Respiratory Medicine (2013) 107, 2009e2013
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Frequency of acute worsening events in fibrotic pulmonary sarcoidosis patients Robert P. Baughman*, Elyse E. Lower Department of Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA Received 9 April 2013; accepted 14 October 2013 Available online 22 October 2013
KEYWORDS Sarcoidosis; Bronchiectasis; Infliximab; Prednisone
Summary Patients with fibrotic sarcoidosis can develop worsening of pulmonary symptoms for various reasons. We studied acute worsening events defined as episodes treated with limited courses of either antibiotics and or increased corticosteroid doses which resolved within four weeks. The prevalence of acute worsening events in patients with fibrotic sarcoidosis was investigated. Of 740 sarcoidosis patients seen in our clinic over a four month period, 129 (17%) had fibrotic sarcoidosis. We noted the age, race, gender, computer tomography (CT) results, and pulmonary function as measured by forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and the FEV1/FVC ratio. In a retrospective manner, the fibrotic sarcoidosis patients reported a median of three acute worsening events (range zero to eight) in the prior year. Bronchiectasis was noted on CT imaging in 63 of 129 (49%) of the fibrotic sarcoidosis patients. Fibrotic sarcoidosis patients reported a higher frequency of acute worsening events (3 (0e6)) than those without bronchiectasis (2 (0e8), p Z 0.0001). Sixteen patients receiving anti-tumor necrosis factor antibodies reported a higher frequency of acute worsening events compared to those not receiving anti-tumor necrosis factor antibodies (p Z 0.0297). There was no relationship between the number of acute worsening events and race, gender, smoking history, or FVC, FEV1, or FEV1/FVC ratio. We conclude that acute worsening events are frequent in patients with fibrotic sarcoidosis patients and are more common in patients with bronchiectasis and those receiving anti-tumor necrosis factor antibody therapies. ª 2013 Elsevier Ltd. All rights reserved.
* Corresponding author. 1001 Holmes, Eden Ave, Cincinnati, OH 45267, USA. E-mail addresses: [email protected], [email protected] (R.P. Baughman). 0954-6111/$ - see front matter ª 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.rmed.2013.10.014
2010
Introduction Pulmonary sarcoidosis patients can develop episodes of acute worsening of pulmonary symptoms. While this can occur in all stages of pulmonary sarcoidosis, an acute worsening in fibrotic sarcoidosis patients can result in significant pulmonary morbidity. There are several causes of acute worsening of pulmonary sarcoidosis, including worsening of the underlying sarcoidosis, infection, acute bronchospasm, or extra-pulmonary causes [1]. Relapse of sarcoidosis can occur during reduction or withdrawal of corticosteroids and/or other systemic therapy for pulmonary sarcoidosis [2,3]. This event has been termed an acute pulmonary exacerbation of sarcoidosis [1]. Patients with acute pulmonary exacerbation of sarcoidosis will often respond to reinstitution or an increase in corticosteroid dosage [4]. Patients relapsing during corticosteroid withdrawal are usually maintained on long term immunosuppressive therapy to prevent further relapses [2,3,5]. Acute pulmonary worsening can also occur in patients receiving stable doses of treatment. These episodes are often related to infection, and patients may respond to a short course of corticosteroids and broad spectrum antibiotics. Because resolution usually occurs in less than 4 weeks, these episodes are considered unique from acute pulmonary exacerbations of sarcoidosis [1]. In addition to infection, patients can also develop airway reactivity that responds to short courses of corticosteroid therapy [6]. Disease worsening can cause significant morbidity in patients with fibrotic sarcoidosis. In order to better understand the frequency and associated features of acute worsening of fibrotic sarcoidosis, we studied patients seen at the University of Cincinnati Sarcoidosis Clinic.
