700

Advanced Pulmonary Sarcoidosis

Rohit Gupta, MD1 Robert P. Baughman, MD2

1 Department of Thoracic Medicine and Surgery, Lewis Katz School of Address for correspondence Robert P. Baughman, MD, 1001 Holmes
Medicine at Temple University, Philadelphia, Pennsylvania Building, 200 Albert Sabin Way, Cincinnati, OH 45267
2 Department of Medicine, University of Cincinnati Medical Center, (e-mail: [email protected]).
Cincinnati, Ohio

Semin Respir Crit Care Med 2020;41:700–715.

Abstract At least 5% of sarcoidosis patients die from their disease, usually from advanced
pulmonary sarcoidosis. The three major problems encountered in advanced pulmonary
sarcoidosis are pulmonary fibrosis, pulmonary hypertension, and respiratory infec-
tions. Pulmonary fibrosis is the result of chronic inflammation, but other factors

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including abnormal wound healing may be important. Sarcoidosis-associated pulmo-
Keywords nary hypertension (SAPH) is multifactorial including parenchymal fibrosis, vascular
► pulmonary fibrosis granulomas, and hypoxia. Respiratory infections can be cause by structural changes in
► pulmonary the lung and impaired immunity due to sarcoidosis or therapy. Anti-inflammatory
hypertension therapy alone is not effective in most forms of advanced pulmonary sarcoidosis. New
► mortality techniques, including high-resolution computer tomography and 18F-fluorodeoxyglu-
► bronchiectasis cose positron emission tomography (PET) have proved helpful in identifying the cause
► fungal infections of advanced disease and directing specific therapy.

Sarcoidosis is a granulomatous disorder of unknown etiology ing pulmonary fibrosis. When addressing a sarcoidosis patient
which characteristically involves multiple organs and is with worsening dyspnea, one needs to be cautious of the
strikingly variable in presentation and progression. Pulmo- multisystem and variable nature of sarcoidosis. A thorough
nary involvement is responsible for the most morbidity, workup is needed to determine pulmonary disease or systemic
mortality, and health-care use, associated with sarcoidosis. etiology for this worsening (►Fig. 2). Presence of specific
In a study of a cohort of French sarcoidosis patients from features may lead to targeted therapy (►Table 1), but it is
2002 to 2011, chronic respiratory disease (20.3%), cardiovas- important to recall that more than one feature may be present.
cular disease (16.7%), and infectious disease (11.0%) were the Advanced pulmonary disease leading to death occurs in
main causes of death.1 In a detailed analysis of deaths in approximately 5% of patients with sarcoidosis.4–7 Respirato-
sarcoidosis patients over a 30-year period in the United ry failure accounts for as many as three quarters of deaths in
States, sarcoidosis was commonly cited as a cause of death the United States and Europe.2,3,8 While advanced lung
on death certificates.2 Retrospective population-based stud- disease can be defined variably, we will discuss the major
ies have identified that respiratory failure was the most pulmonary causes of death in sarcoidosis: pulmonary fibro-
common cause of death.3 In addition, mortality was found sis, sarcoidosis-associated pulmonary hypertension (SAPH),
to be >30% higher in African Americans than Caucasians.2,3 and respiratory infections.
Over half of the deaths for both races was attributed to causes
directly related to sarcoidosis, including respiratory failure,
Pulmonary Fibrosis
pulmonary hypertension, pulmonary fibrosis, pneumonia,
and heart failure.3 ►Fig. 1 summarizes the frequency of these Most patients with pulmonary sarcoidosis have clinical
five major reasons for African Americans and Caucasians. remission leaving minimal residual organ impairment with
Pulmonary involvement in sarcoidosis is highly variable favorable long-term outcomes. However, in the spectrum of
and unpredictable, ranging from asymptomatic cases and pulmonary sarcoidosis, up to 20% develop pulmonary fibro-
spontaneous remission to chronic progressive disease includ- sis and these patients have much poorer prognosis than the

Issue Theme Sarcoidosis: Advances in Copyright © 2020 by Thieme Medical DOI https://doi.org/
Therapy; Guest Editors: Robert P. Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0040-1709495.
Baughman, MD, and Marc Judson, MD New York, NY 10001, USA. ISSN 1069-3424.
Tel: +1(212) 760-0888.
 Advanced Pulmonary Sarcoidosis Gupta, Baughman 701

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Fig. 1 The frequency of the five most commonly cited causes of death related to sarcoidosis or therapy for African Americans versus
Caucasians.3

Fig. 2 Worsening symptoms in a patient with sarcoidosis could be multifactorial and need workup for accurate diagnosis and management. PE,
pulmonary embolism; PFT, pulmonary function test; TTE, transthoracic echocardiogram; RHC, right heart catheterization.

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702 Advanced Pulmonary Sarcoidosis Gupta, Baughman

Table 1 Management aspects in advanced pulmonary Table 2 IPF versus sarcoidosis pulmonary fibrosis
sarcoidosis
Idiopathic pulmonary Sarcoidosis pulmonary
Feature Assessment/treatment fibrosis fibrosis
Assessment of coexisting Immunosuppressive agents Most patients die from Only a small percentage
inflammation progressive fibrosis have progressive fibrosis
Prevention of progression Immunosuppressive agents Honeycombing in basilar Traction bronchiectasis
of fibrosis Antifibrotic agents and subpleural regions in upper lobes
Recognition and treatment Pulmonary hypertension Anti-inflammatory therapy Anti-inflammatory therapy
of complications of Infections has very limited role is useful in most patients
sarcoidosis Respiratory failure Acute exacerbations Acute events occur
Complications related to have a high morbidity frequently and usually
treatment and mortality are self-limited
Recognition and specific Cardiac dysfunction
Abbreviation: IPF, idiopathic pulmonary fibrosis.
treatment of comorbidities Pneumonia
which might or might not Pulmonary embolism
be related to sarcoidosis Asthma fluid correlate with chest radiograph stage. SAA may influence

