- Email: [email protected]
Clinical Course of Sarcoidosis in World Trade Center-Exposed Firefighters
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Original Research
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Clinical Course of Sarcoidosis in World Trade Center-Exposed Firefighters
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Kerry M. Hena, MD; Jennifer Yip, MPH; Nadia Jaber, PA-C; David Goldfarb, MPH; Kelly Fullam, BA;
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Krystal Cleven, MD; William Moir, MPH; Rachel Zeig-Owens, DrPH; Mayris P. Webber, DrPH; Daniel M. Spevack, MD;
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Marc A. Judson, MD; Lisa Maier, MD; Andrew Krumerman, MD; Anthony Aizer, MD; Simon D. Spivack, MD;
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Jessica Berman, MD; Thomas K. Aldrich, MDy; David J. Prezant, MD; and the FDNY Sarcoidosis Clinical Research Group*
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Sarcoidosis is believed to represent a genetically primed, abnormal immune response to an antigen exposure or inflammatory trigger, with both genetic and environmental factors playing a role in disease onset and phenotypic expression. In a population of firefighters with post-World Trade Center (WTC) 9/11/2001 (9/11) sarcoidosis, we have a unique opportunity to describe the clinical course of incident sarcoidosis during the 15 years’ postexposure and, on average, 8 years following diagnosis.
BACKGROUND:
17 18 19 20 21 22
Among the WTC-exposed cohort, 74 firefighters with post-9/11 sarcoidosis were identified through medical records review. A total of 59 were enrolled in follow-up studies. For each participant, the World Association of Sarcoidosis and Other Granulomatous Diseases organ assessment tool was used to categorize the sarcoidosis involvement of each organ system at time of diagnosis and at follow-up.
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METHODS:
24 25 26 27 28
The incidence of sarcoidosis post-9/11 was 25 per 100,000. Radiographic resolution of intrathoracic involvement occurred in 24 (45%) subjects. Lung function for nearly all subjects was within normal limits. Extrathoracic involvement increased, most prominently joints (15%) and cardiac (16%) involvement. There was no evidence of calcium dysmetabolism. Few subjects had ocular (5%) or skin (2%) involvement, and none had beryllium sensitization. Most (76%) subjects did not receive any treatment.
RESULTS:
29 30 31 32 33 34 35
Extrathoracic disease was more prevalent in WTC-related sarcoidosis than reported for patients with sarcoidosis without WTC exposure or for other exposure-related granulomatous diseases (beryllium disease and hypersensitivity pneumonitis). Cardiac involvement would have been missed if evaluation stopped after ECG, 48-h recordings, and echocardiogram. Our results also support the need for advanced cardiac screening in asymptomatic patients with strenuous, stressful, public safety occupations, given the potential fatality of a missed diagnosis. CHEST 2017; -(-):---
CONCLUSIONS:
36 37 38 39 40 41 42 43 44
Q9
KEY WORDS:
clinical course; firefighters; sarcoidosis; World Trade Center
ABBREVIATIONS:
48 49 Q3
51
54 55
75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 99 101
47
53
73 74
100
46
52
71 72
98
45
50
67
Q4
ACE = angiotensin-converting enzyme; EP = electrophysiologic; FDNY = Fire Department of the City of New York; ICD = implantable cardioverter-defibrillator; MUSC = Medical University of South Carolina; WASOG = World Association of Sarcoidosis and Other Granulomatous Diseases; WTC = World Trade Center AFFILIATIONS: From the Pulmonary & Critical Care Division (Dr Hena), Cardiology Division (Dr Aizer), Department of Medicine, NYU School of Medicine, New York, NY; Bureau of Health Services (Mss Yip, Jaber, Fullam, and Zeig-Owens; Messrs Goldfarb and Moir; and Drs Webber, Aldrich, and Prezant), Fire Department of the City of New York, New York, NY; Pulmonary Division (Drs Cleven, Prezant, and Spivack), Department of Medicine, Montefiore
Medical Center and the Albert Einstein College of Medicine, Bronx, NY; Cardiology Division (Drs Spevack and Krumerman), Department of Medicine, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY; Pulmonary & Critical Care Division (Dr Judson), Albany Medical College, Albany, NY; Division of Environmental and Occupational Health Sciences (Dr Maier), Department of Medicine, National Jewish Health, Denver, CO; and the Rheumatology Division (Dr Berman), Hospital for Special Surgery, New York, NY. Some preliminary data from this study have been published in Q5 abstract form at the annual meetings of CHEST 2016 (Los Angeles, CA) and American Thoracic Society 2017 (Washington, DC).
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Sarcoidosis is a multisystem granulomatous disease.1-3 The annual incidence varies widely among races/ ethnicities: 11 per 100,000 in US white subjects and 36 per 100,000 in US black subjects.4,5 In the Fire Department of the City of New York (FDNY), Prezant et al6 found that between 1985 and 1998, FDNY firefighters had a significantly higher annual incidence of sarcoidosis than FDNY Emergency Medical Services workers and historical control subjects. The average annual incidence in firefighters was estimated at 12.9 per 100,000, significantly greater than in Emergency Medical Services workers (0.0 per 100,000) and several times the expected rate (2.5-7.6 per 100,000 for white men in the United States).4
112 113 114 115 116 117 118 119 120 121 122 123 124 125 126
Following the World Trade Center (WTC) attack on 9/11/2001 (9/11), an increase in sarcoidosis was found in WTC-exposed populations,7,8 including FDNY rescue/recovery workers.9 Between 2002 and 2015, we found an age-adjusted incidence rate of 25 per 100,000 in male FDNY rescue/recovery workers.10 By 2015, a total of 74 FDNY firefighters with new post-9/11 sarcoidosis were identified: 65 were diagnosed by using transbronchial or mediastinal biopsy results and nine by typical clinical or radiologic findings without alternate diagnosis. Possible triggering agents/antigens
127 128 129 130 131 132 133 134 135 136 137 138
include particulate matter (calcium carbonate and silica) and fibers (asbestos, fibrous glass, gypsum), organic pollutants (polycyclic aromatic hydrocarbons), gases, combustion byproducts from WTC fires, and metal dusts such as beryllium.11 Although its etiology is unknown, sarcoidosis is believed to represent a genetically primed abnormal immune response to an antigen exposure or inflammatory trigger,1 with both genetic and environmental factors playing a role in disease onset and phenotypic expression, including the distribution of organ involvement. Reports have described the clinical presentation at diagnosis, but few have described its clinical course over time.12-14 Given the extensive phenotyping of this group at diagnosis, via comprehensive medical evaluations and cohort maintenance through the FDNY WTC Health Program, we recognized an opportunity to describe the clinical course of incident sarcoidosis 15 years after WTC exposure, during the follow-up period of 2015 to 2016. In addition, because beryllium was found at the WTC site, and berylliosis is clinically indistinguishable from sarcoidosis, a secondary goal was to evaluate for beryllium sensitization.
139 141
Materials and Methods
142
Study Population
143
All 74 WTC-exposed FDNY firefighters with post-9/11 sarcoidosis were recruited via mailings and telephone calls. The Montefiore/ Einstein Institutional Review Board approved the study, and participants provided written informed consent.
144 145 146 147
Clinical Criteria for Case Definition
148
All cases were WTC exposed and had normal chest radiographs prior to 9/11 (obtained pre-employment and biannually at medical monitoring). For biopsy-proven cases, pathology reports were reviewed to verify histologic culture-negative, noncaseating granulomas. For those without a biopsy (n ¼ 7), charts were reviewed by two pulmonologists, and cases were included if chest CT scans showed bilateral symmetrical mediastinal/hilar adenopathy
149 150 151 152 153 154 156 Q7
158 159 160 Q6 161 163 164 165
(> 1.5 cm), perilymphatic nodules, or fibrosis with bronchial distortion, without alternative etiology.15
169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193
Q8
FUNDING/SUPPORT:
Funding for this study came from the National Institute of Occupational Safety and Health [Grant U01-OH010993 and contracts 200-2011-39383, 200-2011-39378, 200-2017-93326, and 200-2017-93426]. y Deceased. CORRESPONDENCE TO: David J. Prezant, MD, Fire Department of the City of New York, 9 Metrotech Center, Room 8N-7, Brooklyn, NY 11201; e-mail: [email protected] Copyright Ó 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2017.10.014
2 Original Research
195 196 197 198
Evaluation at Diagnosis and Follow-up
199
Diagnostic and follow-up evaluations were similar (Table 1) with the following additions at follow-up: serum angiotensin-converting enzyme (ACE), serum vitamin D (25-hydroxy and 1,25 dihydroxy), and urinary calcium measurements; a gadolinium-enhanced cardiac MRI; and blood beryllium sensitization studies (IFNƴEli spot assay and beryllium lymphocyte proliferation test [BeLPT]) at National Jewish Health (Denver, Colorado).16,17 If joint findings or cardiac findings were suspicious for sarcoidosis involvement, confirmation by a rheumatologist or cardiologist was required. Treatment was recorded at diagnosis and follow-up.
200 201 202 203 204 205 206 207 208 209
Cardiac Studies
155
162
167 168
194
140
157
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Advanced cardiac imaging was performed, despite the absence of symptoms or abnormal screening test results, given the potential for a cardiac fatality resulting from a missed diagnosis in firefighters and the relatively low risk of a gadolinium-enhanced cardiac MRI. Electrophysiologic (EP) studies were used for risk stratification in those patients with abnormal cardiac MRIs (delayed gadoliniumenhancement of infero-lateral-basilar segments).18 Implantable cardioverter-defibrillator (ICD) placement was guided by traditional primary and secondary prevention as well as consideration for the degree of abnormality on MRI. Cardiac PET scanning was performed when treatment with disease-modifying drugs was considered due to a positive EP study result or extensive disease on echocardiogram or MRI.
