Abstract
Objectives
This study describes data from bronchoscopy performed at the diagnosis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).
Methods
We conducted a retrospective study between 2004 and 2019 in patients aged >18 years with a diagnosis of microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) who underwent bronchoscopy at onset of the disease. We collected bronchoalveolar lavage (BAL) and histological findings obtained during bronchoscopy.
Results
274 patients with AAV were identified. Among 92 bronchoscopies, 62 were performed at diagnosis, and 58 procedures were finally analysed. Cough was more frequent in patients with MPA than GPA (p=0.02). The presence of endobronchial lesions (24.1%) was found to be significantly associated with GPA (p<0.0001) and proteinase 3-ANCA (p=0.01). The most frequent endobronchial lesions were inflammation and hyperaemia of the bronchial mucosa (50%), followed by stenoses (28%), ulcerations (21%) and mass-like granulomatosis (7%). The diagnostic yield of bronchial biopsies was useful for visible lesions (66.6% versus 0%; p=0.006). On BAL, diffuse alveolar haemorrhage (DAH) was detected in 31 (53.4%) patients and was more frequent in MPA patients (70.4% versus 38.7%; p=0.016). In 16.1% of DAH cases, BAL confirmed the diagnosis despite the absence of clinical or biological arguments. The incidence of microbial infections on BAL (38%) was similar between MPA and GPA (p=0.54).
Conclusion
Bronchoscopy is an informative procedure at the onset of AAV disease in patients with respiratory manifestations. Endobronchial lesions are more frequently found in GPA and should be biopsied. BAL can be used to confirm DAH or diagnose superadded infection.
Tweetable abstract
Bronchoscopy is an informative procedure at the onset of AAV disease. Endobronchial lesions are more frequently found in granulomatosis with polyangiitis and should be biopsied. BAL can be used to confirm DAH or diagnose superadded infection. https://bit.ly/3pdVYJX
Introduction
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are small-vessel vasculitides associated with anti-neutrophil cytoplasmic antibody (ANCA) [1, 2]. Lung, kidney and ear, nose and throat (ENT) are the most frequently involved organs [3, 4]. Many respiratory presentations including nodular, tracheobronchial and interstitial disease have been described [5]. Despite numerous ANCA-associated vasculitis (AAV) studies, data describing bronchoscopy findings are limited. Our retrospective study describes data from bronchoscopy obtained at the onset of the disease in AAV patients.
Methods
Patients
We conducted a retrospective study between 2004 and 2019 of all patients referred at the Toulouse University Hospital (France) for MPA or GPA. The AAV diagnosis was based on clinical, biological and histological findings. Patients with newly diagnosed MPA or GPA with Chapel Hill Consensus Conference nomenclature were included. Exclusion criteria were defined by age <18 years.
Data collection
Patient demographics (age, gender, smoking history) and multisystem organ involvement were described. Constitutional symptoms (fever, weakness, weight loss), kidney (e.g. glomerulonephritis), nervous system (e.g. mononeuritis multiplex), skin (e.g. palpable purpura), ENT (e.g. sinusitis, epistaxis, subglottic and/or tracheal stenosis), cardiac (e.g. myocarditis), digestive (e.g. ulcerative lesions) and eye involvement (e.g. uveitis, scleritis) were collected. Respiratory involvement was represented by diffuse alveolar haemorrhage (DAH), nodules and masses, interstitial lung diseases (ILDs; excluding DAH), bronchiolitis and tracheobronchial involvement. Plasma Exchange and Glucocorticoids for Treatment of Anti-Neutrophil Cytoplasm Antibody (ANCA)-Associated Vasculitis (PEXIVAS) criteria defined DAH due to active vasculitis as 1) a compatible chest radiograph or computed tomography (CT) scan (diffuse pulmonary infiltrates); 2) the absence of an alternative explanation for all pulmonary infiltrates; 3) at least one of the following criteria applied: evidence of alveolar haemorrhage on bronchoscopic examination or increasingly bloody returns with bronchoalveolar lavage (BAL), observed haemoptysis and unexplained anaemia (<10 g·dL−1), increased diffusing capacity of carbon dioxide [6]. A respiratory radiologist and two pulmonologists independently evaluated chest radiographs and CT scans. A final consensus was required to determine the pattern. Bronchoscopy was performed under local or general anaesthesia. BAL was performed with 50–100 mL sterile 0.9% saline in a single lung segment. Aliquots of lavage material and tracheobronchial secretions were examined for conventional bacterial, viral and fungal pathogens. Endobronchial lesions and histological findings were also collected.
