Forty-two patients with in total 42 TBLB procedures were assessed, of which seven patients (16.7%) were immunosuppressed, but there was no patient with prior lung transplantation. Three patients were on Methotrexate due to rheumatoid arthritis and polymyalgia rheumatica, two patients on Cyclophosphamide pulse therapy due to interstitial lung disease (ILD) associated with hypersensitivity pneumonia and systemic sclerosis, one patient was on neoadjuvant chemotherapy with Cisplatin/Paclitaxel due to non-small cell lung cancer, and one patient received Tacrolimus due to focal segmental glomerulosclerosis. The most common clinical diagnosis leading to mechanical ventilation was pneumonia (52.4%), and 25 patients (59.5%) met the ARDS Berlin criteria [Table 1].
Table 1: Baseline demographics and clinical characteristics on ICU admission – comparison of patients with and without histologically confirmed organizing pneumonia
Variable
|
All patients
(n = 42)
|
Patients with OP
(n = 23)
|
Patients without OP
(n = 14)
|
P valuea
|
Clinical characteristics
|
|
|
|
|
Age (years)
|
60.5 (± 16.1)
|
66.0 (± 15.4)
|
63.4 (± 18.8)
|
0.876c
|
Gender (male)
|
26 (61.9)
|
13 (56.5)
|
9 (64.3)
|
0.645d
|
APACHE II (points)
|
20.2 (± 6.4)
|
19.6 (± 6.3)
|
19.9 (± 7.2)
|
0.887b
|
Albumin (g/dL)
|
2.2 (± 0.7)
|
2.3 (± 0.8)
|
2.0 (± 0.5)
|
0.082c
|
Vasopressors
|
28 (66.7)
|
16 (69.6)
|
9 (64.3)
|
0.054d
|
Hemodialysis
|
6 (14.3)
|
4 (17.4)
|
1 (7.1)
|
0.383d
|
Surgery prior to ARF
|
12 (28.6)
|
10 (43.5)
|
2 (14.3)
|
0.084e
|
Berlin ARDS criteria fulfilled*
|
25 (59.5)
|
15 (65.2)
|
9 (64.3)
|
0.955d
|
Mild (P/F 200-300)
|
2 (8.0)
|
2 (13.3)
|
0 (0.0)
|
–
|
Moderate (P/F 100-200)
|
19 (76.0)
|
11 (73.3)
|
7 (77.8)
|
–
|
Severe (P/F < 100)
|
4 (16.0)
|
2 (13.3)
|
2 (22.2)
|
–
|
ECLA
|
8 (19.0)
|
4 (17.4)
|
4 (28.6)
|
0.445e
|
Cause of respiratory failure
|
|
|
|
|
Pneumonia
|
22 (52.4)
|
12 (52.2)
|
8 (57.1)
|
0.772d
|
AE–ILD
|
8 (19.0)
|
4 (17.4)
|
3 (21.4)
|
1.000e
|
Surgery
|
7 (16.7)
|
5 (21.7)
|
2 (14.3)
|
0.687e
|
Other
|
5 (11.9)
|
2 (8.7)
|
1 (7.1)
|
1.000e
|
Comorbidities
|
|
|
|
|
CCI (points)
|
5.1 (± 2.5)
|
5.2 (± 2.1)
|
4.7 (± 3.1)
|
0.476c
|
Diabetes mellitus
|
10 (23.8)
|
5 (21.7)
|
4 (28.6)
|
0.705e
|
Chronic kidney disease
|
10 (23.8)
|
7 (30.4)
|
3 (21.4)
|
0.710e
|
Coronary artery disease
|
10 (23.8)
|
5 (21.7)
|
3 (21.4)
|
1.000e
|
Immunosuppression
|
7 (16.7)
|
4 (17.4)
|
3 (21.4)
|
1.000d
|
Malignancy
|
6 (14.3)
|
3 (13.0)
|
2 (14.3)
|
1.000e
|
Chronic heart failure
|
5 (11.9)
|
2 (8.7)
|
2 (14.3)
|
0.625e
|
COPD
|
5 (11.9)
|
2 (8.7)
|
1 (7.1)
|
1.000e
|
Interstitial lung disease
|
3 (7.1)
|
1 (4.3)
|
1 (7.1)
|
1.000e
|
Legend
Continuous variables are presented as mean values (± standard deviation); categorical variables are presented as number or number (%).