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TABLE 1 Q19
] FDNY Sarcoidosis Evaluation Protocol at Diagnosis and Follow-up
Variable
Examination Description at Diagnosis Occupational, medical, family, and sarcoidosis history
Questionnaire
225 226 227
Q18
277
Examination Description at Follow-up
278
Occupational, medical, family, and sarcoidosis history
Racial/ethnic background
Racial/ethnic background
WTC exposure details
WTC exposure details
276
279 280 281 282
228
Tobacco use history
Tobacco use history
283
229
Review of systems
Review of systems
284
230
Medication use
Medication use, including current and past treatment for sarcoidosis (corticosteroids and other disease-modifying drugs)
286
Cardiac and pulmonary auscultation
Cardiac and pulmonary auscultation
288
235
Abdominal palpation
Abdominal palpation
290
236
Lymph node, joint, and skin surveys
Lymph node, joint, and skin surveys
291
Cranial nerves, motor and sensory perception assessments
292
Examination of eyelids
Examination of eyelids
294
241
Palpebral fissures
Palpebral fissures
296
242
Conjunctivae for granulomas
Conjunctivae for granulomas
Slit lamp and dilated retina exam
Slit lamp and dilated retina exam
Chest radiographs (PA and lateral) or recreated digitally from CT imaging
Chest radiographs (PA and lateral) or recreated digitally from CT imaging
Noncontrast chest CT scan
Noncontrast chest CT scan
231 232 233 234
General physical examination
237 239 240
Eye examination by an ophthalmologist
243 244 245
Chest imaging
246 247 248
Pulmonary function
249
287 289
Cranial nerves, motor and sensory perception assessments
238
285
293 295
Spirometry
Spirometry
Lung volumes
Lung volumes
297 298 299 300 301 302 303 304
Diffusing capacity
Diffusing capacity
305
251
Oxygen saturation
Resting
Rest and exercise (6-min walk)
306
252
Cardiac evaluation
12-lead ECG
12-lead ECG
307
Transthoracic echocardiogram
Transthoracic echocardiogram
308
24-h continuous recording
48-h continuous recording
250
253 254 255 256
309 310
Cardiac MRI with gadolinium
311
CBC count
CBC count
258
Metabolic panel
Metabolic panel
259
Creatinine and ionized calcium
Creatinine and ionized calcium
260
Liver enzyme levels
Liver enzyme levels
315
Angiotensin-converting enzyme
316
257
Blood analyses
261 262 264 265 267
Urinalyses
Urinalysis (microscopic and chemistry)
317 318
Beryllium testing (IFNƴElispot assay and beryllium lymphocyte proliferation test [BeLPT])
Q20
Urinalysis (microscopic and chemistry)
Q21
319 320 321 322
4-h collection for creatinine and calcium
268 269
313 314
Vitamin D (25-hydroxy and 1,25 dihydroxy)
263
266
312
323 324
FDNY ¼ Fire Department of the City of New York; PA ¼ posterioranterior; WTC ¼ World Trade Center.
270
325
271
326
272 273 274 275
Organ Involvement: At Time of Diagnosis and Follow-up For each participant, the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) organ assessment tool19 was used to categorize sarcoidosis involvement of each organ system both at time of diagnosis and at follow-up (2015-2016). With the exception
of bone/joints, a finding of “highly probable” or “at least probable” was considered diagnostic for organ involvement. For bone/joints, symptoms of arthralgias (“possible” by WASOG criterion) were upgraded to “at least probable” when there was tenderness on examination in two or more symmetrical joints, negative
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rheumatology serologic findings, and response to treatment with disease-modifying drugs other than corticosteroids.20 Indeterminate cardiac MRI results were considered nondiagnostic until a repeat scan was obtained 6 to 12 months later. If abnormalities were too subtle to be characterized as cardiac sarcoidosis by both radiologist and cardiologist or were no longer present or unchanged, the MRI was considered negative.
332 333 334 335 336 337
Clinical Course
338 339 340 341 342
Q10
343
Organ involvement was considered present based on WASOG criteria at follow-up and whether treatment had occurred. If new organ involvement occurred > 1 year following diagnosis but before the follow-up study (2015-2016), it was considered a follow-up finding. This scenario included one patient with cardiac involvement and eight patients with bone/joint involvement for which treatment was
initiated prior to our study. For lung involvement, the clinical course was assessed by using chest imaging and classified with the use of Scadding stages (0 ¼ normal, 1 ¼ bilateral hilar adenopathy with normal lung parenchyma; 2 ¼ bilateral hilar adenopathy with pulmonary infiltrates; 3 ¼ pulmonary infiltrates without hilar adenopathy; and 4 ¼ pulmonary fibrosis)21; pulmonary function test as percent predicted for age, height, and race22,23; and the need for treatment.
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Statistics Demographic characteristics, clinical characteristics, and pulmonary function metrics were compared by using t tests, the Fisher exact test, the Wilcoxon-Mann-Whitney test, or Pearson’s c2 test. Analyses were conducted by using SAS version 9.4 (SAS Institute, Inc).
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344
399
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400
Results
346 347
Demographic and Clinical Characteristics
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Clinical Course of Sarcoidosis From Diagnosis to Follow-up
Q11
353 354 355 356 357 358 359 360
The incidence of sarcoidosis between 9/11 and 1/2015 was 25 per 100,000. Of the 74 WTC-exposed firefighters with post-9/11 sarcoidosis, 59 (80%) were successfully recruited. All cases with biopsy-proven disease had undergone biopsy within 3 months of presentation. At diagnosis, nonparticipants were slightly older (P ¼ .044) but did not significantly differ from study participants in other demographic characteristics (Table 2) or organ involvement (Table 3). Follow-up occurred in late 2015 to early 2016, on average 8 years after diagnosis (interquartile range, 5-11 years).
401
Of 59 cases, pulmonary symptoms were reported by 32 (54%) subjects at diagnosis and 35 (59%) at follow-up, whereas evidence of pulmonary disease on imaging was present in 98% at diagnosis and 51% at follow-up. Resolution of intrathoracic involvement (parenchyma and adenopathy) by follow-up occurred in 24 (45%) of 53 cases who had chest CT scans at diagnosis and follow-up (Table 3). Pulmonary functions were within normal limits for nearly all, changed little over time, and were not significantly different in those with or without intrathoracic involvement according to CT imaging at follow-up (all P > .05) (Fig 1).
361
402 403 404 405 406 407 408 409 410 411 412 413 414 415 416
362
417
363
418
TABLE 2
364 365 366 367 368 369
Q22
] Comparison of Demographic Characteristics Between Nonparticipants and Study Participants Nonparticipants (n ¼ 15)
Characteristic
421
WTC exposure Arrival on the morning of 9/11
3 (20%)
13 (22%)
Arrival in the afternoon of 9/11
9 (60%)
27 (46%)
370
Arrival on 9/12
371
Arrival from 9/13-9/24
372
Age at sarcoidosis diagnosis, median (IQR), y
373
Smoking status at the time of sarcoidosis diagnosis
374 375 376 377 378
419 420
Study Participants (n ¼ 59)
Current
1 (7%)
15 (25%)
2 (13%)
4 (7%)
46 (41-55)
43 (38-47)
Never
423 424 425 426 427 428
0
Former
422
1 (2%)
429 430
5 (33%)
9 (15%)
10 (67%)
49 (83%)
431 432
Sarcoidosis treatment medicationsa
433
379
Ever treatment
5 (33%)
14 (24%)
380
Corticosteroids
5 (33%)
13 (22%)
435
381
Hydroxychloroquine/methotrexate
2 (13%)
9 (15%)
436
382
TNF-a blockers
1 (7%)
6 (10%)
383 384 385
434
437
IQR ¼ interquartile range; TNF ¼ tumor necrosis factor. See Table 1 legend for expansion of other abbreviations. a Medications filled under the FDNY WTC Health Program. None of the comparisons between nonparticipants and participants were statistically significant except age (P ¼ .044).
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441
TABLE 3
] Organ Involvement for Nonparticipants (at Diagnosis) and Study Participants (at Diagnosis and
496
Follow-up)
442
497
443
Nonparticipants (n ¼ 15)
444
Organ Involvement
445
At Diagnosis
Intrathoracic involvement by CT imaging
446
a
498
Study Participants (n ¼ 59) At Diagnosisb
499
Follow-upb
13 (87%)
55 (98%)
29 (51%)
500 501
447
Radiographic stage 1
0
8 (15%)
6 (21%)
448
Radiographic stage 2
12 (92%)
43 (78%)
19 (66%)
503
449
Radiographic stage 3
1 (8%)
4 (7%)
4 (14%)
504
450
Radiographic stage 4
0
0
0
505 506
451
Cardiac
452
Eyes
453 454
Ears/nose/throat
455
Bone-Joints
456
Skin
457
Nervous System
458
Liver
459 460 461
464
9 (16%)
1 (8%)
3 (5%)
3 (5%)
507 508
0
0
1 (2%)
4 (7%)
9 (15%)
1 (7%)
1 (2%)
1 (2%)
511
0
0
1 (2%)
512
1 (7%)
1 (2%)
1 (2%)
513 514
Spleen
0
3 (5%)
3 (5%)
Kidney
0
1 (2%)
0
0
0
0
1 (2%)
0
0
Extrathoracic lymph nodes
463
0
2 (13%)
Calcium
462
0
502
509 510
515 516 517 518
Involvement was based on World Association of Sarcoidosis and Other Granulomatous Diseases criteria. None of the comparisons between nonparticipants and participants were statistically significant. a Nonparticipants had complete data at diagnosis with the following exceptions: skin (n ¼ 14); eye (n ¼ 13); spleen (n ¼ 7); bone/joint (n ¼ 9); cardiac (n ¼ 12); nervous system (n ¼ 5); and extrathoracic lymph nodes (n ¼ 3). b In the study cohort with follow-up, all cases had complete data at diagnosis and follow-up with the following exceptions: chest CT scan at diagnosis (n ¼ 56), at follow-up (n ¼ 57) and at both (n ¼ 53); eye at follow-up (n ¼ 58); spleen at follow-up (n ¼ 57); cardiac at follow-up (n ¼ 57); and ear/nose/ throat at follow-up (n ¼ 57).