Ethics
The local ethics committee approved the study of the University Hospital of Toulouse (MR-004; ANCA-RnIPH 2019-45). According to the French law related to retrospective observational studies and our institutional review board (University Hospital of Toulouse Office of Research, Development and Innovation), the need for written consent was waived.
Statistical analysis
Quantitative variables, expressed as median (interquartile range), were compared with Mann–Whitney tests. Qualitative variables were expressed as numbers (%) and compared using Chi-squared or Fisher's exact tests, as appropriate. For all statistical analyses, a two-tailed p<0.05 defined significance. All statistical analyses were performed using GraphPad version 8.
Results
Demographics
Between 2004 and 2019, we screened 274 patients, with 92 bronchoscopies performed. In these patients, 62 bronchoscopies were done at MPA or GPA diagnosis (figure 1). Four patients were excluded due to missing data and, thus, 58 patients were included in the final analysis. The mean follow-up was 58 months. The clinical characteristics of the population studied are described in table 1. Among these 58 AAV patients, 38 (65.5%) were men and 31 (53.4%) were GPA. The mean age at diagnosis was 62.7 years (median 64.5 years, range 18–83 years). High-resolution CT (HRCT) imaging was available for 48 (80%) patients, and other patients had chest radiographs. Tobacco consumption was noted for 48.3% of patients. 18 (31%) relapses and eight (13.3%) deaths were recorded.
FIGURE 1.
Flow chart of patients. AAV: anti-neutrophil cytoplasmic antibody-associated vasculitis; MPA: microscopic polyangiitis; GPA: granulomatosis with polyangiitis; BAL: bronchoalveolar lavage.
TABLE 1.
Population characteristics
| GPA | MPA | Total | p-value | |
| Patients | 31 (53.4) | 27 (46.6) | 58 (100.0) | |
| Gender | 0.04 | |||
| Male | 24 (77.4) | 14 (51.8) | 38 (65.5) | |
| Female | 7 (22.6) | 13 (48.1) | 20 (34.5) | |
| Age at diagnosis years | 0.26 | |||
| Mean±sd | 60.4±16.7 | 65.3±15.8 | 62.7±16.3 | |
| Median (range) | 63 (18–80) | 70 (18–83) | 64.5 (18–83) | |
| ANCA specificity | <0.0001 | |||
| PR3-ANCA | 25 (80.6) | 5 (18.5) | 30 (51.7) | |
| MPO-ANCA | 6 (19.3) | 22 (81.5) | 28 (48.3) | |
| Smoking history | 0.55 | |||
| Tobacco status | 22 (71.0) | 19 (70.3) | 41 (70.7) | |
| Absent | 6 (19.3) | 7 (25.9) | 13 (22.4) | |
| Active | 5 (16.1) | 2 (7.4) | 7 (12.1) | |
| Past | 11 (35.5) | 10 (37) | 21 (36.2) | |
| Asthma | 2 (6.5) | 2 (7.1) | 4 (6.9) | 0.92 |
| COPD | 4 (12.9) | 3 (10.7) | 7 (12) | 0.93 |
| Follow-up months | ||||
| Patients | 30 (96.8) | 23 (85.2) | 53 (91.4) | 0.38 |
| Mean±sd | 70±46.85 | 59.9±41.35 | 65.2±44.5 | |
| Median (range) | 60.5 (2–180) | 53 (3–128) | 58 (3–128) | |
| Relapses | 9 (29) | 9 (33.3) | 18 (31) | 0.72 |
| Deaths | 4 (12.9) | 4 (14.8) | 8 (13.8) | 0.83 |
Data are presented as n (%), unless otherwise stated. GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; ANCA: anti-neutrophil cytoplasmic antibody; PR3: proteinase 3; MPO: myeloperoxidase.
