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Acute Pulmonary Exacerbations of SarcoidosisAcute Pulmonary Exacerbations of Sarcoidosis FREE TO VIEW

Efstratios Panselinas, MD; Marc A. Judson, MD, FCCP
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Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(4):827-836. doi:10.1378/chest.12-1060
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Exacerbations of sarcoidosis are common. In particular, exacerbations of pulmonary sarcoidosis are reported in more than one-third of patients. Despite their frequent occurrence, there is little medical evidence concerning the definition, diagnosis, and treatment of pulmonary exacerbations of sarcoidosis. In this article, we propose a definition of acute pulmonary exacerbations of sarcoidosis (APES). We review the meager medical literature concerning the risk factors, diagnosis, and treatment of this condition. Given the limited information concerning APES, we acknowledge that this article is not a definitive resource but, rather, a position paper that will encourage greater consideration of the pathogenesis, diagnostic challenges, and treatment approaches to this condition. We believe that further focus on APES will improve the quality of care of patients with pulmonary sarcoidosis.

From the Pulmonary Department (Dr Panselinas), 411 General Army Hospital, Tripoli, Greece; and the Division of Pulmonary and Critical Care Medicine (Dr Judson), Albany Medical College, Albany, NY.

Correspondence to: Marc A. Judson, MD, FCCP, Division of Pulmonary and Critical Care Medicine, MC-91, Albany Medical College, Albany, NY 12208; e-mail: judsonm@mail.amc.edu

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Judson has been a consultant for Pulmonary Reviews; Janssen Biotech, Inc; and Celgene Corp. Dr Panselinas has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors acknowledge Sooyeon Kwon, PhD, for her outstanding assistance with the tables and figures in this manuscript. We also acknowledge Jared N. Kravitz, MD, who, to our knowledge, first coined the term, “APES.”

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Figures in this Article

Acute pulmonary exacerbations of sarcoidosis (APES) have been described in patients treated previously for pulmonary sarcoidosis after reduction or discontinuation of corticosteroid therapy.1,2 Despite the frequent occurrence of APES in patients with pulmonary sarcoidosis, there is a paucity of information regarding this entity. In this review, we discuss the definition, immunopathogenesis, diagnosis, and treatment of APES. Finally, we identify several unresolved issues concerning this entity.

There is no consensus definition of APES. Exacerbations of sarcoidosis (pulmonary and extrapulmonary) have been defined as the worsening of symptoms after the cessation of corticosteroids that was severe enough to warrant treatment.3 APES has been defined using different combinations of the following criteria by different researchers: (1) a decline in pulmonary function, (2) worsening pulmonary symptoms, (3) increases in biomarkers of disease activity, (4) the need to initiate or restart corticosteroid therapy, and (5) exclusion of alternative causes of pulmonary symptoms and pulmonary dysfunction.1,2,46

We suggest that APES should be defined as worsening of pulmonary symptoms in a patient with known sarcoidosis not explained by another cause, combined with a decline in spirometry (≥ 10% decrease from previous baseline FVC and/or FEV1). The pulmonary symptoms should be present for at least 1 month. This 1-month timeframe for the worsening of pulmonary symptoms is arbitrary but is recommended because it may aid in discriminating patients with APES from those with acute pulmonary problems such as asthma and acute lung infections. Our definition allows for APES to be considered in patients receiving corticosteroids or alternative antisarcoidosis therapies.

The prevalence of APES is unknown. Most studies concerning APES are retrospective, and many concern exacerbations of sarcoidosis that are not specific for lung involvement. Extrapolating from these reported data, estimated rates of APES are between 13% to 75%, depending on the population studied, corticosteroid dosing prior to the development of APES, and the criteria used to define exacerbations.24,7Table 1 lists rates of sarcoidosis exacerbations and APES in various cohorts. These rates are not adjusted for subpopulations such as race, sex, or need of previous antisarcoidosis therapy. Table 2 summarizes factors that are associated with the development of APES.

Table Graphic Jump Location
Table 1 —Frequency of Sarcoidosis Exacerbations and APES

APES = acute pulmonary exacerbations of sarcoidosis; NR = not reported.

a 

Initially received corticosteroids of sarcoidosis lung involvement.

b 

Relapse determined only in patients successfully weaned off therapy.

Table Graphic Jump Location
Table 2 —Risk Factors for Sarcoidosis Exacerbations and APES

HAART = highly active antiretroviral therapy; + = some association; ++ = moderate association; +++ = strong association. See Table 1 for expansion of other abbreviations.

Higher rates of sarcoidosis exacerbations and APES appear to be found in black patients3,7 than in white patients.2,3 Certain clinical presentations may affect the probability of relapse (Table 2).