465 466 467 468 469
Q23
519 520 521 522 523 524
470
525
471
526
Extrathoracic involvement increased over time from 10 patients at diagnosis to 23 at follow-up (Table 3), most prominently in joints and cardiac systems, which, at follow-up affected 15% and 16% of the study population, respectively (Fig 2). Several findings at follow-up were noteworthy for not being counted as involvement according to WASOG criterion.19 These findings included 34 (58%) patients with chronic rhinosinusitis (symptoms and inflammation on sinus CT imaging but without nasal/sinus biopsy), two patients with
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small-fiber neuropathy (considered a para-sarcoidosis syndrome), and minor abnormalities of vitamin D/calcium homeostasis (35 cases with low 25-hydroxyand normal 1,25-dihydroxy-vitamin D levels) without hypercalcemia or hypercalciuria.
527 528 529 530 531 532
Cardiac Involvement
533 534
Our initial protocol at diagnosis found no evidence of cardiac involvement by symptoms, ECG, ECG recording, or echocardiogram. At follow-up, cardiac
535 536 537 538
At Diagnosis
160
539
Follow-up
540
140 Percent predicted
472
120 100 80 60 40
493
20
494
0
495
FEV1
FVC
FRC
DLCO
Figure 1 – Pulmonary function at diagnosis and follow-up. Average percent predicted pulmonary function among cases who had complete pulmonary data at diagnosis and follow-up: FVC and FEV1 (n ¼ 57); DLCO (n ¼ 41); and FRC (n ¼ 30). All 59 cases had complete data at follow-up. Differences in pulmonary function metrics between diagnosis and follow-up were not statistically significant. DLCO ¼ carbon monoxide diffusing capacity; FRC ¼ functional residual capacity.
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541 542 543 544 545 546
Q27
547 548
Q25
549 550
551
Intrathoracic 53 (98%)
552
Intrathoracic Lymph Nodes 49 (91%)
553
606 607 608
Lung 45 (83%)
554
609
555
610
556
611
557
612
558
613
559
29 (54%) Intrathoracic
560
25 (46%) Intrathoracic Lymph Nodes 23 (43%) Lung
561
614 615 616
562
617
563
618
564 565 567 568 569 570 571 572 573
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566
576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601
621 622
Cardiac 0 (0%)
623 624
Follow-up
At diagnosis
Figure 2 – Clinical course of sarcoidosis organ involvement at diagnosis and follow-up. Other organs include: eye, spleen, skin, liver, kidney, ears/nose/ throat, and calcium. All 59 cases had complete data at both diagnosis and follow-up for all organs with the following exceptions: chest CT scan (n ¼ 54); eye (n ¼ 58); spleen (n ¼ 57); cardiac (n ¼ 57); and ears/nose/throat (n ¼ 57). Serum calcium levels were assessed at diagnosis, and serum calcium and Vitamin D levels were assessed at follow-up.
MRI was added. Thirty-one (53%) of 59 subjects reported symptoms of possible concern (eg, palpitations, dizziness/syncope), but cardiac attribution was considered likely only for one case. Figure 3 shows how many cases would have been missed at follow-up if the evaluation stopped after an earlier unremarkable test result. For example, an unremarkable ECG would have missed seven cases with abnormal continuous cardiac recording and six cases with abnormal cardiac MRI. Abnormal findings included: ECGs (eg, right ventricular strain, right bundle branch block or intermittent complete atrioventricular block); echocardiogram (left ventricular ejection fraction < 45%); 48-h recording (short runs of ectopy, usually supraventricular, and four with variable block [second-degree, right bundle branch or intermittent complete atrioventricular block]); and cardiac MRI (delayed gadolinium-enhancement of infero-lateral-basilar segments). Eight of the nine cases with abnormal cardiac MRI underwent an EP study; two had inducible ventricular tachycardia, of which one had the low ejection fraction noted on both echocardiogram and MRI but a negative cardiac PET scan. One case with a negative EP study and normal echocardiogram had extensive scarring on cardiac MRI with a positive cardiac PET scan.
602 603
Bone/Joint Involvement
604
Eight cases presented with symmetrical polyarticular arthritis involving swelling and tenderness of the small
605
620
Bone Joint 4 (7%)
574 575
619
10 (18%) Other organs 9 (16%) Cardiac 9 (15%) Bone/joint
Other organs 9 (16%)
6 Original Research
625 626 627 628 629
joints, of which five also involved large joints. One additional case had asymptomatic vertebral bone involvement. In all cases, serum markers for other autoimmune diseases, in particular rheumatoid factor and anti-cyclic citrullinated peptide antibody, were negative on initial presentation.
630 631 632 633 634 635 636 637
Additional Studies (ACE and Beryllium)
638
None of the subjects had evidence of beryllium sensitization. At follow-up, mean ACE levels were 47 U/L (interquartile range, 32 U/L); nine (15%) had mildly elevated ACE levels (> 67 U/L).
640
Treatment
644
639 641 642 643
The average number of organs involved decreased by 0.59, from 1.88 to 1.29 organs per patient after an average of 8 years of follow-up. Five (8%) cases were treated with oral corticosteroids for dyspnea with reductions in pulmonary function. Eight cases with joint symptoms underwent a stepwise treatment algorithm to achieve adequate disease control,2 ultimately with hydroxychloroquine and methotrexate in one patient and tumor necrosis factor-a blockers in seven cases. For the entire study cohort, regardless of why treatment was initiated, the course of pulmonary functions (FVC, FEV1, carbon monoxide diffusing capacity, and functional residual capacity) was similar in patients who were ever treated with any disease-modifying drug compared with those who were never treated (all P > .05). Among 24
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661
716
662
717 Echocardiogram
ECG
663
48-h Cardiac Recording
Cardiac MRI
718
664
719 Total Abnormal: 20 Total Unremarkable: 39
665 666
Total Abnormal: 1 Total Unremarkable: 57a
Total Abnormal: 13 Total Unremarkable: 44b
Total Abnormal: 9 Total Unremarkable: 46c
720 721
667
722 Abnormal echocardiogram n=0
668 669 670
723 724
Unremarkable ECG
671
Abnormal Recording n=7
n = 39
672 673
Unremarkable echocardiogram n = 38
674 675
Unremarkable Recording n = 30
676 677
725
Abnormal Cardiac MRI n =1
726
Unremarkable Cardiac MRI n=6
728
Abnormal Cardiac MRI n=5
730
Unremarkable Cardiac MRI n = 25
732
727 729 731
678
733
679
734
680 681 682
Abnormal ECG
683
688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715
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685 687
Abnormal Recording n=6
n = 20
684 686
Abnormal Cardiac MRI n=1
Abnormal echocardiogram n=1
Unremarkable echocardiogram n = 19 Unremarkable Recording n = 13
735 736 737
Abnormal Cardiac MRI n=1
738
Unremarkable Cardiac MRI n=5
740
Abnormal Cardiac MRI n=1
742
Unremarkable Cardiac MRI n = 10
744
739 741 743
Figure 3 – Cardiac assessments at follow-up examination for sarcoidosis cases. Cardiac evaluation at follow-up demonstrating how many cases would have been missed if the evaluation stopped after an earlier test result was unremarkable. For example, an unremarkable ECG would have missed seven cases with abnormal continuous cardiac recording and six cases with abnormal cardiac MRI. The same would have occurred if the evaluation stopped after both an unremarkable ECG and echocardiogram. An abnormal ECG with an unremarkable echocardiogram would have missed six cases with abnormal continuous cardiac recording and two cases with abnormal cardiac MRI. aOne participant missing an echocardiogram. bTwo participants missing cardiac recordings. One participant missing an echocardiogram, had an unremarkable 48-h cardiac recording (not shown) and a missing cardiac MRI. cFour participants missing cardiac MRIs.
cases who demonstrated resolution of intrathoracic involvement at follow-up, six were treated. Three cases with cardiac sarcoidosis were treated with an ICD: two for inducible ventricular tachycardia on EP study and one for severe scarring on MRI. One of the three had a positive cardiac PET scan and was treated with corticosteroids. In the three cases with ICDs, none have discharged, and all patients (study participants and nonparticipants) remain alive (as of 2017).
