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. 2022 Nov 30;108(1):22–26. doi: 10.4269/ajtmh.22-0412

Sensitivity of Antigen, Serology, and Microbiology Assays for Diagnosis of the Subtypes of Chronic Pulmonary Aspergillosis at a Teaching Hospital in São Paulo, Brazil

Vítor Falcão de Oliveira 1,*, Joshua Araújo Viana 2, Marcio Valente Yamada Sawamura 2, Adriana Satie Gonçalves Kono Magri 1, Andre Nathan Costa 3, Edson Abdala 1, Alessandro Wasum Mariani 4, Gil Benard 5, Marcello Mihailenko Chaves Magri 1
PMCID: PMC9833085  PMID: 36450228

ABSTRACT.

Chronic pulmonary aspergillosis (CPA) is divided into five subtypes. The diagnosis of CPA is complicated due to poor sensitivity of the laboratory tests. Diagnostic performance of different antigen, serological, and microbiological methods in subtypes of CPA is unknown. The purpose of this study was to evaluate the diagnostic performance in different subtypes of CPA. A total of 91 participants with CPA were included, and the study was performed at Hospital das Clínicas of University of São Paulo. Bronchoalveolar lavage galactomannan (73%, 11/15), serology by immunodiffusion test (81%, 61/75), and histology (78%, 39/50) had the best sensitivity. The counterimmunoelectrophoresis (CIE) titers had a significant statistical difference between the CPA subtypes (P < 0.001), in which the forms chronic fibrosing pulmonary aspergillosis (CFPA) and subacute invasive aspergillosis (SAIA) had higher titers: 1/64 (interquartile range [IQR]: 1/32–1/256) and 1/64 (1/32–1/128). C-reactive protein generally presented lower values (median 15 mg/L, IQR: 6–33), with higher values in SAIA and lower values for Aspergillus nodule. Overall, we found a low diagnostic sensitivity of current tests. Regarding the CPA subtypes, we did not find great differences in the performance of the tests, but it is observed that the inflammatory markers and CIE titers tend to be higher in forms of the more extensive lung parenchyma involvement, such as SAIA and CFPA.

INTRODUCTION

Chronic pulmonary aspergillosis (CPA) is a disease caused by filamentous fungi of the genus Aspergillus,1 usually seen in immunocompetent or mildly immunosuppressed patients with underlying structural lung diseases.2,3

According to the European guidelines, CPA is divided into five subtypes: chronic cavitary pulmonary aspergillosis (CCPA), chronic fibrosing pulmonary aspergillosis (CFPA), simple aspergilloma (SA), Aspergillus nodule (AN), and subacute invasive aspergillosis (SAIA).4

Diagnosing CPA requires a combination of characteristics, one of which is the presence of evidence of Aspergillus infection or immunological response to Aspergillus spp.4 There are several assays that contribute to the diagnosis of CPA, such as histology, microscopy, culture, polymerase chain reaction of respiratory samples, galactomannan (GM) antigen, and antibodies.4

The diagnosis of CPA is complicated due to poor sensitivity of culture methods and GM.5 In addition, the precipitin test had imprecision and instability in the sensitivity analysis.6 Diagnostic performance of different antigen, serological, and microbiological methods in CPA is variable and uncertain. Furthermore, the impact of the subtypes of CPA in the diagnostic performance of these tests is also unknown. The purpose of this study was to evaluate the diagnostic performance in different subtypes of CPA. Regarding the CPA subtypes, we did not find great differences in the performance of the tests.

MATERIALS AND METHODS

Study design.

We evaluated the diagnostic performance of microbiological and serological tests and of inflammatory markers in CPA cases according to subtype. This study was performed at Hospital das Clínicas of University of São Paulo, a quaternary care teaching hospital in São Paulo, Brazil. We retrospectively reviewed the medical records of consecutive patients between January 2010 and June 2021.

We included all cases diagnosed with CPA that were followed up at outpatient clinics. Subjects with any of the following were excluded: 1) respiratory and blood samples taken from each patient after the administration of antifungal agents or 2) subjects with others forms of pulmonary aspergillosis (allergic bronchopulmonary aspergillosis or invasive aspergillosis). Ethical approval for the study was obtained from the local ethics committee.

Case definition of CPA.