Treatment with corticosteroids has been implicated as a risk factor for APES. This has been demonstrated in several large retrospective studies.3,10,11 Two additional studies have demonstrated that patients with sarcoidosis who do not receive corticosteroids initially have a lower chance of requiring corticosteroids long term.34,35 Finally, it has been demonstrated that patients with sarcoidosis who suffered exacerbations received statistically significant higher doses of prednisone compared with patients who did not relapse.2 Although these results could be explained by the fact that these studies were retrospective and patients initially receiving corticosteroids or higher-dose corticosteroids might have more severe disease that would make them more prone to relapse, it is possible that initial corticosteroid therapy promoted their relapse (see “The Pathogenesis of APES” section).3

Several cases of new-onset sarcoidosis and exacerbations of sarcoidosis including APES have been reported after treatment with interferon (IFN)-α for viral hepatitis and other disorders.1214,36 This is consistent with the postulation that IFN-α is an important building block of the sarcoid granuloma.37,38 The majority of these cases of sarcoidosis develop 1 to 9 months after initiation of IFN-α therapy but the disease may occur up to 2 years later.39

New-onset sarcoidosis and exacerbations of sarcoidosis including APES have been reported in patients with HIV after initiation of highly active antiretroviral therapy (HAART).15,16,4045 This has been considered a form of immune reconstitution inflammatory syndrome, whereby the HAART-induced rise of CD4+ cells allows granulomatous inflammation against the unknown sarcoidosis antigens to occur.43 Sarcoidosis has developed in as short as 3 months to as long as 4 years after starting HAART.16,4446 At the time of the diagnosis of sarcoidosis, the CD4+ count has always exceeded 125 cells/mm3, and is usually above 200 cells/mm3.15,17,40,44,45

APES (“recurrent sarcoidosis”) may develop in the lung allograft after lung transplant for pulmonary sarcoidosis.1829 APES typically occurs within 15 months after lung transplant,18 although it has occurred within 100 days21 and as late as 56 months after the procedure.23 APES usually occurs in this setting in lung allograft recipients without pulmonary symptoms and is usually detected by identifying chest radiographic abnormalities or by identifying granulomatous inflammation on transbronchial bronchoscopies done for surveillance for lung rejection.20,21,28 On occasion, post-lung-transplantation APES may present with pulmonary symptoms or pulmonary dysfunction.18,20,22,26 Patients often improve spontaneously18,20,21 or when their corticosteroid dose is raised.18,25,47 It has been determined that the granulomatous inflammation of post-lung-transplantation APES is derived from recipient cells.48,49

Although tumor necrosis factor (TNF)-α antagonists have been shown to be of benefit for sarcoidosis,50,51 these agents have also induced APES.3032 TNF-α-antagonist-induced APES usually occurs with entanercept,3033 which, unlike infliximab and adalimumab, may not be routinely effective for pulmonary sarcoidosis.52 However, TNF-α-antagonist-induced APES has also been reported with infliximab.53 It has been postulated that these agents may stimulate IFN-γ production, leading to the development of granulomatous inflammation.30

There is ample evidence to suggest that sarcoidosis, similar to other granulomatous diseases, involves the interaction of inflammatory cells, human leukocyte antigen molecules, cell receptors, and cytokines.5456 It has been postulated that the granulomatous response in sarcoidosis represents an attempt by the host to clear the putative antigen that has become persistent.57 If the antigen can be cleared, the granulomatous reaction will cease.54,57

This concept suggests that APES may develop when the putative sarcoidosis antigen is not cleared. Treatment of sarcoidosis may interfere with the very process of antigen clearance by impeding granulomatous inflammation. If the antigen is still present, the granulomatous process might resume once antigranulomatous therapy is withdrawn, resulting in APES. As already mentioned, several studies have demonstrated that corticosteroid use is associated with the development of APES.

Furthermore, it has never been demonstrated clearly that the treatment of sarcoidosis affects the natural course of the disease.54,5860 To that end, in patients treated previously for pulmonary sarcoidosis, APES may be more closely related to the duration of the initial therapy than to the use of specific medications at specific doses. As long as the duration of an antisarcoidosis regimen exceeds the presence of the antigen in the host, the therapy will be “effective.” On the other hand, if the regimen is discontinued while the antigen is still present, the patient will develop APES (Fig 1).54 It is also possible that APES results from exposure to a new antigen or reexposure to the original antigen that was, initially, completely cleared.

Figure Jump LinkFigure 1. The duration of therapy could determine the chance of relapse because sarcoidosis treatment may not affect the natural course of disease. If the duration of therapy exceeds the duration of disease activity (Therapy A), then the patient will not relapse when therapy is withdrawn. If the duration of therapy is shorter than the duration of disease activity (Therapy B), then the patient will relapse when therapy is withdrawn. (Reproduced with permission from Judson.54)Grahic Jump Location

APES could possibly develop by mechanisms other than granulomatous inflammation. Not only does sarcoidosis have a predilection for the airways,61 but airways hyperresponsiveness may develop.62 Therefore, it is possible that a subset of patients with APES may have bronchospasm as the primary cause of their exacerbation. We have cared for patients with APES who have responded to corticosteroid therapy within 48 h in terms of pulmonary function and pulmonary symptoms (documented in terms of spiromtery and visual analog scales of symptoms). This rapid response might have been too rapid for resolution of granulomatous inflammation, suggesting the possibility that bronchospasm and other mechanisms may cause APES.

Finally, the immunopathogenesis of APES may vary depending on the clinical presentation of the condition. It has been demonstrated that patients who have “sudden onset of disease with symptoms of at least one month duration” have a different profile of serum inflammatory mediators than do patients with “subacute disease.”63

In summary, we suspect that APES may occur via a number of different pathophysiologic mechanisms, some of which may be only indirectly related to granulomatous inflammation. This may explain the heterogeneity of the radiographic, physiologic, and treatment responses of APES.