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outcomes in sarcoidosis by mediating differentiation of profi-
Alleviation of symptoms Pulmonary rehabilitation
brotic alternatively activated macrophages.19
Oxygen supplementation
It is unlikely that a single pathway underlies all progres-
Prevention of Vaccination
sive fibrotic sarcoidosis phenotypes. Different pathways
complications due to Monitoring (laboratories,
disease or therapy imaging) might explain why treatment with immunosuppressants in
some patients is able to stabilize fibrotic disease in the face of
Increasing life expectancy Lung transplantation
evaluation previous progression, while in others the fibrotic process
appears more difficult to control, with ongoing progression
toward respiratory failure and death in a small minority.8
ones whose disease resolves.9 Fibrotic pulmonary sarcoido- The fibrosis of pulmonary sarcoidosis is considered quite
sis is generally diagnosed after a long-term follow-up in different from IPF (►Table 2). 12,20 The most important differ-
sarcoidosis patients but can be the presenting feature in ence is the outcome; most IPF patients eventually die from their
some patients.10,11 disease, while less than a quarter of patients with fibrotic
sarcoidosis die from respiratory failure.8,9 This is mostly
Pathophysiology because of the differences in the underlying cause of
Persistent granulomatous inflammation is likely to be only the fibrosis. In sarcoidosis, the inflammation appears to be
one of the drivers of the fibrotic process as not all patients the major cause of fibrosis. It is worth mentioning that there are
with granulomas develop fibrosis. There is evidence that cases and explant studies which reported coexisting usual
alveolitis known to precede granulomatous changes may interstitial pneumonia (UIP) pattern in patients with end-stage
play a key role in the development of fibrosis in pulmonary sarcoidosis.21–23 In this situation, abnormal wound healing may
sarcoidosis.12,13 In one study, there was overexpression of be the cause of fibrosis or that sarcoidosis patients may develop
genes regulating immune activation in transbronchial biop- other lung diseases accounting for their end-stage fibrosis.20 It
sies from fibrotic sarcoidosis patients and persistent T-cell has also been suggested that “combined sarcoidosis and IPF”
response resembling chronic hypersensitivity pneumonitis (CSIPF) is a distinct phenotype defined by clinical and histolog-
and not idiopathic pulmonary fibrosis (IPF).14 ical features of sarcoidosis and high-resolution computed
Another plausible mechanism of fibrosis could be abnormal tomographic (HRCT) scan features of possible or definite UIP
inflammatory pathways with respect to persistence of inflam- or UIP by histopathology, with similar outcomes as IPF.24
mation (failure to downregulate) and dysregulation in the
healing process.15 Augmented transforming growth factor-β Clinical Features
(TGF-β) activity, macrophage phenotype switching, and a Th1 Clinical features of fibrotic pulmonary sarcoidosis are not
to Th2 transition may be important reasons for the failure of specific and include dyspnea (80%), chronic cough, and
resolution of the granuloma.16,17 A defect in regulatory T-cells hemoptysis. Crackles, wheezing, and digital clubbing are
(Treg), a subset of lymphocytes which downregulate inflam- present in some patients. While dyspnea and cough can
mation has been reported in sarcoidosis, with an imbalance occur in fibrotic and nonfibrotic pulmonary sarcoidosis,
between anti-inflammatory Treg and proinflammatory Th17 wheezing is more common in those with fibrosis, where it
cells, the latter found to be upregulated in the periphery and is attributed to airway-centric fibrosis.25 Fibrotic disease is
the lungs of patients with sarcoidosis.18 Serum amyloid A more common in African Americans than Caucasians.26
(SAA), an acute phase protein, is highly increased in sarcoidosis
tissues and has been observed to upregulate cytokine Pulmonary Function Testing
responses in sarcoidosis bronchoalveolar lavage (BAL) cells. Restrictive ventilatory defect and a reduction in diffusing
This occurs in part through stimulation of toll like receptor-2 capacity are the most common abnormalities in patients
(TLR2). Interestingly, measurements of SAA in sarcoidosis BAL with fibrotic pulmonary sarcoidosis.27 Extent of disease on

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 Advanced Pulmonary Sarcoidosis Gupta, Baughman 703

HRCT correlates with level of restriction.28 Obstruction in Fibrotic cysts, bullae, traction bronchiectasis, and para-
sarcoidosis can be multifactorial and due to airway distortion cicatricial emphysema (air space enlargement and lung
and luminal disease. It is more likely to occur in fibrotic lung destruction developing adjacent to areas of pulmonary scar-
disease.29–31 The extent of reticulation (including honey- ring) represent advanced fibrotic sarcoidosis. Honeycombing
combing) rather than air trapping was found to be stronger may occur in fibrotic sarcoidosis, usually affecting the upper
radiographic predictor of airflow obstruction in one study.25 and perihilar regions and tends to be macrocystic.34–37
In another study of chest X-ray staging, obstruction was Inflammatory lesions are evidenced by positive pulmo-
significantly associated with stage-IV disease.32 nary 18F-fluorodeoxyglucose positron emission tomogra-
The relationship between pulmonary function and out- phy (PET) findings in up to 85% of advanced pulmonary
comes in sarcoidosis may differ from that in IPF. In a review of sarcoidosis (►Fig. 4).38,39 The presence of increased PET
patients awaiting lung transplantation, those with sarcoido- activity in lung has been found to correlate with response
sis had a significantly lower forced vital capacity (FVC) and to anti-inflammatory therapy.40,41
forced expiratory volume in 1 second (FEV1) yet required less
supplemental oxygen compared with those with IPF.33 No- Pathologic Findings
tably, functional limitation and survival were similar be- Sarcoidosis granulomas either resolve or heal by fibrosis of
tween the groups. individual granulomas or small groups of confluent granulo-