Clinical involvement
Multisystem organ involvement and symptoms are summarised in table 2. All patients had at least two or more organs involved in vasculitis. Pulmonary involvement was noted in 84.5% of patients (table 2). The most common respiratory symptoms included dyspnoea (63.8%), cough (53.4%) and haemoptysis (27.6%). Cough was more frequent in GPA than MPA (p=0.019). Wheezing was noted only in two GPA patients. Eye and ENT manifestations were significantly associated with GPA (p<0.05). DAH was the most frequent manifestation (53.4%), followed by nodules and masses (20.7%), tracheobronchial involvement (10.3%), ILDs (6.9%) and bronchiolitis (3.4%) (table 2). DAH was associated with MPA (p=0.016), while nodular disease (p=0.0003) and tracheobronchial involvement (p=0.016) were significantly associated with GPA.
TABLE 2.
Clinical data of anti-neutrophil cytoplasmic antibody-associated vasculitis patients
| GPA | MPA | Total | p-value | |
| Patients | 31 (53.4) | 27 (46.6) | 58 (100.0) | |
| Respiratory symptoms | ||||
| Dyspnoea | 20 (64.5) | 17 (63) | 37 (63.8) | 0.90 |
| Thoracic pain | 4 (12.9) | 1 (3.7) | 5 (8.6) | 0.21 |
| Cough | 21 (67.7) | 10 (37) | 31 (53.4) | 0.020 |
| Haemoptysis | 9 (29) | 7 (25.9) | 16 (27.6) | 0.79 |
| Respiratory involvement | 25 (80.6) | 24 (88.9) | 49 (84.5) | 0.39 |
| Diffuse alveolar haemorrhage | 12 (38.7) | 19 (70.4) | 31 (53.4) | 0.02 |
| Nodules and masses | 12 (38.7) | 0 (0) | 12 (20.7) | 0.0003 |
| Interstitial lung disease | 1 (3.2) | 3 (11.1) | 4 (6.9) | 0.24 |
| Tracheobronchial involvement | 6 (19.3) | 0 (0) | 6 (10.3) | 0.016 |
| Bronchiolitis | 0 (0) | 2 (7.4) | 2 (3.4) | 0.12 |
| Oxygen therapy | 9 (29.0) | 10 (37.0) | 19 (32.7) | 0.52 |
| Intensive care unit | 4 (12.9) | 7 (25.9) | 11 (18.9) | 0.21 |
| Mechanical ventilation | 4 (12.9) | 4 (14.8) | 8 (13.8) | 0.83 |
| Nonrespiratory symptoms | ||||
| Fatigue | 25 (80.6) | 24 (88.9) | 49 (84.5) | 0.39 |
| Weight loss | 15 (48.4) | 10 (37) | 25 (43.1) | 0.38 |
| Fever | 17 (54.8) | 14 (51.8) | 31 (53.4) | 0.82 |
| Arthritis | 11 (35.5) | 9 (33.3) | 20 (34.5) | 0.86 |
| Renal manifestations | 19 (61.3) | 23 (85.18) | 42 (72.4) | 0.04 |
| Cardiovascular involvement | 2 (6.4) | 3 (11.1) | 5 (8.6) | 0.53 |
| Cutaneous manifestations | 11 (35.5) | 13 (48.1) | 24 (41.3) | 0.33 |
| Gastrointestinal involvement | 3 (9.7) | 1 (3.7) | 4 (6.9) | 0.37 |
| Neurological involvement | 11 (35.5) | 5 (18.5) | 16 (27.6) | 0.15 |
| Eye involvement | 6 (19.3) | 0 (0) | 6 (10.3) | 0.015 |
| Ear, nose and throat involvement | 16 (51.6) | 1 (3.7) | 17 (29.3) | <0.0001 |
Data are presented as n (%), unless otherwise stated. GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis.