Methods Patients were recruited from those seen at the University of Cincinnati Interstitial Lung Disease and Sarcoidosis Clinic. Patients with sarcoidosis based on ATS/ERS/WASOG criteria who had chest imaging consistent with pulmonary fibrosis were eligible for evaluation. This retrospective study was part of an ongoing investigation of pulmonary infections in sarcoidosis and it was approved by the University of Cincinnati Institutional Review Board. This study examined a subset of sarcoidosis patients with pulmonary fibrosis seen during a four month period in our clinic. The presence of pulmonary fibrosis was decided by the radiologist who made the official interpretation of prior chest X-ray and high resolution CT (HRCT) scan which were performed as part of routine evaluation of the patient’s sarcoidosis. Although we reviewed these films, we chose to use the radiologist interpretation. All patients had both a routine chest X-ray and HRCT scan to review. Acute worsening was defined as an episode in which the patient was either prescribed an antibiotic for 5e21 days and/or a short increase in systemic glucocorticoids for increased cough and/or dyspnea. Although some patients underwent chest roentgenograms during these episodes, an abnormal imaging was not required.
R.P. Baughman, E.E. Lower During a four month period, each fibrotic sarcoidosis patient was asked to estimate the number of acute worsening events that had occurred during the prior twelve months. When possible, this number was verified by chart review. In addition to the number of episodes, additional demographic information including age, gender, self-declared race, smoking history, and sarcoidosis duration and organ involvement was recorded from the chart review. Chest imaging was reviewed for the presence or absence of bronchiectasis along with the most recent pulmonary function tests including FEV1, FVC, and FEV1/FVC ratio and the predicted values [7]. Current and past systemic sarcoidosis medications were categorized as glucocorticoids, cytotoxic drugs such as methotrexate, leflunomide, and azathioprine, and anti-tumor necrosis factor (TNF) monoclonal antibodies infliximab and adalimumab. Since the dosage of prednisone varied over the course of the year of study for most patients, we were not able to calculate an average dose of prednisone. Statistics: The distribution of acute worsening events was not normally distributed and therefore the Mann Whitney U test, Spearman Rank, and other non-parametric tests were used. A p value of less than 0.05 was considered significant.
Results During the four month period of the study from May to September 2012, 740 patients with sarcoidosis were seen in the Interstitial Lung Disease and Sarcoidosis Clinic. A total of 129 (17%) sarcoidosis patients with pulmonary fibrosis were studied. Of these, 63 (49%) had bronchiectasis identified on chest imaging, usually high resolution computer tomography (HRCT). Table 1 summarizes the demographics of the patients enrolled in the study, including age, race, gender, disease duration, pulmonary function studies,
Table 1 studied.
Demographics of fibrotic sarcoidosis patients Total
Number Female:Male Black:White Age years Disease duration, years FVC, l FVC % predicted FEV1, l FEV1 % predicted FEV1/FVC % DLCO DLCO % predicted Smoking history Current/Prior/Nonsmokers Bronchiectasis Yes/No Acute worsening events in prior year a
Median (Range).
129 92/37 78/51 57 (35e87)a 13 (1e42) 2.57 (1.11e5.43) 79 (33e131)% 1.90 (0.77e3.51) 56 (17e106)% 73 (35e100)% 17.5 (7.68e41.56) 74 (37e128)% 16/33/80 63/66 3 (0e8)
Acute events in fibrotic sarcoidosis serum IgE level, and number of acute worsening events in the past year. Ninety-four (73%) of patients reported two or more acute worsening events in the past year with the median number of acute worsening events three with range from 0 to 8. No significant correlation was noted between number of acute worsening events and age, FVC, FVC % predicted, FEV1,FEV1% predicted, FEV1/FVC, or DLCO % predicted. We did not have lung volumes on all patients, so could not analyze residual volume or total lung capacity % predicted versus number of events. Additionally, there was no difference in the number of acute worsening events based on race or gender or among current smokers, prior smokers, and nonsmokers. However, patients with bronchiectasis on HRCT experienced a higher number of acute worsening events (3 (0e6)) compared to those without bronchiectasis (2 (0e8), p Z 0.0001) (Fig. 1). Table 2 compares the demographic features of those patients with or without bronchiectasis. There was no significant difference between the presence of bronchiectasis and gender, race, age, FVC, FVC % predicted, FEV1, FEV1/FVC, DLCO, DLCO % predicted, or smoking history. Table 3 summarizes patient’s current and prior sarcoidosis treatments. Patients could receive more than one therapy, and 34 patients received no immunosuppressants during the study period. There was no difference in the frequency of acute worsening events for those patients receiving prednisone, methotrexate, or azathioprine. The eight patients receiving leflunomide were significantly more likely to have experienced acute events in the prior year. In addition, the 16 patients receiving anti-TNF antibodies experienced significantly higher number of acute worsening events compared to those who had never received anti-TNF therapies (N Z 16,p Z 0.0297). Fig. 2 demonstrates the number of acute worsening events for those patients. There was no significant difference in pulmonary function or the rate of bronchiectasis for those receiving or not receiving anti-TNF antibodies. This would suggest that pulmonary function tests alone are not