The gold standard for the diagnosis of CPA was considered the updated criteria of the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the European Respiratory Society (ERS) guidelines for the management of CPA.4

All patients with proven CPA had the following characteristics: 1) computerized tomography scan of the chest findings suggestive of aspergillosis (one or more cavities with or without a fungal ball present or nodules); 2) microbiological evidence of Aspergillus infection (microscopy or culture from sputum, bronchoalveolar lavage [BAL] or, biopsy, histology, positive serum, or BAL GM) or serological evidence (serum immunodiffusion test [ID] and counterimmunoelectrophoresis [CIE]); 3) all present for at least 3 months or at least a 1-month duration in SAIA; and 4) exclusion of alternative diagnoses, such as tuberculosis, malignancy, and other similar pathological conditions.4

Patients were classified further into SA, CCPA, CFPA, AN, and SAIA. The classification was established by consensus in a working group composed of members from professionals representing the disciplines of infectious diseases, pneumology, thoracic surgery, and radiology.

Sample and assays.

We evaluated the following index tests, currently performed at our center: serum C-reactive protein (CRP), serum and BAL GM, serum ID and serum titers of CIE, microscopy, culture, and histology on respiratory samples (sputum, BAL, and lung biopsy). A normal CRP value was < 5.0 mg/L. GM was defined as positive with a cutoff of 0.5 for serum. Because the optimal cutoff for BAL is controversial, we analyzed two cutoffs, 0.5 and 1.0, as recommended by the ESCMID/ERS guidelines.7 GM analysis on BAL and serum was performed by sandwich ELISA (Platelia ASPERGILLUS Ag, Bio-Rad, Watford, United Kingdom) as per the manufacturer’s instruction.

Both ID and CIE assays used a culture filtrate of three isolates of A. fumigatus grown in sabouraud-dextrose broth. These techniques involve the detection of antibody–antigen binding as a “precipitation band” within a gel. CIE was performed with electrophoresis. In ID, the serum samples were undiluted. These tests have been used routinely in our laboratories, ID being the test of choice for diagnosis and CIE used for diagnosis and follow-up of aspergillosis patients during treatment.

For the purpose of fungal culture, respiratory samples were inoculated on Sabouraud agar with chloramphenicol at 30°C. Aspergillus spp. were identified by culture characteristics supplemented with Matrix-Assisted Laser Desorption/Ionisation-Time of Flight (Vitek MS instrument, Marcy-L’Etoile, bioMérieux, Craponne, France).

Statistical analysis.

All analyses were conducted by using the RStudio (1.4 version) software (Posit, Boston, MA). Continuous variables were reported as median and interquartile range (IQR) and categorical variables as percentages and total counts. Sensitivity was calculated to evaluate diagnostic performance. Sensitivity was defined as the number of positive test results divided by the number of cases for which the diagnostic test was performed.

We compared each variable between the CPA subtypes. We performed the Kruskal–Wallis rank-sum test for continuous variables and the Fisher’s exact test for categorical variables. P value < 0.05 was considered statistically significant.

RESULTS

Clinical characteristics.

A total of 91 patients with CPA were included in this study (Table 1). Thirty-nine patients had the diagnosis of proven CPA by histopathology. All diagnosed CPA cases were classified into SA (27.5%, N = 25), CCPA (37.4%, N = 34), CFPA (19.8%, N = 18), SAIA (12%, N = 11), od AN (3.3%, N = 3).

Table 1.

Characteristics of patients with chronic pulmonary aspergillosis and comparison of characteristics between the subtypes

