Diagnosis of sarcoidosis is made by microscopic demonstration of granulomas along with compatible clinicoradiologic profile, after excluding other causes.1 Transbronchial needle aspiration (TBNA) is the preferable diagnostic modality for patients having suspected sarcoidosis with mediastinal lymphadenopathy.2 Endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) as a standalone modality is superior to other bronchoscopic modalities for the diagnosis of sarcoidosis.3,4 It has been reported that for optimal diagnostic yield, endobronchial biopsy (EBB) and transbronchial lung biopsy (TBLB) should be simultaneously obtained.5 Overall procedure yields are similar for conventional transbronchial needle aspiration (c-TBNA)-based and EBUS-TBNA-based approaches provided EBB and TBLB are also performed.6 The yield of c-TBNA is low as a standalone modality and this may possibly deter bronchoscopists from adopting a purely conventional bronchoscopy-based approach utilizing c-TBNA for the diagnosis of sarcoidosis.7,8
Transbronchial needle cytology specimens can be examined by rapid staining by an on-site pathologist, the technique termed as rapid on-site evaluation (ROSE). Randomized trials suggest that ROSE influences neither the diagnostic yield nor specimen adequacy of either c-TBNA or EBUS-TBNA specimens.9,10 The reported benefit of utilization of ROSE is limited to observational studies with inherent selection bias.10 The utility of ROSE in the bronchoscopic diagnostic algorithm of sarcoidosis is not clearly defined. A comparison of EBUS-TBNA versus c-TBNA, with or without utilization of ROSE, has not been previously evaluated. We conducted a randomized controlled trial (with and without concomitant ROSE) comparing comprehensive conventional bronchoscopy (including TBLB, EBB with c-TBNA) with EBUS approach (including TBLB, EBB with EBUS-TBNA) for the detection of granulomas in patients with suspected pulmonary sarcoidosis.
Consecutive patients with suspected sarcoidosis presenting to the pulmonary outpatient clinic underwent screening. Patients were eligible for inclusion and randomization if they met all of the following criteria: (i) age above 18 years; (ii) clinicoradiologic features consistent with stage I/stage II sarcoidosis; and (iii) mediastinal lymphadenopathy (short-axis lymph node diameter on CT>10 mm) with involvement at lower right paratracheal (station 4R) and/or subcarinal (station 7) stations with or without enlarged hilar or interlobar nodes. Patients with any one of the following were excluded: (i) obvious organ involvement at another site with feasibility of confirming diagnosis using a minimally invasive procedure (skin biopsy or superficial lymph nodes); (ii) suspected stage III and IV sarcoidosis; (iii) intake of systemic glucocorticoids for >2 weeks in preceding 3 months; (iv) hypoxemia (oxygen saturation on room air <90%); (v) coagulopathy [platelet count <50000/mm3 and/or prolonged prothrombin time (INR>1.3) and/or activated partial thromboplastin time 10 s above control]; (vi) pregnancy; and (vii) refusal of consent.
The decision regarding randomization was taken after a detailed discussion with the patient. Detailed clinical history, physical examination, and baseline investigations (hemogram, liver function tests, serum calcium, 24-hour urine calcium, serum angiotensin-converting enzyme levels, tuberculin skin test, electrocardiography, chest radiograph, CT scan of the thorax, and spirometry) were performed. Written informed consent was obtained from all the study participants.
This trial was an investigator-initiated, prospective, randomized study carried out at the Department of Pulmonary Medicine and Sleep Disorders, All India Institute of Medical Sciences (AIIMS), New Delhi, India. Ethical clearance for the study was obtained (AIIMS Institute Ethics Committee-IESC/T-206). Patients satisfying the inclusion criteria were randomized to one of the 4 groups in 1:1:1:1 ratio: (i) TBNA-NR: conventional TBNA without ROSE+TBLB+EBB; (ii) TBNA-R: conventional TBNA with ROSE+TBLB+EBB; (iii) EBUS-NR: EBUS-TBNA without ROSE+TBLB+EBB; and (iv) EBUS-R: EBUS-TBNA with ROSE+TBLB+EBB. Therefore, in addition to the TBNA procedure, EBB and TBLB were performed in all. Computer-generated block randomization with variable block size was used (RALLOC software). The group allocated was concealed till the time the proposed algorithm had been explained to the patient and the consent for randomization had been obtained. Patients with nondiagnostic bronchoscopy result in the conventional TBNA groups (TBNA-NR and TBNA-R) underwent EBUS-TBNA with ROSE later.