Discussion We described the phenotypic expression of sarcoidosis at diagnosis and follow-up in a relatively homogeneous cohort of WTC-exposed firefighters. Nearly 68% were highly exposed (present on 9/11), and none had evidence of beryllium sensitization. Consistent with recent studies in patients with sarcoidosis without WTC
exposure,12,24,25 the median age at diagnosis was 43 years, nearly every case had intrathoracic involvement (predominantly radiographic stage I and II), and 45% had resolution of intrathoracic findings. WTC sarcoidosis differed, however, in terms of its extrathoracic manifestations, demonstrating more joint and cardiac disease and less hypercalcemia, ocular, and skin involvement than usually found in white male patients with sarcoidosis but without WTC exposure. This outcome is interesting because other exposurerelated granulomatous diseases (chronic beryllium disease and hypersensitivity pneumonitis) are confined to the lungs, whereas this study shows that WTC sarcoidosis is a multisystem disease. The ACCESS study found that white patients developed Q12 an average of 0.17 new organ involvements over a 2-year follow-up.13 In the cohort from the Medical University
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of South Carolina (MUSC), white male subjects developed an average of 0.8 new organ involvements over a 6-year follow-up.14 In contrast, in the present study, the average number of involved organs decreased by 0.59, from 1.88 to 1.29 organs per patient, after an average of 8 years of follow-up. Organ assessment in our study, however, included extensive cardiac studies that were not performed in the two aforementioned studies. If we excluded asymptomatic patients who were found to have cardiac sarcoidosis, rates of new organ involvement would have decreased by 0.74, from 1.88 to 1.13 organs per patient. More than 76% (n ¼ 45) of the present cohort did not receive treatment for sarcoidosis. This finding is higher than described in the MUSC cohort, in which nearly 40% did not receive treatment.14 Our percent treated (34%), however, is similar to the MUSC-treated subset of white subjects (35%). Treatment occurred due to dyspnea with declining pulmonary function, joint symptoms, or potentially life-threatening cardiac or neurologic involvement. As far as bone/joints, although our criteria for organ involvement did not technically meet WASOG criteria (“possible” upgraded to “at least probable”), the instrument does acknowledge that multiple lesser manifestations may raise the probability of organ involvement. Therefore, joint involvement was deemed “probable” if the patient had symmetrical arthritis with swelling and morning stiffness, with the assumption that this qualified as inflammatory rather than osteoarthritis. Furthermore, if those patients with clinical inflammatory polyarthritis simultaneously demonstrated negative rheumatoid factor and anti-cyclic citrullinated peptide, and had radiographs without the typical erosive changes of rheumatoid arthritis at the time of initial rheumatologic evaluation, the arthritis was assumed to be related to the underlying sarcoidosis. In addition, response to treatment with disease-modifying antirheumatic drugs other than corticosteroids alone, such as hydroxychloroquine, methotrexate, and/or anti-tumor necrosis factor biologic therapy, provided further support for sarcoidosis-related bone/joint involvement. Our study has several limitations and strengths. First, the FDNY cohort was entirely composed of male firefighters, all but one of whom was white. This homogeneity precludes us from drawing conclusions about the clinical course of sarcoidosis in WTC-exposed female subjects, non-white subjects, and non-firefighters,
8 Original Research
although our previous findings have proven to be generalizable to more diverse WTC-exposed cohorts.7,8 Close monitoring of this study cohort, however, did allow us to be certain that all participants were WTC exposed; had granulomatous disease that was not due to beryllium sensitization; and that sarcoidosis occurred post-exposure because we had pre-employment and preexposure medical examinations, including chest radiographs, on all FDNY firefighters. Second, although the majority of those affected participated, 20% of the base cohort declined follow-up. Although these patients were similar at diagnosis, we cannot determine whether their disease was stable or in which direction it evolved. An important study strength was the long-term followup (mean, 8 years) of participants. Another strength was the standardization of the evaluation protocol for organ involvement at diagnosis and follow-up, which was independent of symptoms. This approach allowed us to more accurately determine the prevalence of cardiac involvement, because all patients had a full assessment, even those who were asymptomatic or had normal ECGs. Of particular significance is the relatively high percentage found to have unrecognized cardiac involvement. Clinically evident cardiac sarcoidosis has been noted in only 2% to 7% of patients with sarcoidosis with manifestations, including conduction abnormalities, ventricular arrhythmias, and heart failure, whereas the rate in asymptomatic patients is unknown.26,27 Cardiac sarcoidosis was clinically detected in 16% of the study cohort at follow-up. We cannot comment on whether cardiac involvement was present at the initial diagnostic evaluation, or its annual incidence, because cardiac MRI was only added to the follow-up protocol. We believe that our initial diagnostic protocol likely underestimated its frequency, because in 56% of the cases with a positive cardiac MRI at follow-up, the other cardiac studies (ECG, echocardiogram, and continuous ECG recording) repeated at follow-up remained normal. This finding is in contrast to the study by Mehta et al,26 which reported a specificity of Q13 87% and a sensitivity of 100% for diagnosing cardiac sarcoidosis with at least one abnormal screening test (ECG, 24-h recording, or echocardiogram) and/or significant cardiac symptoms. Our data suggest that cardiac sarcoidosis may frequently be missed, even when results of screening tests are normal (Fig 3). The prognostic significance, however, of a positive cardiac MRI in this setting requires further studies with larger enrollment and longer follow-up.
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Current guidelines recommend cardiac MRI only in patients with symptoms, abnormal ECG, or abnormal echocardiogram.28-31 We believe that our results support the need for advanced cardiac screening in asymptomatic patients with strenuous, high-stress, public safety occupations, although additional follow-up is warranted. Firefighting is extremely stressful; firefighters operate at workloads $ 12 METs, in high heat and potentially toxic environments leading to maximum heart rates, high catecholamine levels, and an increased rate of myocardial infarction.28-31 In addition, should a firefighter experience a cardiac event while in this environment, it would place not only that firefighter but also other firefighters on that team and civilians being rescued at grave risk. A large prospective study would be needed to determine if screening patients with sarcoidosis, with or without symptoms, by using cardiac MRI, and treating those with positive results, produces a measureable benefit on outcomes. For now, we must rely on individualized clinical risk-benefit analyses.
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Conclusions We describe the clinical course of sarcoidosis in this WTC-exposed firefighter cohort followed up for many years. Intrathoracic involvement resolved in 45% of patients. Pulmonary function was normal in nearly all subjects and remained stable in all but one. Stability of pulmonary function was not associated with radiographic stage at diagnosis or follow-up, or with treatment. Extrathoracic disease was more prevalent than reported for sarcoidosis without WTC exposure or for other exposure-related granulomatous diseases (beryllium disease and hypersensitivity pneumonitis). Treatment was most often instituted for symptomatic joint involvement or potentially life-threatening cardiac or neurologic involvement rather than for lung, ocular, or skin involvement. Given the limited number of longitudinal studies of sarcoidosis, we hope these findings will help guide the management of all patients with sarcoidosis, including those with WTC exposure.
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Author contributions: All authors have participated in at least one aspect of the study (design, recruitment, testing, analyses, and writing); read and approved the manuscript for submission; and accept responsibility for the manuscript’s contents.
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Financial/nonfinancial disclosures: None declared. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. *Writing Committee Members for the FDNY Sarcoidosis Clinical Research Group: Vasilios Christodoulou, BA (Bureau of Health Services, Fire Department of the City of New York, New York, NY); Zachary Hena, MD (Cardiology Division, Department of Pediatrics, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY); Steven M. Plotycia, MD (New York Eye and Ear Infirmary of Mount Sinai, Department of Ophthalmology, New York, NY); Israa Soghier, MD (Pulmonary & Critical Care Division, Jacobi Medical Center and the Albert Einstein College of Medicine, Bronx, NY); David Gritz, MD (Department of Ophthalmology, The John Hopkins Wilmer Eye Institute, Baltimore, MD); Dianne S. Acuna, MD (Bureau of Health Services, Fire Department of the City of New York, New York, NY); Michael D. Weiden, MD (Pulmonary & Critical Care Division, Department of Medicine, NYU School of Medicine, New York, NY; and Bureau of Health Services, Fire Department of the City of New York, New York, NY); Anna Nolan,
MD (Pulmonary & Critical Care Division, Department of Medicine, NYU School of Medicine, New York, NY; and Bureau of Health Services, Fire Department of the City of New York, New York, NY); Keith Diaz, MD (Bureau of Health Services, Fire Department of the City of New York, New York, NY); Viola Ortiz, MD (Bureau of Health Services, Fire Department of the City of New York, New York, NY); and Kerry Kelly, MD (Bureau of Health Services, Fire Department of the City of New York, New York, NY). Other contributions: During this study, Thomas K. Aldrich died of pancreatic cancer. He was more than just the principal investigator. He was a mentor and friend to all of us. He deeply believed in the importance of our work characterizing the health effects after the WTC attack on 9/11. He will be missed but never forgotten. We also thank Neeti Parikh for her eye examinations in this study.
References 1. Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet PY, MullerQuernheim J. Sarcoidosis. Lancet. 2014;383(9923):1155-1167. 2. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007;357(21): 2153-2165. 3. O’Regan A, Berman JS. Sarcoidosis. Ann Intern Med. 2012;156(9):ITC5-1, ITC5-2, ITC5-3, ITC5-4, ITC5-5, ITC5-6, ITC5-7, ITC5-8, ITC5-9, ITC5-10, ITC15-11, ITC15-12, ITC15-13, ITC15-14, ITC1515; quiz ITC15-16.
4. Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Iannuzzi MC. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol. 1997;145(3):234-241.
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5. Rybicki BA, Maliarik MJ, Major M, Popovich J Jr, Iannuzzi MC. Epidemiology, demographics, and genetics of sarcoidosis. Semin Respir Infect. 1998;13(3):166-173.
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6. Prezant DJ, Dhala A, Goldstein A, et al. The incidence, prevalence, and severity of sarcoidosis in New York City firefighters. Chest. 1999;116(5):1183-1193.
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7. Jordan HT, Stellman SD, Prezant D, Teirstein A, Osahan SS, Cone JE. Sarcoidosis diagnosed after September 11, 2001, among adults exposed to the World Trade Center disaster. J Occup Environ Med. 2011;53(9):966-974.
