ORIGINAL ARTICLE

https://doi.org/10.5005/jp-journals-11010-1098
Indian Journal of Respiratory Care
Volume 13 | Issue 2 | Year 2024

Evaluation of Diagnostic Markers Serum Angiotensin-converting Enzyme and Soluble Interleukin-2 Receptor Levels in Newly Diagnosed Cases of Sarcoidosis: A Case–control Study

Praveen Raj S1https://orcid.org/0009-0001-7318-7940, Balaji Kalimuthu2https://orcid.org/0009-0007-7373-0345, Vignesh K3https://orcid.org/0000-0003-2530-0280

1Department of Respiratory Medicine, SRM Medical College Hospital & Research Centre, Chennai, Tamil Nadu, India

2Department of Respiratory Medicine, Aarupadai Veedu Medical College & Hospital, Puducherry, India

3Department of Pulmonary Medicine, Aarupadai Veedu Medical College & Hospital, Puducherry, India

Corresponding Author: Vignesh K, Department of Pulmonary Medicine, Aarupadai Veedu Medical College & Hospital, Puducherry, India, Phone: +91 7200656274, e-mail: vigneshk104@gmail.com

Received: 08 November 2023; Accepted: 03 April 2024; Published on: 18 June 2024

ABSTRACT

Background: Sarcoidosis is a chronic inflammatory disease that primarily affects the lungs and lymph nodes. The formation of noncaseating granulomas is one of the characteristics of this multisystem disorder of unknown etiology. The purpose of this study was to assess the value of soluble interleukin-2 receptor (SIL2R) and serum angiotensin-converting enzyme (SACE) levels in the diagnosis of sarcoidosis.

Materials and methods: This case–control study recruited 37 patients with newly diagnosed pulmonary sarcoidosis and 31 healthy controls. All subjects had blood samples taken in order to determine their levels of SACE and SIL2R. Chest X-rays, spirometry with diffusion capacity for carbon monoxide (DLCO), and high-resolution computed tomography (HRCT) scans were performed on the sarcoidosis patients.

Results: The mean values of serological parameters SACE and SIL2R were (79.49 ± 35.78 U/mL and 672.84 ± 408.86 pg/mL) in cases and (35.81 ± 9.45 U/mL and 300.03 ± 529.77 pg/mL) in controls, respectively. Differences were statistically significant for all these parameters, with a significantly higher mean in sarcoidosis patients. Sensitivity and specificity for SACE and SIL2R were 94.59, 93.55, 91.89, and 87.10%, respectively.

Conclusion: This study suggests that SACE and SIL2R are useful markers for the diagnosis and monitoring of sarcoidosis. In sarcoidosis patients, SIL2R levels may also serve as a predictor of the disease progression and pulmonary function.

How to cite this article: S PR, Kalimuthu B, K V. Evaluation of Diagnostic Markers Serum Angiotensin-converting Enzyme and Soluble Interleukin-2 Receptor Levels in Newly Diagnosed Cases of Sarcoidosis: A Case–control Study. Indian J Respir Care 2024;13(2):78–82.

Source of support: Nil

Conflict of interest: None

Keywords: High-resolution computed tomography thorax, Sarcoidosis, Serum angiotensin-converting enzyme, Soluble interleukin-2 receptor

