The utility of RDW in discrimination of sarcoidosis and tuberculous lymphadenitis diagnosed by ebus
KLİNİK ÇALIŞMA RESEARCH ARTICLE
Mevlüt KARATAŞ1
Ayperi ÖzTüRK2 1 Department of Respiratory Diseases, Ankara Occupational Diseases Hospital, Ankara, Turkey
1 Ankara Meslek Hastalıkları Hastanesi, Solunum Hastalıkları Bölümü, Ankara, Türkiye
2 Department of Interventional Pulmonology, Atatürk Chest Diseases and Chest Surgery Training and Research Hospital, Ankara, Turkey
2 Atatürk Göğüs Hastalıkları ve Göğüs Cerrahisi Eğitim ve Araştırma Hastanesi, Girişimsel Pulmonoloji Bölümü, Ankara, Türkiye
suMMARY
The utility of RDW in discrimination of sarcoidosis and tuberculous lymphadenitis diagnosed by ebus
Introduction: Erythrocyte distribution width (RDW) is an important indicator of anisocytosis, which is used in the differential diagno- sis of anemia and is easily accessible in the complete blood count results. Increased RDW values in coronary artery diseases, pulmo- nary hypertension and malignancies were detected in the studies. We aimed to demonstrate the usefulness of blood RDW level for the differential diagnosis of granulomatous lymphadenitis associated with tuberculosis and sarcoidosis in our study.
Materials and Methods: A total of 331 patients, 229 with sarcoidosis (stage I and stage II) and 102 with TB-LA and 50 healthy control group were included in the study. The biopsies were obtained via EBUS-TBNA from 705 lymph nodes of 331 patients. Of tissue diagnosis was non-erosive granulomatous inflammation patients with tuberculosis negative proved by microbiological tests were accepted as sarcoidosis after other causes of granulomatous disease were excluded.
Results: Of the sarcoidosis patients, 169 (73.7%) were in stage I, and 60 (26.3%) were in stage II. The mean RDW was 14.31 (±
1.6) in the stage I group, 14.99 (± 2.3) in the stage II group, 14.11 (± 2.0) in the TB-LA group, and 13.89 (± 1.3) in the control group.
There was a significant difference between the stage II group and the stage I, TB-LA, and control groups (p< 0.05 for all). There was a significant difference in the C-reactive protein levels between the TB-LA and stage I groups (p< 0.01). The eritrocyte sedimentation rate values were higher in the TB-LA group than in both the stage I and stage II groups (p< 0.05).
Conclusion: This is the first study to demonstrate the diagnostic value of RDW in patients with TB-LA and sarcoidosis (Stage I-II) patients diagnosed by EBUS-TBNA. Higher RDW in stage II sarcoidosis than in stage I, TB-LA and control group is related with parenchymal involvement and indicates active inflammation.
Key words: Red blood cell distribution; sarcoidosis; tuberculous;
lymphadenitis; RDW; EBUS ÖzeT
ebus ile tanı konulan tüberküloz ve sarkoidoza bağlı granüloma- töz lenfadenitte RDW’nin tanı değeri
Giriş: Eritrosit dağılım genişliği (RDW), aneminin ayırıcı tanısında kullanılan, tam kan sayımı sonuçlarında kolaylıkla ulaşılabilen, ani- zositozun önemli bir göstergesidir. Yapılan çalışmalarda RDW
Dr. Ayperi ÖzTüRK
Atatürk Göğüs Hastalıkları ve Göğüs Cerrahisi Eğitim ve Araştırma Hastanesi, Girişimsel Pulmonoloji Bölümü, ANKARA - TüRKİYE
e-mail: drayperi@yahoo.com
Yazışma Adresi (Address for Correspondence)
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INTRODuCTION
Sarcoidosis and tuberculosis are the most common causes of granulomatous lymphadenitis (GLA). GLA can be infectious (as seen in tuberculosis) or noninfec- tious (as seen in sarcoidosis) (1). Sarcoidosis is a mul- tisystemic inflammatory disease of unknown etiology.