Bronchoscopy and EBUS-TBNA were performed by operators experienced with both c-TBNA and EBUS-TBNA. Moderate conscious sedation was utilized, according to the prevalent sedation protocol (combination of midazolam and fentanyl). Monitoring of pulse rate, respiratory rate, blood pressure, pulse oximetric saturation, and ECG was routinely done. None of the procedures required general anesthesia.
Conventional TBNA Groups (TBNA-NR and TBNA-R)
Flexible bronchoscopy was performed through the nasal/oral route using the Olympus BF-TE2 fiberoptic bronchoscope/Olympus 1T180 video bronchoscope. Local anesthesia was provided using 2% nasal lignocaine jelly and 2% lignocaine solution “spray as you go.” Anticholinergic premedication was not administered. c-TBNA was performed from the subcarinal (station 7) and/or lower right paratracheal (4R) stations using the 21-G TBNA needle (smooth shot NA-401D-1521; Olympus). At least 3 passes were obtained from each of the sampled node stations in the TBNA-NR group, whereas in the TBNA-R group, number of passes was based upon the ROSE findings. No further aspiration was performed once sampling adequacy was established and sufficient material had been obtained as judged by the on-site cytopathologist. Following c-TBNA, EBB and TBLB specimens were obtained through the same bronchoscope.
EBUS-TBNA Groups (EBUS-NR and EBUS-R)
EBUS-TBNA was performed through the oral route under moderate sedation after insertion of a bite block, using the EBUS scope (BF-UC-180F; Olympus). Image acquisition was obtained using the dedicated ultrasound image processor (EU-ME1; Olympus) and lymph node sizes and character were recorded. The 21-G dedicated EBUS-TBNA aspiration needles (Vizishot, NA-201 SX-4021A; Olympus) were used. For EBUS-TBNA, at least one of the stations 4R or 7 or both were sampled. The choice of primarily targeted station and sampling other stations was based on the number and sonographic characteristics of nodes identified by ultrasound, their accessibility, and were at the discretion of the operator. At least 3 passes were obtained from each of the sampled stations in the EBUS-NR group, whereas in the EBUS-R group, number of passes was based upon the ROSE findings. No further aspiration was performed once sampling adequacy was established and sufficient material had been obtained as judged by the on-site cytopathologist. Following EBUS-TBNA, EBUS scope was removed and flexible bronchoscopy was performed to obtain EBB and TBLB specimens.
EBB and TBLB Procedure
In all patients, at least 4 pieces each of EBB and TBLB were obtained. Both were performed using the disposable 2-mm cupped jaws forceps. EBB was performed from areas of visualized mucosal granularity, if present. TBLB was performed from the site of maximal involvement on thoracic high resolution computed tomography scan. In case of normal lung CT appearance, TBLB was obtained from the basal segments of the right lower lobe. Fluoroscopy was not utilized. Postprocedure, a chest x-ray and ultrasound examination of the thorax was performed to exclude pneumothorax.
In all patients, aspirates were smeared on glass slides and both air dried and alcohol fixed. In ROSE groups, rapid staining of air-dried aspirates with toluidine blue stain was performed by an on-site cytopathologist and feedback provided to the operator. Cell-block preparations were not routine. Detailed cytopathologic examination was performed in the pathology laboratory. Acid-fast staining was routinely performed. EBB and TBLB samples were fixed in formaldehyde and transported to the histopathology laboratory. Samples were also sent for mycobacterial cultures.
Diagnosis of Sarcoidosis
The diagnosis of sarcoidosis was based on the European Respiratory Society/American Thoracic Society/World Association of Sarcoidosis and Other Granulomatous Disorders consensus statement.1 Diagnosis was made if all the following criteria were fulfilled: (i) supportive clinical profile and radiologic features; (ii) presence of noncaseating granulomas; and (iii) exclusion of similar presenting disease [like fungal infection, malignancy, or tuberculosis (TB)]. All patients were regularly followed up till 6 months subsequent to randomization for treatment response assessment. If a definite histopathologic or cytologic diagnosis could not be established with bronchoscopy, patients were managed based on clinicoradiologic profile and were closely followed up for 6 months. The final diagnosis at the end of 6 months based on response to treatment was taken as the reference diagnostic standard. All the cytologic/histopathologic specimens were independently evaluated at the time of study completion by 2 trained experienced pathologists.
The primary end point was the demonstration of findings consistent with granulomatous inflammation in any of the bronchoscopic samples, for the overall procedure. Diagnostic yield was defined as the proportion of patients in each group where granulomas were detected divided by the total number of patients who received a final diagnosis of sarcoidosis in that group based on the diagnostic reference standard.