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mas. In 10 to 30% of cases the lungs undergo progressive
Imaging fibrosis, which, in some cases, results in end-stage “honeycomb
On chest X-ray, linear opacities radiating laterally from the lung” characterized by parenchymal fibrosis, bronchiolectasis,
hilum into the middle and upper zones are characteristic. and enlarged and dilated air spaces. Honeycombing may be
The hila are shifted upward, and vessels and fissures are accompanied by pulmonary hypertensive arteriopathy.
distorted.34 Emphysema, sometimes bullous, may develop possibly by
HRCT provides more details regarding fibrotic changes seen airspace dilatation and rupture secondary to granulomatous
in sarcoidosis (►Fig. 3).25,28 On HRCT, fibrotic changes are bronchostenosis, airspace dilatation and rupture at the periph-
represented by fibrous bands, hilar retraction, displacement of ery of fibrotic and collapsed lung tissue, and destruction of
fissures, and irregular reticular opacities, including intralob- alveolar walls by alveolitis.42 Cavitation rarely occurs in sar-
ular lines and irregular septal thickening. Fibrosis is seen coidosis and radiographic cystic changes seen in advanced
predominantly in the upper and middle lobes, in a patchy pulmonary sarcoidosis, sometimes interpreted as cavitation,
distribution. A common feature of fibrotic sarcoidosis is the are thought to reflect the presence of either or both saccular
presence of conglomerated masses surrounding and encom- bronchiectasis and bullous emphysema.43
passing vessels and bronchi leading to deformation. It occurs in Granulomatous distribution along the lymphatic routes is
60% of fibrotic sarcoidosis and is associated with bronchial the scaffold for the fibrotic changes. They may form large
distortion. There are three CT patterns of fibrosis described, conglomerates resulting in perihilar and parenchymal masses,
namely, bronchial distortion, marked by traction bronchiecta- which may create a mechanical stretch responsible for gradu-
sis and airway angulation; honeycomb pattern; and linear ally progressive fibrotic changes.44 Peribronchovascular fibro-
fibrosis in 40, 26, and 14% of cases, respectively. There might be sis is likely the result of peribronchovascular localization of
functional correlation of these radiographic patterns; FEV1 granulomas and is likely responsible for bronchial distortion
was most reduced in bronchial distortion, whereas the total marked by traction bronchiectasis and airway angulation.45–47
lung capacity and diffusing capacity for carbon monoxide There appear to be three types of end-stage sarcoid lung
(DLCO) were most reduced with honeycombing. However, diseases.13,20,21,24 The first is the “active type” with multiple
patients often have an overlap of patterns.27 cellular granulomas causing widespread parenchymal disease.

Fig. 3 Imaging findings in fibrotic pulmonary sarcoidosis. HRCT images show predominantly upper lobe abnormalities including reticular and
cystic changes and traction bronchiectasis (A), airway distortion (B), ground glass changes (C), and subpleural bullous changes.

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704 Advanced Pulmonary Sarcoidosis Gupta, Baughman

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Fig. 4 PET finding of active inflammation in pulmonary sarcoidosis. Conglomerate mass/fibrosis seen on CT (A) which has avid fluorodeox-
yglucose uptake on corresponding PET canning (B). CT, computed tomography; PET, positron emission tomography.

The next is “fibrotic type” with fibrotic granulomas limited chronic increase in disease activity or relapse of disease in a
to small clusters of macrophages with few lymphocytes patient with remission or worsening symptoms in an other-
embedded in the fibrotic scar. This is also characterized by wise stable end stage patient. These were sometimes related to
the presence of honeycombing; however, the large cysts were infection, particularly in patients with bronchiectasis.53
observed with a central preponderance in contrast with the Other types of clinical progression include slow progression
subpleural honeycombing in UIP, and fibroblast foci are rare or of pulmonary fibrosis, development of complications like
absent. Finally, a fibrotic pattern, with UIP features including pulmonary hypertension, hemoptysis because of aspergilloma,
fibroblastic foci and subpleural honeycombing has been and other possibly related issues like left cardiac dysfunction or
described.21,24 pulmonary embolism.2,3,54 A significant proportion of patients
may improve with treatment or stabilize.
Monitoring and Prognosis Survival is lowered, and most fatalities result from refrac-
In a retrospective review from France, a 10-year mortality rate tory pulmonary hypertension, chronic respiratory insuffi-
of 16% in patients with fibrotic sarcoidosis was significantly ciency, or massive hemoptysis.8 ►Table 3 summarizes the
higher than that projected for the general population of a mortality for three studies across Europe and United States.
similar age.8 The extent and stability of fibrosis and the While they all report a significant mortality for stage-4
development of secondary complications are likely important pulmonary sarcoidosis, the overall mortality for fibrotic
determinants of survival in fibrotic sarcoidosis. Once patients pulmonary sarcoidosis is less than 25%.
are sick enough to be listed for lung transplant, mortality rates Predicting which patients will die from pulmonary sarcoid-
are high and similar to those for patients listed for IPF.33 osis would be very helpful for elaborating recommendations for
Longitudinal monitoring by pulmonary function testing management of fibrotic pulmonary disease. Recently, an algo-
and imaging may provide useful management and prognostic rithm captured the severity of pulmonary impairment using the
information.48 Serial comparison of pulmonary infiltration in composite physiological index (CPI), a score used for survival
serial X-rays is more significant than a change in radiographic prediction in IPF, and an estimation of fibrosis extent on CT and
stages.49,50 Pulmonary function can remain stable in fibrotic an estimation of pulmonary hypertension through the measure
sarcoidosis over periods of observation (1–20 years). In one of main pulmonary artery diameter (Walsh’s model), was
study of patients with stage-IV disease, nearly 40% patients shown to be highly predictive of survival.5 Another study
improved.8 Serial spirometry, particularly forced vital capaci- confirmed the Walsh model but found that pulmonary hyper-
ty, is the most reliable tool as evidenced by the good agreement tension and the presence of more than 20% fibrosis on HRCT
with serial CT used as a morphologic reference. Addition of were independent predictors of mortality.4
serial chest radiography and DLCO did not improve accuracy of
spirometry. However, when a decline occurs, chest radiogra- Management
phy is indispensable to elucidate its mechanism.51 Treatment of advanced pulmonary sarcoidosis is challenging,
Acute clinical worsening is frequent. In one prospective as there is no major large prospective studies in this popula-
study of fibrotic pulmonary sarcoidosis, the mean number of tion of patients. Immunosuppressive therapy may still be
events was three per year.52 These episodes reflect an acute on effective in treating patients with fibrotic disease. In one

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 Advanced Pulmonary Sarcoidosis Gupta, Baughman 705