Diagnosis of sarcoidosis is based on a histological examination of noncaseous epithelioid cell granulo- mas supported by clinical and radiological findings after excluding the other granulomatous disease. In sarcoidosis, GLA involvement is seen in hilar and mediastinal (93.5%), cervical (12.2%), axillary (5.2%) and inguinal (3.3%) lymph nodes (2).
Tuberculous LA (TB-LA) is the most common form of extrapulmonary tuberculosis. Lymph node involvement is mostly seen in the cervical lymph nodes, followed by the mediastinal lymph nodes (3). A definite diagnosis of TB-LA is made by a histological examination of the epithelioid cell layer in lymph node biopsy material, the presence of necrosis surrounded by Langhans giant cells and/or the presence of acid-fast bacteria in the ziehl Neelsen stain, microbiological examination, and culture positivity.
The differentiation of sarcoidosis LA and TB-LA is challenging because both diseases may involve the lymph nodes. Currently, there is no serologic biomarker that can be used in the diagnosis or follow-up of LA, which is caused by sarcoidosis and TB.
Red blood cell distribution width (RDW) is a marker that indicates the volume of erythrocytes in the circulation; it can be measured quickly, cheaply, and
easily through a routine CBC analysis (4). Recent studies have shown that inflammatory processes raise the RDW by affecting erythropoiesis (5). It is also known that a high RDW value is associated with poor prognosis of community-acquired pneumonia (6,7).
There is no literature information showing the relationship between RDW value and LA. In this study, we aimed to demonstrate the utility of blood RDW in the differential diagnoses of sarcoidosis (stage I and II) and TB-LA.
MATeRIALs and MeTHODs Patient Groups
We analyzed 2208 patients who applied to the Interventional Pulmonology Clinic of Atatürk Chest Diseases and Chest Surgery Training and Research Hospital for EBUS-TBNA between 2010 and 2016. The study has been approved by the ethics comitte. Of the patients selected for the study, 229 had sarcoidosis, 102 had TB-LA, and 50 were healthy control patients with no complaints who had been referred to the chest diseases policlinics for routine health checks. This is a retrospective study. The demographic and laboratory data of the patients were collected by screening the hospital registry system. Flow chart of patients enrollment is seen in Figure 1.
Diagnosis of sarcoidosis
From 331 patients who had EBUS-TBNA, 705 mediastinal and hilar lymph node biopsies were obtained. After other causes of granulomatous disease (berylliosis, tularemia, yersinia, lymphogranuloma değerinin koroner arter hastalıklarında, pulmoner hipertansiyonda, malignitelerde arttığı saptanmıştır. Çalışmamızda tüberküloz ve sarkoidoza bağlı granülomatöz lenf adenitlerin ayırıcı tanısı için kan RDW seviyesinin kullanılabilirliğini göstermeyi amaçladık.
Materyal ve Metod: Çalışmaya toplamda 331 hasta, 229'u sarkoidoz (evre I ve evre II) ve 102'si TB-LA ile 50 sağlıklı kontrol grubu dahil edilmiştir. Biyopsi, 331 hastanın 705 lenf düğümünden EBUS-TBİA ile elde edildi. Doku tanısı nonkazeifiye granülomatöz iltihap olup balgam, bronş lavajı ARB’si ve kültürü negatif, PPD’si negatif hastalar, granülomatöz hastalık yapan diğer sebepler dışlandıktan sonra sarkoidoz kabul edildi. Tüm sarkoidoz hastaları evre I ve II olarak gruplandırıldı. EBUS-TBİA patoloji sonucu kazeifiye nekrozlu granülomatöz ve/veya granülomatöz iltihap olarak rapor edilip ya da TBİA materyalinde ARB ya da kültürü pozitif olan hastalar tüberküloz lenfadenit (TB-LA) kabul edildi.