2011 Table 2 Comparison bronchiectasis.
Number Female:Male Black:White Age years Disease duration, years FVC, l FVC % predicted FEV1, l FEV1/FVC % DLCO DLCO % predicted Smoking history Current/Prior/ Nonsmokers Acute worsening events in prior year a b
of
patients
with
or
without
Bronchiectasis
No bronchiectasis
63 44/19 37/26 57 (35e87)a 11 (1e42)
66 48/18 41/25 56 (39e75)a 14.5 (1e39)
2.70 (1.35e5.00) 82 (34e131)% 1.96 (0.77e3.32) 73 (42e89)% 16.9 (7.68e33.88) 70 (38e128)%
2.35 (1.11e5.43) 78 (33e110)% 1.80 (0.89e3.59) 73 (35e100)% 17.7 (7.70e41.56) 77 (37e103)%
8/15/40
8/18/40
3 (0e6)
2 (0e8)b
Median (Range). Differs from bronchiectasis, p Z 0.0001.
sufficient to identify severity of sarcoidosis or which patients are more likely to have acute worsening events.
Discussion We conclude that acute worsening events occur frequently in patients with fibrotic sarcoidosis. Although these episodes were correlated with underlying bronchiectasis, acute events were not associated with race, gender, age, smoking history, or underlying airway obstruction. Patients who received anti-TNF therapies experience higher rates of acute worsening events, which may reflect more severe pulmonary disease or increased immunosuppression in these patients.
Table 3 Systemic therapy for sarcoidosis versus number of acute worsening events in prior year.
Figure 1 Number of acute worsening events in prior year for those with or without bronchiectasis. Patients with bronchiectasis were more likely to have acute worsening events (p Z 0.0001).
Number Current prednisone Current methotrexate Current azathioprine Current leflunomide Current anti-TNF therapy Current or past anti-TNF therapy No therapy a b c
Total
Number of acute worsening events in prior year
129 79 (61%)b 35 (27%) 14 (11%) 8 (6%) 16 (12%) 29 (22%)
3 3 3 2.5 4 3.5 3
34 (26%)
(0e8)a (0e8) (0e8) (1e4) (2e6)c (1e6)c (1e8)c
3 (0e6)
Median (Range). Number (percent of total). Differs from those not on therapy, p < 0.05.
2012
Figure 2 Number of acute worsening events in prior year for those receiving anti-TNF antibody (N Z 16) versus not currently receiving anti-TNF antibody (p Z 0.0364).