Biological findings
We reported 25 proteinase 3 (PR3)-ANCA (80.5%) in GPA and 22 myeloperoxidase-ANCA (81.5%) in MPA. No significant difference was observed in C-reactive protein levels in patients with or without BAL pathogens (mean±sd 123.3±113.1 mg·L−1 versus 128.4±83.2 mg·L−1; p=0.086). Patients with DAH had significantly lower levels of haemoglobin <10 g·dL−1 (79% versus 19% in patients without DAH) (p=0.006) and higher proteinuria level (mean±sd 1.60±1.06 g·L−1 versus 0.92±1.34 g·L−1; p=0.04), but no difference in creatinine level (mean±sd 244.6±367.1 µmol·L−1 versus 277.5±220.7 µmol·L−1; p=0.69) was found.
Bronchial aspiration and alveolar lavage
Results from 52 BAL (89.6%) are described in table 3. The most common indication for BAL was the investigation of DAH and concurrent lower respiratory tract infection. BAL fluids (n=52) were done mainly in the right middle lobe (44.2%). Alveolitis (cells >150 mm3) was present in 47 (90.4%) patients. No difference in subtypes of the cell population was noted except for siderophages (p=0.007) associated with MPA. DAH was observed in 31 (53.4%) patients and was more frequent in MPA (70.4%) than GPA (p=0.02). BAL with progressively bloody returns was noted in 14 (24.1%) procedures (figure 2a). Mean±sd Golde score (n=36) was higher in MPA than GPA patients (146.8±80.1 versus 71.2±68.1; p=0.005). BAL confirmed the diagnosis of DAH in five (16.1%) patients who presented opacities or ground-glass opacities on CT despite the absence of clinical (haemoptysis) and biological (anaemia) arguments. BAL or bronchial aspiration identified a lower respiratory tract microbial infection in 22 patients (38% of procedures). 16 bacterial pathogens (including Staphylococcus aureus, Pseudomonas aeruginosa, Haemophilus parainfluenzae, Enterobacter cloacae, Stenotrophomonas maltophilia), fungal infections (including Pneumocystis jirovecii, Aspergillus spp., Candida spp.) and three viral infections (including respiratory syncytial virus, influenza) were found. No difference in the incidence of microbial infections was observed in AAV patients (p=0.54). Patients with lung infections were significantly older than others (mean±sd age 59.2±17.1 years versus 69.8±12 years; p=0.02), but no gender difference (p=0.40) and difference in induction-remission therapy (p=0.14) were noted. Antibiotic therapy was given to 31% (16 out of 52) of patients either during the waiting period for bronchoscopy or immediately following the procedure. After obtaining the bronchoscopy results, empiric antibiotic treatment was modified in 50% (eight out of 16) of the patients. In cases of fungal infection, treatment was administered for two out of three Aspergillus infections and two out of two Pneumocystis infections, one of which necessitated mechanical ventilation. Among the eight recorded mortality causes, two were bacterial infections.
TABLE 3.
Bronchoalveolar lavage (BAL) and bronchial aspiration findings in anti-neutrophil cytoplasmic antibody-associated vasculitis patients
| Diagnosis | ||||
| GPA | MPA | Total | p-value | |
| Patients | 31 (53.4) | 27 (46.6) | 58 (100.0) | |
| BAL | 25 (80.6) | 27 (100) | 52 (89.6) | <0.0001 |
| Location | ||||
| Imprecise data | 5 (20) | 2 (74) | 7 (13.5) | |