INTRODUCTION

The etiology of sarcoidosis remains obscure, and the condition involves multiple systems and is characterized by noncaseating granulomatous inflammation at affected sites. Most individuals with sarcoidosis experience involvement in either the lungs or intrathoracic lymph nodes.1 The theory that sarcoidosis is brought on by exposure to microbial agents in individuals with genetic susceptibility to the disease is supported by clinical, epidemiologic, and family studies.2 Sarcoidosis is defined by an “immune paradox” in which there is peripheral energy despite inflammation occurring at sites of disease.3 The histopathological, radiographic, and clinical features bear a resemblance to those observed in other granulomatous conditions, particularly tuberculosis. Sarcoidosis is confirmed by the presence of typical clinicoradiological findings, along with histology suggestive of noncaseating granulomas in multiple organs and the exclusion of granulomatous disorders with identifiable causes. Epithelioid and giant cells are responsible for the production of angiotensin-converting enzyme (ACE) in sarcoid granulomas.4 Sarcoidosis is associated with elevated serum angiotensin-converting enzyme (SACE) activity in 60% of patients.5 While the values may differ based on factors, such as the timing of diagnosis, disease severity, etc., they serve as a valuable tool for diagnosis and prognosis. Normal levels do not exclude the presence of sarcoidosis, and it is common to encounter false positive results. Moreover, elevated SACE levels can also be observed in a range of granulomatous and nongranulomatous conditions.6,8 Therefore, the activity of SACE in sarcoidosis serves as an indicator of granuloma formation, albeit with restricted sensitivity and specificity. T-cells in the lungs of individuals with pulmonary sarcoidosis exhibit various early and late activation cell surface markers, among which the interleukin-2 (IL-2) receptor is extensively researched. The levels of IL-2 receptors are heightened and readily identifiable in both the serum and bronchoalveolar lavage (BAL) of sarcoidosis patients due to the amplified presence and activation of macrophages and T-cells in granulomatous inflammation.9 So, the present study aimed to evaluate SACE and SIL2R levels in newly diagnosed cases of sarcoidosis.

MATERIALS AND METHODS

This study was conducted for 1 year in a tertiary care center in northern India. Participants in the study gave consent after the ethics committee approved it. The study included 37 patients who were newly diagnosed with pulmonary sarcoidosis (cases), selected based on specific inclusion and exclusion criteria. Additionally, 31 healthy controls were included in order to establish the normal reference range of parameters in the Indian context.

Inclusion Criteria

  • Individuals must be at least 18 years of age.

  • Patients who have recently been diagnosed with pulmonary sarcoidosis.

  • Patients with clinical, radiological, and histopathological features consistent with pulmonary sarcoidosis as per ATS/ERS/WASOG guidelines.1

Exclusion Criteria

  • Patients with other systemic diseases or comorbidities.

  • Pregnant women.

  • Patients are unable to maintain saturation of peripheral oxygen of > 90 mm Hg on room air.

  • Patients received or are receiving steroids or disease-modifying drugs during the past 4 weeks.

Sample Size

A total of 37 patients with the diagnosis of pulmonary sarcoidosis were recruited after receiving informed written consent from all patients. The sample size is calculated as per the following equation.10

Where N is the sample size of the single study group, p is the prevalence of disease for the group,1Z is the confidence level, and D is the precision. It is estimated that a sample size of 31 will be needed to demonstrate a 0.02% prevalence of sarcoidosis1 with a 90% confidence interval and 8% precision, assuming an effectively unlimited population. The diagnosis of sarcoidosis will be determined by evaluating clinical and radiological evidence, confirming the presence of noncaseating granulomas through histological examination, and ruling out other granulomatous disorders of known cause. A total of 37 patients with newly diagnosed pulmonary sarcoidosis were recruited as per the inclusion and exclusion criteria after receiving written consent from all patients. A total of 31 healthy matched controls were included in the study to know the normal reference range of parameters in the Indian scenario. A total of 68 subjects (37 cases and 31 controls) were subjected to a detailed clinical examination. In all subjects, SACE and soluble interleukin-2 receptor (SIL2R) were measured. Chest X-rays, spirometry with diffusion capacity for carbon monoxide (DLCO), high-resolution computed tomography (HRCT) scanning of the chest for HRCT scoring, and grouping were done only for 37 cases. Lung parenchyma sections are divided into six zones before scoring. The degree of radiological involvement is scored based on the HRCT scoring system given by Drent et al., Oberstein et al., and Ors et al.11-13 for 37 sarcoidosis patients. Fiberoptic bronchoscopy and BAL, transbronchial biopsy (TBLB), endobronchial biopsy (EBLB), and transbronchial needle aspiration (TBNA) were performed wherever feasible according to the stage of the disease. Histological evidence of sarcoidosis was obtained either by TBLB, EBLB, or TBNA or by CT-guided fine-needle aspiration cytology (FNAC).