The symptoms of APES are not specific and cannot be used to make a diagnosis of APES. However, cough is the most common symptom associated with APES, occurring in nearly 90% in one series.5 Therefore, the lack of cough suggests that APES is unlikely. Wheeze and dyspnea are also common, whereas fever and night sweats rarely occur.5

Our definition of APES, described earlier, requires the presence of pulmonary symptoms, spirometric criteria, and the exclusion of alternative causes for these findings. Only the exclusion of alternative causes for symptoms is problematic. Table 3 shows the differential diagnosis of APES, and these entities must be excluded for the diagnosis of APES to be made. Some of the conditions listed in Table 3 are chronic and are unlikely to result in APES. However, they may contribute to the severity of the pulmonary symptoms.

Table Graphic Jump Location
Table 3 —The Differential Diagnosis of APES

See Table 1 for expansion of abbreviations. (Adapted with permission from Judson.54)

Because exclusion of several of the entities listed in Table 3 requires radiographic imaging, a chest radiograph needs to be performed routinely when APES is considered. Chest radiographic findings that suggest APES include parenchymal lung nodules and opacities composed of conglomerations of these nodules.6469 These nodules are thought to represent granulomatous inflammation and usually have a perilymphatic distribution.64,65,69 Mediastinal adenopathy alone is inadequate evidence for APES. It is important to note that chest radiographs in APES are often unchanged or improved from previous films.6 Therefore, chest radiographic findings should never be used to exclude the possibility of APES. To summarize, a chest radiograph should be performed routinely in the evaluation of APES to exclude alternative pulmonary diagnoses, although it is often inadequate to confirm the diagnosis of APES.

Although the structure of the lung parenchyma is assessed more clearly by chest CT scanning than by chest radiograph, we do not recommend chest CT scan as part of the initial evaluation for APES. Chest CT scans expose patients to significant radiation, especially if they are performed serially.70 Chest CT scans may be useful to detect APES in a patient with a normal or equivocal chest radiograph.

Because sarcoidosis is a systemic disease, exacerbations may occur simultaneously in multiple organs. Therefore, APES may be associated with worsening of sarcoidosis in extrapulmonary organs where sarcoidosis had been detected previously or may develop in new extrapulmonary organs.

A suggested algorithm for APES and the decision to empirically treat it is presented in Table 4. It should be noted that, in most cases, this algorithm allows for empirical corticosteroid treatment of APES without a confirming biopsy. Such empirical therapy needs to be done with caution, even in situations in which the diagnosis of APES is very likely. Because APES usually responds briskly to corticosteroids within 3 weeks,5 we recommend that all patients empirically treated be evaluated within 1 month of such therapy. Patients who fail to demonstrate a clinical response are suspected of not having APES, and potential alternative diagnoses should be explored. Patients with a lower likelihood of APES may also be treated empirically with 2 to 3 weeks of corticosteroids provided their risks in terms of comorbidities or having an alternative diagnosis (eg, infection) are not prohibitive. Otherwise, further investigations, including BAL and transbronchial lung biopsy, may be appropriate.

Table Graphic Jump Location
Table 4 —An Algorithm for the Diagnosis of APES and Consideration of Empirical Treatment of APES

CXR = chest radiograph; dx = diagnosis; N/A = not applicable; − = condition absent; + = condition present.

a 

Nil by spirometry criterion for APES. However, this presentation may be pathophysiologically similar to APES. Therefore, if clinically indicated, would proceed in this table as if there was ≥ 10% decline in FVC and/or FEV1.

b 

A response in 2 to 3 wk strongly supports the diagnosis. The diagnosis is suspect if there is no response in 2 to 3 wk.5 In this case, an evaluation for alternative diagnoses or a confirmatory transbronchial biopsy and/or BAL may be required.

c 

Empirical therapy may still be given with caution if the risks of such therapy, in terms of patient comorbidities and risks from potential alternative diagnoses (eg, infection), are reasonable. A response to such therapy should be evident within 2 to 3 wk.5 If there is an inadequate response, an evaluation for alternative diagnoses or a confirmatory transbronchial biopsy and/or BAL may be required.

The American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Diseases Consensus Statement recommends an initial corticosteroid dose of 20 to 40 mg of daily prednisone equivalent for pulmonary sarcoidosis.71 Using the lower end of that dosing range, a study of 36 patients treated for APES with a median dose of 20 mg of daily prednisone for a median of 21 days resulted in a return of spirometry to baseline and a marked diminution in pulmonary symptoms.5 Even lower initial corticosteroid doses may be effective, such as the lowest corticosteroid dose at which APES did not occur.

Because most of the side effects of corticosteroids are cumulative (eg, weight gain, osteoporosis, cataracts), the additional corticosteroid treatment required for APES significantly increases the risk of such toxicities. For this reason, the addition of a corticosteroid-sparing agent is recommended for most patients with APES. These agents should certainly be considered in patients with APES who have previously received corticosteroids for > 1 year or have signs or symptoms of corticosteroid toxicity.