bulgular: Sarkoidoz hastalarının 169’u evre I (%73.7), 60’ı evre II (%26.3) hastalardı. Ortalama RDW değerleri evre I ve evre II sarkoi- dozda 14.31 (± 1.6) ve 14.99 (± 2.3), TB-LA’da 14.11 (± 2.0) ve kontrol grubunda 13.89 (± 1.3) (p< 0.05) saptandı. Bazal RDW seviye- si gruplar arasında karşılaştırıldığında evre II ile evre I, TB-LA ve kontrol grup arasında anlamlı fark saptandı (p< 0.05). TB-LA ve evre I grupları arasında C-reaktif protein düzeylerinde anlamlı bir fark vardı (p< 0.01). Eritrosit sedimentasyon hızı değerleri TB-LA grubunda hem evre I hem de evre II gruplara göre daha yüksekti (p< 0.05).
sonuç: Bu çalışma EBUS-TBİA ile TB-LA ve sarkoidoz tanısı almış (evre I-II) hastalarda RDW’nin tanısal değerini gösteren ilk çalışma- dır. Evre II sarkoidozda kan ortalama RDW seviyesinin evre I sarkoidoz,TB-LA ve kontrol grubuna göre anlamlı derecede yüksekliği parankim tutulumuyla ilşkili olup aktif inflamasyonu işaret etmektedir.
Anahtar kelimeler: Eritrosit dağılım hacmi; sarkoidoz; tüberküloz; lenfadenit; endobronşiyal ultrasonografi
venereum, fungal infection, toxoplasma lymphadenitis, atypical mycobacterial infection, BCG-lymphadenitis, leprosy, syphilis, brucellosis, fungal infection, etc.) were excluded, patients were accepted as having sarcoidosis who were negative for acid fast bacille (AFB) and/or culture in their EBUS-TBNA biopsy materials or culture in the sputum or who had pathology reports of noncaseous epithelioid cell granulomas. The patients included in the study were categorized as stage I or stage II according to the criteria of the 1999 American Thoracic Society/
European Respiratory Society Statement 1999; none of the patients met the criteria for Stages 0, III, or IV (8).
Tuberculous Lymphadenitis Diagnosis
The patients with an EBUS-TBNA biopsy pathology report of caseating granulomatous inflammation and the patients with positive AFB and/or culture in their EBUS-TBNA biopsy material were accepted as having TB-LA.
ebus-TbNA Procedure
The CP-EBUS (EU-C2000; Olympus) was used with a convex transducer (frequency of 7.5 MHz) at the tip of a flexible bronchoscope. The 22-Gauge needle was used and at least three passes were done for sampling
the lymph nodes. The procedure was applied under deep sedation in an operation room by two experienced interventional pulmonologist.
exclusion Criteria
The exclusion criteria were: being under the age of 18, being pregnant, using steroids, or having an active infection, acute coronary syndrome, malignancy, hematologic disease, immunosuppressive treatment, active bleeding, or chronic inflammatory and autoim- mune disease.
ResuLTs
A total of 381 patients, 229 with sarcoidosis, 102 with TB-LA and 50 healthy controls, were included in the study. A total of 705 lymph nodes were sampled with EBUS-TBNA. Of the sarcoidosis patients, 169 (73.7%) were in stage I, and 60 (26.3%) were in stage II. The mean RDW was 14.31 (± 1.6) in the stage I group, 14.99 (± 2.3) in the stage II group, 14.11 (± 2.0) in the TB-LA group, and 13.89 (± 1.3) in the control group.
When the mean RDW values were compared among the groups, there was a significant difference between the stage II group and the stage I, TB-LA, and control groups (p< 0.05 for all). There was no significant differ- ence between the control group and the stage I or TB-LA groups (p> 0.05; Figure 2; Table 1).
The CRP levels were 0.57 (0.01-12.6) in the stage I group, 0.66 (0.02-22) in the stage II group, 0.79 (0.04- 19.5) in the TB-LA group, and 0.37 (0.01-1.7) in the control group. Although the CRP levels were higher in the stage II group than the stage I, no significant difference was found (p= 0.05). There was a significant difference in the CRP levels between the TB-LA and stage I groups (p< 0.01).