Statistical Analysis

Unpaired t-tests and Mann–Whitney U tests are utilized for comparing numerical variables between different groups, while Fisher’s exact test is employed to examine categorical variables presented as frequencies or percentages. Pearson’s correlation coefficient is applied to assess the relationship between numerical variables. Receiver operating characteristic (ROC) curves are constructed to determine optimal threshold values for various parameters. Subsequently, metrics such as sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), and accuracy were computed to identify the most favorable option among these. A significance level of p < 0.05 is deemed statistically meaningful. The data has been assessed using Statistical Package for the Social Sciences version 16.0 software.

RESULTS

Table 1 shows that 18.92% of cases were in the age-group of 31–40 years, 29.73% were in 41–50 years, 29.73% were in 51–60 years, 5.41% were in <30 years, and only 16.22% were below 60 years, which means most of the sarcoidosis patients were <50 years of age. In cases out of a total of 37 subjects, females were 51.35% (n = 19), whereas males were 48% (n = 18), and in controls, females were 67.74% (n = 16), and males were 40.74% (n = 11), with no significant difference between the group in terms of gender distribution.

Table 1: Study population characteristics
Variable Cases Controls
n % n %
Age (years) ≤30 2 5.41% 8 26.67%
31–40 7 18.92% 7 23.33%
41–50 11 29.73% 6 16.67%
51–60 11 29.73% 10 33.33%
61–70 6 16.22% 0 0.00%
Total 37 100% 31 100%
Gender Male 18 48.65% 21 67.74%
Female 19 51.35% 10 32.26%
Total 37 100% 31 100%

Based on Table 2, most of the sarcoidosis cases are in total HRCT score (THS) group II (32.43%) and THS group III (29.73%), respectively. Chest radiograph staging of sarcoidosis in cases shows stage II (pulmonary infiltrates with bilateral hilar adenopathy) predominate with 48.65%.

Table 2: Distribution of cases according to total HRCT score and chest radiograph staging
THS group n (cases) % (percentage) Chest radiograph staging of sarcoidosis in cases n (cases) % (percentage)
I (no parenchymal involvement) 6 16.22% Stage 0 (normal chest X-ray) 0 0%
II (mild parenchymal involvement) 12 32.43% Stage I (bilateral hilar adenopathy without infiltrates) 9 24.32%
III (moderate parenchymal involvement) 11 29.73% Stage II (pulmonary infiltrates with bilateral hilar adenopathy) 18 48.65%
IV (severe parenchymal involvement) 8 21.62% Stage III (pulmonary infiltrates without hilar adenopathy) 6 16.22%
Stage IV (obvious scarring with fibrocystic changes) 4 10.81%
Total 37 100% 37 100%

Table 3 shows that the mean level of SACE in the cases was 79.49 U/mL, and the mean level of SACE in the control group was 35.81 U/mL only (p-value < 0.001). The mean level of SIL2R in the cases was 672.84 pg/mL, and in the control group, the mean level of SIL2R was 300.03 ng/mL only (p-value < 0.001). Higher mean levels of SACE and SIL2R in sarcoidosis patients proved that this marker could be used to diagnose sarcoidosis.

Table 3: Mean value of SACE, SIL2R in cases and controls
Variables Cases Controls
Mean ±Standard deviation Mean ±Standard deviation p-value
Mean SACE (U/mL) 79.49 ±35.78 35.81 ±9.45 <0.001
Mean SIL2R (pg/mL) 672.84 ±408.86 300.03 ±529.77 <0.001

Table 4 shows sensitivity, specificity, PPV, and NPV results, suggesting that SACE and SIL2R are relatively accurate tests for diagnosing sarcoidosis. For SACE and SIL2R, the area under the curve was 0.979 and 0.915, with a p-value of < 0.001. The AUC for SACE, SIL2R, is very good and can be used as a test to discriminate between people who have sarcoidosis and people who do not have sarcoidosis.