Characteristics Total (N = 91) SA (N = 25) CCPA (N = 34) CFPA (N = 18) SAIA (N = 11) AN (N = 3) P value
Age median (years) 51 (42–59) 56 (42–63) 48 (42–56) 50 (46–61) 38 (34–58) 56 (44–62) 0.2
Male 58 (64%) 14 (56%) 26 (76%) 9 (50%) 6 (55%) 3 (100%) 0.2
BMI median (kg/m2) 21.3 (18.0–24.2) 23.1 (19.0–26.0) 22.6 (18.9–24.2) 18.3 (17.4–21.3) 21.0 (18.5–24.0) 28.0 (28.0–28.0) 0.037
Pulmonary TB 70 (76.9%) 18 (72%) 26 (76%) 16 (89%) 8 (73%) 2 (67%) 0.8
NTM lung disease 8 (8.8%) 2 (8%) 6 (18%) 0 (0%) 0 (0%) 0 (0%) 0.3
COPD 11 (12%) 5 (20%) 5 (15%) 0 (0%) 0 (0%) 1 (33%) 0.10
HIV 3 (3.3%) 0 (0%) 1 (3%) 0 (0%) 2 (18%) 0 (0%) 0.13
Smoking 48 (52.7%) 12 (48%) 21 (62%) 7 (39%) 6 (55%) 2 (67%) 0.5
Alcoholism 27 (30%) 8 (32%) 12 (35%) 5 (28%) 2 (18%) 0 (0%) > 0.9
Other pneumopathy 20 (22%) 6 (24%) 7 (21%) 3 (17%) 3 (27%) 1 (33%) 0.9
Thoracic surgery 11 (12%) 2 (8%) 5 (15%) 2 (11%) 2 (18%) 0 (0%) > 0.9
Diabetes mellitus 16 (18%) 7 (28%) 3 (8.8%) 3 (17%) 3 (27%) 0 (0%) 0.3

AN = Aspergillus nodule; BMI = body mass index; CCPA = chronic cavitary pulmonary aspergillosis; CFPA = chronic fibrosing pulmonary aspergillosis; COPD = chronic obstructive pulmonary disease; NTM = nontuberculous mycobacterial; SA = simple aspergilloma; SAIA = subacute invasive aspergillosis; TB = tuberculosis.

There was a predominance of middle-aged male adults, with a tendency toward lower body mass index (BMI), tuberculosis as the main pulmonary disease, and few immunocompromised patients. Five (5.5%) patients had active tuberculosis. The characteristics between the CPA subtypes are homogeneous, including immunocompromised patients, with a statistically significant difference only in BMI. The BMI median was 21.3 kg/m2 (18.0–24.2), CFPA and SAIA groups had lower BMI.

Laboratory and microbiology.

Inflammatory markers and GM antigen data are summarized in Table 2. Regarding inflammatory markers, CRP generally presented lower values in the diagnosis of CPA. However, there was a statistically significant difference between the CPA subtypes, with higher values in SAIA and lower values for AN.

Table 2.

Comparison of inflammatory markers, GM antigen, and serology performance between the subtypes of CPA

Laboratory tests Total (N = 91) SA (N = 25) CCPA (N = 34) CFPA (N = 18) SAIA (N = 11) AN (N = 3) P value
Inflammatory marker, median (IQR)
 CRP, mg/L (N = 81) 15 (6–33) 10 (5–17) 13 (7–29) 19 (13–38) 31 (18–55) 2 (2–4) 0.018
Antigen, sensitivity % (n) or median (IQR)
 Serum GM 0.21 (0.10–0.36) 0.23 (0.21–0.26) 0.09 (0.07–0.11) 0.24 (0.14–0.42) 0,29 (0.15–0.94) 0.41 (0.41–0.41) 0.4
  Cutoff 0.5 11% (2/18) 0% (0/3) 0% (0/5) 0% (0/3) 33% (2/6) 0% (0/1) 0.6
 BAL GM 2.29 (0.55–4.64) 3.57 (2.39–4.73) 4.68 (3.53–5.48) 0.30 (0.26–0.54) 0.56 (0.44–0.68) NA 0.14
  Cutoff 0.5 73% (11/15) 83% (5/6) 100% (4/4) 33% (1/3) 50% (1/2) 0.2
  Cutoff 1.0 53% (8/15) 83% (5/6) 75% (3/4) 0% (0/3) 0% (0/2) 0.03
Serology, sensitivity % (n) or median (IQR)
 ID 81% (61/75) 74% (14/19) 86% (25/29) 88% (14/16) 89% (8/9) 0% (0/2) 0.083
 CIE 1/32 (1/8–1/32) 1/8 (1/4–1/16) 1/16 (1/16–1/32) 1/64 (1/32–1/256) 1/64 (1/32–1/128) NA < 0.001

AN = Aspergillus nodule; BAL = bronchoalveolar lavage; CCPA = chronic cavitary pulmonary aspergillosis; CFPA = chronic fibrosing pulmonary aspergillosis; CIE = counterimmunoelectrophoresis; CPA = chronic pulmonary aspergillosis; CRP = C-reactive protein; GM = galactomannan; ID = immunodiffusion test; IQR = interquartile range; NA = not available; SA = simple aspergilloma; SAIA = subacute invasive aspergillosis.

