As the development of chest computer tomography, a variety of pulmonary diseases can be diagnosed. The classic halo sign and air crescent sign are frequent in neutropenic hosts with IPA. However, the above signs are rare and less specific among nonneutropenic patients [
Galactomannan (GM) is a polysaccharide component of the cell wall of
All nonneutropenic patients coming from Affiliated Hospital of Ningbo University, who were admitted to Respiratory Medicine Department from April 2014 to February 2017, were reviewed. Written informed consent was obtained from each patient. And the Institutional Review Board approved this work.
Experienced doctors performed all bronchoscopies with bronchoalveolar lavage (20 ml for three times). The site of bronchoscopy was guided by the lung CT scan at first. Based on the infiltration location on the chest radiograph, the sampling area was selected. If there were diffuse lesions in bilateral lungs, the bronchoscope would be wedged into the middle lobe. If there were multiple lesions in bilateral lungs, the bronchoscope would be wedged into the most serious segment of left and right lung, respectively; then the lavage samples were mixed. If there were multiple lesions in unilateral lung, the bronchoscope would be wedged into the most serious segment or the involved segments and then the lavage samples mixed.
The lavage samples were submitted for direct microscopic examination and microbiological culture. Besides, a vortex was done for the remaining BALF samples and the supernatant was used for GM detection by using the Platelia Aspergillus EIA (Bio-Rad). An OD index ≧ 0.8 for BALF GM was considered positive [
Each of the included IPA patients was classified based on the criteria of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) revised in 2008. Proven cases required histopathological evidence. Probable cases required at least a host factor, a radiological criterion, and a kind of microbiological evidence. Possible cases only required hosts and radiological criteria without microbiological proofs.
Receipt of an allogeneic stem cell transplantation, prolonged use of corticosteroids, hematological diseases, solid-organ transplantation, and treatment with T cell immunosuppressants were classic risk factors. In recent years, critically ill patients with COPD [
The “non-IPA” patients included those with ABPA, aspergilloma, and the colonization or contamination, except for the IPA patients. To compare the characteristics of IPA patients with that of non-IPA ones, patients in whom there was no evidence of IPA were classified as the “non-IPA” group, which excluded ABPA, aspergilloma, and the colonization or contamination group. Colonization or contamination group was defined as positive
To analyze the influences of different risk factors on BALF GM detection, non-IPA patients were divided into two groups: patients with positive BALF GM results (case patients) and patients with negative BALF GM results (control patients). Both groups excluded the IPA, ABPA, aspergilloma, and the colonization or contamination patients.
BALF GM assay should be calculated sensitivity, specificity, positive predictive index (PPV), and negative predictive index (NPV). Although we considered an ODI ratio ≧ 0.8 in BALF GM as the positive result for referenced diagnosis of IPA, the receiver operating characteristic (ROC) curve was used to acquire the optimal cutoff index. Furthermore, factors causing false-positive results in the BALF GM assay were analyzed. Quantitative variables were compared using
During the study period, a total of 226 inpatients were enrolled in. Of those, 43 patients were excluded from the study, including 30 patients without the performance of bronchoscopy, 1 patient with lack clinical information, and 12 patients without undergoing the BALF GM assay. Thus, 183 patients participated in our final analysis (Figure
Baseline clinical characteristics of the study population
IPA |
Non-IPA |
|
---|---|---|
Age, mean years | 58.97 | 55.62 |
Male gender | 20 (64.5) | 82 (53.9) |
High-risk environment exposed | 2 (6.5) | 1 (0.7) |
Underlying disease | ||
Emphysema | 5 (16.1) | 22 (14.5) |
COPD | 1 (3.2) | 8 (5.3) |
Bronchial asthma | 0 | 8 (5.3) |
Pulmonary tuberculosis | 2 (6.5) | 10 (6.6) |
Solid tumor | 3 (9.7) | 8 (5.3) |
Bronchiectasis | 3 (9.7) | 24 (15.8) |
Diabetes | 5 (16.1) | 16 (10.5) |
Liver cirrhosis | 0 | 1 (0.7) |
Hematologic malignancy | 0 | 1 (0.7) |
Autoimmune disease | 2 (6.5) | 2 (1.3) |
Kidney non-malignant disease | 0 | 3 (2.0) |
Organ failure | 2 (6.5) | 1 (0.7) |
No underlying disease | 9 (29.0) | 57 (37.5) |
Final diagnosis | ||
Proven: 0 | ABPA: 1 (0.7) | |
Probable: 10 (32.3) | Aspergilloma: 3 (2.0) | |
Possible: 21 (67.7) | Colonization or contamination: 5 (3.3) | |
Others: 143 (94.1) |
IPA, invasive pulmonary aspergillosis; COPD, chronic obstructive pulmonary disease; ABPA, allergic bronchopulmonary aspergillosis.