Table 5 lists corticosteroid-sparing alternative agents useful for the treatment of pulmonary sarcoidosis and, therefore, APES. These drugs are rarely effective as a sole treatment of sarcoidosis but often allow for a reduction in the maintenance corticosteroid dose (corticosteroid sparing). When a corticosteroid-sparing medication is added for the treatment of APES, it is recommended that corticosteroids not be tapered more rapidly than if they were used alone, unless the patient has significant corticosteroid side effects. This is because most corticosteroid-sparing agents for pulmonary sarcoidosis require several months to reach maximal efficacy.7375 Infliximab may be an exception to this premise, because it has been demonstrated to maximize improvement in spirometry within 2 weeks.50 These data imply that it is unrealistic to expect that an immediate switch from corticosteroids to an alternative agent will be effective for the treatment of APES, and complete withdrawal of corticosteroids is likely to result in another APES episode.76

Table Graphic Jump Location
Table 5 —Alternative/Corticosteroid-Sparing Drugs for the Treatment of APES

LFT = serum liver function test. See Table 1 for expansion of other abbreviations. (Adapted with permission from Judson54 and Baughman et al.59)

a 

Level A: at least one double-blind, placebo-controlled trial with positive results with one or more case series supporting the results. Level B: majority of case series showing positive results. Level C: case series with mixed reports of effectiveness, or only a small number of cases reported. 1: strong recommendation; 2: weak recommendation (proposed by Guyatt et al72).

b 

All can increase the risk of infection.

c 

Usually given after another strong (grade 1) recommended alternative medication has been ineffective/inadequate in terms of corticosteroid sparing.

Although relatively low-dose corticosteroid therapy is universally effective for the immediate treatment of APES, the long-term corticosteroid dosing regimen with or without additional agents is unknown because limited clinical data are available concerning this issue. In a study of patients treated for active sarcoidosis including APES, 37% (30 of 82) relapsed (including APES) when the corticosteroid dose was discontinued.2 In a cohort of 192 predominantly black patients with sarcoidosis with severe pulmonary dysfunction, in only 30% did relapse fail to occur on corticosteroid withdrawal.77 Relapses tended to be recurrent and usually occurred when the corticosteroid dose was tapered to < 15 mg of daily prednisone equivalent.77Figure 2 outlines a suggested algorithm for the treatment of APES. Because sarcoidosis is a systemic disease that commonly affects extrapulmonary organs, the management of APES should also include an evaluation of the development or worsening of extrapulmonary sarcoidosis.

Figure Jump LinkFigure 2. A proposed treatment algorithm for APES (see “Therapy for APES” section). APES = acute pulmonary exacerbations of sarcoidosis.Grahic Jump Location

Although APES is a very common entity, there are many unanswered questions concerning this condition. First, a definition of APES should be established. Ideally, this definition should be linked to the immunopathogenic and genetic aspects of the disease. The definition may require some flexibility because it is possible that APES represents several varied pathophysiologic mechanisms that each cause pulmonary symptoms and pulmonary dysfunction. Second, a standardized therapeutic regimen for APES needs to be established. Although corticosteroid therapy is almost always effective in the short term, little is known concerning the long-term management of APES. Third, therapy for APES may need to be modified based on the phenotypic expression and pathophysiologic derangements of the disease. Fourth, it would be important to identify biomarkers that would predict or confirm APES.

APES is a common clinical condition, concerning which there is a paucity of evidence-based information. Currently, there is no standard definition of APES, and its immunopathogenesis may be varied. Physicians should carefully exclude other potential causes of pulmonary symptoms and pulmonary dysfunction before concluding that APES is the correct diagnosis and initiating antisarcoidosis therapy. Corticosteroid therapy is the treatment of choice, although the exact dose and duration of therapy remain unknown. Corticosteroid-sparing agents should be considered in patients with multiple APES episodes.

This article serves not only to describe this condition, but, hopefully, to encourage greater consideration of the pathogenesis, presentation, diagnostic challenges, and treatment approaches to APES. We believe that further focus on APES will improve the quality of care of patients with pulmonary sarcoidosis.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Judson has been a consultant for Pulmonary Reviews; Janssen Biotech, Inc; and Celgene Corp. Dr Panselinas has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors acknowledge Sooyeon Kwon, PhD, for her outstanding assistance with the tables and figures in this manuscript. We also acknowledge Jared N. Kravitz, MD, who, to our knowledge, first coined the term, “APES.”

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Judson has been a consultant for Pulmonary Reviews; Janssen Biotech, Inc; and Celgene Corp. Dr Panselinas has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors acknowledge Sooyeon Kwon, PhD, for her outstanding assistance with the tables and figures in this manuscript. We also acknowledge Jared N. Kravitz, MD, who, to our knowledge, first coined the term, “APES.”

APES

acute pulmonary exacerbations of sarcoidosis

HAART

highly active antiretroviral therapy

IFN

interferon

TNF

tumor necrosis factor.