There is no standard definition for an acute exacerbation that occurs in sarcoidosis patients [1]. Because of concerns about disease progression, we chose to limit our study to fibrotic sarcoidosis patients who usually require chronic therapy with minimal dosage changes over time [5]. Most patient reported events did not represent disease worsening since the events were usually not preceded by a treatment reduction and they were limited to four weeks of additional therapy without increased immunosuppression. It has been suggested that acute sarcoidosis exacerbations as defined by a decline in FVC of >10% may respond to short course of increased corticosteroids [4]. However, it is unclear if all patients have disease worsening since the events are often unaccompanied by any chest roentgenogram changes [8]. Patients with pulmonary fibrosis usually have restrictive lung disease, but an obstructive component can be seen [9,10]. The average FEV1/FVC ratio was 73% in this study, the same as that reported in a large study of stage 4 sarcoidosis patients followed in France [11]. For this group of patients, acute worsening was likely was related to an infection rather than other causes. Our definition of acute worsening required that patients receive antibiotics for the episode since our practice is to prescribe a short antibiotic course for one or more symptoms of increased dyspnea, sputum volume, or sputum purulence [12]. For patients with chronic obstructive pulmonary disease (COPD), the official ATS/ ERS statement says: An exacerbation of COPD is an event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management [13]. Risk factors for acute exacerbation chronic bronchitis (AECB) in chronic obstructive pulmonary disease (COPD) include physician diagnosed asthma [14] and low FEV1 [15,16], and smoking history does not seem to influence the rate of AECB in COPD patients [14,15]. In the current study, smoking history was also not associated with an increased rate of acute worsening events. We also feel that the response to a short course of increased prednisone (5e21 days) was a reflection of bacterial infection rather than sarcoidosis itself. While others have found that short course
R.P. Baughman, E.E. Lower corticosteroid therapy may improve underlying sarcoidosis [4], our practice is to give a more prolonged course of corticosteroids for those patients we believe are suffering from a worsening of their underlying sarcoidosis. The presence of chronic cough and sputum are risk factors for AECB in COPD patients [15,16], and these are the clinical features of patients with bronchiectasis. Studying moderate to severe COPD patients with HRCT, Patel et al. identified bronchiectasis in half of their study patients [17]. In COPD, the finding of bronchiectasis on HRCT was associated with more prolonged recovery from the exacerbation, but not a change in frequency of AECB events [17]. In the current study, we found that patients with bronchiectasis were more likely to have acute worsening events. Bronchiectasis is a complication of fibrotic sarcoidosis [18,19]. Bronchiectasis will not improve with antiinflammatory treatments, although other inflammatory changes around the area of bronchiectasis may improve with therapy [19]. The presence of bronchiectasis is associated with aspergillomas, a severe complication of sarcoidosis [20]. Bronchiectasis is also associated with increased colonization of bacteria and a source of repeat infection [17]. In the current study, patients with evidence of bronchiectasis on HRCT scan experienced a higher rate of acute worsening events. Additionally, the use of immunosuppression may lead to higher infection rates. We noted that patients receiving antiTNF antibodies developed higher rates of acute worsening events. This could relate to the immunosuppression associated with anti-TNF antibodies. Use of anti-TNF antibodies for rheumatoid arthritis is associated with an increased rate of serious infections from organisms such as Mycobacteria tuberculosis as well as bacterial infections [21,22]. Patients receiving infliximab may also develop an increased risks for influenza and influenza-like illnesses which could lead to an acute worsening event [23]. However, the rate of complicated respiratory infections appears unchanged for those treated with anti-TNF antibodies. In one large study of rheumatoid arthritis patients, there was no increased risk for patients hospitalized for bronchitis compared to patients receiving other immunosuppressants [24]. Hence, it is possible that the increased rate of acute worsening events may reflect of more severe underlying pulmonary disease in these patients. However, no difference was identified in the pulmonary function status or rate of bronchiectasis between those receiving or not receiving anti-TNF antibodies. There are several potential limitations of our study. We chose to use the official radiologic interpretation to identify pulmonary fibrosis. We did not re-review all the films, nor did we have two readers evaluate all films to provide a kappa. We have previously determined that review of chest x-ray may identify some variability in the detection of pulmonary fibrosis in sarcoidosis patients [25]. There may be less variability when evaluating fibrosis using HRCT. The diagnosis of an acute worsening event was retrospective and based on patient recall, although we did try to verify these events by review of the patient’s chart. These events may have represented acute worsening of the sarcoidosis rather than infections. Since we were unable to calculate an average prednisone dose during the year of the study, we could not evaluate the effect of prednisone dosage on the frequency of acute worsening events.
Acute events in fibrotic sarcoidosis We conclude that acute worsening events were more likely to occur in fibrotic sarcoidosis patients with underlying bronchiectasis who were receiving anti-TNF antibody therapy. These associations would suggest that acute worsening events in fibrotic sarcoidosis patients were more likely infections. In these patients, treatment with antibiotics and/or short term increases in corticosteroid therapy was usually associated with symptomatic improvement. Treatments which can minimize the episodes of acute worsening events may improve the quality of life of pulmonary sarcoidosis patients with fibrosis.
Conflict of interest Neither Dr. Baughman nor Lower have any conflict of interest regarding this manuscript.