*: Refers to the day of intubation, which might be different from the day of ICU admission
a: P value for differences between patients with and without histologically confirmed organizing pneumonia (excluding five patients without a specific histopathology)
b: Student`s t-test
c: Mann-Whitney U-test
d: Chi square test
e: Fisher`s Exact test
Abbreviations: OP, organizing pneumonia; APACHE II, Acute Physiology and Chronic Health Evaluation II score; ARF, acute respiratory failure; ARDS, acute respiratory distress syndrome; P/F, quotient of partial pressure of oxygen to fraction of inspired oxygen (mmHg); ECLA, extracorporeal lung assistance; AE–ILD, acute exacerbation of interstitial lung disease; CCI, Charlson comorbidity index; COPD, chronic obstructive pulmonary disease
Table S1 describes the CT features of each patient in detail [see Additional file 1]; all patients had bilateral infiltrates on chest CT scan at the time of the TBLB. Median time from intubation to TBLB was 12 days (range 4–98 days). A transbronchial forceps biopsy was performed in 92.9% of cases, 83.3% of the biopsies were performed in the ICU, and fluoroscopy was used in 11.9% of all procedures (and always for cryobiopsy). Transbronchial cryobiopsy in three patients (7.1%) was performed in the bronchoscopy unit using either a rigid bronchoscope (twice) or an endotracheal tube (once), without prophylactic balloon placement. Right lung biopsy was performed in 57.1% and 50% of all samples were taken from two lung lobes (most often from the right upper [RUL] and right lower lobe [RLL]). 42.9% of all biopsies were performed under chest drainage protection [Table 2].
Table 2: Modality of transbronchial lung biopsy
Modality
|
n (%)
|
No. of procedures
|
42
|
Type of procedure
|
|
Forceps biopsy
|
39 (92.9)
|
Cryobiopsy
|
3 (7.1)
|
Fluoroscopy-guided biopsy
|
5 (11.9)
|
Place of procedure
|
|
Intensive care unit
|
35 (83.3)
|
Bronchoscopy unit
|
7 (16.7)
|
Airway access
|
|
Endotracheal tube
|
27 (64.3)
|
Tracheal cannula
|
13 (31.0)
|
Rigid bronchoscope
|
2 (4.8)
|
Ventilator variables & respiratory indices
|
|
P/F ratio (mmHg)
|
192.2 (± 89.8)
|
FiO2
|
0.58 (± 0.22)
|
IPAP (cmH2O)
|
27.2 (± 4.8)
|
PEEP (cmH2O)
|
8.6 (± 2.9)
|
LTCdyn (mL/cmH2O)
|
31.6 (± 15.4)
|
Mechanical power (J/min)
|
26.2 (± 9.3)
|
Coagulation parameters
|
|
aPTT (sec)
|
39 (± 12)
|
INR
|
1.2 (± 0.2)
|
Platelet count (per µL)
|
263 (± 139)
|
Anticoagulants/Antiaggregants
|
|
No. of patients
|
21 (50.0)
|
Thrombosis Prophylaxis
|
12 (28.6)
|
Thrombosis Prophylaxis & ASS
|
7 (16.7)
|
ASS
|
2 (4.8)
|
Legend
Continuous variables are presented as mean values (± standard deviation); categorical variables are presented as number or number (%). Thrombosis Prophylaxis refers to Enoxaparin (≤ 40 mg/day s.c.) or unfractionated heparin (≤ 15.000 U/day s.c.)
Abbreviations: P/F ratio, ratio of partial pressure of oxygen to fraction of inspired oxygen; FiO2, fraction of inspired oxygen; IPAP, inspiratory positive airway pressure; PEEP, positive end-expiratory pressure; LTCdyn, dynamic lung-thorax compliance; INR, International Normalized Ratio; aPTT, activated partial thromboplastin time; ASS, acetylsalicylic acid (100 mg/day)
The median effective number of specimens obtained (and ultimately analyzed by the pathologists) in 40 patients was 4 (range 2–9) and the median size of these specimens was 3 mm (range 2–7 mm); this information was missing in two patients (4.8%). Diagnostic yield of the TBLB was 88.1%, meaning that TBLB revealed a specific histological diagnosis in 37 patients, with OP as the most common one in the whole study population (54.8%) [see Additional file 1: Table S2] and in patients fulfilling the ARDS criteria (60.0%). Sixteen patients (38.1%) were clinically classified as SOP (9 patients with pneumonia as the leading cause of intubation, 6 postoperative patients, and 1 patient with ANCA-associated vasculitis) and seven patients (16.7%) as COP. A diagnosis of drug-induced lung injury (DILI) was made in four patients, of which three patients experienced Amiodarone-induced pulmonary toxicity, and another four patients showed diffuse alveolar damage (DAD). In five patients (11.9%), either there was no lung tissue in the biopsy sample or the histological pattern was not classifiable. No biopsy showed more than one histological diagnosis, and no patient underwent subsequent SLB. Bronchial lavage (BL) was performed in 41 patients (97.6%), and 21 patients (50.0%) were subjected to BAL. There was evidence of infection from BL in 11 patients (26.8%). The mean amount of aspirated liquid in the BAL was 33 mL (± 10 mL); with pure neutrophilia as the most frequent cell distribution in the whole population (61.9%) and in patients with OP (66.7%) [Table 3, see Additional file 1: Table S3].