Table 4: Sensitivity, specificity, PPV, NPV, and area under the curve of each of the parameters
Asymptomatic 95% confidence interval
Variable Sensitivity Specificity PPV NPV Accuracy Area Standard errora p-valueb Lower bound Upper bound
SACE 94.59% 93.55% 94.59% 93.55% 94.12% 0.979 0.013 <0.001 0.953 1
SIL2R 91.89% 87.10% 89.47% 90.00% 89.71% 0.915 0.04 <0.001 0.835 0.994

a, Under the nonparametric assumption; b, null hypothesis—true area = 0.5

From Table 5, a Kruskal–Wallis H test showed that there was a statistically significant difference found in values of SIL2R among different THS groups of sarcoidosis, χ2(2) = 8.238, p = 0.041, with a mean rank (SIL2R) of 30.25 for group I (highest), 18.14 for group II, 14.94 for group III, and 16.63 for group IV. In other words, the SIL2R value is highest in patients with THS group I sarcoidosis and decreases as the THS group progresses to THS group IV. This shows that SIL2R is a useful marker for disease activity in sarcoidosis.

Table 5: Comparison of SACE/SIL2R among various THS groups of sarcoidosis
THS group n Mean rank Chi-square Degree of freedom p-value
SACE Group I 6 19.08 0.468 3 0.926
Group II 14 19.29
Group III 9 20.39
Group IV 8 16.88
SIL2R Group I 6 30.25 8.238 3 0.041
Group II 14 18.14
Group III 9 14.94
Group IV 8 16.63

In Table 6, The findings indicated that the correlation between the mean initial SACE and any of the spirometry with DLCO was not statistically significant.

Table 6: Correlation between blood parameters and spirometry with DLCO parameters
Variable SACE p-value SIL2R p-value
r r
FVC 0.271 0.104 0.224 0.183
FEV1 0.287 0.085 0.264 0.115
FEV1/FVC −0.06 0.725 0.075 0.661
FEF25–75 pre 0.203 0.228 0.133 0.432
FEF25–75 post 0.2 0.235 0.086 0.611
SVC −0.243 0.147 0.021 0.903
FRC 0.13 0.442 0.264 0.115
IC −0.044 0.797 0.218 0.194
ERV 0.341 0.039 −0.011 0.949
RV −0.073 0.667 0.316 0.057
TLC 0.054 0.749 0.351 0.033
RV/TLC −0.185 0.272 0.248 0.138
DLCO 0.189 0.261 0.155 0.361
VA 0.16 0.344 0.015 0.928
DLCO/VA 0.076 0.654 0.311 0.061

r, Pearson’s correlation coefficient; FVC, forced vital capacity; FEV1, forced expired volume in one second; SVC, slow vital capacity; FRC, functional residual capacity; IC, inspiratory capacity; ERV, expiratory reserve volume; RV, residual volume; TLC, total lung capacity; DLCO, diffusion capacity for carbon monoxide; VA, alveolar volume; FEF, forced expiratory flow

The SIL2R significantly and positively correlated with total lung capacity (p-value of 0.033, r = 0.351).