2013
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[14]
[15]
[16]
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Frequency of acute worsening events in fibrotic pulmonary sarcoidosis patients Robert P. Baughman*, Elyse E. Lower Department of Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA Received 9 April 2013; accepted 14 October 2013 Available online 22 October 2013
KEYWORDS Sarcoidosis; Bronchiectasis; Infliximab; Prednisone
Summary Patients with fibrotic sarcoidosis can develop worsening of pulmonary symptoms for various reasons. We studied acute worsening events defined as episodes treated with limited courses of either antibiotics and or increased corticosteroid doses which resolved within four weeks. The prevalence of acute worsening events in patients with fibrotic sarcoidosis was investigated. Of 740 sarcoidosis patients seen in our clinic over a four month period, 129 (17%) had fibrotic sarcoidosis. We noted the age, race, gender, computer tomography (CT) results, and pulmonary function as measured by forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and the FEV1/FVC ratio. In a retrospective manner, the fibrotic sarcoidosis patients reported a median of three acute worsening events (range zero to eight) in the prior year. Bronchiectasis was noted on CT imaging in 63 of 129 (49%) of the fibrotic sarcoidosis patients. Fibrotic sarcoidosis patients reported a higher frequency of acute worsening events (3 (0e6)) than those without bronchiectasis (2 (0e8), p Z 0.0001). Sixteen patients receiving anti-tumor necrosis factor antibodies reported a higher frequency of acute worsening events compared to those not receiving anti-tumor necrosis factor antibodies (p Z 0.0297). There was no relationship between the number of acute worsening events and race, gender, smoking history, or FVC, FEV1, or FEV1/FVC ratio. We conclude that acute worsening events are frequent in patients with fibrotic sarcoidosis patients and are more common in patients with bronchiectasis and those receiving anti-tumor necrosis factor antibody therapies. ª 2013 Elsevier Ltd. All rights reserved.
* Corresponding author. 1001 Holmes, Eden Ave, Cincinnati, OH 45267, USA. E-mail addresses: [email protected], [email protected] (R.P. Baughman). 0954-6111/$ - see front matter ª 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.rmed.2013.10.014
2010
Introduction Pulmonary sarcoidosis patients can develop episodes of acute worsening of pulmonary symptoms. While this can occur in all stages of pulmonary sarcoidosis, an acute worsening in fibrotic sarcoidosis patients can result in significant pulmonary morbidity. There are several causes of acute worsening of pulmonary sarcoidosis, including worsening of the underlying sarcoidosis, infection, acute bronchospasm, or extra-pulmonary causes [1]. Relapse of sarcoidosis can occur during reduction or withdrawal of corticosteroids and/or other systemic therapy for pulmonary sarcoidosis [2,3]. This event has been termed an acute pulmonary exacerbation of sarcoidosis [1]. Patients with acute pulmonary exacerbation of sarcoidosis will often respond to reinstitution or an increase in corticosteroid dosage [4]. Patients relapsing during corticosteroid withdrawal are usually maintained on long term immunosuppressive therapy to prevent further relapses [2,3,5]. Acute pulmonary worsening can also occur in patients receiving stable doses of treatment. These episodes are often related to infection, and patients may respond to a short course of corticosteroids and broad spectrum antibiotics. Because resolution usually occurs in less than 4 weeks, these episodes are considered unique from acute pulmonary exacerbations of sarcoidosis [1]. In addition to infection, patients can also develop airway reactivity that responds to short courses of corticosteroid therapy [6]. Disease worsening can cause significant morbidity in patients with fibrotic sarcoidosis. In order to better understand the frequency and associated features of acute worsening of fibrotic sarcoidosis, we studied patients seen at the University of Cincinnati Sarcoidosis Clinic.