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8. Crowley LE, Herbert R, Moline JM, et al. “Sarcoid like” granulomatous pulmonary disease in World Trade Center disaster responders. Am J Ind Med. 2011;54(3): 175-184. 9. Izbicki G, Chavko R, Banauch GI, et al. World Trade Center “sarcoid-like” granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest. 2007;131(5):1414-1423. 10. Webber MP, Yip JY, Zeig-Owens R, et al. Post-9/11 sarcoidosis in WTC-exposed firefighters and emergency medical service workers [published online ahead of print June 7, 2017]. Respir Med. https://doi. org/10.1016/j.rmed.2017.06.004. 11. Lioy PJ, Weisel CP, Millette JR, et al. Characterization of the dust/smoke aerosol that settled east of the World
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Trade Center (WTC) in lower Manhattan after the collapse of the WTC 11 September 2001. Environ Health Perspect. 2002;110(7):703-714. 12. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Cared Med. 2001;164(10 pt 1): 1885-1889. 13. Judson MA, Baughman RP, Thompson BW, et al. Two year prognosis of sarcoidosis: the ACCESS experience. Sarcoidosis Vasc Diffuse Lung Dis. 2003;20(3):204-211. 14. Judson MA, Boan AD, Lackland DT. The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a large white and black cohort in the United States. Sarcoidosis Vasc Diffuse Lung Dis. 2012;29(2):119-127. 15. Valeyre D, Bernaudin JF, Uzunhan Y, et al. Clinical presentation of sarcoidosis and diagnostic work-up. Semin Respir Crit Care Med. 2014;35(3):336-351. 16. Kreiss K, Newman LS, Mroz MM, Campbell PA. Screening blood test identifies subclinical beryllium disease. J Occup Med. 1989;31(7):603-608. 17. Martin AK, Mack DG, Falta MT, et al. Beryllium-specific CD4þ T cells in blood as a biomarker of disease progression. J Allergy Clin Immunol. 2011;128(5). 1100-1106.e1101-1105. 18. Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac
sarcoidosis. Heart Rhythm. 2014;11(7): 1305-1323. 19. Judson MA, Costabel U, Drent M, et al. The wasog sarcoidosis organ assessment instrument: an update of a previous clinical tool. Sarcoidosis Vasc Diffuse Lung Dis. 2014;31(1):19-27. 20. Loupasakis K, Berman J, Jaber N, et al. Refractory sarcoid arthritis in World Trade Center-exposed New York City firefighters: a case series. J Clin Rheumatol. 2015;21(1):19-23. 21. Scadding JG. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years’ observation. BMJ. 1961;2(5261):1165-1172. 22. Hankinson JL, Odencrantz JR, Fedan KB. Spirometric reference values from a sample of the general US population. Am J Respir Crit Care Med. 1999;159(1): 179-187. 23. Miller A, Thornton JC, Warshaw R, Anderson H, Teirstein AS, Selikoff IJ. Single breath diffusing capacity in a representative sample of the population of Michigan, a large industrial state. Predicted values, lower limits of normal, and frequencies of abnormality by smoking history. Am Rev Respir Dis. 1983;127(3):270-277. 24. Ungprasert P, Carmona EM, Utz JP, Ryu JH, Crowson CS, Matteson EL. Epidemiology of sarcoidosis 1946-2013: a population-based study. Mayo Clinic Proc. 2016;91(2):183-188. 25. Girvin F, Zeig-Owens R, Gupta D, et al. Radiologic features of World
Trade Center-related sarcoidosis in exposed NYC fire department rescue workers. J Thorac Imaging. 2016;31(5): 296-303. 26. Hulten E, Aslam S, Osborne M, Abbasi S, Bittencourt MS, Blankstein R. Cardiac sarcoidosis-state of the art review. Cardiovasc Diagn Ther. 2016;6(1):50-63.
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27. Mehta D, Lubitz SA, Frankel Z, et al. Cardiac involvement in patients with sarcoidosis: diagnostic and prognostic value of outpatient testing. Chest. 2008;133(6):1426-1435.
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28. Malley KS, Goldstein AM, Aldrich TK, et al. Effects of fire fighting uniform (modern, modified modern, and traditional) design changes on exercise duration in New York City Firefighters. J Occup Environ Med. 1999;41(12): 1104-1115.
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29. von Heimburg ED, Rasmussen AK, Medbo JI. Physiological responses of firefighters and performance predictors during a simulated rescue of hospital patients. Ergonomics. 2006;49(2):111-126.
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30. Huang CJ, Webb HE, Garten RS, Kamimori GH, Acevedo EO. Psychological stress during exercise: lymphocyte subset redistribution in firefighters. Physiol Behav. 2010;101(3): 320-326.
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31. Kales SN, Soteriades ES, Christophi CA, Christiani DC. Emergency duties and deaths from heart disease among firefighters in the United States. N Engl J Med. 2007;356(12):1207-1215.
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10 Original Research
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Clinical Course of Sarcoidosis in World Trade Center-Exposed Firefighters
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Kerry M. Hena, MD; Jennifer Yip, MPH; Nadia Jaber, PA-C; David Goldfarb, MPH; Kelly Fullam, BA;
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Krystal Cleven, MD; William Moir, MPH; Rachel Zeig-Owens, DrPH; Mayris P. Webber, DrPH; Daniel M. Spevack, MD;
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Jessica Berman, MD; Thomas K. Aldrich, MDy; David J. Prezant, MD; and the FDNY Sarcoidosis Clinical Research Group*
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Sarcoidosis is believed to represent a genetically primed, abnormal immune response to an antigen exposure or inflammatory trigger, with both genetic and environmental factors playing a role in disease onset and phenotypic expression. In a population of firefighters with post-World Trade Center (WTC) 9/11/2001 (9/11) sarcoidosis, we have a unique opportunity to describe the clinical course of incident sarcoidosis during the 15 years’ postexposure and, on average, 8 years following diagnosis.
BACKGROUND:
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Among the WTC-exposed cohort, 74 firefighters with post-9/11 sarcoidosis were identified through medical records review. A total of 59 were enrolled in follow-up studies. For each participant, the World Association of Sarcoidosis and Other Granulomatous Diseases organ assessment tool was used to categorize the sarcoidosis involvement of each organ system at time of diagnosis and at follow-up.
23
METHODS:
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The incidence of sarcoidosis post-9/11 was 25 per 100,000. Radiographic resolution of intrathoracic involvement occurred in 24 (45%) subjects. Lung function for nearly all subjects was within normal limits. Extrathoracic involvement increased, most prominently joints (15%) and cardiac (16%) involvement. There was no evidence of calcium dysmetabolism. Few subjects had ocular (5%) or skin (2%) involvement, and none had beryllium sensitization. Most (76%) subjects did not receive any treatment.
RESULTS:
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Extrathoracic disease was more prevalent in WTC-related sarcoidosis than reported for patients with sarcoidosis without WTC exposure or for other exposure-related granulomatous diseases (beryllium disease and hypersensitivity pneumonitis). Cardiac involvement would have been missed if evaluation stopped after ECG, 48-h recordings, and echocardiogram. Our results also support the need for advanced cardiac screening in asymptomatic patients with strenuous, stressful, public safety occupations, given the potential fatality of a missed diagnosis. CHEST 2017; -(-):---
CONCLUSIONS:
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Q9
KEY WORDS:
clinical course; firefighters; sarcoidosis; World Trade Center
ABBREVIATIONS:
48 49 Q3
51
54 55
75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 99 101
47
53
73 74
100
46
52
71 72
98
45
50
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Q4
ACE = angiotensin-converting enzyme; EP = electrophysiologic; FDNY = Fire Department of the City of New York; ICD = implantable cardioverter-defibrillator; MUSC = Medical University of South Carolina; WASOG = World Association of Sarcoidosis and Other Granulomatous Diseases; WTC = World Trade Center AFFILIATIONS: From the Pulmonary & Critical Care Division (Dr Hena), Cardiology Division (Dr Aizer), Department of Medicine, NYU School of Medicine, New York, NY; Bureau of Health Services (Mss Yip, Jaber, Fullam, and Zeig-Owens; Messrs Goldfarb and Moir; and Drs Webber, Aldrich, and Prezant), Fire Department of the City of New York, New York, NY; Pulmonary Division (Drs Cleven, Prezant, and Spivack), Department of Medicine, Montefiore
Medical Center and the Albert Einstein College of Medicine, Bronx, NY; Cardiology Division (Drs Spevack and Krumerman), Department of Medicine, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY; Pulmonary & Critical Care Division (Dr Judson), Albany Medical College, Albany, NY; Division of Environmental and Occupational Health Sciences (Dr Maier), Department of Medicine, National Jewish Health, Denver, CO; and the Rheumatology Division (Dr Berman), Hospital for Special Surgery, New York, NY. Some preliminary data from this study have been published in Q5 abstract form at the annual meetings of CHEST 2016 (Los Angeles, CA) and American Thoracic Society 2017 (Washington, DC).
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Sarcoidosis is a multisystem granulomatous disease.1-3 The annual incidence varies widely among races/ ethnicities: 11 per 100,000 in US white subjects and 36 per 100,000 in US black subjects.4,5 In the Fire Department of the City of New York (FDNY), Prezant et al6 found that between 1985 and 1998, FDNY firefighters had a significantly higher annual incidence of sarcoidosis than FDNY Emergency Medical Services workers and historical control subjects. The average annual incidence in firefighters was estimated at 12.9 per 100,000, significantly greater than in Emergency Medical Services workers (0.0 per 100,000) and several times the expected rate (2.5-7.6 per 100,000 for white men in the United States).4
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Following the World Trade Center (WTC) attack on 9/11/2001 (9/11), an increase in sarcoidosis was found in WTC-exposed populations,7,8 including FDNY rescue/recovery workers.9 Between 2002 and 2015, we found an age-adjusted incidence rate of 25 per 100,000 in male FDNY rescue/recovery workers.10 By 2015, a total of 74 FDNY firefighters with new post-9/11 sarcoidosis were identified: 65 were diagnosed by using transbronchial or mediastinal biopsy results and nine by typical clinical or radiologic findings without alternate diagnosis. Possible triggering agents/antigens
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include particulate matter (calcium carbonate and silica) and fibers (asbestos, fibrous glass, gypsum), organic pollutants (polycyclic aromatic hydrocarbons), gases, combustion byproducts from WTC fires, and metal dusts such as beryllium.11 Although its etiology is unknown, sarcoidosis is believed to represent a genetically primed abnormal immune response to an antigen exposure or inflammatory trigger,1 with both genetic and environmental factors playing a role in disease onset and phenotypic expression, including the distribution of organ involvement. Reports have described the clinical presentation at diagnosis, but few have described its clinical course over time.12-14 Given the extensive phenotyping of this group at diagnosis, via comprehensive medical evaluations and cohort maintenance through the FDNY WTC Health Program, we recognized an opportunity to describe the clinical course of incident sarcoidosis 15 years after WTC exposure, during the follow-up period of 2015 to 2016. In addition, because beryllium was found at the WTC site, and berylliosis is clinically indistinguishable from sarcoidosis, a secondary goal was to evaluate for beryllium sensitization.
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Materials and Methods
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Study Population
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All 74 WTC-exposed FDNY firefighters with post-9/11 sarcoidosis were recruited via mailings and telephone calls. The Montefiore/ Einstein Institutional Review Board approved the study, and participants provided written informed consent.