Figure 1. Flow chart of patients enrollment.
Number of EBUS-TBNA for diagnostic n= 2208
Patients diagnosed with tuberculous lymphadenitis
n= 102
Patients diagnosed with the other causes of granulomatous lymphadenitis
n= 280 Patients diagnosed with
sarciodosis n= 229
Patients diagnosed with granulomatous lymphadenitis n= 611
Figure 2. Blood RDW levels of groups.
p= 0.08
p= 0.004
p= 0.01 p= 0.01 p= 0.48
30.00
25.00
20.00
15.00
10.00
Stage I
Sarcoidosis Stage II
Sarcoidosis Tuberculous
Lymphadenitis Control Group
RDW %
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Table 1. Demographic and characteristic features and laboratory parameters Control Groupsarcoidosis (stage I)sarcoidosis (stage II)
Tuberculosis Lymphadenitis (Tb-LA)p*p**p***p+p++p+++ Number5016960102 ∞Age, year, median42.9 (18-79)45 (20-84)45.5 (20-69)51 (18-82) Sex, female, n (%)28 (56)117 (69)40 (66)75 (73) Laboratory findings WBC (/mm3)7.42 ( ± 1.9)6.91 ( ± 1.7)6.73 (± 2.1)6.62 ( ± 1.9)= 0.05> 0.05> 0.05< 0.05< 0.05< 0.05 Neutrophil (/mm3)4.19 ( ± 1.6)4.50 ( ± 1.3)4.39 (± 1.7)4.10 ( ± 1.5)> 0.05< 0.05> 0.05> 0.05> 0.05> 0.05 Lymphocyte (/mm3)2.07 ( ± 0.5)1.61 ( ± 0.5)1.52 (± 0.4)1.38 ( ± 0.6)> 0.05< 0.01> 0.05< 0.01< 0.01< 0.01 RDW (fl)13.89 ( ± 1.3)14.31 ( ± 1.6)14.99 (± 2.3)14.11 ( ± 2.0)< 0.05> 0.05< 0.05> 0.05< 0.01> 0.05 Hb (mg/dL)14.03 ( ± 1.5)13.06 ( ± 1.6)13.46 (± 1.9)13.24 ( ± 1.5)> 0.05> 0.05> 0.05> 0.05> 0.05< 0.05 ∞CRP (mg/dL)0.37 (0.01-1.7)0.57 (0.01-12.6)0.66 (0.02-22)0.79 (0.04-19.5)= 0.05< 0.01> 0.05< 0.01< 0.01< 0.01 ∞ESR (mm/h)2.64 (1-8)32.0 (2-100)26.5 (5-108)40.0 (10-120)> 0.05< 0.01< 0.05< 0.01< 0.01< 0.01 ∞ACE (U/L)NA71.13 (2.3-189.4)81.24 (26.5-159)NA< 0.05NANANANANA p: p value. ∞Data are median (interquartile range) unless otherwise indicated. MpV: Mean platelet volume. (fl) = [plateletcrit (%)/plateletcount (×109/L] × 105. CRP: C-reactive protein. ESR: Erythrocyte sedimentation rate. ACE: Angiotensin converting enzyme. NA: Not applicable. SD: Standard deviation. p*: Stage I vs stage II sarcoidosis, p**: Stage I sarcoidosis vs TB-LA, p***: Stage II sarcoidosis vs TB-LA, p+: Control group vs stage I sarcoidosis, p++: Control group vs stage II sarcoidosis, p+++: Control group vs TB-LA.
There was no significant difference between the ESR values of the stage I and stage II groups (p> 0.05). The ESR values were higher in the TB-LA group than in both stage I and stage II groups (p< 0.05).
There was a positive correlation between the RDW and ESR values in stage I, and stage II groups (p< 0.05, and p< 0.05 respectively; Figures 3 and 4). There was no significant positive correlation between the RDW and CRP in the stage I, stage II, and TB-LA groups (p> 0.05). The level of ACE was 71.13 (2.3-189.4) in the stage I group and 81.24 (26.5-159) in the stage II group. There was a significant difference between ACE levels in both groups (p< 0.05).