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Wittram C, Fogg J, Farber H. Immune restoration syndrome manifested by pulmonary sarcoidosis. AJR Am J Roentgenol 2001;177(6):1427. [PubMed]
 
Trevenzoli M, Cattelan AM, Marino F, Marchioro U, Cadrobbi P. Sarcoidosis and HIV infection: a case report and a review of the literature. Postgrad Med J 2003;79(935):535-538. [PubMed] [CrossRef]
 
Foulon G, Wislez M, Naccache JM, et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis 2004;38(3):418-425. [PubMed] [CrossRef]
 
Ottenhoff TH, Kumararatne D, Casanova JL. Novel human immunodeficiencies reveal the essential role of type-I cytokines in immunity to intracellular bacteria. Immunol Today 1998;19(11):491-494. [PubMed] [CrossRef]
 
Martel S, Carré PC, Carrera G, Pipy B, Léophonte PJ; Toulouse Lung Transplantation Group Toulouse Lung Transplantation Group. Tumour necrosis factor-alpha gene expression by alveolar macrophages in human lung allograft recipient with recurrence of sarcoidosis. Eur Respir J 1996;9(5):1087-1089. [PubMed] [CrossRef]
 
Ionescu DN, Hunt JL, Lomago D, Yousem SA. Recurrent sarcoidosis in lung transplant allografts: granulomas are of recipient origin. Diagn Mol Pathol 2005;14(3):140-145. [PubMed] [CrossRef]
 
Milman N, Andersen CB, Burton CM, Iversen M. Recurrent sarcoid granulomas in a transplanted lung derive from recipient immune cells. Eur Respir J 2005;26(3):549-552. [PubMed] [CrossRef]
 
Baughman RP, Drent M, Kavuru M, et al;; Sarcoidosis Investigators Sarcoidosis Investigators. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174(7):795-802. [PubMed] [CrossRef]
 
Judson MA, Baughman RP, Costabel U, et al;; Centocor T48 Sarcoidosis Investigators Centocor T48 Sarcoidosis Investigators. Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial. Eur Respir J 2008;31(6):1189-1196. [PubMed] [CrossRef]
 
Utz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003;124(1):177-185. [PubMed] [CrossRef]
 
O’Shea FD, Marras TK, Inman RD. Pulmonary sarcoidosis developing during infliximab therapy. Arthritis Rheum 2006;55(6):978-981. [PubMed] [CrossRef]
 
Judson MA. The treatment of pulmonary sarcoidosis. Respir Med 2012;106(10):1351-1361. [PubMed] [CrossRef]
 
Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357(21):2153-2165. [PubMed] [CrossRef]
 
Gerke AK, Hunninghake G. The immunology of sarcoidosis. Clin Chest Med 2008;29(3):379-390. [PubMed] [CrossRef]
 
Chen ES, Song Z, Willett MH, et al. Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2. Am J Respir Crit Care Med 2010;181(4):360-373. [PubMed] [CrossRef]
 
Paramothayan NS, Lasserson TJ, Jones PW. Corticosteroids for pulmonary sarcoidosis. Cochrane Database Syst Rev. 2005;; (2):CD001114.
 
Baughman RP, Culver DA, Judson MA. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med 2011;183(5):573-581. [PubMed] [CrossRef]
 
Panselinas E, Rodgers JK, Judson MA.. Clinical outcomes in sarcoidosis after cessation of infliximab treatment.Respirology 2009;;14(4):522-528..
 
Shorr AF, Torrington KG, Hnatiuk OW. Endobronchial biopsy for sarcoidosis: a prospective study. Chest 2001;120(1):109-114. [PubMed] [CrossRef]
 
Shorr AF, Torrington KG, Hnatiuk OW. Endobronchial involvement and airway hyperreactivity in patients with sarcoidosis. Chest 2001;120(3):881-886. [PubMed] [CrossRef]
 
Prasse A, Katic C, Germann M, Buchwald A, Zissel G, Müller-Quernheim J. Phenotyping sarcoidosis from a pulmonary perspective. Am J Respir Crit Care Med 2008;177(3):330-336. [PubMed] [CrossRef]
 
Nishino M, Lee KS, Itoh H, Hatabu H. The spectrum of pulmonary sarcoidosis: variations of high-resolution CT findings and clues for specific diagnosis. Eur J Radiol 2010;73(1):66-73. [PubMed] [CrossRef]
 
Oberstein A, von Zitzewitz H, Schweden F, Müller-Quernheim J. Non invasive evaluation of the inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc Diffuse Lung Dis 1997;14(1):65-72. [PubMed]
 
Leung AN, Brauner MW, Caillat-Vigneron N, Valeyre D, Grenier P. Sarcoidosis activity: correlation of HRCT findings with those of67Ga scanning, bronchoalveolar lavage, and serum angiotensin-converting enzyme assay. J Comput Assist Tomogr 1998;22(2):229-234. [PubMed] [CrossRef]
 
Criado E, Sánchez M, Ramírez J, et al. Pulmonary sarcoidosis: typical and atypical manifestations at high-resolution CT with pathologic correlation. Radiographics 2010;30(6):1567-1586. [PubMed] [CrossRef]
 
Hamper UM, Fishman EK, Khouri NF, Johns CJ, Wang KP, Siegelman SS. Typical and atypical CT manifestations of pulmonary sarcoidosis. J Comput Assist Tomogr 1986;10(6):928-936. [PubMed] [CrossRef]
 