Table 3 Mortality for stage-4 sarcoidosis

Study Total number Number with Duration of Overall Mortality of

of patients Stage-4 disease follow up, median mortality (%) stage 4 (%)
n (%) or mean (y)
Nardi et al8 142 142 (100) 7 11 11
Walsh et al5 503 503 (100) 4.2 21 21
4
Kirkil et al 452 78 (17.3) 7 8.40 16.63

analysis, a third of patients showed improvement and an Increased levels of serum KL-6, a marker of alveolar epithe-
additional fifty percent stabilized after increased immuno- lial damage increased in several fibrotic interstitial lung dis-
suppression.8 ►Table 4 summarizes factors which may pre- eases (ILDs), including IPF and scleroderma-associated ILD,
dict a response or nonresponse to immunosuppressive have been correlated with increased parenchymal involve-
therapy. ment in patients with sarcoidosis although further studies are
A commonly used method is to give a 1- to 2-month needed to ascertain whether Krebs von den Lungen 6 (KL-6) is
a marker of progressive fibrotic sarcoidosis.61–63 Both fibrotic

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regimen of high-dose prednisone or anti–tumor necrosis
factor (TNF) therapy to determine responsiveness. Studies sarcoidosis and IPF lungs are characterized by an increase in
have shown that improvement in FVC is seen within 2 weeks myeloid related protein 14 (MRP14), a molecule shown to
of initiating or increasing prednisone therapy.55,56 Inflixi- promote fibroblast activation, also correlated with chest ra-
mab therapy improves chest X-ray and FVC within 6 weeks diograph stage in sarcoidosis.64 These biomarkers have not
(►Fig. 5).57 Therefore, a patient who has not responded been useful in clinical practice yet. An elevated soluble inter-
within 2 months of intensive therapy is not likely to improve leukin-2 receptor (sIL-2r) has been found to be a marker of
with more prolonged treatment. ongoing inflammation65,66 and may be an indication for anti-
In established fibrosis, some CT findings point to coexisting inflammatory therapy. On the other hand, elevated angioten-
active inflammation, for example, clusters of small nodules sin converting enzyme (ACE) levels do not predict response to
and interstitial or peribronchial opacities without architectur- anti-inflammatory therapy.67
al distortion.27,58 Mostard and colleagues reported increased Targeted treatment options are being developed for
uptake on PET scanning in patients with underlying fibrosis.59 progressive fibrotic sarcoidosis. A recent report of progres-
The fluorodeoxyglucose PET signal has also been shown to sive fibrotic lung disease, including patients with sarcoido-
correlate with established functional and serological markers sis, found that nintedanib significantly slowed progression
in assessing both disease activity and response to therapy, with of disease compared with placebo.68 Pirfenidone (another
reductions in PET signal associated with improvements in antifibrotic) was shown to decrease disease progression and
symptoms and pulmonary function data.40,60 decreased deaths in IPF with acceptable side effect profile.69
A phase-IV study of pirfenidone is underway to assess the
response of this antifibrotic to determine time to clinical
Table 4 Predictors of response to anti-inflammatory therapy in worsening (timeframe of 2 years) in fibrotic pulmonary
fibrotic sarcoidosis patients sarcoidosis (clinical study identifier, NCT03260556).
Treatment of some of the complications of fibrotic pul-
Responders Nonresponders monary sarcoidosis is discussed in detail further. Supportive
HRCT Reticulonodular Traction bronchiectasis aspects of therapy are important to consider, for example,
pattern oxygen supplementation, pulmonary rehabilitation, and vac-
Ground glass Subpleural cinations. Most of these are practice-based recommenda-
opacities honeycombing tions and need further evaluation in the field of pulmonary
Airway distortion sarcoidosis.

Bullous changes
Lung Transplantation in Advanced (“End Stage”)
Conglomerate masses Pulmonary Sarcoidosis
PET Increased As in other aspects of sarcoidosis, evidence-based data on
scanning uptake in lung lung transplantation (LTx) in sarcoidosis are not ideal but
Serum High s-IL2 level continue to grow. In addition, different combinations of
markers organ transplantation based on the organ involvement in a
Response Improvement particular sarcoidosis patient, for example, lung–liver, lung–
to therapy with short-term kidney, and heart–liver, can be done if needed. Sarcoidosis
intense represents 2.5% of all indications for lung transplantation,70
immunosuppression with long-term outcomes matching those obtained for other
Abbreviations: HRCT, high resolution somputed tomography; IL, inter- conditions (median survival of 8.5 years in those patients
leukin; PET, positron emission tomography. surviving to 1 year according to the International Society for

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706 Advanced Pulmonary Sarcoidosis Gupta, Baughman

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Fig. 5 (A) CT showing predominantly fibrotic changes. (B) Improvement of disease on follow up CT after 3 months of infliximab therapy. CT,
computed tomography.

Heart and Lung Transplantation [ISHLT] database; www. exhausted for patients with either resting hypoxemia at
ishlt.org/registries/).71 Sarcoidosis patients may experience rest, mean pulmonary artery pressure at least 35 mm Hg, or
a significantly poorer survival in the 30 days posttransplan- right atrial pressure at least 15 mm Hg, which have been
tation period and during first year of follow-up. End-stage associated with increased mortality on the waiting list.78
fibrotic disease is associated with more difficult surgical A recent single-center study found that increased bilirubin,
pleural dissections and thus a higher risk of postoperative higher CPI, and reduced DLCO and FEV1/FVC at trans-
hemothorax. An increase in rate of hemothorax, decreased plant listing (but not pulmonary hypertension) were pre-
ventilator-free days, increased length of stay in intensive care dictors of death on the transplant list.79 Sudden death was
unit (ICU), and hospital have been shown in LTx for sarcoid- found to be high (18%) amongst sarcoidosis patients listed
osis.72,73 Despite a significantly higher risk of primary graft for LTx and was more common than that for COPD or IPF
dysfunction compared with other lung transplantation patients.
recipients, increased short-term mortality may just be relat- Bilateral lung transplantation has been preferred over
ed to other confounders, including the likelihood of heart– single transplantation, based on patients’ age, the presence
lung transplantation and being African American.74 There of associated pulmonary hypertension, suppurative bronchi-
was no difference in the incidence of acute and chronic ectasis, and technical reasons. Pleural thickening and adhe-
rejections in the sarcoid population in the largest cohort in sions, especially in the presence of aspergilloma, as well as
the literature. An analysis of 695 cases of LTx for sarcoidosis mediastinal, hilar fibrosis make surgery trickier. Despite a
over a 25-year time period (3.3% of 20,896 LTx recipients pejorative effect on posttransplantation survival,80 aspergil-
overall) showed similar median survival rates compared loma should not definitely disqualify potential transplanta-
with the nonsarcoidosis LTx recipients.75 Regression analysis tion candidates. Pretransplantation and posttransplantation
did not identify sarcoidosis as an independent factor for aggressive medical antifungal therapy is promoted by several
survival post LTx. Moreover, sarcoidosis LTx recipients did authors, whereas others recommend irrigating the pleural
not have higher incidences of bronchiolitis obliterans syn- space with amphotericin B–enriched solution after implan-
drome (BOS) or recurrent hypoxemia after LTx, and seemed tation to avoid the risk of contamination.
to have lower rates of redo LTx, despite the potential of While histopathologic recurrence in the allograft is
sarcoidosis recurrence after LTx.75 frequently documented on surveillance bronchoscopies
The optimal timing for LTx in sarcoidosis is difficult to (14–35%), it is usually asymptomatic, without major effect
discern as quantitative models predicting mortality in on functional parameters and survival, and easy to control
sarcoidosis are lacking and functional parameters might with medical therapy.81–83 Based on studies, based on donor/
not reflect clinical behavior of disease.76 Improperly recipient chimerisms, recurrent granulomas appear to origi-
delayed transplantation consideration may explain the rel- nate from the host immune cells migrating into the new
atively high death rates observed for listed sarcoid patients organ.84,85 Recurrence of granulomas can be considered
(53% in a single-center U.S. based study and 27.4% in the “clinically irrelevant granulomatosis,” life-long posttrans-
United Network for Organ Sharing [UNOS] database).77,78 plantation immunosuppression probably allows sufficient
Referral appears reasonable after medical therapy is disease control and prevents fibrosis in most patients.