DIsCussION
To our knowledge, this is the first study to show different RDW values between patients with sarcoidosis (stage I and II) and TB-LA diagnosed with EBUS-TBNA. The main result of this study was that mean RDW values in patients with stage II sarcoidosis were significantly higher than in patients with stage I sarcoidosis, TB-LA, or in the control group (Figure 2).
There is still no specific biomarker used in the diagnosis and follow-up of sarcoidosis (9). Although sIL2R, angiotensin converting enzyme (ACE), serum chitotriosidase, neopterin, KL-6, and ykl-40 have been previously studied as biomarkers, they are not used in routine clinical practice (10-15). Patients are followed through physical examination, respiratory function tests, radiology tests (chest X-Ray and/or thorax high resolution computed tomography), simple laboratory values (hemogram, biochemical, and urine analysis), and exercise tests (6-minute walking test) in routine practice.
There is only one article investigating the relationship between sarcoidosis and RDW levels. Ozsu et al.
investigated the prognostic value of RDW in 138 patients with sarcoidosis. The study compared the stage I sarcoidosis group with the stage II, III, and IV sarcoidosis groups. They revealed that mean RDW levels were higher in the radiologically advanced stage groups than in the stage I group. In additional to that mean RDW levels in patients with stage IV sarcoidosis were higher than in patients in the stage I, II, or III groups but RDW levels were not significantly higher between stage I and stage II (16). In contrast to these results, the present study found a significant difference between the mean RDW levels in stage I and stage II sarcoidosis (p< 0.05). This is a unique result of RDW in sarcoidosis which may be leading to increased inflammation.
CRP is an acute phase reactant that elevates as a nonspecific response to tissue injury induced inflammation in blood. Since sarcoidosis is also a multi-systemic inflammatory disease, the majority of patients with sarcoidosis have elevated CRP levels as a marker of inflammatory activity (17). Drent et al.
compared the CRP levels of patients with sarcoidosis with parenchymal infiltration (n= 16) to those without parenchymal infiltration (n= 8). They showed that the CRP level was significantly higher in patients with sarcoidosis with parenchymal infiltration than in the other group (p< 0.01) (18). Similarly, Hind et al.
Figure 3. Corelation between RDW and ESR in stage I sarcoi- dosis.
22.00
20.00
18.00
16.00
14.00
12.00
10.00 0.00
Erythrocyte Sedimentation Rate/h
20.00 40.00 60.00 80.00
R Sq Linear= 0.023 p< 0.05
100.00
RDW %
Figure 4. Corelation between RDW and ESR in stage II sarcoidosis.
24.00
21.00
12.00 15.00
0.00
Erythrocyte Sedimentation Rate/h
20.00 40.00 60.00 80.00
R Sq Linear= 0.094 p= 0.01 100.00 120.00 18.00
RDW %
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showed that the level of CRP was elevated in 22% of sarcoidosis patients with parenchymal involvement and that the level of CRP did not increase in cases of sarcoidosis without parenchymal involvement (19). It is thought that an increased burden of inflammation may lead to RDW elevation (6). In the present study, we also found that the level of CRP due to increased inflammation load was higher in stage II sarcoidosis than in stage I sarcoidosis. Smilarly to this result, our research revealed that mean blood RDW levels were higher in the stage II sarcoidosis group (p< 0.01).
Myeloid-related protein-14 (MRP14) which has been used in recent studies to evaluate the lung parenchymal inflammation, is thought to play a role in inflammatory conditions. Korthagen et al. examined the level of MRP14 in bronchoalveolar lavage fluid (BALF) and revealed that the mean level of MRP14 was higher in patients with sarcoidosis than in the healthy control group. They found that the MRP14 level was higher in stage II, which had higher parenchymal involvement and granulation density, than in stage I. The highest MRP level was detected in stage IV. There was a significant difference between MRP14 levels in stage I and stage IV (p< 0.05) (20). The presence of parenchymal involvement and concomitant inflammatory burden may be responsible for the high level of MRP4 in these cases. In this study, higher levels of RDW, which was detected in patients with stage II sarcoidosis, may be thought to be related with intense of inflammation.