Müller NL, Kullnig P, Miller RR. The CT findings of pulmonary sarcoidosis: analysis of 25 patients. AJR Am J Roentgenol 1989;152(6):1179-1182. [PubMed]
 
Smith-Bindman R, Lipson J, Marcus R, et al. Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med 2009;169(22):2078-2086. [PubMed] [CrossRef]
 
Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999;16(2):149-173. [PubMed]
 
Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest 2006;129(1):174-181. [PubMed] [CrossRef]
 
Lower EE, Baughman RP. The use of low dose methotrexate in refractory sarcoidosis. Am J Med Sci 1990;299(3):153-157. [PubMed] [CrossRef]
 
Baltzan M, Mehta S, Kirkham TH, Cosio MG. Randomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis. Am J Respir Crit Care Med 1999;160(1):192-197. [PubMed]
 
Zabel P, Entzian P, Dalhoff K, Schlaak M. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med 1997;155(5):1665-1669. [PubMed]
 
Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995;155(8):846-851. [PubMed] [CrossRef]
 
Johns CJ, Michele TM. The clinical management of sarcoidosis. A 50-year experience at the Johns Hopkins Hospital. Medicine (Baltimore) 1999;78(2):65-111. [PubMed] [CrossRef]
 

Figures

Figure Jump LinkFigure 1. The duration of therapy could determine the chance of relapse because sarcoidosis treatment may not affect the natural course of disease. If the duration of therapy exceeds the duration of disease activity (Therapy A), then the patient will not relapse when therapy is withdrawn. If the duration of therapy is shorter than the duration of disease activity (Therapy B), then the patient will relapse when therapy is withdrawn. (Reproduced with permission from Judson.54)Grahic Jump Location
Figure Jump LinkFigure 2. A proposed treatment algorithm for APES (see “Therapy for APES” section). APES = acute pulmonary exacerbations of sarcoidosis.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Frequency of Sarcoidosis Exacerbations and APES

APES = acute pulmonary exacerbations of sarcoidosis; NR = not reported.

a 

Initially received corticosteroids of sarcoidosis lung involvement.

b 

Relapse determined only in patients successfully weaned off therapy.

Table Graphic Jump Location
Table 2 —Risk Factors for Sarcoidosis Exacerbations and APES

HAART = highly active antiretroviral therapy; + = some association; ++ = moderate association; +++ = strong association. See Table 1 for expansion of other abbreviations.

Table Graphic Jump Location
Table 3 —The Differential Diagnosis of APES

See Table 1 for expansion of abbreviations. (Adapted with permission from Judson.54)

Table Graphic Jump Location
Table 4 —An Algorithm for the Diagnosis of APES and Consideration of Empirical Treatment of APES

CXR = chest radiograph; dx = diagnosis; N/A = not applicable; − = condition absent; + = condition present.

a 

Nil by spirometry criterion for APES. However, this presentation may be pathophysiologically similar to APES. Therefore, if clinically indicated, would proceed in this table as if there was ≥ 10% decline in FVC and/or FEV1.

b 

A response in 2 to 3 wk strongly supports the diagnosis. The diagnosis is suspect if there is no response in 2 to 3 wk.5 In this case, an evaluation for alternative diagnoses or a confirmatory transbronchial biopsy and/or BAL may be required.

c 

Empirical therapy may still be given with caution if the risks of such therapy, in terms of patient comorbidities and risks from potential alternative diagnoses (eg, infection), are reasonable. A response to such therapy should be evident within 2 to 3 wk.5 If there is an inadequate response, an evaluation for alternative diagnoses or a confirmatory transbronchial biopsy and/or BAL may be required.

Table Graphic Jump Location
Table 5 —Alternative/Corticosteroid-Sparing Drugs for the Treatment of APES

LFT = serum liver function test. See Table 1 for expansion of other abbreviations. (Adapted with permission from Judson54 and Baughman et al.59)

a 

Level A: at least one double-blind, placebo-controlled trial with positive results with one or more case series supporting the results. Level B: majority of case series showing positive results. Level C: case series with mixed reports of effectiveness, or only a small number of cases reported. 1: strong recommendation; 2: weak recommendation (proposed by Guyatt et al72).

b 

All can increase the risk of infection.

c 

Usually given after another strong (grade 1) recommended alternative medication has been ineffective/inadequate in terms of corticosteroid sparing.

References

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Lenner R, Bregman Z, Teirstein AS, DePalo L. Recurrent pulmonary sarcoidosis in HIV-infected patients receiving highly active antiretroviral therapy. Chest 2001;119(3):978-981. [PubMed] [CrossRef]
 
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Morris DG, Jasmer RM, Huang L, Gotway MB, Nishimura S, King TE Jr. Sarcoidosis following HIV infection: evidence for CD4+lymphocyte dependence. Chest 2003;124(3):929-935. [PubMed] [CrossRef]
 
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Martinez FJ, Orens JB, Deeb M, Brunsting LA, Flint A, Lynch JP III. Recurrence of sarcoidosis following bilateral allogeneic lung transplantation. Chest 1994;106(5):1597-1599. [PubMed] [CrossRef]
 
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Kazerooni EA, Cascade PN. Recurrent miliary sarcoidosis after lung transplantation. Radiology 1995;194(3):913. [PubMed]
 