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Table 5 Common causes of sarcoidosis associated pulmonary multiple factors,94 it has been placed in World Health
hypertension Organization (WHO) group V.
Patients with moderate to severe pulmonary hyperten-
Vascular disease sion have reduced survival.95 As noted earlier, pulmonary
Granulomatous vascular involvement hypertension is an independent risk factor for mortality in
Venoocclusive disease sarcoidosis.4 It has been shown that precapillary pulmonary
hypertension has significantly higher mortality than pulmo-
Pulmonary embolism
nary hypertension associated with left ventricular disease.89
Interstitial lung disease Therefore, sarcoidosis patients with advanced pulmonary
Parenchymal lung disease due to fibrosis and/or granulomas disease should be evaluated for pulmonary hypertension.
Hilar and mediastinal distortion
Screening
Pulmonary artery extrinsic compression
Almost all patients with SAPH are dyspneic. In an asymp-
Fibrosing mediastinitis tomatic SAPH patient, therapy would probably not be indi-
Extra pulmonary disease cated. Therefore, dyspnea has a high negative predictive
Left ventricular dysfunction value. ►Table 6 lists the most commonly used methods for

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screening for pulmonary hypertension.
Sleep apnea
The 6-minute walk test (6MWT) is commonly used to
Liver disease screen for SAPH. SAPH is an independent predicter of a
reduced 6-minute walk distance (6MWD).96,97 Most patients
Sarcoidosis Associated Pulmonary with clinically significant SAPH have a 6MWD of less than
Hypertension 300 to 450 m. However, reduced 6MWD can be seen due to
multiple other factors, including parenchymal lung disease,
SAPH is a major cause of morbidity and mortality in sarcoid- muscle weakness, fatigue, and cardiovascular disease.98
osis. The incidence ranges from 5 to 70%, depending on which Desaturation during a 6MWT is a more specific indicator
population is studied. Several general surveys of sarcoidosis of SAPH.88 However, desaturation can still occur due to other
patients have reported between 5 to 20% of patients in a factors.
sarcoidosis clinic to have SAPH.86 The high incidence was Serum B-type natriuretic peptide (BNP) is a marker of
reported in sarcoidosis specialty clinics, which often consist cardiac decompensation. It has been noted to be elevated in
of more severe disease.87,88 In patients with persistent some patients with pulmonary hypertension, including
dyspnea despite anti-inflammatory therapy, the incidence SAPH.87 However, elevated BNP can also be seen in conges-
is about 50%.89,90 In series of sarcoidosis patients listed for tive heart failure due to left ventricular disease. It can also be
lung transplant, over 70% were found to have SAPH.91,92 normal in compensated heart failure due to pulmonary
Pulmonary hypertension in sarcoidosis can be due to many hypertension.
factors. ►Table 5 lists some of the more common factors Chest imaging, especially HRCT, is commonly performed
associated with SAPH.93 Since sarcoidosis can be caused by in evaluating sarcoidosis. It has been noted that main

Table 6 Screening for sarcoidosis-associated pulmonary hypertension

Sensitivity Specificity Relative Comments

cost
History of dyspnea þ4 þ2 þ1 An asymptomatic patient unlikely to have
clinically significant PH
Reduced 6-minute þ3 þ2 þ2 Reduced distance usually multifactorial
walk disease
Desaturation with þ3 þ3 þ2 Goes with 6-minute walk test
6-minute walk test
Serum BNP þ2 þ2 þ3 Incomplete data
MRI heart þ3 þ3 þ4 Minimal data
Measurement of aorta for þ3 þ3 þ3 May not be as accurate as in other conditions
pulmonary artery ratio
Echocardiogram þ3 þ3 þ3 Not sensitive for mild PH. Cannot distinguish
type of PH. RV dysfunction useful information,
but not well quantitated
Right heart catheterization þ4 þ4 þ4 Considered the gold standard for assessing
pulmonary hypertension

Abbreviations: BNP, B-type natriuretic peptide; MRI, magnetic resonance imaging; PH, pulmonary hypertension; RV, right ventricle.