Methods Patients were recruited from those seen at the University of Cincinnati Interstitial Lung Disease and Sarcoidosis Clinic. Patients with sarcoidosis based on ATS/ERS/WASOG criteria who had chest imaging consistent with pulmonary fibrosis were eligible for evaluation. This retrospective study was part of an ongoing investigation of pulmonary infections in sarcoidosis and it was approved by the University of Cincinnati Institutional Review Board. This study examined a subset of sarcoidosis patients with pulmonary fibrosis seen during a four month period in our clinic. The presence of pulmonary fibrosis was decided by the radiologist who made the official interpretation of prior chest X-ray and high resolution CT (HRCT) scan which were performed as part of routine evaluation of the patient’s sarcoidosis. Although we reviewed these films, we chose to use the radiologist interpretation. All patients had both a routine chest X-ray and HRCT scan to review. Acute worsening was defined as an episode in which the patient was either prescribed an antibiotic for 5e21 days and/or a short increase in systemic glucocorticoids for increased cough and/or dyspnea. Although some patients underwent chest roentgenograms during these episodes, an abnormal imaging was not required.
R.P. Baughman, E.E. Lower During a four month period, each fibrotic sarcoidosis patient was asked to estimate the number of acute worsening events that had occurred during the prior twelve months. When possible, this number was verified by chart review. In addition to the number of episodes, additional demographic information including age, gender, self-declared race, smoking history, and sarcoidosis duration and organ involvement was recorded from the chart review. Chest imaging was reviewed for the presence or absence of bronchiectasis along with the most recent pulmonary function tests including FEV1, FVC, and FEV1/FVC ratio and the predicted values [7]. Current and past systemic sarcoidosis medications were categorized as glucocorticoids, cytotoxic drugs such as methotrexate, leflunomide, and azathioprine, and anti-tumor necrosis factor (TNF) monoclonal antibodies infliximab and adalimumab. Since the dosage of prednisone varied over the course of the year of study for most patients, we were not able to calculate an average dose of prednisone. Statistics: The distribution of acute worsening events was not normally distributed and therefore the Mann Whitney U test, Spearman Rank, and other non-parametric tests were used. A p value of less than 0.05 was considered significant.
Results During the four month period of the study from May to September 2012, 740 patients with sarcoidosis were seen in the Interstitial Lung Disease and Sarcoidosis Clinic. A total of 129 (17%) sarcoidosis patients with pulmonary fibrosis were studied. Of these, 63 (49%) had bronchiectasis identified on chest imaging, usually high resolution computer tomography (HRCT). Table 1 summarizes the demographics of the patients enrolled in the study, including age, race, gender, disease duration, pulmonary function studies,
Table 1 studied.
Demographics of fibrotic sarcoidosis patients Total
Number Female:Male Black:White Age years Disease duration, years FVC, l FVC % predicted FEV1, l FEV1 % predicted FEV1/FVC % DLCO DLCO % predicted Smoking history Current/Prior/Nonsmokers Bronchiectasis Yes/No Acute worsening events in prior year a
Median (Range).
129 92/37 78/51 57 (35e87)a 13 (1e42) 2.57 (1.11e5.43) 79 (33e131)% 1.90 (0.77e3.51) 56 (17e106)% 73 (35e100)% 17.5 (7.68e41.56) 74 (37e128)% 16/33/80 63/66 3 (0e8)
Acute events in fibrotic sarcoidosis serum IgE level, and number of acute worsening events in the past year. Ninety-four (73%) of patients reported two or more acute worsening events in the past year with the median number of acute worsening events three with range from 0 to 8. No significant correlation was noted between number of acute worsening events and age, FVC, FVC % predicted, FEV1,FEV1% predicted, FEV1/FVC, or DLCO % predicted. We did not have lung volumes on all patients, so could not analyze residual volume or total lung capacity % predicted versus number of events. Additionally, there was no difference in the number of acute worsening events based on race or gender or among current smokers, prior smokers, and nonsmokers. However, patients with bronchiectasis on HRCT experienced a higher number of acute worsening events (3 (0e6)) compared to those without bronchiectasis (2 (0e8), p Z 0.0001) (Fig. 1). Table 2 compares the demographic features of those patients with or without bronchiectasis. There was no significant difference between the presence of bronchiectasis and gender, race, age, FVC, FVC % predicted, FEV1, FEV1/FVC, DLCO, DLCO % predicted, or smoking history. Table 3 summarizes patient’s current and prior sarcoidosis treatments. Patients could receive more than one therapy, and 34 patients received no immunosuppressants during the study period. There was no difference in the frequency of acute worsening events for those patients receiving prednisone, methotrexate, or azathioprine. The eight patients receiving leflunomide were significantly more likely to have experienced acute events in the prior year. In addition, the 16 patients receiving anti-TNF antibodies experienced significantly higher number of acute worsening events compared to those who had never received anti-TNF therapies (N Z 16,p Z 0.0297). Fig. 2 demonstrates the number of acute worsening events for those patients. There was no significant difference in pulmonary function or the rate of bronchiectasis for those receiving or not receiving anti-TNF antibodies. This would suggest that pulmonary function tests alone are not