| Right upper lobe | 3 (12) | 4 (14.8) | 7 (13.5) | |
| Right middle lobe | 12 (48) | 11 (40.7) | 23 (44.2) | |
| Right lower lobe | 3 (12) | 3 (11.1) | 6 (11.5) | |
| Left upper lobe | 0 (0) | 4 (14.8) | 6 (11.5) | |
| Left lower lobe | 2 (8) | 3 (11.1) | 5 (9.6) | |
| WBC cells·mm−3 | ||||
| Patients | 25 | 27 | 52 | |
| Mean±sd | 628±1318 | 630±915 | 629±1116 | 0.99 |
| Median (range) | 300 (45–6800) | 230 (10–3500) | 255 (10–6800) | |
| RBC cells·mm−3 | ||||
| Patients | 25 | 27 | 53 | |
| Mean±sd | 26 116±53 906 | 58 945±137 609 | 42 840±105 545 | 0.26 |
| Median (range) | 2800 (15–250 000) | 3150 (10–650 000) | 2900 (10–650 000) | |
| Macrophages % | ||||
| Patients | 24 | 21 | 45 | |
| Mean±sd | 62±25.3 | 58.6±29.9 | 60.4±27.3 | 0.68 |
| Median (range) | 67 (5.0–97) | 68 (1.0–92.0) | 68 (1.0–97.0) | |
| Siderophages % | ||||
| Patients | 23 | 20 | 43 | |
| Mean±sd | 31.8±32.9 | 59.8±31.7 | 44.8±34.9 | 0.007 |
| Median (range) | 30 (0.0–90.0) | 59 (0.0–95.0) | 44 (0.0–95.0) | |
| Golde score | ||||
| Patients | 16 | 20 | 36 | |
| Mean±sd | 71.19±68.1 | 146.8±80.1 | 11.5±83.2 | 0.005 |
| Median (range) | 49.0 (0–198) | 127.0 (0–354) | 108 (0–354) | |
| Lymphocytes % | ||||
| Patients | 24 | 22 | 46 | |
| Mean±sd | 9.88±10.3 | 6.13±4.55 | 8.01±8.19 | 0.12 |
| Median (range) | 7 (0.0–45.0) | 5 (0.0–20.0) | 5 (0.0–45.0) | |
| Neutrophils % | ||||
| Patients | 24 | 22 | 46 | |
| Mean±sd | 25.9±25.43 | 29.75±31.55 | 30.4±28.6 | 0.27 |
| Median (range) | 21 (0.0–95.0) | 27 (1.0–98.0) | 23 (0.0–98.0) | |
| Eosinophils % | ||||
| Patients | 23 | 20 | 43 | |
| Mean±sd | 1.61±3.26 | 1.1±3.8 | 1.37±3.485 | 0.64 |
| Median (range) | 0 (0.0–14.0) | 0 (0.0–17.0) | 0 (0.0–17.0) | |
| Bacterial pathogens | ||||
| Patients | 28 | 25 | 53 | |
| Positive | 8 (28.6) | 8 (32) | 16 (30.2) | 0.79 |
| Viral pathogens | ||||
| Patients | 28 | 25 | 52 | |
| Positive | 1 (3.6) | 2 (8.0) | 3 (5.8) | 0.49 |
| Fungal pathogens | ||||
| Patients | 28 | 25 | 53 | |
| Positive | 4 (14.3) | 5 (20) | 9 (17.0) | 0.58 |
Data are presented as n (%) or n, unless otherwise stated. GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; WBC: white blood cells; RBC: red blood cells.
FIGURE 2.
Panel of airway involvement in anti-neutrophil cytoplasmic antibody-associated vasculitis patients and bronchoalveolar lavage (BAL) findings. a) Serial aliquots of BAL fluid with increasingly bloody returns in diffuse alveolar haemorrhage. b) Axial computed tomography scan of subglottic stenosis from a patient with granulomatosis with polyangiitis. c and d) Flow–volume tracings in a 52-year-old woman with subglottic stenosis with major airway obstruction with flattening of both the inspiratory and expiratory flow–volume curves c) before and d) after interventional bronchoscopy. e) Mucosal erythema visualised during bronchoscopy. f) Bronchoscopic appearance of stenotic segmental bronchi with mucosal haemorrhage.
Endobronchial and pathological findings
Among 58 patients, 17 (29.3%) histological samples were performed. When vasculitis was suspected clinically, endobronchial biopsies were performed when visible lesions were seen during procedures and transbronchial biopsies were performed when any other organ sample (skin, kidney, ENT) was informative for the diagnosis.