Carré P, Rouquette I, Durand D, et al. Recurrence of sarcoidosis in a human lung allograft. Transplant Proc 1995;27(2):1686. [PubMed]
 
Müller C, Briegel J, Haller M, et al. Sarcoidosis recurrence following lung transplantation. Transplantation 1996;61(7):1117-1119. [PubMed] [CrossRef]
 
Kazerooni EA, Jackson C, Cascade PN. Sarcoidosis: recurrence of primary disease in transplanted lungs. Radiology 1994;192(2):461-464. [PubMed]
 
Collins J, Hartman MJ, Warner TF, et al. Frequency and CT findings of recurrent disease after lung transplantation. Radiology 2001;219(2):503-509. [PubMed]
 
Bjørtuft O, Foerster A, Boe J, Geiran O. Single lung transplantation as treatment for end-stage pulmonary sarcoidosis: recurrence of sarcoidosis in two different lung allografts in one patient. J Heart Lung Transplant 1994;13(1 pt 1):24-29. [PubMed]
 
Louie GH, Chitkara P, Ward MM. Relapse of sarcoidosis upon treatment with etanercept. Ann Rheum Dis 2008;67(6):896-898. [PubMed] [CrossRef]
 
van der Stoep D, Braunstahl GJ, van Zeben J, Wouters J. Sarcoidosis during anti-tumor necrosis factor-alpha therapy: no relapse after rechallenge. J Rheumatol 2009;36(12):2847-2848. [PubMed] [CrossRef]
 
Burns AM, Green PJ, Pasternak S. Etanercept-induced cutaneous and pulmonary sarcoid-like granulomas resolving with adalimumab. J Cutan Pathol 2012;39(2):289-293. [PubMed] [CrossRef]
 
Verschueren K, Van Essche E, Verschueren P, Taelman V, Westhovens R. Development of sarcoidosis in etanercept-treated rheumatoid arthritis patients. Clin Rheumatol 2007;26(11):1969-1971. [PubMed] [CrossRef]
 
Gibson GJ, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax 1996;51(3):238-247. [PubMed] [CrossRef]
 
Baughman RP, Judson MA, Teirstein A, et al. Presenting characteristics as predictors of duration of treatment in sarcoidosis. QJM 2006;99(5):307-315. [PubMed] [CrossRef]
 
Benali S, Boustière C, Castellani P, et al. Sarcoidosis following pegylated interferon therapy: two cases [in French]. Gastroenterol Clin Biol 2006;30(4):615-619. [PubMed] [CrossRef]
 
Sweiss NJ, Zhang W, Franek BS, et al. Linkage of type I interferon activity and TNF-alpha levels in serum with sarcoidosis manifestations and ancestry. PLoS ONE 2011;6(12):e29126. [PubMed] [CrossRef]
 
Katchar K, Söderström K, Wahlstrom J, Eklund A, Grunewald J. Characterisation of natural killer cells and CD561 T-cells in sarcoidosis patients. Eur Respir J 2005;26(1):77-85. [PubMed] [CrossRef]
 
López V, Molina I, Monteagudo C, Jordá E. Cutaneous sarcoidosis developing after treatment with pegylated interferon and ribavirin: a new case and review of the literature. Int J Dermatol 2011;50(3):287-291. [PubMed] [CrossRef]
 
Haramati LB, Lee G, Singh A, Molina PL, White CS. Newly diagnosed pulmonary sarcoidosis in HIV-infected patients. Radiology 2001;218(1):242-246. [PubMed]
 
Naccache JM, Antoine M, Wislez M, et al. Sarcoid-like pulmonary disorder in human immunodeficiency virus-infected patients receiving antiretroviral therapy. Am J Respir Crit Care Med 1999;159(6):2009-2013. [PubMed]
 
Gomez V, Smith PR, Burack J, Daley R, Rosa U. Sarcoidosis after antiretroviral therapy in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2000;31(5):1278-1280. [PubMed] [CrossRef]
 
Wittram C, Fogg J, Farber H. Immune restoration syndrome manifested by pulmonary sarcoidosis. AJR Am J Roentgenol 2001;177(6):1427. [PubMed]
 
Trevenzoli M, Cattelan AM, Marino F, Marchioro U, Cadrobbi P. Sarcoidosis and HIV infection: a case report and a review of the literature. Postgrad Med J 2003;79(935):535-538. [PubMed] [CrossRef]
 
Foulon G, Wislez M, Naccache JM, et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin Infect Dis 2004;38(3):418-425. [PubMed] [CrossRef]
 
Ottenhoff TH, Kumararatne D, Casanova JL. Novel human immunodeficiencies reveal the essential role of type-I cytokines in immunity to intracellular bacteria. Immunol Today 1998;19(11):491-494. [PubMed] [CrossRef]
 
Martel S, Carré PC, Carrera G, Pipy B, Léophonte PJ; Toulouse Lung Transplantation Group Toulouse Lung Transplantation Group. Tumour necrosis factor-alpha gene expression by alveolar macrophages in human lung allograft recipient with recurrence of sarcoidosis. Eur Respir J 1996;9(5):1087-1089. [PubMed] [CrossRef]
 