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Clinical Criteria for Case Definition
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All cases were WTC exposed and had normal chest radiographs prior to 9/11 (obtained pre-employment and biannually at medical monitoring). For biopsy-proven cases, pathology reports were reviewed to verify histologic culture-negative, noncaseating granulomas. For those without a biopsy (n ¼ 7), charts were reviewed by two pulmonologists, and cases were included if chest CT scans showed bilateral symmetrical mediastinal/hilar adenopathy
149 150 151 152 153 154 156 Q7
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(> 1.5 cm), perilymphatic nodules, or fibrosis with bronchial distortion, without alternative etiology.15
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FUNDING/SUPPORT:
Funding for this study came from the National Institute of Occupational Safety and Health [Grant U01-OH010993 and contracts 200-2011-39383, 200-2011-39378, 200-2017-93326, and 200-2017-93426]. y Deceased. CORRESPONDENCE TO: David J. Prezant, MD, Fire Department of the City of New York, 9 Metrotech Center, Room 8N-7, Brooklyn, NY 11201; e-mail: [email protected] Copyright Ó 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: https://doi.org/10.1016/j.chest.2017.10.014
2 Original Research
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Evaluation at Diagnosis and Follow-up
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Diagnostic and follow-up evaluations were similar (Table 1) with the following additions at follow-up: serum angiotensin-converting enzyme (ACE), serum vitamin D (25-hydroxy and 1,25 dihydroxy), and urinary calcium measurements; a gadolinium-enhanced cardiac MRI; and blood beryllium sensitization studies (IFNƴEli spot assay and beryllium lymphocyte proliferation test [BeLPT]) at National Jewish Health (Denver, Colorado).16,17 If joint findings or cardiac findings were suspicious for sarcoidosis involvement, confirmation by a rheumatologist or cardiologist was required. Treatment was recorded at diagnosis and follow-up.
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Cardiac Studies
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Advanced cardiac imaging was performed, despite the absence of symptoms or abnormal screening test results, given the potential for a cardiac fatality resulting from a missed diagnosis in firefighters and the relatively low risk of a gadolinium-enhanced cardiac MRI. Electrophysiologic (EP) studies were used for risk stratification in those patients with abnormal cardiac MRIs (delayed gadoliniumenhancement of infero-lateral-basilar segments).18 Implantable cardioverter-defibrillator (ICD) placement was guided by traditional primary and secondary prevention as well as consideration for the degree of abnormality on MRI. Cardiac PET scanning was performed when treatment with disease-modifying drugs was considered due to a positive EP study result or extensive disease on echocardiogram or MRI.
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TABLE 1 Q19
] FDNY Sarcoidosis Evaluation Protocol at Diagnosis and Follow-up
Variable
Examination Description at Diagnosis Occupational, medical, family, and sarcoidosis history
Questionnaire
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Q18
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Examination Description at Follow-up
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Occupational, medical, family, and sarcoidosis history
Racial/ethnic background
Racial/ethnic background
WTC exposure details
WTC exposure details
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279 280 281 282
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Tobacco use history
Tobacco use history
283
229
Review of systems
Review of systems
284
230
Medication use
Medication use, including current and past treatment for sarcoidosis (corticosteroids and other disease-modifying drugs)
286
Cardiac and pulmonary auscultation
Cardiac and pulmonary auscultation
288
235
Abdominal palpation
Abdominal palpation
290
236
Lymph node, joint, and skin surveys
Lymph node, joint, and skin surveys
291
Cranial nerves, motor and sensory perception assessments
292
Examination of eyelids
Examination of eyelids
294
241
Palpebral fissures
Palpebral fissures
296
242
Conjunctivae for granulomas
Conjunctivae for granulomas
Slit lamp and dilated retina exam
Slit lamp and dilated retina exam
Chest radiographs (PA and lateral) or recreated digitally from CT imaging
Chest radiographs (PA and lateral) or recreated digitally from CT imaging
Noncontrast chest CT scan
Noncontrast chest CT scan
231 232 233 234
General physical examination
237 239 240
Eye examination by an ophthalmologist
243 244 245
Chest imaging
246 247 248
Pulmonary function
249
287 289
Cranial nerves, motor and sensory perception assessments
238
285
293 295
Spirometry
Spirometry
Lung volumes
Lung volumes
297 298 299 300 301 302 303 304
Diffusing capacity
Diffusing capacity
305
251
Oxygen saturation
Resting
Rest and exercise (6-min walk)
306
252
Cardiac evaluation
12-lead ECG
12-lead ECG
307
Transthoracic echocardiogram
Transthoracic echocardiogram
308
24-h continuous recording
48-h continuous recording
250
253 254 255 256
309 310
Cardiac MRI with gadolinium
311
CBC count
CBC count
258
Metabolic panel
Metabolic panel
259
Creatinine and ionized calcium
Creatinine and ionized calcium
260
Liver enzyme levels
Liver enzyme levels
315
Angiotensin-converting enzyme
316
257
Blood analyses
261 262 264 265 267
Urinalyses
Urinalysis (microscopic and chemistry)
317 318
Beryllium testing (IFNƴElispot assay and beryllium lymphocyte proliferation test [BeLPT])
Q20
Urinalysis (microscopic and chemistry)
Q21
319 320 321 322
4-h collection for creatinine and calcium
268 269
313 314
Vitamin D (25-hydroxy and 1,25 dihydroxy)
263
266
312
323 324
FDNY ¼ Fire Department of the City of New York; PA ¼ posterioranterior; WTC ¼ World Trade Center.
270
325
271
326
272 273 274 275
Organ Involvement: At Time of Diagnosis and Follow-up For each participant, the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) organ assessment tool19 was used to categorize sarcoidosis involvement of each organ system both at time of diagnosis and at follow-up (2015-2016). With the exception
of bone/joints, a finding of “highly probable” or “at least probable” was considered diagnostic for organ involvement. For bone/joints, symptoms of arthralgias (“possible” by WASOG criterion) were upgraded to “at least probable” when there was tenderness on examination in two or more symmetrical joints, negative
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331
rheumatology serologic findings, and response to treatment with disease-modifying drugs other than corticosteroids.20 Indeterminate cardiac MRI results were considered nondiagnostic until a repeat scan was obtained 6 to 12 months later. If abnormalities were too subtle to be characterized as cardiac sarcoidosis by both radiologist and cardiologist or were no longer present or unchanged, the MRI was considered negative.
332 333 334 335 336 337
Clinical Course
338 339 340 341 342
Q10
343
Organ involvement was considered present based on WASOG criteria at follow-up and whether treatment had occurred. If new organ involvement occurred > 1 year following diagnosis but before the follow-up study (2015-2016), it was considered a follow-up finding. This scenario included one patient with cardiac involvement and eight patients with bone/joint involvement for which treatment was
initiated prior to our study. For lung involvement, the clinical course was assessed by using chest imaging and classified with the use of Scadding stages (0 ¼ normal, 1 ¼ bilateral hilar adenopathy with normal lung parenchyma; 2 ¼ bilateral hilar adenopathy with pulmonary infiltrates; 3 ¼ pulmonary infiltrates without hilar adenopathy; and 4 ¼ pulmonary fibrosis)21; pulmonary function test as percent predicted for age, height, and race22,23; and the need for treatment.
386 387 388 389 390 391 392 393 394
Statistics Demographic characteristics, clinical characteristics, and pulmonary function metrics were compared by using t tests, the Fisher exact test, the Wilcoxon-Mann-Whitney test, or Pearson’s c2 test. Analyses were conducted by using SAS version 9.4 (SAS Institute, Inc).
395 396 397 398
344
399
345
400
Results
346 347
Demographic and Clinical Characteristics
348 349 350 351 352
Clinical Course of Sarcoidosis From Diagnosis to Follow-up
Q11
353 354 355 356 357 358 359 360
The incidence of sarcoidosis between 9/11 and 1/2015 was 25 per 100,000. Of the 74 WTC-exposed firefighters with post-9/11 sarcoidosis, 59 (80%) were successfully recruited. All cases with biopsy-proven disease had undergone biopsy within 3 months of presentation. At diagnosis, nonparticipants were slightly older (P ¼ .044) but did not significantly differ from study participants in other demographic characteristics (Table 2) or organ involvement (Table 3). Follow-up occurred in late 2015 to early 2016, on average 8 years after diagnosis (interquartile range, 5-11 years).
401
Of 59 cases, pulmonary symptoms were reported by 32 (54%) subjects at diagnosis and 35 (59%) at follow-up, whereas evidence of pulmonary disease on imaging was present in 98% at diagnosis and 51% at follow-up. Resolution of intrathoracic involvement (parenchyma and adenopathy) by follow-up occurred in 24 (45%) of 53 cases who had chest CT scans at diagnosis and follow-up (Table 3). Pulmonary functions were within normal limits for nearly all, changed little over time, and were not significantly different in those with or without intrathoracic involvement according to CT imaging at follow-up (all P > .05) (Fig 1).
361
402 403 404 405 406 407 408 409 410 411 412 413 414 415 416
362
417
363
418
TABLE 2
364 365 366 367 368 369
Q22
] Comparison of Demographic Characteristics Between Nonparticipants and Study Participants Nonparticipants (n ¼ 15)
Characteristic
421
WTC exposure Arrival on the morning of 9/11
3 (20%)
13 (22%)
Arrival in the afternoon of 9/11
9 (60%)
27 (46%)
370
Arrival on 9/12
371
Arrival from 9/13-9/24
372
Age at sarcoidosis diagnosis, median (IQR), y
373
Smoking status at the time of sarcoidosis diagnosis
374 375 376 377 378
419 420
Study Participants (n ¼ 59)
Current
1 (7%)
15 (25%)
2 (13%)
4 (7%)
46 (41-55)
43 (38-47)
Never
423 424 425 426 427 428
0
Former
422
1 (2%)
429 430
5 (33%)
9 (15%)
10 (67%)
49 (83%)
431 432
Sarcoidosis treatment medicationsa
433
379
Ever treatment
5 (33%)
14 (24%)
380
Corticosteroids
5 (33%)
13 (22%)
435
381
Hydroxychloroquine/methotrexate
2 (13%)
9 (15%)
436
382
TNF-a blockers
1 (7%)
6 (10%)
383 384 385
434
437
IQR ¼ interquartile range; TNF ¼ tumor necrosis factor. See Table 1 legend for expansion of other abbreviations. a Medications filled under the FDNY WTC Health Program. None of the comparisons between nonparticipants and participants were statistically significant except age (P ¼ .044).