Bronchoscopies were done under local (n=52) or general anaesthesia (n=6). Table 4 shows macroscopic and histopathological findings. Endobronchial abnormalities were found in 14 AAV patients (24.1% of total population) and were associated with GPA (p<0.0001) and PR3-ANCA (p=0.01) patients. No association between endobronchial abnormalities and the presence of DAH (p=0.36), nodular (p=0.09), tracheobronchial (p=0.08) and interstitial involvement (p=0.99) on CT scans were found. The most common endobronchial findings (figure 2e–f) were bronchial inflammation with mucosal haemorrhage (50%), followed by stenosis (28.6%), ulceration (14.1%) and mass-like granulomatosis (7%). For stenosis, the subglottic region was most commonly involved (three out of four). One patient had a pseudomembrane, and mucosal ulceration was revealed after removing the pseudomembrane. The mean number of biopsies per procedure was 3.75 and 2.3 for bronchial and transbronchial biopsies, respectively. The pathological analysis confirmed AAV diagnosis in six patients with GPA. The diagnosis yield of bronchial biopsies was better for visible lesions in GPA (six out of eight). No specific findings were obtained on transbronchial biopsies (n=7). Only one patient needed interventional treatment for subglottic stenosis (figure 2b). Intralesional methylprednisolone injection combined with carbon-dioxide laser resections was done to treat him. Abnormalities of the flow–volume tracing before and after interventional procedures are illustrated in figures 2c and 2d. The interventional procedure was repeated 15 years after restenosis with intralesional injections of corticosteroids and balloon dilatation.
TABLE 4.
Endobronchial abnormalities and biopsies in anti-neutrophil cytoplasmic antibody-associated vasculitis patients
| GPA | MPA | Total | p-value | |
| Patients | 31 (53.4) | 27 (46.6) | 58 (100.0) | |
| Endobronchial abnormalities | ||||
| Total | 13 (41.2) | 1 (3.7) | 14 (24.1) | 0.0007 |
| Mucosal inflammatory/haemorrhage | 6 (19.3) | 1 (3.7) | 7 (50) | |
| Ulcerations | 2 (6.45) | 0 (0) | 2 (14.3) | |
| Mass-like lesions | 1 (3.2) | 0 (0) | 1 (7.1) | |
| Inflammatory stenosis | 4 (12.9) | 0 (0) | 4 (28.6) | |
| Biopsy | ||||
| Patients | 11 (35.5) | 5 (18.5) | 16 (54.0) | 0.09 |
| Mean±sd | 4.09±2.02 | 3.0±1.22 | 3.75±1.84 | 0.29 |
| Median (range) | 3 (2–8) | 3 (2–5) | 3 (2–8) | |
| Proximal | 8 (66.6) | 1 (20) | 9 (52.9) | 0.08 |
| Histological diagnosis | 6 (50) | 0 (0) | 6 (35.2) | |
| Distal | 3 (25) | 4 (80) | 7 (41.2) | 0.83 |
| Histological diagnosis | 0 (0) | 0 (0) | 0 (0) | |
| Biopsy location | ||||
| Imprecise data | 2 (16.67) | 0 (0) | 2 (12.5) | |
| Left upper lobe | 2 (16.67) | 0 (0) | 2 (12.5) | |
| Right lower lobe | 4 (33.3) | 2 (40) | 6 (37.5) | |
| Right upper lobe | 1 (8.33) | 1 (20) | 2 (12.5) | |
| Right middle lobe | 1 (8.33) | 0 (0) | 1 (6.25) | |
| Left lower lobe | 0 (0) | 2 (40) | 2 (12.5) |
Data are presented as n (%), unless otherwise stated. GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis.
Prognosis and safety
Clinically indicated bronchoscopies in AAV patients are usually carried out in life-threatening conditions. Oxygen therapy was necessary for one-third of the patients in our study (table 2). DAH, the most critical lung injury (alone or in combination with renal failure), was the leading cause of intensive care unit (ICU) admission (72.7%). Finally, 13.8% of patients required mechanical ventilation due to respiratory failure. In two (3.5%) patients, within the 24 h following bronchoscopy, we noted temporary acute worsening of the patient's respiratory status requiring a higher level of respiratory support and mechanical ventilation for 48 h in one instance. No pneumothorax or severe bleeding was observed after transbronchial biopsies.