DISCUSSION

The case–control study conducted at our tertiary care center revealed that most patients fall within the 40–60 age range, with a slight majority of females (51.35%). The ACCESS study of 700 sarcoidosis patients performed in Western countries14 showed that the typical age of onset falls between 20 and 60 years, with a slightly higher likelihood of women being affected compared to men. Overall, the demographic data from the two studies were generally similar, with a similar average age of onset and female predominance. In our research, based on Table 2, the majority of sarcoidosis cases (60%) were stage II, with stage I accounting for 20%, stage III for 10%, stage IV for 5%, and stage 0 (0%). In a retrospective analysis of 1,000 sarcoidosis cases, stage II was found to be the most prevalent (35%), followed by stage I (25%), stage III (25%), and only 5% had stage 0 disease; none of the patients were diagnosed with stage IV.15 Another study by Al-Essa et al.,16 which is a retrospective cohort study done in Jordan, and the Rinaldi et al.17 study done in Italy showed 20% of the patients had stage 0, 40% had stage I, 25% had stage II, 15% had stage III, and 0% had stage IV (the most common stage was stage I). These studies hint that the distribution of sarcoidosis cases across the four stages can vary depending on the population studied. The THS is a score utilized to evaluate the extent of pulmonary sarcoidosis on an HRCT scan. It ranges from 0 to 4, where 0 signifies no parenchymal involvement and 4 indicates significant parenchymal involvement.18 In our study, most patients had a THS score of 2 (32.43%), followed by THS 3 (29.73%), THS 1 (16.22%), and THS 4 (21.62%). These results differ from those of the ACCESS study, in which the distribution of cases was more evenly distributed across all THS categories. The difference in the distribution of THS scores may be attributed to the sample size of the two studies, which may have affected the distribution of THS scores. In our study, the sample size was 37 cases, whereas the ACCESS study had a larger sample size of 700 cases. The current study revealed that patients with sarcoidosis had notably higher mean SACE and SIL2R values compared to the control group (79.49 vs 35.81 U/mL and 672.84 vs 300.03 ng/mL, respectively, p < 0.05). The findings suggest a direct correlation between SACE and SIL2R levels and sarcoidosis. Elevated levels of SACE and SIL2R are linked to a higher likelihood of developing the condition. Zhang et al.19 found that the mean values of SACE and SIL2R were significantly higher in patients with sarcoidosis than in controls (62.5 vs 37.5 U/mL and 125 vs 50 pg/mL, p = 0.002). The mean SIL2R value was also significantly higher in patients with sarcoidosis than in controls (125 vs 50 pg/mL, p = 0.001). Another study by Wang et al.20 also found that the mean values of SACE and SIL2R values were significantly elevated in individuals diagnosed with sarcoidosis. The sensitivity and specificity of SACE mentioned in the current study (94.59, 93.55%) were in the range reported by Sharma et al.21 (86, 92%) and Al-Khair et al.22 (87 and 91%), respectively. In our research, the sensitivity and specificity of SIL2R (91.89, 87.10%) were similar to those found in a study conducted by Singh et al., which involved around 100 sarcoidosis patients (90, 80%).23 Compared to other studies, SACE and SIL2R are relatively good markers for sarcoidosis, with high sensitivity and specificity.

The AUC of 0.979 for SACE and 0.915 for SIL2R are both very good, consistent with the latest studies,19,20 and can be used to discriminate between people who have sarcoidosis and those who do not. SIL2R levels were highest in THS group I and lowest in THS groups III and IV (Table 5). Similar findings were reported in a study done by Mishra et al.24 and may be due to an increase in inflammation and tissue damage in the later stages of sarcoidosis, leading to a decrease in activated T cells, which decreases the SIL2R levels. Therefore, the SIL2R level has the potential to serve as an indicator of disease advancement in sarcoidosis. Table 6 demonstrated that SIL2R levels were elevated in sarcoidosis patients with higher TLC, aligning with the findings of El-Ghobashy et al. studies.25 These findings indicate that SIL2R levels may serve as a more significant indicator of pulmonary function status in individuals with sarcoidosis when compared to SACE levels.

CONCLUSION

Overall, the study concludes that SACE and SIL2R are useful biomarkers for the diagnosis of sarcoidosis. SIL2R levels can especially be used to monitor disease progression and pulmonary function in patients with sarcoidosis, unlike SACE.

Clinical Significance

The SACE and SIL2R are both sensitive markers for sarcoidosis diagnosis. For example, if a person shows increased SACE or SIL2R levels alongside relevant clinical, histopathological, and radiological manifestations, it indicates a possible diagnosis of sarcoidosis.

ORCID

Praveen Raj S https://orcid.org/0009-0001-7318-7940

Balaji Kalimuthu https://orcid.org/0009-0007-7373-0345

Vignesh K https://orcid.org/0000-0003-2530-0280

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