Study flow diagram. BAL, bronchoalveolar lavage; BALF, bronchoalveolar lavage fluid; GM, galactomannan; IPA, invasive pulmonary aspergillosis; ABPA, allergic bronchopulmonary aspergillosis.
In the proven, probable, and possible IPA patients, the pulmonary diseases were the main underlying condition, such as emphysema (
Table
Comparison of seasonal distribution, clinical symptoms, and chest CT between proven/probable IPA patients and non-IPA patients.
Characteristics | Proven/probable IPA |
Non-IPA |
|
---|---|---|---|
Age ≥ 60 years | 6 (60.0) | 63 (44.1 ) | 0.515 |
Male gender | 8 (80.0) | 77 (53.8) | 0.201 |
Seasonal distribution, |
|||
March–October | 7 (70.0) | 93 (65.0) | 1.000 |
Clinical symptoms, |
|||
Cough | 9 (90.0) | 101 (70.6) | 0.340 |
Fever | 2 (20.0) | 37 (25.9) | 0.971 |
Dyspnoea | 3 (30.0) | 16 (11.2) | 0.212 |
Haemoptysis | 2 (20.0) | 21 (14.7) | 1.000 |
Chest tightness | 1 (10.0) | 12 (8.4) | 0.600 |
Chest pain | 1 (10.0) | 18 (12.6) | 1.000 |
Chest CT, |
|||
Infiltrate/Nodules | 8 (80.0) | 100 (69.9) | 0.751 |
Bronchiectasis | 3 (30.0) | 28 (19.6) | 0.700 |
Cavity | 3 (30.0) | 18 (12.6) | 0.284 |
Air crescent sign | 1 (10.0) | 0 | 0.065 |
Halo sign | 1 (10.0) | 10 (7.0) | 0.537 |
Other | 1 (10.0) | 12 (8.4) | 0.600 |
IPA, invasive pulmonary aspergillosis; CT, computer tomography.
The sensitivity, specificity, PPV, and NPV of BALF GM assay are shown in Table
Performance of GM detection for diagnosis of IPA in BALF.
Cutoff value | Sensitivity% | Specificity% | PPV% | NPV% |
---|---|---|---|---|
BALF GM ≥ 0.5 | 100.0% | 64.3% | 16.4% | 100.0% |
BALF GM ≥ 0.76 | 100.0% | 76.2% | 22.7% | 100.0% |
BALF GM ≥ 0.8 | 90.0% | 78.3% | 22.5% | 99.1% |
BALF GM ≥ 1.0 | 70.0% | 82.5% | 21.9% | 97.5% |
BALF GM ≥ 1.5 | 60.0% | 86.0% | 23.1% | 96.8% |
BALF GM ≥ 2.0 | 50.0% | 88.8% | 23.8% | 96.2% |
GM, galactomannan; IPA, invasive pulmonary aspergillosis; BALF, bronchoalveolar lavage fluid; PPV, positive predictive value; NPV, negative predictive value.
Receiver operating characteristic (ROC) curves for galactomannan assay in 183 study populations. Areas under the ROC curve was 0.88 (95% CI 0.82–0.94).
The positive BALF GM assay result occurred in 55 patients, 9 were diagnosed as probable IPA, 10 were classified as possible IPA, 1 was considered as ABPA, 2 were diagnosed as aspergilloma, 3 were defined as colonization or contamination, and the remaining 30 were regarded as other diagnoses. To assess the factors of BALF GM assay with false-positive results, we performed a case-control analysis. Univariate and multivariate analysis of the date are shown in Table
Risk factors for false-positive galactomannan results in bronchoalveolar lavage assays with univariate analysis and logistic regression analysis, respectively.