Discussion
Different retrospective series have found a respiratory involvement between 25% and 70% for MPA [4, 7–10] and between 50% and 80% in GPA [3, 11–13]. Classically, bronchoscopy is indicated for 1) the identification of DAH; 2) the diagnosis of lower respiratory tract infections; and 3) the assessment of the large airways for complications such as stenosis or endobronchial lesions [14, 15]. In this life-threatening disease, the evaluation of the risk–benefit ratio of bronchoscopy is mandatory; the lack of data about usefulness or benefits of this examination is damaging. In this retrospective study, we describe data from bronchoscopy performed at the onset of AAV.
We noted in our cohort a male predominance (65.5%) and an age at diagnosis around the sixth decade of life for both GPA and MPA, according to other epidemiological studies [4, 16–18]. The high rate of respiratory manifestations (83.3%) is explained by the fact that bronchoscopies were performed on symptomatic patients or patients with pathological CT imaging. The respiratory comorbidity (smoking status, asthma and COPD) rate was similar in AAV patients. Cough occurred more frequently in GPA than MPA (p=0.02), perhaps due to more endobronchial lesions. CT imaging or, rarely, chest radiography before bronchoscopies are helpful to analyse lung lesions, exclude other aetiologies and guide sampling before bronchoscopy [19].
Differential diagnoses for nodular lesions are numerous and can be challenging, especially when granulomatous inflammation is the only manifestation of the disease in a given patient [20, 21]. Primary lung cancer, metastatic disease or lung infections (S. aureus, tuberculosis, nocardiosis, other) must be systematically evoked. Microbiological and cytological specimens obtained during bronchoscopy are usually valuable for eliminating infectious differential diagnoses. In the entire population, bronchial aspiration and BAL could find superadded infection in approximately four out of 10 patients, with no significant difference between MPA and GPA. Various bacterial, viral and fungal pathogens were noted. These data are critical in clinical practice because AAV patients receive highly immunosuppressive treatments as induction-remission therapy (rituximab or cyclophosphamide). Bronchoscopy for microbial analysis seems to be mandatory when clinical or CT findings are potentially related to a lung infection and can be helpful to tailor antibiotic therapy in nearly one out of two cases.
DAH is a frequent pulmonary manifestation of AAV. In our population, 31 (53.4%) patients had BAL findings compatible with DAH. In the PEXIVAS trial, bronchoscopy criteria to define DAH due to active vasculitis was “evidence of alveolar haemorrhage on bronchoscopic examination or increasingly bloody returns with bronchoalveolar lavage” [6]. The exact percentage of hemosiderin-laden macrophages to confirm DAH is debated (between 5% and >20%) [22, 23]. Classically, BAL confirms DAH features with one of the following features: bloodier BAL fluid return, Golde score >20 (>100 for severe) or siderophages >20%. Our study highlights the role of bronchoscopy in diagnosing DAH and excluding other aetiologies for infiltrates (infections in particular). Indeed, in 16% of patients with DAH, any clinical or biological arguments were present to confirm DAH. BAL is the only exam that could confirm the diagnosis in these cases. In our study, transbronchial biopsies were never informative in finding capillaritis to confirm DAH. Schnabel et al. [24] previously demonstrated the same findings in eosinophilic GPA and GPA. DAH is commonly associated with glomerulonephritis (constituting pulmonary–renal syndrome) [6], and a percutaneous renal biopsy using ultrasound guidance is preferred due to a lower risk of complications [25]. However, we must consider a significant bias, because transbronchial biopsies have been performed in our study when any other organ samples (skin, kidney, ENT) were informative for the diagnosis. Although more invasive, surgical lung biopsies provide a much higher diagnostic yield; however, they are no longer used routinely due to the risk of serious complications (bleeding, pleural clotting, pneumothorax, other) [26, 27]. The diagnostic accuracy of transbronchial lung cryobiopsy has yet to be evaluated in this setting.