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708 Advanced Pulmonary Sarcoidosis Gupta, Baughman

pulmonary artery to aorta ratio of greater than one predicts been with bosentan. That study demonstrated significant
pulmonary hypertension.99 Correcting for body mass index improvement in hemodynamics but not in 6MWD for the
may improve the predictability of this ratio.100 However, not bosentan group versus placebo-treated patients.102 ►Table 7
all groups have found the ratio as reliable in SAPH.101 summarizes several reports that examined single-treatment
Transthoracic echocardiogram (TTE) is one of the most regimens and the results of hemodynamics, 6MWD, and
widely used tests to assess for pulmonary hypertension. It is health-related quality of life (HRQoL) when reported. In general,
widely available and safe. If a tricuspid regurgitant (TR) jet can hemodynamic parameters often improve in these short studies,
be visualized, an estimate can be made of the systolic pulmo- but most studies do not show changes in 6MWD or HRQoL.
nary artery pressure. However, a TR jet is not seen in up to a Several studies have reported the results of using one or
third of TTEs. Another limitation of the estimate of the PA more treatment of SAPH patients for longer periods of
systolic pressure is that it assumes a normal right atrial time.87,95,103 One large series found significant improvement
pressure. Other factors can influence the TR jet, so that the in BNP but no improvement in 6MWD or survival.104 While
estimated PA systolic pressure has been shown to have limited some patients may have improvement of 6MWD after a year
value for detecting pulmonary hypertension in sarcoidosis and or more of therapy, it appears to be more likely to occur in
other interstitial lung diseases. TTE can also provide evidence those patients with only mild to moderate restriction (FVC of
for right heart dysfunction and support the diagnosis of 55% predicted or greater).103

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pulmonary hypertension. The presence of pulmonary hyper- Two recent large registries have reported on SAPH in
tension by TTE is not the same as precapillary pulmonary France, the United States, Europe, and Middle East.95,105
hypertension; this requires hemodynamic measurements. These two registries found that many patients had moder-
Since treatment and clinical outcome are different for pulmo- ate–to-severe pulmonary hypertension. Most patients were
nary hypertension due to left ventricular dysfunction and treated with vasodilator therapy. ►Fig. 6 summarizes the
precapillary pulmonary hypertension, right heart catheteriza- frequency of the three major treatment classes for these
tion remains a crucial part of evaluation on SAPH.89 studies. There is some geographical variation of medications
Cardiac MRI can evaluate right ventricular function. It used to treat SAPH. In the French registry, the endothelin
therefore may help to detect pulmonary hypertension. While receptor antagonists were the most commonly used. For
this is a promising technique, it has not yet been widely used. other areas of world, phosphodiesterase-5 inhibitors were
more commonly used. It should be noted that nearly a third
Therapy of the U.S. patients were given no specific therapy for their
There have been several studies of specific therapy for SAPH. SAPH. Ongoing studies are evaluating other treatments for
The only double-blind randomized study reported to date has SAPH. These include a trial of riociguat (NCT02625558).

Table 7 Evidence for treatments of SAPH

Drug Study and RHC 6MWD HRQoL

study type
Prostacyclines
Epoprostenol/ Bonham et al130 Improvement Significant improvement in RHC
trepostenol and RCS
Inhaled iloprost Baughman et al131 6/15 with 3/15 with Significant improvement
and PCS improved >30 m improvement in SGRQ activity
hemodynamic
Endothelin receptor
antagonist
Bosentan Baughman et al102 Significant No change No change SGRQ
and DBPC improved
hemodynamics
versus placebo
Ambrisentan Judson et al132 Not studied No change No significant improvement
and PCS in SGRQ
Phosphodiesterase-
5 inhibitor
Sildenafil Milman et al92 Significant No change Not studied
and RCS improvement
Tadalafil Ford et al133 Not studied No change No change in SGRQ
and PCS

Abbreviations: 6MWD, 6-minute walk distance; DBPC, double blind placebo controlled study; HRQoL, health related quality of life; PCS, placebo-
controlled study; RCS, randomized controlled study; RHC, right heart catheterization; SAPH, sarcoidosis-associated pulmonary hypertension; SGRQ,
St. George’s Respiratory Questionnaire.

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 Advanced Pulmonary Sarcoidosis Gupta, Baughman 709

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Fig. 6 Use of medications in SAPH based on region from international registries, France,). ERA, endothelin receptor antagonist; nonUS, England,
Netherlands, and Saudi Arabia; PDE-5, phosphodiesterase 5 inhibitor; SAPH, sarcoidosis-associated pulmonary hypertension; US, United States.

Some of these infections occur during the course of the disease

and are difficult to differentiate clinically and pathologically
from underlying sarcoidosis.
The immune status in sarcoidosis is “paradoxical.”Although
the local inflammatory is characterized by a proinflammatory
Th1 profile, there is also an anergic state, as shown by the
suppression of the tuberculin response.18 Lymphopenia and
neutropenia,106 imbalances between Treg and T17 cells, and
abnormal monocyte recruitment have been described in
literature.107
In a study of 129 sarcoidosis patients with pulmonary
fibrosis, patients had, on an average, three acute worsening
events in the prior year mostly due to viral or bacterial
infections.52 Those with worsening sarcoidosis were more
likely to be on some immunosuppressive agents, especially
infliximab, suggesting that many acute worsening events
may have been related to impaired immunity due to the
immunosuppressive medications. Patients who had bron-
chiectasis had a higher rate of worsening events over the
prior year. No correlation was found between number of
events and baseline FVC or FEV1/FVC ratio, as well as no
difference in the number of events, when race, sex, age, or
smoking history were taken into account.
The pathophysiology of infections in sarcoidosis is illustrated
in ►Fig. 7. There is still a need for more research to understand
Fig. 7 Pathophysiology of infections in sarcoidosis.
the risk factors and determine optimal management strategies.
Sarcoidosis patients can have bronchiectasis leading to obstruc-
Respiratory Infections tion and infections, specifically recurrent bacterial, atypical
mycobacterial, and fungal infections. Chronic pulmonary
While microbial causation of granulomatous inflammation in aspergillosis occurs most commonly in fibrotic pulmonary
sarcoidosis continues to be under investigation, it is well sarcoidosis. Immunodeficiency related to sarcoidosis itself or
known that infections can complicate the course of sarcoidosis. medications given to treat it, can contribute to development of
Infections are a leading cause of mortality in sarcoidosis.1,3 infections. But primary immunodeficiency, namely, common

