance corticosteroid dose should be sought.

Once this dose is achieved, a decision can be made as to whether long-term corticosteroid therapy at the maintenance dose poses less risk than use of an alternative anti-inflammatory agent. Corticosteroid dependence should not be considered corticosteroid failure. The relatively successful long-term use of corticosteroids and relatively few side effects must be kept in mind when considering alternative therapies, such as other toxic pharmacotherapy or lung transplantation. Low-dose corticosteroid dependence may be superior to alternative therapies, or to no therapy, which has a high likelihood of severe relapse. An alternative agent may also be considered for a steroid-sparing effect.

	Alternative Therapy

TOP Abstract Introduction Natural History of Pulmonary... Corticosteroid Therapy: The... Treatment of Acute Pulmonary... Treatment of Chronic Pulmonary... Alternative Therapy Conclusions References

 
Alternative agents should be considered for patients with pulmonary sarcoidosis who fail to respond to corticosteroid therapy or cannot tolerate corticosteroid side effects. A detailed discussion of alternative agents for sarcoidosis has been discussed elsewhere^{42 ,43} and is beyond the scope of this review. Of these alternative agents, methotrexate has been studied in most detail. Acute pulmonary sarcoidosis patients given methotrexate (10 mg/wk) were shown to have a similar improvement in spirometry results as patients given corticosteroids (40 mg daily for 2 months, then 20 mg daily).⁴⁴ Methotrexate is the only alternative agent that has been shown to be effective for chronic sarcoidosis, but long-term treatment with this drug may be hampered by the cumulative risk of hepatotoxicity.⁴⁵ Other alternative medications for acute sarcoidosis that have shown some usefulness include azathioprine^{46 ,47} and pentoxifylline.⁴⁸ Chlorambucil also is effective for acute flares of sarcoidosis,^{49 ,50} but cumulative toxic reactions, including the risk of malignancy, prevent its long-term use. Hydroxychloroquine has been found useful for cutaneous sarcoidosis,⁵¹ but its efficacy for severe pulmonary sarcoidosis is limited.⁴² It may be useful as a corticosteroid-sparing agent. Several studies of inhaled corticosteroids for pulmonary sarcoidosis^{52 ,53 ,54 ,55 ,56 ,57} have suggested that inhaled corticosteroids are beneficial in pulmonary sarcoidosis, although other studies have failed to demonstrate a benefit.^{58 ,59}

	Conclusions

TOP Abstract Introduction Natural History of Pulmonary... Corticosteroid Therapy: The... Treatment of Acute Pulmonary... Treatment of Chronic Pulmonary... Alternative Therapy Conclusions References

 
Treatment of pulmonary sarcoidosis is not mandatory because its natural course may be one of stabilization or resolution. Treatment decisions are based on the presence of clinically significant symptoms, progressive disease, or severe pulmonary dysfunction. Corticosteroids are the first-line agents for acute pulmonary sarcoidosis. Because high-dose corticosteroids are usually required for a brief period of time but relapse is common when corticosteroid therapy is discontinued, it is rational to partition the treatment of acute pulmonary sarcoidosis into six phases: initial dosing, taper to maintenance, maintenance dosing, corticosteroid taper, monitoring without therapy, and treatment of relapse. Chronic pulmonary sarcoidosis usually requires a more aggressive approach with corticosteroids. Corticosteroid therapy in these patients is usually required for years, if not life-long. Alternative anti-inflammatory agents or corticosteroid-sparing agents may be considered when the toxic reactions of corticosteroids become significant.

	Acknowledgements

 
ACKNOWLEDGMENT: The author wishes to acknowledge Drs. Steven A. Sahn and Patrick A. Flume for their thoughtful review of this manuscript.

	Footnotes

 
Correspondence to: Marc A. Judson, MD, FCCP, Associate Professor, Division of Pulmonary and Critical Care Medicine, 600 MUSC Complex, No. 812 CSB, Charleston, SC 29425; e-mail: judsonma@MUSC.edu

Received for publication June 10, 1998. Accepted for publication October 6, 1998.

	References

TOP Abstract Introduction Natural History of Pulmonary... Corticosteroid Therapy: The... Treatment of Acute Pulmonary... Treatment of Chronic Pulmonary... Alternative Therapy Conclusions References

 

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