Table 3: Results of transbronchial lung biopsy, bronchial lavage and BAL
Specimen
|
n (%)
|
Transbronchial lung biopsy
|
42
|
Organizing pneumonia
|
23 (54.8)
|
Diffuse alveolar damage
|
4 (9.5)
|
Drug-induced lung toxicity
|
4 (9.5)
|
Purulent bronchopneumonia
|
2 (4.8)
|
Acute exacerbation of ILD
|
1 (2.4)
|
Granulomatous disease (Tb)
|
1 (2.4)
|
Non-small cell lung cancer
|
1 (2.4)
|
Silicosis
|
1 (2.4)
|
Bronchial lavage
|
41
|
Cytomegalovirus (PCR)
|
3
|
Pseudomonas aeruginosa (culture)
|
3
|
Herpes simplex virus (PCR)
|
1
|
Aspergillus fumigatus (culture)
|
1
|
Klebsiella oxytoca (culture)
|
1
|
Stenotrophomonas maltophilia (culture)
|
1
|
Enterococcus faecalis (culture)
|
1
|
Pneumocystis jiroveci (PCR)
|
1
|
Mycobacterium tuberculosis (culture)
|
1
|
Broncho-alveolar lavage (BAL)
|
21
|
Neutrophilia
|
13 (61.9%)
|
Neutrophilia, Eosinophilia
|
3 (14.3%)
|
Neutrophilia, Eosinophilia, Lymphocytosis
|
2 (9.5%)
|
Neutrophilia, Lymphocytosis
|
1 (4.8%)
|
Lymphocytosis
|
1 (4.8%)
|
Normal cell distribution
|
1 (4.8%)
|
Legend
Normal cell distribution of BAL refers to ≥ 85% of alveolar macrophages, ≤ 15% lymphocytes, ≤ 3% neutrophils, and ≤ 1% eosinophils.
Abbreviations: OP, organizing pneumonia; ILD, interstitial lung disease; Tb, tuberculosis; PCR, polymerase chain reaction
Eight adverse events were recorded in five patients (11.9%). Pneumothorax, occurring in three patients (7.1%) who all required a chest drainage, was amongst the most common AE. However, TBLB was performed with chest drainage protection in 18 patients, so that frequency increased to 12.5% when pneumothoraces were related to patients without such a protection. One pneumothorax occurred after cryobiopsy and the others occurred as a result of forceps biopsy, but no patient developed a persistent air leak. Biopsies leading to pneumothorax were performed in the RUL/RLL (twice) and in the RLL (once). Minor bleeding occurred in 7.1%, but there was no major bleeding event. One patient died as result of forceps biopsy with tension pneumothorax and persistent hemodynamic instability with shock despite immediate chest tube insertion [Table 4].
Table 4: Adverse events of transbronchial lung biopsy
Adverse events
|
n (%)
|
No. of patients with AE
|
5 (11.9)
|
No. of AE
|
8
|
Pneumothorax
|
|
All patients
|
3 (7.1)
|
Patients without chest drainage
|
3 (12.5)
|
Minor bleeding
|
3 (7.1)
|
Major bleeding
|
0 (0.0)
|
Hemodynamic instability
|
1 (2.4)
|
Death
|
1 (2.4)
|
Legend
Categorical variables are presented as number (%).
Abbreviations: AE, adverse event(s)
The histopathological results of the TBLB resulted in a change in therapy in 17 patients (40.5%). Corticosteroids were initiated in 15 patients (12 patients with OP, two patients with DILI, and one patient with DAD); one patient with pre-existing and acute exacerbated ILD was switched from cyclophosphamide pulse therapy to rituximab, and one patient with a histological diagnosis of DAD discontinued corticosteroid treatment.
In patients with corticosteroid induction a median cumulative dose of 600 mg [range 500–4000 mg] of prednisolone was administered within the first week. Responsiveness to corticosteroids with marked improvement in gas exchange (as defined above) could be observed in five patients (which all had histologically confirmed OP; median increase in P/F ratio by day seven of 127 mmHg [105–137 mmHg], compared to 15.5 mmHg [-32–84 mmHg] in ten non-responders [seven OP, one DAD, two DILI]). There was no significant difference in the cumulative prednisolone dose between responders and non-responders (median 500 mg [500–4000 mg] vs 600 mg [500–1180 mg]; p = 0.292).
ICU and hospital mortality in the whole population were as high as 35.7% and 40.5%, respectively. Patients with a histological diagnosis of OP showed a trend towards lower ICU mortality (21.7% vs 50.0%; p = 0.079) and lower hospital mortality (26.1% vs 57.1%; p = 0.062). In contrast, there was no difference in ICU mortality (29.4% vs 35.0%; p = 0.721) or hospital mortality (29.4% vs 45.0%; p = 0.337) of patients with and without a change in therapy due to the histopathological result of the TBLB.
In the multivariable binary logistic regression analysis, age (odds ratio 1.070, 95%CI 1.006–1.138; p = 0.031) and the presence of a histological pattern of OP (0.182, [0.036–0.926]; p = 0.040) were independently associated with hospital mortality [see Additional file 1: Table S4]. This benefit in terms of survival in patients with OP was confirmed by Kaplan-Meier analysis [Figure 1].
There was no independent association of AE with coagulation parameters, the presence of anticoagulants, or with ventilator variables and respiratory indices (e.g. PEEP, IPAP or mechanical power), and no variable could reliably predict a histological diagnosis of OP before TBLB or a response to glucocorticoid treatment.