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710 Advanced Pulmonary Sarcoidosis Gupta, Baughman

variable immunodeficiency (CVID) and its late-onset counter- mainly associated with corticosteroid treatment.113 Another
part (LOCID), can cause granulomatous lung disease and recur- review of 280 cases between 1974 and 2014 concluded that
rent infections need to be considered as well.108 In spite of OI are rare in the setting of sarcoidosis. Most patients were
CD4 þ T-lymphocytopenia and treatment-induced immune receiving steroid therapy but a substantial number of infec-
suppression, the risk of severe or opportunistic infection (OI) tions occurred, while the patients were not receiving any
is not usually considered to be higher in sarcoidosis than in treatment and the mean blood CD4 rate did not seem to
general population but this is still being debated.107,109,110 influence the risk of infections. For some infections, mostly
tuberculosis, epidemiologic and geographic factors need to
Spectrum of Opportunistic Infections in Sarcoidosis be considered strongly.107
Multiple microbes have potential to cause disease in sarcoid- A large retrospective cohort study of 585 patients with
osis patients based on the underlying disease, airway distor- sarcoidosis in a tertiary referral specialist clinic in France
tion, bronchiectasis, and immunosuppression (►Table 8). compared 29 patients (4.9%) with severe infections to 116
Anti–TNF therapy has been associated with a marked in- control patients with sarcoidosis, matched according to their
creased risk for mycobacterial infection.111 However, corti- gender, ethnicity, age at diagnosis, and treatment with
costeroids remain the major risk factor for opportunistic corticosteroids. Overall, 38 severe infections (mycobacterial
infections.109 infections [n ¼ 14], fungal infections [n ¼ 10], bacterial
[n ¼ 8], viral [n ¼ 3] and parasitic (n ¼ 1]) were observed in

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Data on OI in sarcoidosis comes from case reports, case
series, and retrospective reviews. The data are divided on the 30 patients (5.1% of the patients, 0.71% persons-year) after a
real incidence of OI in sarcoidosis, as well as whether sarcoido- median follow-up of 8 years. Risk factors included neurolog-
sis itself is a risk factor for infections, or other factors play a ical or cardiac involvement of sarcoidosis, the use of immu-
bigger role, especially immunosuppression. Winterbauer and nosuppressive agents and mainly cyclophosphamide.114
Kraemer reported five (4.1%) OI with three cases of pulmonary Few studies have specifically looked at particular infec-
aspergilloma, one case of pulmonary tuberculosis and one tious agents in sarcoidosis. ►Table 9 summarizes a few of
patient with disseminated herpes zoster infection in a cohort such studies targeting fungal infections (not specifically
of 122 patients over 7.2 years.112 Rubinstein et al did not report looking at aspergillus) in sarcoidosis. Some parasitic (e.g.,
any infection in 197 sarcoidosis patients followed for 18 months Leshmania) and fungal (e.g., Histoplasma and Rhodococcus)
in the 1980s.110 infections have been described in patients after travel to
A systematic literature review conducted between 1966 endemic areas. Jamilloux et al reported 10 cases of progres-
and 2004 documented 65 cases reports of sarcoidosis com- sive multifocal encephalopathy (PML) associated with sar-
plicated by OI. Cryptococcus was the most reported infection coidosis and 20 observations from the literature. They noted
with 41 cases (59%) followed by mycobacterial infections that PML was often misdiagnosed, it is not associated with
(13%), nocardiosis (11%), histoplasmosis and pneumocysto- severe CD4 lymphopenia and has a high fatality rate is high in
sis (9%), and aspergillosis (7%). Except for cryptococcosis, the comparison with PML associated with other conditions.115
authors concluded that sarcoidosis by itself was not a risk Opportunistic infections presenting with extrapulmo-
factor for OI and proposed that opportunistic infections were nary features might be misdiagnosed as new localizations
of sarcoidosis unless careful exclusion of infectious mecha-
Table 8 Common infections and risk factors in sarcoidosis nism is undertaken (e.g., PML, cryptococcosis, and nocardio-
sis). Atypical symptoms are encountered more frequently in
Type Examples Risk factors immunocompromised patients as well and add to the diffi-
Bacterial Streptococcus pneumoniae Immunosuppression culty in recognition of these. Hence infections should be kept
Haemophilus influenzae Airway distortion in differential diagnosis when sarcoidosis patients worsen on
Bronchiectasis immunosuppression and workup should be aggressively
Legionella Immunosuppression targeted toward them based on the level of immunosuppres-
Nocardia
sion and endemic characteristics.
Mycobacterial Mycobacterium tuberculosis Anti-TNF therapy
Atypical mycobacteria Bronchiectasis Chronic Pulmonary Aspergillosis
Immunosuppression
Chronic pulmonary aspergillosis (CPA) includes several dis-
Fungal Histoplasmosis Anti-TNF therapy ease patterns, including aspergilloma, Aspergillus nodules,
Cryptococcus Corticosteroids
Blastomycosis
chronic cavitary pulmonary aspergillosis, and chronic fibros-
Coccidioidomycosis ing pulmonary aspergillosis.116 The most common of these
Aspergillosis Corticosteroids patterns is mycetoma in patients with sarcoidosis. Myceto-
Bronchiectasis mas are masses of fungal mycelia, most commonly of the
Pneumocystis Corticosteroids Aspergillus genus (most commonly A. fumigatus), that colo-
Viral Varicella zoster virus Corticosteroids nize preexisting lung cavities.117 The burden of mycetomas
Human herpes virus 8 in patients with advanced pulmonary sarcoidosis is uncer-
JC virus tain but it is estimated to be present in 3 to 12% of cases.116
Cytomegalovirus
Although mycetomas are usually the result of colonization by
Abbreviation: TNF, tumor necrosis factor. Aspergillus spp. they may occasionally be produced by other

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 Advanced Pulmonary Sarcoidosis Gupta, Baughman 711

Table 9 Comparison of case studies of invasive fungal infections in sarcoidosis

Study Specific Type of study Number Duration Number Comments

(year) infection of patients of study and type
Rubinstein Fungal Retrospective, 197 11.7 years 0 Perhaps ethnic or environmental
et al infections single center factors or both exist in the
(1985)110 in Israel pathogenesis of invasive fungal
infections in pulmonary sarcoidosis
Baughman Fungal Retrospective, 753 18 months 7 (0.9%): All patients were on
and Lower infections single center histoplasma,2 immunosuppressive therapy
(2005)109 in USA blastomyces,2 All responded to antifungal therapy
cryptococcus3
Bernard Cryptococcus Retrospective 18 cryptococcosis 6 years 1/3 cases in patients without
et al case control, cases with sarcoidosis immunosuppressive therapy
(2013)134 multicenter compared with 36 Not associated with severe CD4
nation-based sarcoidosis patients lymphocytopenia
study in France without cryptococcosis 89% responded to antifungal
therapy