Serum GM had a sensitivity of 11% (2/18) based on a cutoff 0.5, with a median value of 0.21 (IQR: 0.10–0.36). Among the subtypes, SAIA presented the best sensitivity (33%, 2/6), but there was no statistically significant difference. BAL GM presented a sensitivity of 73% (11/15) and 53% (8/15), based on a cutoff of 0.5 and 1.0, respectively, with a median of 2.29 (IQR: 0.55–4.64), also without statistical difference for cutoff 0.5. However, there was a statistically significant difference between the CPA subtypes with a cutoff 1.0.

Given the similarity between groups of CPA subtypes, with the exception of BMI, we performed a linear regression to evaluate whether there was a correlation between the two variables (BMI and GM). However, there was no correlation between BMI and GM.

ID had a sensitivity of 81% (61/75), which was adequate sensitivity in all subtypes, except the AN (0%, 0/2). There was no statistical difference in diagnostic performance. The CIE titers had a significant statistical difference between the CPA subtypes, in which the forms CFPA and SAIA had higher titers, with the respective medians titers: 1/64 (IQR: 1/32–1/256) and 1/64 (IQR: 1/32–1/128).

Microbiology data are summarized in Table 3. The microscopy of respiratory samples showed low sensitivity, ranging from 0% to 23%, with no significant statistical difference between CPA subtypes. The best sensitivity in microscopy was from biopsy samples (23%, 5/22).

Table 3.

Comparison of microbiology performance between the subtypes of CPA

Microbiology Sensitivity % (n) SA (N = 25) CCPA (N = 34) CFPA (N = 18) SAIA (N = 11) AN (N = 3) P value
Sputum microscopy 3.4% (2/59) 0% (0/13) 0% (0/24) 7,1% (1/14) 17% (1/6) 0% (0/2) 0.2
BAL microscopy 0% (0/52) 0% (0/14) 0% (0/22) 0% (0/8) 0% (0/7) 0% (0/1)
Biopsy microscopy 23% (5/22) 29% (2/7) 11% (1/9) 50% (1/2) 33% (1/3) 0% (0/1) 0.6
Sputum culture 39% (22/57) 45% (5/11) 38% (9/24) 29% (4/14) 33% (2/6) 100% (2/2) 0.5
BAL culture 18% (9/51) 21% (3/14) 9.5% (2/21) 12% (1/8) 43% (3/7) 0% (0/1) 0.4
Biopsy culture 27% (6/22) 29% (2/7) 22% (2/9) 50% (1/2) 33% (1/3) 0% (0/1) > 0.9
Histology 78% (39/50) 88% (14/16) 71% (12/17) 60% (3/5) 82% (9/11) 100% (1/1) 0.6

AN = Aspergillus nodule; BAL = bronchoalveolar lavage; CCPA = chronic cavitary pulmonary aspergillosis; CFPA = chronic fibrosing pulmonary aspergillosis; CPA = chronic pulmonary aspergillosis; SA = simple aspergilloma; SAIA = subacute invasive aspergillosis.

Thirty seven positive cultures were found. Most cultures of respiratory samples were identified as Aspergillus spp. (N = 32, 86.5%). In the samples that identified the species, three (8.1%) were Aspergillus niger, and two (5.4%) were Aspergillus fumigatus.

The culture of respiratory samples showed better sensitivity than microscopy, but still with low diagnostic yield, ranging from 18% to 39%, with no significant statistical difference between CPA subtypes. The best sensitivity in culture was from sputum samples (39%, 22/57). Histology had a higher sensitivity (78%, 39/50) compared with microscopy and culture. There was also no difference between the CPA subtypes.

DISCUSSION

Bronchoalveolar lavage GM, serology by ID and CIE, and histology are the methods that had the best diagnostic performance in our study. Inflammatory marker and titer CIE had a statistically significant difference between the subtypes of CPA.

Similar to the study by Zhong et al.,8 we found that CRP had a statistically significant difference between the CPA subtypes, with higher values of CRP in the forms CFPA and SAIA. Another study showed high values of CRP in SAIA compared with other subtypes.9 CRP is not specific in diagnosing CPA. However, the utility of CRP levels can be a tool in differentiating subtypes because the classification into subtypes based on image can be difficult in some situations.