After the suspected infection and the confirmation of DAH, a suspicion of endobronchial damage and particularly stenosis (based on clinical presentation or pulmonary function test) was the third situation where endoscopy seems essential to the diagnosis. Pulmonary function testing with inspiratory and expiratory flow–volume tracings helped manage airway disease and assess the therapeutic success of systemic and bronchoscopic treatments [28]. The presence of bronchial lesions in AAV patients can help direct the diagnosis toward GPA. The most common airway abnormalities include mucosal oedema, ulcerated lesions and inflammatory pseudotumour [28]. The frequency of lower respiratory tract lesions reported in past GPA studies varies from 52.9% in the study of Daum et al. [29], 27% in Cordier et al. [30] and 23.8% in Schnabel et al. [24]. We reported similar data with a prevalence of 41.2% endobronchial lesions in patients with GPA who benefited from bronchoscopy. No data are available for MPA in the literature. We report only one patient with mucosal haemorrhage. Retrospective series (with selected patients) may overdiagnose the frequency of endobronchial lesions in GPA. Throughout the GPA population screened in the study (n=133), we highlight a minimal prevalence of endobronchial lesions of 9.8%. The high rate of contributive biopsies of macroscopic endobronchial lesions can also be meaningful in isolated disease (mainly subglottic stenosis) and when the ANCA test is negative (not included in our study) [31]. GPA-related stenoses are mostly subglottic (three out of four in our study) and circumferential. Subglottic location can be a life-threatening presentation, with symptoms of wheezing and stridor. Compared to patients without tracheobronchial stenosis (TBS), those with TBS are younger and more frequently female [32, 33]. TBS relapse is common, and management requires a multidisciplinary approach [32]. Immunosuppressive treatment is often less effective than other systemic manifestations [34]. Bronchoscopy allows for a precise mapping of inflammatory lesions (subglottic, bronchial stenosis) before therapeutic interventions. Endoscopic dilatation, local steroid injection and conservative laser surgery can improve airway flow obstruction, while airway stents must be avoided in this inflammatory context [33].
Diagnosis of ILD cases requires combining clinical information, HRCT imaging and BAL findings to ensure a reliable diagnosis [35]. The presence of siderophages was described in 70% of ILD-AAV and seems more frequently observed than in patients with idiopathic pulmonary fibrosis [36]. Our data are consistent with these findings, with three out of four patients with ILD-AAV presenting siderophages on BAL.
DAH is the most common vasculitis manifestation which puts AAV patients in the ICU [37]. When bronchoscopy was clinically indicated, one-third of patients required oxygen therapy. The safety profile of the procedure represents original data in this population. Bronchoscopy could temporarily worsen the patient's respiratory status, especially in acute respiratory failure due to DAH. It is essential to have the possibility to upgrade the level of care before performing the examination. Bronchoscopy complications (bleeding or pneumothorax) do not appear to be increased in our population of patients with AAV, but the number of patients is low. Our results do not represent an indication for transbronchial biopsy, due to lack of diagnostic performance, and caution should be exercised in patients with active disease and the theoretical risk of bleeding.
Our retrospective and monocentric studies have several limitations. Not all patients have had a CT scan prior to endoscopy, which may reduce the relevance of the procedure. Collected data were inevitably missing. Indications for bronchoscopy were not standardised and clinically determined by pulmonologists. A selection bias towards patients with respiratory symptoms was present. The most severe (ICU) patients could not benefit from bronchoscopy due to life-threatening disease and high procedure risk. Nevertheless, we report the most extensive series of BAL comparing macroscopic and BAL findings in MPA and GPA patients.
Conclusion
Bronchoscopy is an informative procedure at the onset of AAV disease in patients with respiratory manifestations. BAL can be used to confirm DAH or diagnose superadded infection in patients scheduled for immunosuppressive therapy as induction treatment. Endobronchial lesions are more frequently found in GPA and should be biopsied.
Footnotes
Provenance: Submitted article, peer reviewed.
Conflict of interest: S. Faguer reports consulting fees from Abionyx Pharma, consulting fees and support for a symposium from CSL-Vifor, consulting fees from Sanofi-Genzyme and Novartis SA, travel support to attend a congress from Alexion, and support for a symposium from Baxter.
Conflict of interest: The remaining authors have nothing to disclose.
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