ESR values increase in the presence of arthritis and erythema nodosum in patients with sarcoidosis (21,22). In the present study, ESR values were found to be significantly different between the control group and the stage I and stage II sarcoidosis groups. It was observed that parenchyma involvement did not affect the ESR values. There was a significant positive correlation between ESR and RDW values in stage I and stage II sarcoidosis groups. ESR values were higher in the TB-LA group than in the other groups. This result is consistent with the literature (23).
In a study of 50 patients with pulmonary tuberculosis conducted by Abakay et al., the patients were divided into three groups, mild, moderate, and advanced, according to the intensity of lung parenchymal involvement (24). In the advanced group, the researchers revealed that blood RDW levels were significantly higher than in the group with mild-
moderate pulmonary parenchymal involvement. In the same study, patients with pulmonary tuberculosis with advanced parenchymal involvement were reported to have a higher inflammatory burden and higher RDW levels. As a result, the researchers reported that RDW could be used as an inflammatory marker. In our study, RDW levels were not compared between pulmonary tuberculosis and TB-LA cases. There was a significant difference in RDW values between the group with TB-LA and that with stage II sarcoidosis with parenchymal involvement. Cases with pulmonary tuberculosis were not included in the study.
ACE is a biomarker that exhibits the extreme body granulomatous burden of sarcoidosis that does not yet show lung involvement (25). ACE values may also increase in various diseases such as asbestosis, berylliosis, tuberculosis, and silicosis (26).
Papadopoulos et al. found a high level of ACE in stage III sarcoidosis cases with large granuloma (27). In our study, serum ACE level was found to be significantly higher in stage II cases than in stage I cases. The granulomatous burden due to pulmonary parenchymal involvement in the stage II sarcoidosis group was higher and may have caused increased ACE values.
Since there is no record of extrapulmonary involvement of sarcoidosis, no further discussion was made about the ACE levels between the groups.
Blood RDW values may be high in cases of anemia-re- lated conditions. In our study, despite the differences in RDW levels between groups (stages I and II, TB-LA), no significant difference was found in hemoglobin values (p> 0.05).
There are few limiting factors for the present study.
First, pulmonary tuberculosis cases were not included in the study. Therefore, mean RDW values between pulmonary tuberculosis cases and the TB-LA group could not be compared. Second, the inability to include stage 0, stage III, and stage IV sarcoidosis cases in the study. The RDW relationship between these groups and other stages (stage I and stage II) is unknown. The absence of extrapulmonary involve- ment data from sarcoidosis patients was another limit- ing factor. The absence of extrapulmonary involve- ment data restricts further comment on biomarkers such as RDW, CRP, and ACE. It is known that vitamin B12 deficiency also increases RDW. The last limiting factor was that absence of data about patients’ B12 vitamin levels.
The strength of the present study is that it provides information about RDW values in a large number of patients with granulomatous lymphadenitis which was diagnosed via EBUS-TBNA. Contrary to the limited number of studies in the literature about RDW values in sarcoidosis LA and TB-LA, a large number of patients were included in this study.
In conclusion, this study revealed that mean RDW values alone are insufficient for differential diagnosis of sarcoidosis LA (stage II) and TB-LA. RDW values can be obtained quickly, cheaply, and easily from routine CBC analysis. Hence, RDW values may be used in clinical management and differential diagnosis of stage I and stage II sarcoidosis in addition to other diagnostic methods. Despite the need for more exten- sive data analysis to enable RDW to be used in clinical practice, this article may shed light on new research.
ACKNOWLeDGMeNTs
We would like to thank Prof. Dr. Aydın Yılmaz who have made a great effort in the formation of this study’s and the archive staff who helped to collect the clinical data of patients.
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