The value of serum and BAL GM in diagnosing CPA remains unclear.10 We used a cutoff of 0.5 for BAL GM and found 73% sensitivity. Accordingly, Izumikawa et al. found the sensitivity of GM in BAL at a cutoff of 0.4 was 77.2%.5 We observed a lower sensitivity of BAL GM (cutoff 1.0) in CFPA and SAIA compared with SA. However, the result should be interpreted with caution due to the low number of patients in these groups.

In another study, the sensitivity of serum GM was 23%; for this reason, serum GM antigen test could not be used for the serologic diagnosis of CPA.11 We also found a low sensitivity of serum GM (11%, 2/18), but with better sensitivity in the SAIA (33%, 2/6) compared with the other subtypes. Patients with SAIA are more likely to have detectable Aspergillus antigen in blood.12 This is because the SAIA occurs in mildly immunocompromised patients, who have more rapid progression, with the presence of hyphae invading lung parenchyma in a biopsy.4,13

The sensitivity of CIE is similar to ID, but CIE is preferred over ID in most laboratories due to its rapid method.14,15 In a systematic review and meta-analysis study about serological tests for the diagnosis of CPA, a sensitivity of 64% was found in ID and/or CIE, suggesting that the diagnostic accuracy of ELISA is greater than the ID and CIE tests.16 However, we found a higher sensitivity compared with literature (81%, 61/75), which proved to be the best diagnostic tool among the tests performed in our study. The median of CIE titers found was 1/32 (IQR: 1/8–1/32), which demonstrates that titers in the diagnosis of CPA are not high. In the CFPA and SAIA subtypes, we found significantly higher CIE titers values in our study. This suggests that more severe forms of lung parenchyma involvement generate a greater immune response. Likewise, the Chinese study showed that SAIA had higher titers of Aspergillus specific IgG antibodies with statistical significance (P = 0.01) compared with the other subtypes of CPA.8

Microscopy of sputum or BAL often reveals fungi, but has not been systematically studied; the ESCMID/ERS guidelines demonstrate strength of recommendation A and quality of evidence II.4 We found low sensitivity of sputum, BAL, and biopsy microscopy at 3.4%, 0%, and 23%, respectively.

In the literature, A. fumigatus was responsible for almost half of cases (40.9–42.0%), followed by A. flavus (27.3–28.9%), and A. niger (9.1–10.1%).17,18 Culture-positive rates in series are 23.3% to 65%.1922 We found better culture sensitivity for sputum (39%) among respiratory samples. In another recent study, sputum culture was positive in 32.7% cases, also no difference was found between the subtypes.8 Histology, despite being an invasive method, showed the best yield, with a sensitivity of 78%, maintaining, in general, adequate sensitivity in all subtypes. However, different from what we found, a study carried out in Pakistan reported a higher culture positivity rate of sputum/BAL culture compared with histopathology (66.7% versus 44.9%).17

Our study better characterized the microbiology and serological diagnostic performance of CPA by tests commonly present in emerging countries, for which we have little information. However, there are some limitations. It is a retrospective study, which made it difficult to access some information in medical records. Furthermore, the sample number is small, which limits an adequate amount of diagnostic testing for all subtypes of CPA and can thus underestimate or overestimate sensitivity. Nearly half of the cases did not have histopathology as the gold standard, but we strictly followed the case definition based on the main guideline (ESCMID/ERS).

Another limitation of this study is that the species of most Aspergillus isolates was not identified. This made it difficult to determine whether there is a difference in causative organisms according to disease subtype because there were few culture-positive cases within each subtype, and even in culture-positive cases, the species of the organism has not been identified.

In conclusion, we found a low diagnostic sensitivity of current tests, which demonstrates that the diagnosis of CPA is difficult. BAL GM, serology by ID and CIE, and histology are the ones that had the best diagnostic performance. For this reason, it is important to associate different tests, aiming to improve the diagnosis of CPA.

Regarding the CPA subtypes, we did not find great differences in the performance of the tests, but it was observed that the inflammatory markers and CIE titers tend to be higher in forms of the more extensive lung parenchyma involvement, such as SAIA and CFPA.

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