Sample size calculation (using uncorrected χ2 test) was based on the hypothesized granuloma detection yield of 40% with c-TBNA and 85% with EBUS-TBNA with a power of 0.8 and α=0.05. Sixty patients were required. To account for possibility of withdrawal after randomization and loss to follow-up, 80 patients were included in the study.
Intention-to-treat analysis was performed based on the final diagnosis as the reference. Differences between the groups for categorical variables were analyzed by the χ2 test/Fisher exact test. For continuous variables, differences were compared among the groups by 1-way analysis of variance (ANOVA)/Kruskal-Wallis test followed by post hoc comparison using Bonferroni test/Wilcoxon rank-sum test with Bonferroni correction. Data were analyzed using Stata Statistical analysis package (version 11.2). P<0.05 was considered significant.
A total of 102 consecutive patients with clinicoradiologic features consistent with sarcoidosis were screened. Twenty-two patients were excluded (6 had lymph node size <1 cm, 6 refused consent, 4 had received steroids for >2 wk in the recent 3 mo, 4 had an accessible peripheral tissue site for diagnosis, and 2 had contraindications to bronchoscopy). Eighty patients were randomized (20 to each group): TBNA-NR, TBNA-R, EBUS-NR, and EBUS-R as previously described. Of the 80 patients, a final diagnosis of sarcoidosis was made in 74 patients (19 TBNA-NR, 18 TBNA-R, 19 EBUS-NR, and 18 EBUS-R). The diagnosis was definitive (based on either cytologic/histologic demonstration of granulomatous inflammation) in 62 patients. In 12 patients, diagnosis of sarcoidosis was clinical (7 patients improved with corticosteroids and 5 showed clinicoradiologic improvements on observation alone). Remaining 6 of the 80 patients were diagnosed as TB. The study flowchart (CONSORT diagram) is shown in Figure 1.
There was no significant difference between baseline characteristics of the study groups. Baseline characteristics are summarized in Table 1. Mean age was 37.7 (9.7) years and majority (n=48, 60%) were males. Dry cough (70%), dyspnea (49%), and fever (34%) were the commonest symptoms. Twenty patients (25%) had prior history of intake of antituberculous medications with no clinical improvement. On chest radiograph, 45 (56%) patients had stage II disease, whereas 35 (44%) had stage I disease. Lung parenchymal nodularity was present on thoracic high resolution computed tomography in 45 (56%) patients. Mean serum angiotensin-converting enzyme level was 85 (35) U/L. Hypercalciuria was present in 10 (12.5%) patients. Tuberculin skin test demonstrated induration <5 mm in all patients. Spirometry was normal in 60 (75%) patients. Mean paratracheal and subcarinal lymph node sizes on CT were similar in all the groups.
All randomized patients underwent all the planned bronchoscopy procedures according to protocol. EBB and TBLB samples could be successfully performed in addition to the TBNA procedure in all the patients (Fig. 1). Endobronchial nodularity was detected in 32 (40%) patients. Fewer patients in EBUS-NR and EBUS-R groups had bronchial nodularity (20% and 35%, respectively) than TBNA-NR and TBNA-R groups (50% and 55%, respectively); however, the difference was statistically not significant (P=0.10). A median of 4 TBLB and 5 EBB samples were taken. Adequacy of aspirates by ROSE could be achieved in 34 out of 40 patients (85%). The bronchoscopy procedure details are summarized in Table 2.
The detection of non-necrotizing granulomatous inflammation consistent with sarcoidosis in any of the bronchoscopically obtained samples was attained in 62 of the 80 patients (78%). In 2 patients, granulomas in conjunction with AFB positivity and necrosis were diagnostic for TB. The primary end point, that is, yield for granuloma detection in the combined procedures in the allocated group, was not significantly different between the 4 groups (68% in TBNA-NR, 89% in TBNA-R, 84% in EBUS-NR, and 83% in EBUS-R groups, P=0.49) (Table 3). However, the individual yield of c-TBNA in the TBNA-NR group was significantly lower compared with that of c-TBNA in the TBNA-R group or EBUS-TBNA in EBUS groups (32%, 72%, 68%, and 67% for TBNA-NR, TBNA-R, EBUS-NR, and EBUS-R groups, respectively, P=0.04). Addition of EBB and TBLB to the TBNA procedure increased the diagnostic yield by 36%, 17%, 16%, and 16% for TBNA-NR, TBNA-R, EBUS-NR, and EBUS-R groups, respectively. As an individual procedure, conventional TBNA with ROSE had the highest yield (72%) followed by EBUS-TBNA (68% without ROSE, 67% with ROSE). The diagnostic yield of TBLB was 58% and EBB was 26%. The yield of TBLB and EBB was not different in the 4 groups (P=0.32 and 0.27, respectively) (Table 3).