Ionescu DN, Hunt JL, Lomago D, Yousem SA. Recurrent sarcoidosis in lung transplant allografts: granulomas are of recipient origin. Diagn Mol Pathol 2005;14(3):140-145. [PubMed] [CrossRef]
 
Milman N, Andersen CB, Burton CM, Iversen M. Recurrent sarcoid granulomas in a transplanted lung derive from recipient immune cells. Eur Respir J 2005;26(3):549-552. [PubMed] [CrossRef]
 
Baughman RP, Drent M, Kavuru M, et al;; Sarcoidosis Investigators Sarcoidosis Investigators. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174(7):795-802. [PubMed] [CrossRef]
 
Judson MA, Baughman RP, Costabel U, et al;; Centocor T48 Sarcoidosis Investigators Centocor T48 Sarcoidosis Investigators. Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial. Eur Respir J 2008;31(6):1189-1196. [PubMed] [CrossRef]
 
Utz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003;124(1):177-185. [PubMed] [CrossRef]
 
O’Shea FD, Marras TK, Inman RD. Pulmonary sarcoidosis developing during infliximab therapy. Arthritis Rheum 2006;55(6):978-981. [PubMed] [CrossRef]
 
Judson MA. The treatment of pulmonary sarcoidosis. Respir Med 2012;106(10):1351-1361. [PubMed] [CrossRef]
 
Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357(21):2153-2165. [PubMed] [CrossRef]
 
Gerke AK, Hunninghake G. The immunology of sarcoidosis. Clin Chest Med 2008;29(3):379-390. [PubMed] [CrossRef]
 
Chen ES, Song Z, Willett MH, et al. Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2. Am J Respir Crit Care Med 2010;181(4):360-373. [PubMed] [CrossRef]
 
Paramothayan NS, Lasserson TJ, Jones PW. Corticosteroids for pulmonary sarcoidosis. Cochrane Database Syst Rev. 2005;; (2):CD001114.
 
Baughman RP, Culver DA, Judson MA. A concise review of pulmonary sarcoidosis. Am J Respir Crit Care Med 2011;183(5):573-581. [PubMed] [CrossRef]
 
Panselinas E, Rodgers JK, Judson MA.. Clinical outcomes in sarcoidosis after cessation of infliximab treatment.Respirology 2009;;14(4):522-528..
 
Shorr AF, Torrington KG, Hnatiuk OW. Endobronchial biopsy for sarcoidosis: a prospective study. Chest 2001;120(1):109-114. [PubMed] [CrossRef]
 
Shorr AF, Torrington KG, Hnatiuk OW. Endobronchial involvement and airway hyperreactivity in patients with sarcoidosis. Chest 2001;120(3):881-886. [PubMed] [CrossRef]
 
Prasse A, Katic C, Germann M, Buchwald A, Zissel G, Müller-Quernheim J. Phenotyping sarcoidosis from a pulmonary perspective. Am J Respir Crit Care Med 2008;177(3):330-336. [PubMed] [CrossRef]
 
Nishino M, Lee KS, Itoh H, Hatabu H. The spectrum of pulmonary sarcoidosis: variations of high-resolution CT findings and clues for specific diagnosis. Eur J Radiol 2010;73(1):66-73. [PubMed] [CrossRef]
 
Oberstein A, von Zitzewitz H, Schweden F, Müller-Quernheim J. Non invasive evaluation of the inflammatory activity in sarcoidosis with high-resolution computed tomography. Sarcoidosis Vasc Diffuse Lung Dis 1997;14(1):65-72. [PubMed]
 
Leung AN, Brauner MW, Caillat-Vigneron N, Valeyre D, Grenier P. Sarcoidosis activity: correlation of HRCT findings with those of67Ga scanning, bronchoalveolar lavage, and serum angiotensin-converting enzyme assay. J Comput Assist Tomogr 1998;22(2):229-234. [PubMed] [CrossRef]
 
Criado E, Sánchez M, Ramírez J, et al. Pulmonary sarcoidosis: typical and atypical manifestations at high-resolution CT with pathologic correlation. Radiographics 2010;30(6):1567-1586. [PubMed] [CrossRef]
 
Hamper UM, Fishman EK, Khouri NF, Johns CJ, Wang KP, Siegelman SS. Typical and atypical CT manifestations of pulmonary sarcoidosis. J Comput Assist Tomogr 1986;10(6):928-936. [PubMed] [CrossRef]
 
Müller NL, Kullnig P, Miller RR. The CT findings of pulmonary sarcoidosis: analysis of 25 patients. AJR Am J Roentgenol 1989;152(6):1179-1182. [PubMed]
 
Smith-Bindman R, Lipson J, Marcus R, et al. Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med 2009;169(22):2078-2086. [PubMed] [CrossRef]
 
Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999;16(2):149-173. [PubMed]
 
Guyatt G, Gutterman D, Baumann MH, et al. Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest 2006;129(1):174-181. [PubMed] [CrossRef]
 
Lower EE, Baughman RP. The use of low dose methotrexate in refractory sarcoidosis. Am J Med Sci 1990;299(3):153-157. [PubMed] [CrossRef]
 
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NOTE:
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    Print ISSN: 0012-3692
    Online ISSN: 1931-3543