2011 Table 2 Comparison bronchiectasis.
Number Female:Male Black:White Age years Disease duration, years FVC, l FVC % predicted FEV1, l FEV1/FVC % DLCO DLCO % predicted Smoking history Current/Prior/ Nonsmokers Acute worsening events in prior year a b
of
patients
with
or
without
Bronchiectasis
No bronchiectasis
63 44/19 37/26 57 (35e87)a 11 (1e42)
66 48/18 41/25 56 (39e75)a 14.5 (1e39)
2.70 (1.35e5.00) 82 (34e131)% 1.96 (0.77e3.32) 73 (42e89)% 16.9 (7.68e33.88) 70 (38e128)%
2.35 (1.11e5.43) 78 (33e110)% 1.80 (0.89e3.59) 73 (35e100)% 17.7 (7.70e41.56) 77 (37e103)%
8/15/40
8/18/40
3 (0e6)
2 (0e8)b
Median (Range). Differs from bronchiectasis, p Z 0.0001.
sufficient to identify severity of sarcoidosis or which patients are more likely to have acute worsening events.
Discussion We conclude that acute worsening events occur frequently in patients with fibrotic sarcoidosis. Although these episodes were correlated with underlying bronchiectasis, acute events were not associated with race, gender, age, smoking history, or underlying airway obstruction. Patients who received anti-TNF therapies experience higher rates of acute worsening events, which may reflect more severe pulmonary disease or increased immunosuppression in these patients.
Table 3 Systemic therapy for sarcoidosis versus number of acute worsening events in prior year.
Figure 1 Number of acute worsening events in prior year for those with or without bronchiectasis. Patients with bronchiectasis were more likely to have acute worsening events (p Z 0.0001).
Number Current prednisone Current methotrexate Current azathioprine Current leflunomide Current anti-TNF therapy Current or past anti-TNF therapy No therapy a b c
Total
Number of acute worsening events in prior year
129 79 (61%)b 35 (27%) 14 (11%) 8 (6%) 16 (12%) 29 (22%)
3 3 3 2.5 4 3.5 3
34 (26%)
(0e8)a (0e8) (0e8) (1e4) (2e6)c (1e6)c (1e8)c
3 (0e6)
Median (Range). Number (percent of total). Differs from those not on therapy, p < 0.05.
2012
Figure 2 Number of acute worsening events in prior year for those receiving anti-TNF antibody (N Z 16) versus not currently receiving anti-TNF antibody (p Z 0.0364).