Ten patients with nondiagnostic procedure (all bronchoscopic samples negative for granulomas) in the c-TBNA groups (7 TBNA-NR and 3 TBNA-R) underwent EBUS-TBNA (with ROSE) at a later date. The gain in granuloma yield after the addition of EBUS was evident only in the TBNA-NR group (4 out of 7 showed granulomas on EBUS-TBNA), whereas there were no additional cases detected in TBNA-R group (Table 4).
The doses of midazolam and fentanyl used and mean procedure duration were significantly lower in conventional TBNA groups than the EBUS groups (P<0.001). All the procedures could be successfully performed under moderate sedation and no patient required general anesthesia. Post-TBLB pneumothorax occurred in 4 (5%) patients, 1 in each TBNA-NR and EBUS-NR, and 2 in EBUS-R groups and all recovered uneventfully. There were no other significant complications (Table 2).
A comprehensive bronchoscopic approach using either of the TBNA cytology modalities (c-TBNA or EBUS-TBNA), with or without ROSE and in combination with transbronchial and endobronchial mucosal biopsies, was equally efficacious in detection of granulomas for diagnosis of sarcoidosis. This study also found that either TBNA cytology (EBUS-TBNA/c-TBNA) alone or a combination of bronchoscopic biopsies (EBB+TBLB) alone are insufficient for the diagnosis of sarcoidosis as combining both adds to the granuloma detection yield in all the groups regardless of c-TBNA/EBUS-TBNA approach. The greatest addition to diagnostic yield by concurrent performance of EBB and TBLB occurs in the TBNA-NR group without ROSE and this is primarily due to the significantly lower yield of c-TBNA in that group. Yields of EBUS-TBNA whether performed with or without ROSE were not different. These findings highlight the utility of ROSE whenever adopting a conventional TBNA-based bronchoscopic approach for a diagnosis of sarcoidosis.
The utility of EBUS-TBNA for lung cancer staging is firmly established and it has also evolved into a useful diagnostic modality for evaluation of undiagnosed mediastinal lymphadenopathy.2,11–13 However, with the increasing adoption of EBUS-TBNA in evaluation of mediastinal lymphadenopathy, utilization of c-TBNA has exponentially declined. This is not surprising given the fact that since even before the advent of EBUS-TBNA, c-TBNA has remained an underutilized bronchoscopic modality despite studies asserting the need of its performance routinely during initial diagnostic bronchoscopy in patients with mediastinal involvement.14–16 c-TBNA, however, offers certain advantages. The procedure is highly specific with a short performance time, is minimally invasive, safe, and cost-effective.17 In our study, the doses of sedation and analgesia used and procedure time were significantly lower during conventional TBNA as compared with the EBUS-TBNA. Gupta et al6 also reported a shorter procedure time with conventional bronchoscopy. The reduction in procedure time and sedation use may not only increase patient comfort but also reduce the possible risk of complications. In the context of sarcoidosis, c-TBNA provides a unique single procedure opportunity for comprehensive bronchoscopic evaluation in combination with TBLB and EBB.18 All 3 procedures can be performed in the same sitting using the same bronchoscope. This is in contrast to EBUS-centered approach, wherein subsequent to EBUS-TBNA the EBUS bronchoscope needs to be removed and the conventional bronchoscopy needs to be performed subsequently to obtain TBLB and EBB.
A limited number of studies have compared EBUS-TBNA with conventional bronchoscopic modalities for the diagnosis of sarcoidosis.2,4,6,12,19–22 However, only Gupta et al6 compared a comprehensive conventional bronchoscopy protocol utilizing c-TBNA with EBUS-TBNA, wherein EBB and TBLB were performed in both the groups. The results of our study concur with the findings of Gupta et al,6 wherein the authors demonstrated that c-TBNA and EBUS-TBNA are equally efficacious modalities for diagnosis of sarcoidosis provided EBB and TBLB are combined with TBNA cytology. In the GRANULOMA trial, endosonographic nodal aspiration was reported to have a greater diagnostic yield than bronchoscopic biopsies (EBB+TBLB) among patients with suspected stage I/II pulmonary sarcoidosis.4 The findings from our study and Gupta and colleagues differ from and highlight an important limitation of the GRANULOMA trial and most of the other studies in this regard, that is, nonperformance of c-TBNA in the conventional bronchoscopy arm. It is likely that addition of c-TBNA might have nullified the superior characteristics of endosonographic nodal aspiration. Thus, emerges the indispensible need to perform c-TBNA whenever conventional bronchoscopy is utilized for diagnosis in sarcoidosis.18 EBB and TBLB were obtained in all patients regardless of ROSE findings. The pathologist primarily commented on the specimen adequacy. In certain instances, the pathologist could comment on the observation of granulomas but we wanted to minimize the likelihood of a false-positive ROSE. Termination of the bronchoscopy procedure based on ROSE diagnosis and a subsequent negative final pathology result would lead to a repeat bronchoscopy procedure to obtain EBB and TBLB specimens. Therefore, EBB and TBLB were performed in all the patients. This also ensured uniformity in samples obtained in all 4 groups for comparison. This was explained to the patients in detail before randomization. We had no patients with false-positive ROSE results in our study.