Variables | Case patients |
Control patients |
| |
---|---|---|---|---|
Univariate analysis | Logistic regression analysis | |||
Age ≥ 60 years | 12 (40.0) | 51 (45.1) | 0.615 | 0.533 |
Male gender | 13 (43.3) | 64 (56.6) | 0.194 | 0.067 |
Seasonal distribution | ||||
March–October | 23 (76.7) | 70 (61.9) | 0.133 | 0.129 |
Underlying disease | ||||
Emphysema | 2 (6.7) | 10 (8.8) | 0.990 | 0.608 |
COPD | 3 (10.0) | 5 (4.4) | 0.463 | 0.121 |
Bronchial asthma | 2 (6.7) | 5 (4.4) | 0.976 | 0.273 |
Pulmonary tuberculosis | 7 (23.3) | 10 (8.8) | 0.063 | 0.117 |
Solid tumor | 0 | 11 (9.7) | 0.164 | 0.999 |
Bronchiectasis | 7 (23.3) | 16 (14.2) | 0.349 | 0.431 |
Diabetes | 0 | 11 (9.7) | 0.164 | 0.999 |
Liver cirrhosis | 0 | 1 (0.9) | 1.000 | 0.999 |
Hematologic malignancy | 0 | 1 (0.9) | 1.000 | 1.000 |
Autoimmune disease | 0 | 2 (1.8) | 1.000 | 0.999 |
Kidney non-malignant disease | 1 (3.3) | 1 (0.9) | 0.377 | 1.000 |
Antibiotics | ||||
Piperacillin/tazobactam | 9 (30.0) | 22 (19.5) | 0.213 | 0.479 |
Mezlocillin/sulbactam | 2 (6.7) | 5 (4.4) | 0.976 | 0.726 |
Cephalosporins | 7 (23.3) | 49 (43.4) | 0.046 | 0.157 |
Quinolones | 7 (23.3) | 37 (32.7) | 0.321 | 0.404 |
COPD, chronic obstructive pulmonary disease.
IPA is a life-threatening disease, especially in immunocompromised hosts. The classic risk factors for IPA include neutropenia, receipt of an allogeneic stem cell transplant, long-time use of corticosteroids and treatment with immunosuppressants [
Rapid initiation of systemic antifungal treatment is the key to improve the prognosis of IPA patients. Diagnosis of IPA is always an arduous task, although a large number of reports have demonstrated that the detection of GM in blood samples coming from neutropenic patients is helpful for early diagnosis. However, the utility of BALF GM assay still needs to be investigated by many clinical studies, especially in nonneutropenic hosts. Based on the previous findings [
Various factors can cause false-positive result in BALF GM detection, such as BALF sample pretreatment with Sputasol [
This study has several limitations. First, the present study was retrospective. We may perform a prospective research in the future. Secondly, the number of patients with proven IPA was small; in fact, none of them had proven IPA. Besides, the patients came from a single center. So we will enlarge the number of target population and invite other hospitals to participate in the following research. Thirdly, we used GM detection in BALF as part of mycological criterion for diagnosing, which may cause incorporation bias. If the results of BALF GM were excluded from mycological criteria of IPA, 3 of 10 probable IPA patients were reclassified as possible cases. The sensitivity of BALF GM assay may be higher than it really is.
In conclusion, our retrospective study suggests that the optimal value of GM detection in BALF is 0.76 in nonneutropenic patients. However, the utility of GM in BALF for diagnosing IPA in nonneutropenic hosts still needs to be evaluated by lots of multicenter studies.
The authors declare that they have no conflicts of interest.
Zhongbo Chen and Zaichun Deng participated in study design; Qidong Zhuang, Hongying Ma, Yun Zhang, Lei Chen, Li Wang, and Lin Zheng participated in data collection and analysis; Qidong Zhuang also participated in writing.
This work was supported by Ningbo Social and Scientific Development Fund (no. 2012C50006, no. 2015C50012) and Natural Science Foundation of Ningbo (no. 2016A610132, no. 2017A610250).