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441
TABLE 3
] Organ Involvement for Nonparticipants (at Diagnosis) and Study Participants (at Diagnosis and
496
Follow-up)
442
497
443
Nonparticipants (n ¼ 15)
444
Organ Involvement
445
At Diagnosis
Intrathoracic involvement by CT imaging
446
a
498
Study Participants (n ¼ 59) At Diagnosisb
499
Follow-upb
13 (87%)
55 (98%)
29 (51%)
500 501
447
Radiographic stage 1
0
8 (15%)
6 (21%)
448
Radiographic stage 2
12 (92%)
43 (78%)
19 (66%)
503
449
Radiographic stage 3
1 (8%)
4 (7%)
4 (14%)
504
450
Radiographic stage 4
0
0
0
505 506
451
Cardiac
452
Eyes
453 454
Ears/nose/throat
455
Bone-Joints
456
Skin
457
Nervous System
458
Liver
459 460 461
464
9 (16%)
1 (8%)
3 (5%)
3 (5%)
507 508
0
0
1 (2%)
4 (7%)
9 (15%)
1 (7%)
1 (2%)
1 (2%)
511
0
0
1 (2%)
512
1 (7%)
1 (2%)
1 (2%)
513 514
Spleen
0
3 (5%)
3 (5%)
Kidney
0
1 (2%)
0
0
0
0
1 (2%)
0
0
Extrathoracic lymph nodes
463
0
2 (13%)
Calcium
462
0
502
509 510
515 516 517 518
Involvement was based on World Association of Sarcoidosis and Other Granulomatous Diseases criteria. None of the comparisons between nonparticipants and participants were statistically significant. a Nonparticipants had complete data at diagnosis with the following exceptions: skin (n ¼ 14); eye (n ¼ 13); spleen (n ¼ 7); bone/joint (n ¼ 9); cardiac (n ¼ 12); nervous system (n ¼ 5); and extrathoracic lymph nodes (n ¼ 3). b In the study cohort with follow-up, all cases had complete data at diagnosis and follow-up with the following exceptions: chest CT scan at diagnosis (n ¼ 56), at follow-up (n ¼ 57) and at both (n ¼ 53); eye at follow-up (n ¼ 58); spleen at follow-up (n ¼ 57); cardiac at follow-up (n ¼ 57); and ear/nose/ throat at follow-up (n ¼ 57).
465 466 467 468 469
Q23
519 520 521 522 523 524
470
525
471
526
Extrathoracic involvement increased over time from 10 patients at diagnosis to 23 at follow-up (Table 3), most prominently in joints and cardiac systems, which, at follow-up affected 15% and 16% of the study population, respectively (Fig 2). Several findings at follow-up were noteworthy for not being counted as involvement according to WASOG criterion.19 These findings included 34 (58%) patients with chronic rhinosinusitis (symptoms and inflammation on sinus CT imaging but without nasal/sinus biopsy), two patients with
473 474 475 476 477 478 479 480 482 483 484 485 486 487 488 489 490 491 492
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small-fiber neuropathy (considered a para-sarcoidosis syndrome), and minor abnormalities of vitamin D/calcium homeostasis (35 cases with low 25-hydroxyand normal 1,25-dihydroxy-vitamin D levels) without hypercalcemia or hypercalciuria.
527 528 529 530 531 532
Cardiac Involvement
533 534
Our initial protocol at diagnosis found no evidence of cardiac involvement by symptoms, ECG, ECG recording, or echocardiogram. At follow-up, cardiac
535 536 537 538
At Diagnosis
160
539
Follow-up
540
140 Percent predicted
472
120 100 80 60 40
493
20
494
0
495
FEV1
FVC
FRC
DLCO
Figure 1 – Pulmonary function at diagnosis and follow-up. Average percent predicted pulmonary function among cases who had complete pulmonary data at diagnosis and follow-up: FVC and FEV1 (n ¼ 57); DLCO (n ¼ 41); and FRC (n ¼ 30). All 59 cases had complete data at follow-up. Differences in pulmonary function metrics between diagnosis and follow-up were not statistically significant. DLCO ¼ carbon monoxide diffusing capacity; FRC ¼ functional residual capacity.
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541 542 543 544 545 546
Q27
547 548
Q25
549 550
551
Intrathoracic 53 (98%)
552
Intrathoracic Lymph Nodes 49 (91%)
553
606 607 608
Lung 45 (83%)
554
609
555
610
556
611
557
612
558
613
559
29 (54%) Intrathoracic
560
25 (46%) Intrathoracic Lymph Nodes 23 (43%) Lung
561
614 615 616
562
617
563
618
564 565 567 568 569 570 571 572 573
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566
576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601
621 622
Cardiac 0 (0%)
623 624
Follow-up
At diagnosis
Figure 2 – Clinical course of sarcoidosis organ involvement at diagnosis and follow-up. Other organs include: eye, spleen, skin, liver, kidney, ears/nose/ throat, and calcium. All 59 cases had complete data at both diagnosis and follow-up for all organs with the following exceptions: chest CT scan (n ¼ 54); eye (n ¼ 58); spleen (n ¼ 57); cardiac (n ¼ 57); and ears/nose/throat (n ¼ 57). Serum calcium levels were assessed at diagnosis, and serum calcium and Vitamin D levels were assessed at follow-up.
MRI was added. Thirty-one (53%) of 59 subjects reported symptoms of possible concern (eg, palpitations, dizziness/syncope), but cardiac attribution was considered likely only for one case. Figure 3 shows how many cases would have been missed at follow-up if the evaluation stopped after an earlier unremarkable test result. For example, an unremarkable ECG would have missed seven cases with abnormal continuous cardiac recording and six cases with abnormal cardiac MRI. Abnormal findings included: ECGs (eg, right ventricular strain, right bundle branch block or intermittent complete atrioventricular block); echocardiogram (left ventricular ejection fraction < 45%); 48-h recording (short runs of ectopy, usually supraventricular, and four with variable block [second-degree, right bundle branch or intermittent complete atrioventricular block]); and cardiac MRI (delayed gadolinium-enhancement of infero-lateral-basilar segments). Eight of the nine cases with abnormal cardiac MRI underwent an EP study; two had inducible ventricular tachycardia, of which one had the low ejection fraction noted on both echocardiogram and MRI but a negative cardiac PET scan. One case with a negative EP study and normal echocardiogram had extensive scarring on cardiac MRI with a positive cardiac PET scan.
602 603
Bone/Joint Involvement
604
Eight cases presented with symmetrical polyarticular arthritis involving swelling and tenderness of the small
605
620
Bone Joint 4 (7%)
574 575
619
10 (18%) Other organs 9 (16%) Cardiac 9 (15%) Bone/joint
Other organs 9 (16%)
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625 626 627 628 629
joints, of which five also involved large joints. One additional case had asymptomatic vertebral bone involvement. In all cases, serum markers for other autoimmune diseases, in particular rheumatoid factor and anti-cyclic citrullinated peptide antibody, were negative on initial presentation.
630 631 632 633 634 635 636 637
Additional Studies (ACE and Beryllium)
638
None of the subjects had evidence of beryllium sensitization. At follow-up, mean ACE levels were 47 U/L (interquartile range, 32 U/L); nine (15%) had mildly elevated ACE levels (> 67 U/L).
640
Treatment
644
639 641 642 643
The average number of organs involved decreased by 0.59, from 1.88 to 1.29 organs per patient after an average of 8 years of follow-up. Five (8%) cases were treated with oral corticosteroids for dyspnea with reductions in pulmonary function. Eight cases with joint symptoms underwent a stepwise treatment algorithm to achieve adequate disease control,2 ultimately with hydroxychloroquine and methotrexate in one patient and tumor necrosis factor-a blockers in seven cases. For the entire study cohort, regardless of why treatment was initiated, the course of pulmonary functions (FVC, FEV1, carbon monoxide diffusing capacity, and functional residual capacity) was similar in patients who were ever treated with any disease-modifying drug compared with those who were never treated (all P > .05). Among 24
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645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660
661
716
662
717 Echocardiogram
ECG
663
48-h Cardiac Recording
Cardiac MRI
718
664
719 Total Abnormal: 20 Total Unremarkable: 39
665 666
Total Abnormal: 1 Total Unremarkable: 57a
Total Abnormal: 13 Total Unremarkable: 44b
Total Abnormal: 9 Total Unremarkable: 46c
720 721
667
722 Abnormal echocardiogram n=0
668 669 670
723 724
Unremarkable ECG
671
Abnormal Recording n=7
n = 39
672 673
Unremarkable echocardiogram n = 38
674 675
Unremarkable Recording n = 30
676 677
725
Abnormal Cardiac MRI n =1
726
Unremarkable Cardiac MRI n=6
728
Abnormal Cardiac MRI n=5
730
Unremarkable Cardiac MRI n = 25
732
727 729 731
678
733
679
734
680 681 682
Abnormal ECG
683
688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715
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685 687
Abnormal Recording n=6
n = 20
684 686
Abnormal Cardiac MRI n=1
Abnormal echocardiogram n=1
Unremarkable echocardiogram n = 19 Unremarkable Recording n = 13
735 736 737
Abnormal Cardiac MRI n=1
738
Unremarkable Cardiac MRI n=5
740
Abnormal Cardiac MRI n=1
742
Unremarkable Cardiac MRI n = 10
744
739 741 743
Figure 3 – Cardiac assessments at follow-up examination for sarcoidosis cases. Cardiac evaluation at follow-up demonstrating how many cases would have been missed if the evaluation stopped after an earlier test result was unremarkable. For example, an unremarkable ECG would have missed seven cases with abnormal continuous cardiac recording and six cases with abnormal cardiac MRI. The same would have occurred if the evaluation stopped after both an unremarkable ECG and echocardiogram. An abnormal ECG with an unremarkable echocardiogram would have missed six cases with abnormal continuous cardiac recording and two cases with abnormal cardiac MRI. aOne participant missing an echocardiogram. bTwo participants missing cardiac recordings. One participant missing an echocardiogram, had an unremarkable 48-h cardiac recording (not shown) and a missing cardiac MRI. cFour participants missing cardiac MRIs.
cases who demonstrated resolution of intrathoracic involvement at follow-up, six were treated. Three cases with cardiac sarcoidosis were treated with an ICD: two for inducible ventricular tachycardia on EP study and one for severe scarring on MRI. One of the three had a positive cardiac PET scan and was treated with corticosteroids. In the three cases with ICDs, none have discharged, and all patients (study participants and nonparticipants) remain alive (as of 2017).