The reported yield of c-TBNA without ROSE for the diagnosis of sarcoidosis is variable and often low.7 We have recently reported that by utilizing ROSE with c-TBNA for evaluation of undiagnosed mediastinal lymphadenopathy, diagnostic yields similar to EBUS-TBNA can be obtained.23 Considering the global scenario, facilities for EBUS-TBNA are available at a select few centers in contrast to the wider availability of conventional bronchoscopy. Especially in the context of diagnosis of sarcoidosis, encouraging c-TBNA training and adoption of ROSE may possibly circumvent the need for routine EBUS-TBNA for diagnostic purpose in majority of patients. Further evaluation of c-TBNA with ROSE can also help in identifying other subsets of patients with undiagnosed mediastinal lymphadenopathy, wherein c-TBNA is an equally efficacious alternative to EBUS-TBNA. Importantly, no gain in diagnostic yield was obtained with a follow-up EBUS-TBNA performed in patients with a nondiagnostic bronchoscopy in the TBNA-R group. This is likely because ROSE eliminates the proportion of inadequate nodal aspirates and may enable the operators in improving their skill in performing c-TBNA reducing the median number of passes and shortening procedure time. Addition of ROSE did not increase procedure duration. Our study highlights the importance of performing ROSE in c-TBNA aspirates during conventional bronchoscopy for diagnosis of sarcoidosis. In certain settings, ROSE is considered to add to the cost of the bronchoscopy procedure. However, in resource-constrained settings, utilization of ROSE to optimize the yield of c-TBNA may possibly be a more cost-effective alternative to procuring of and establishing an EBUS-TBNA facility and studies specifically looking into this aspect are needed. The setting-up cost of an EBUS-TBNA facility is still far from the reach of most of the practicing pulmonary physicians, especially in developing countries perspective, whereas flexible bronchoscopy is widely available. Centers that already have conventional bronchoscopy capabilities should focus on routine performance of c-TBNA as part of the diagnostic workup of sarcoidosis patients with mediastinal lymphadenopathy and ROSE may be considered to optimize c-TBNA yield. Although the TNBA-NR group had a lower overall yield (though not significant), some of this is due to a 20% lower diagnostic yield of TBLB in that arm (likely a chance finding given that this was done in all cases). In high TB prevalence settings, all efforts should be made in establishing a definitive diagnosis of sarcoidosis as TB is a close differential diagnosis.24 Six patients (7.5%) were diagnosed with TB, wherein the initial clinicoradiologic consideration was sarcoidosis in this study.
One of the limitations of the study is that we did not routinely perform cell-block preparation of any of the lymph node aspirates. Chee et al25 have reported that liquid-based cytology and cell-block specimens are important in maximizing the diagnostic yield in EBUS-TBNA and c-TBNA samples in suspected sarcoidosis. Cell-block preparations can be processed like histopathologic samples after embedding them in paraffin blocks. Cells in liquid-based cytology specimens can be centrifuged into a pellet, which can be used for a cell block after formalin fixation. It is possible that addition of cell-block preparations might have improved the diagnostic yield further. Another limitation of the study is that the sample size calculation was based on a 2-group randomization and this does limit the power to demonstrate differences between the groups. The study would not be expected to show a difference if the true difference was <45%. But despite this, the results strengthen the fact that for optimal diagnostic yield in sarcoidosis, EBB and TBLB need to be combined with the TBNA cytology procedure. The strengths of this study include the rigorous diagnostic protocol and follow-up.
This prospective randomized study shows that when performing TBNA in the setting of suspected sarcoidosis, c-TBNA with ROSE and EBUS-TBNA (with or without ROSE) are superior to c-TBNA alone. Whether c-TBNA with ROSE is equivalent to EBUS TBNA cannot be determined from our study due to small sample size/low power. During c-TBNA, performance of ROSE is preferable to optimize diagnostic yield.
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