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fungi, including Candida, Pseudoallescheria, Scedosporium, these patients,121 although the results seem to be getting
Coccidioides, and Monosporium, as well as Nocardia, a bacte- better.122 Bronchial artery embolization can terminate life-
rial microorganism. As only a proportion of patients with threatening bleeding and/or or prevent recurrent episodes of
sarcoidosis-related parenchymal destruction develop Asper- large hemoptysis. However, revascularization commonly
gillus infection, research into the role played by the host’s occurs that often leads to future recurrent bleeding.123
immune factors is needed. Mycetomas are usually asymp- Systemic antifungal therapy with amphotericin B is ineffec-
tomatic, but patients might present with hemoptysis, which tive for mycetoma because of inadequate drug penetration.124
can range from minimal to massive and life-threatening.118 Although azoles achieve adequate fungicidal levels within the
Underlying fibrocystic sarcoidosis is a risk factor for life- aspergilloma, they are ineffective as an acute treatment for
threatening hemoptysis from mycetomas.119 mycetomas because effective therapy must exceed 6 months
Mycetomas are found almost exclusively in patients with duration and few patients have a complete response.125 Use of
stage-4 sarcoidosis. Early studies stressed the increased mor- itraconazole, voriconazole, and caspofungin has been associ-
tality associated with disease.119 More recent studies suggest ated with symptomatic improvement and even complete
that mycetomas may be controlled with therapy. In a single- resolution in some patients.126 In a randomized controlled
center retrospective study from a large tertiary center in trial, itraconazole was superior to supportive care alone for
France, the increased mortality appeared to be related mainly aspergilloma in pulmonary sarcoidosis patients.127 In patients
to the severity of the underlying pulmonary sarcoidosis rather with refractory aspergillomas, intracavitary instillation of
than by CPA and most common pattern was chronic cavitary medication, such as amphotericin B and voriconazole, has
pulmonary aspergillosis. The best predictors of survival were been reported as effective.128,129
CPI scoring, fibrosis extent and SAPH.6 As previously noted,
increased CPI and SAPH are factors predictive of increased
mortality in advanced pulmonary sarcoidosis.4,5
Diagnosis is made on the basis of imaging and is con-
firmed by direct evidence of Aspergillus or a positive gal-
actomannan test on sputum and/or BAL samples, and a
serological response to Aspergillus.117,120 Precipitins against
Aspergillus are positive in more than 90% of cases. Mycetoma
appears as a mass of soft tissue density within preexisting
bullae or cysts that are colonized by fungi. It is mobile within
a thickened wall cavity. It may be single or multiple, unilat-
eral or bilateral. It is surrounded by a peripheral rim of air
known as the air crescent sign or Monod sign (►Fig. 8).
Thickening of the pleural surface adjacent to the cavity wall is
an early sign of mycetoma formation and can be apparent on
chest radiographs or CT.
Treatment for CPA is indicated for patients who have
symptoms including hemoptysis.120 However, there are no
guidelines on the treatment of sarcoidosis-associated myce-
toma and recommendations are based on clinical experience,
expert statements, and case reports. Surgical resection is
often precluded because of poor underlying lung function in Fig. 8 Mycetoma in right upper lobe with crescent sign.

Seminars in Respiratory and Critical Care Medicine Vol. 41 No. 5/2020

712 Advanced Pulmonary Sarcoidosis Gupta, Baughman

In the French study mentioned earlier, mycetomas were not 12 Crystal RG, Roberts WG, Hunninghake GW, Gadek JE, Fulmer JD,
associated with increased mortality.6 The improved outcome Line BR. NIH conference. Pulmonary sarcoidosis: a disease
for aspergillomas may be due to long term use of azoles, which characterized and perpetuated by activated lung T-lymphocytes.
Ann Intern Med 1981;94(01):73–94
have been shown in a randomized trial to improve outcome in
13 Xu L, Kligerman S, Burke A. End-stage sarcoid lung disease is
pulmonary aspergillosis in sarcoidosis.127 distinct from usual interstitial pneumonia. Am J Surg Pathol
2013;37(04):593–600
14 Lockstone HE, Sanderson S, Kulakova N, et al. Gene set analysis of
Conclusion lung samples provides insight into pathogenesis of progressive,
fibrotic pulmonary sarcoidosis. Am J Respir Crit Care Med 2010;
Advanced pulmonary sarcoidosis remains a major challenge
181(12):1367–1375
in the management of the enigmatic disease of sarcoidosis.
15 Moller DR, Rybicki BA, Hamzeh NY, et al. Genetic, immunologic,
Recognition of the various patterns of disease, which are not and environmental basis of sarcoidosis. Ann Am Thorac Soc
mutually exclusive, is important for optimal management. 2017;14(Suppl 6):S429–S436
More evidence-based guidelines are needed for tailored 16 Patterson KC, Hogarth K, Husain AN, Sperling AI, Niewold TB. The
therapies in the age of personalized medicine. Expert centers clinical and immunologic features of pulmonary fibrosis in
sarcoidosis. Transl Res 2012;160(05):321–331
which take a multidisciplinary and collaborative approach to
17 Pechkovsky DV, Prasse A, Kollert F, et al. Alternatively activated
clinical and research aspects of this disease are needed for alveolar macrophages in pulmonary fibrosis-mediator produc-

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Conflict of Interest 19 Chen ES, Song Z, Willett MH, et al. Serum amyloid A regulates
R.P.B. reports grants from Bayer, Genentech, aTyr, grants granulomatous inflammation in sarcoidosis through Toll-like
and personal fees from Mallinckrodt, grants from Novartis, receptor-2. Am J Respir Crit Care Med 2010;181(04):360–373
Gilead, personal fees from KinBio, during the conduct of the 20 Zhang C, Chan KM, Schmidt LA, Myers JL. Histopathology of
study, grants from Foundation for Sarcoidosis research, Explanted Lungs From Patients With a Diagnosis of Pulmonary
Sarcoidosis. Chest 2016;149(02):499–507
National Institutes of Health, outside the submitted work.
21 Shigemitsu H, Oblad JM, Sharma OP, Koss MN. Chronic interstitial
pneumonitis in end-stage sarcoidosis. Eur Respir J 2010;35(03):
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