There is no standard definition for an acute exacerbation that occurs in sarcoidosis patients [1]. Because of concerns about disease progression, we chose to limit our study to fibrotic sarcoidosis patients who usually require chronic therapy with minimal dosage changes over time [5]. Most patient reported events did not represent disease worsening since the events were usually not preceded by a treatment reduction and they were limited to four weeks of additional therapy without increased immunosuppression. It has been suggested that acute sarcoidosis exacerbations as defined by a decline in FVC of >10% may respond to short course of increased corticosteroids [4]. However, it is unclear if all patients have disease worsening since the events are often unaccompanied by any chest roentgenogram changes [8]. Patients with pulmonary fibrosis usually have restrictive lung disease, but an obstructive component can be seen [9,10]. The average FEV1/FVC ratio was 73% in this study, the same as that reported in a large study of stage 4 sarcoidosis patients followed in France [11]. For this group of patients, acute worsening was likely was related to an infection rather than other causes. Our definition of acute worsening required that patients receive antibiotics for the episode since our practice is to prescribe a short antibiotic course for one or more symptoms of increased dyspnea, sputum volume, or sputum purulence [12]. For patients with chronic obstructive pulmonary disease (COPD), the official ATS/ ERS statement says: An exacerbation of COPD is an event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management [13]. Risk factors for acute exacerbation chronic bronchitis (AECB) in chronic obstructive pulmonary disease (COPD) include physician diagnosed asthma [14] and low FEV1 [15,16], and smoking history does not seem to influence the rate of AECB in COPD patients [14,15]. In the current study, smoking history was also not associated with an increased rate of acute worsening events. We also feel that the response to a short course of increased prednisone (5e21 days) was a reflection of bacterial infection rather than sarcoidosis itself. While others have found that short course
R.P. Baughman, E.E. Lower corticosteroid therapy may improve underlying sarcoidosis [4], our practice is to give a more prolonged course of corticosteroids for those patients we believe are suffering from a worsening of their underlying sarcoidosis. The presence of chronic cough and sputum are risk factors for AECB in COPD patients [15,16], and these are the clinical features of patients with bronchiectasis. Studying moderate to severe COPD patients with HRCT, Patel et al. identified bronchiectasis in half of their study patients [17]. In COPD, the finding of bronchiectasis on HRCT was associated with more prolonged recovery from the exacerbation, but not a change in frequency of AECB events [17]. In the current study, we found that patients with bronchiectasis were more likely to have acute worsening events. Bronchiectasis is a complication of fibrotic sarcoidosis [18,19]. Bronchiectasis will not improve with antiinflammatory treatments, although other inflammatory changes around the area of bronchiectasis may improve with therapy [19]. The presence of bronchiectasis is associated with aspergillomas, a severe complication of sarcoidosis [20]. Bronchiectasis is also associated with increased colonization of bacteria and a source of repeat infection [17]. In the current study, patients with evidence of bronchiectasis on HRCT scan experienced a higher rate of acute worsening events. Additionally, the use of immunosuppression may lead to higher infection rates. We noted that patients receiving antiTNF antibodies developed higher rates of acute worsening events. This could relate to the immunosuppression associated with anti-TNF antibodies. Use of anti-TNF antibodies for rheumatoid arthritis is associated with an increased rate of serious infections from organisms such as Mycobacteria tuberculosis as well as bacterial infections [21,22]. Patients receiving infliximab may also develop an increased risks for influenza and influenza-like illnesses which could lead to an acute worsening event [23]. However, the rate of complicated respiratory infections appears unchanged for those treated with anti-TNF antibodies. In one large study of rheumatoid arthritis patients, there was no increased risk for patients hospitalized for bronchitis compared to patients receiving other immunosuppressants [24]. Hence, it is possible that the increased rate of acute worsening events may reflect of more severe underlying pulmonary disease in these patients. However, no difference was identified in the pulmonary function status or rate of bronchiectasis between those receiving or not receiving anti-TNF antibodies. There are several potential limitations of our study. We chose to use the official radiologic interpretation to identify pulmonary fibrosis. We did not re-review all the films, nor did we have two readers evaluate all films to provide a kappa. We have previously determined that review of chest x-ray may identify some variability in the detection of pulmonary fibrosis in sarcoidosis patients [25]. There may be less variability when evaluating fibrosis using HRCT. The diagnosis of an acute worsening event was retrospective and based on patient recall, although we did try to verify these events by review of the patient’s chart. These events may have represented acute worsening of the sarcoidosis rather than infections. Since we were unable to calculate an average prednisone dose during the year of the study, we could not evaluate the effect of prednisone dosage on the frequency of acute worsening events.
Acute events in fibrotic sarcoidosis We conclude that acute worsening events were more likely to occur in fibrotic sarcoidosis patients with underlying bronchiectasis who were receiving anti-TNF antibody therapy. These associations would suggest that acute worsening events in fibrotic sarcoidosis patients were more likely infections. In these patients, treatment with antibiotics and/or short term increases in corticosteroid therapy was usually associated with symptomatic improvement. Treatments which can minimize the episodes of acute worsening events may improve the quality of life of pulmonary sarcoidosis patients with fibrosis.
Conflict of interest Neither Dr. Baughman nor Lower have any conflict of interest regarding this manuscript.
2013
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[14]
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