Discussion We described the phenotypic expression of sarcoidosis at diagnosis and follow-up in a relatively homogeneous cohort of WTC-exposed firefighters. Nearly 68% were highly exposed (present on 9/11), and none had evidence of beryllium sensitization. Consistent with recent studies in patients with sarcoidosis without WTC
exposure,12,24,25 the median age at diagnosis was 43 years, nearly every case had intrathoracic involvement (predominantly radiographic stage I and II), and 45% had resolution of intrathoracic findings. WTC sarcoidosis differed, however, in terms of its extrathoracic manifestations, demonstrating more joint and cardiac disease and less hypercalcemia, ocular, and skin involvement than usually found in white male patients with sarcoidosis but without WTC exposure. This outcome is interesting because other exposurerelated granulomatous diseases (chronic beryllium disease and hypersensitivity pneumonitis) are confined to the lungs, whereas this study shows that WTC sarcoidosis is a multisystem disease. The ACCESS study found that white patients developed Q12 an average of 0.17 new organ involvements over a 2-year follow-up.13 In the cohort from the Medical University
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771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825
of South Carolina (MUSC), white male subjects developed an average of 0.8 new organ involvements over a 6-year follow-up.14 In contrast, in the present study, the average number of involved organs decreased by 0.59, from 1.88 to 1.29 organs per patient, after an average of 8 years of follow-up. Organ assessment in our study, however, included extensive cardiac studies that were not performed in the two aforementioned studies. If we excluded asymptomatic patients who were found to have cardiac sarcoidosis, rates of new organ involvement would have decreased by 0.74, from 1.88 to 1.13 organs per patient. More than 76% (n ¼ 45) of the present cohort did not receive treatment for sarcoidosis. This finding is higher than described in the MUSC cohort, in which nearly 40% did not receive treatment.14 Our percent treated (34%), however, is similar to the MUSC-treated subset of white subjects (35%). Treatment occurred due to dyspnea with declining pulmonary function, joint symptoms, or potentially life-threatening cardiac or neurologic involvement. As far as bone/joints, although our criteria for organ involvement did not technically meet WASOG criteria (“possible” upgraded to “at least probable”), the instrument does acknowledge that multiple lesser manifestations may raise the probability of organ involvement. Therefore, joint involvement was deemed “probable” if the patient had symmetrical arthritis with swelling and morning stiffness, with the assumption that this qualified as inflammatory rather than osteoarthritis. Furthermore, if those patients with clinical inflammatory polyarthritis simultaneously demonstrated negative rheumatoid factor and anti-cyclic citrullinated peptide, and had radiographs without the typical erosive changes of rheumatoid arthritis at the time of initial rheumatologic evaluation, the arthritis was assumed to be related to the underlying sarcoidosis. In addition, response to treatment with disease-modifying antirheumatic drugs other than corticosteroids alone, such as hydroxychloroquine, methotrexate, and/or anti-tumor necrosis factor biologic therapy, provided further support for sarcoidosis-related bone/joint involvement. Our study has several limitations and strengths. First, the FDNY cohort was entirely composed of male firefighters, all but one of whom was white. This homogeneity precludes us from drawing conclusions about the clinical course of sarcoidosis in WTC-exposed female subjects, non-white subjects, and non-firefighters,
8 Original Research
although our previous findings have proven to be generalizable to more diverse WTC-exposed cohorts.7,8 Close monitoring of this study cohort, however, did allow us to be certain that all participants were WTC exposed; had granulomatous disease that was not due to beryllium sensitization; and that sarcoidosis occurred post-exposure because we had pre-employment and preexposure medical examinations, including chest radiographs, on all FDNY firefighters. Second, although the majority of those affected participated, 20% of the base cohort declined follow-up. Although these patients were similar at diagnosis, we cannot determine whether their disease was stable or in which direction it evolved. An important study strength was the long-term followup (mean, 8 years) of participants. Another strength was the standardization of the evaluation protocol for organ involvement at diagnosis and follow-up, which was independent of symptoms. This approach allowed us to more accurately determine the prevalence of cardiac involvement, because all patients had a full assessment, even those who were asymptomatic or had normal ECGs. Of particular significance is the relatively high percentage found to have unrecognized cardiac involvement. Clinically evident cardiac sarcoidosis has been noted in only 2% to 7% of patients with sarcoidosis with manifestations, including conduction abnormalities, ventricular arrhythmias, and heart failure, whereas the rate in asymptomatic patients is unknown.26,27 Cardiac sarcoidosis was clinically detected in 16% of the study cohort at follow-up. We cannot comment on whether cardiac involvement was present at the initial diagnostic evaluation, or its annual incidence, because cardiac MRI was only added to the follow-up protocol. We believe that our initial diagnostic protocol likely underestimated its frequency, because in 56% of the cases with a positive cardiac MRI at follow-up, the other cardiac studies (ECG, echocardiogram, and continuous ECG recording) repeated at follow-up remained normal. This finding is in contrast to the study by Mehta et al,26 which reported a specificity of Q13 87% and a sensitivity of 100% for diagnosing cardiac sarcoidosis with at least one abnormal screening test (ECG, 24-h recording, or echocardiogram) and/or significant cardiac symptoms. Our data suggest that cardiac sarcoidosis may frequently be missed, even when results of screening tests are normal (Fig 3). The prognostic significance, however, of a positive cardiac MRI in this setting requires further studies with larger enrollment and longer follow-up.
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881
Current guidelines recommend cardiac MRI only in patients with symptoms, abnormal ECG, or abnormal echocardiogram.28-31 We believe that our results support the need for advanced cardiac screening in asymptomatic patients with strenuous, high-stress, public safety occupations, although additional follow-up is warranted. Firefighting is extremely stressful; firefighters operate at workloads $ 12 METs, in high heat and potentially toxic environments leading to maximum heart rates, high catecholamine levels, and an increased rate of myocardial infarction.28-31 In addition, should a firefighter experience a cardiac event while in this environment, it would place not only that firefighter but also other firefighters on that team and civilians being rescued at grave risk. A large prospective study would be needed to determine if screening patients with sarcoidosis, with or without symptoms, by using cardiac MRI, and treating those with positive results, produces a measureable benefit on outcomes. For now, we must rely on individualized clinical risk-benefit analyses.
882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902
936
Conclusions We describe the clinical course of sarcoidosis in this WTC-exposed firefighter cohort followed up for many years. Intrathoracic involvement resolved in 45% of patients. Pulmonary function was normal in nearly all subjects and remained stable in all but one. Stability of pulmonary function was not associated with radiographic stage at diagnosis or follow-up, or with treatment. Extrathoracic disease was more prevalent than reported for sarcoidosis without WTC exposure or for other exposure-related granulomatous diseases (beryllium disease and hypersensitivity pneumonitis). Treatment was most often instituted for symptomatic joint involvement or potentially life-threatening cardiac or neurologic involvement rather than for lung, ocular, or skin involvement. Given the limited number of longitudinal studies of sarcoidosis, we hope these findings will help guide the management of all patients with sarcoidosis, including those with WTC exposure.
903
937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 952 953 954 955 956 957 958
904
959
905
960
Acknowledgments
906
Author contributions: All authors have participated in at least one aspect of the study (design, recruitment, testing, analyses, and writing); read and approved the manuscript for submission; and accept responsibility for the manuscript’s contents.
907 908 909 910 911 912 913
Q14 Q15
914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935
Q17 Q16
Financial/nonfinancial disclosures: None declared. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. *Writing Committee Members for the FDNY Sarcoidosis Clinical Research Group: Vasilios Christodoulou, BA (Bureau of Health Services, Fire Department of the City of New York, New York, NY); Zachary Hena, MD (Cardiology Division, Department of Pediatrics, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY); Steven M. Plotycia, MD (New York Eye and Ear Infirmary of Mount Sinai, Department of Ophthalmology, New York, NY); Israa Soghier, MD (Pulmonary & Critical Care Division, Jacobi Medical Center and the Albert Einstein College of Medicine, Bronx, NY); David Gritz, MD (Department of Ophthalmology, The John Hopkins Wilmer Eye Institute, Baltimore, MD); Dianne S. Acuna, MD (Bureau of Health Services, Fire Department of the City of New York, New York, NY); Michael D. Weiden, MD (Pulmonary & Critical Care Division, Department of Medicine, NYU School of Medicine, New York, NY; and Bureau of Health Services, Fire Department of the City of New York, New York, NY); Anna Nolan,
MD (Pulmonary & Critical Care Division, Department of Medicine, NYU School of Medicine, New York, NY; and Bureau of Health Services, Fire Department of the City of New York, New York, NY); Keith Diaz, MD (Bureau of Health Services, Fire Department of the City of New York, New York, NY); Viola Ortiz, MD (Bureau of Health Services, Fire Department of the City of New York, New York, NY); and Kerry Kelly, MD (Bureau of Health Services, Fire Department of the City of New York, New York, NY). Other contributions: During this study, Thomas K. Aldrich died of pancreatic cancer. He was more than just the principal investigator. He was a mentor and friend to all of us. He deeply believed in the importance of our work characterizing the health effects after the WTC attack on 9/11. He will be missed but never forgotten. We also thank Neeti Parikh for her eye examinations in this study.
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