Serum IgA levels and survival in patients with idiopathic pulmonary fibrosis: association with serum cytokine levels and peripheral monocyte counts
Original Article

Serum IgA levels and survival in patients with idiopathic pulmonary fibrosis: association with serum cytokine levels and peripheral monocyte counts

Toru Arai ORCID logo, Masaki Hirose, Kazuyoshi Hatsuda, Tomoko Kagawa

Clinical Research Center, NHO Kinki Chuo Chest Medical Center, Osaka, Japan

Contributions: (I) Conception and design: T Arai; (II) Administrative support: None; (III) Provision of study materials or patients: M Hirose, T Kagawa, K Hatsuda; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: T Arai, M Hirose; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Toru Arai, MD, PhD. Clinical Research Center, NHO Kinki Chuo Chest Medical Center, 1180 Nagasone-cho, Kita-ku, Sakai City, Osaka 591-855, Japan. Email: toarai1192296@gmail.com.

Background: Idiopathic pulmonary fibrosis (IPF) is an idiopathic fibrotic interstitial lung disease with poor prognosis. Recently, the prognostic value of serum platelet-derived growth factor (PDGF) levels in patients with IPF has been clarified. Monocyte counts in the peripheral blood have also been reported to be an important predictor of survival in IPF. This study aimed to clarify the prognostic value of serum immunoglobulin (Ig) A levels in patients with IPF to predict survival and occurrence of acute exacerbations (AE).

Methods: This retrospective study included 71 patients diagnosed with IPF based on the 2022 guidelines. Serum PDGF and interleukin (IL)-10 levels were measured using the Bio-Plex method. IgA levels were measured by a clinical testing company.

Results: Of the enrolled patients, 59 were male, and the median age of the sample was 67 [interquartile range (IQR): 61–72] years. The median serum IgA level was 307 (IQR: 232–408) mg/dL and 18 patients had serum IgA levels of >400 mg/dL. Univariate Cox proportional hazard regression analysis revealed that high IgA levels (>400 mg/dL) were a significant predictor of poor prognosis; however, monocyte counts were not. A high IgA level was a significant prognostic factor after adjusting for the percent predicted value of forced vital capacity, age, gender, and body mass index. Serum PDGF levels tended to be higher in patients with high IgA levels than in those with low IgA levels. IL-10 was not significantly correlated with IgA levels; however, IgA levels tended to be negatively correlated with monocyte counts. High IgA levels did not significantly predict AE. High monocyte counts (>600/µL) significantly predicted the early incidence of AE by univariate Cox analysis but was not confirmed by multivariate analysis. However, monocyte counts, and a monocyte count of >600/µL were significant predictors of AE occurrence for patients with low IgA ≤400 mg/dL.

Conclusions: The serum IgA level is an independent prognostic predictor of survival in patients with IPF. Serum IgA levels might suggest serum fibrogenic cytokine levels. Serum IgA levels might be associated with prognosis differently from peripheral monocyte counts. The pathophysiological role of IgA needs to be elucidated in future studies.

Keywords: Idiopathic pulmonary fibrosis (IPF); prognosis; acute exacerbation (AE); platelet-derived growth factor (PDGF); interleukin-10 (IL-10)


Submitted Dec 10, 2024. Accepted for publication Mar 05, 2025. Published online Apr 28, 2025.

doi: 10.21037/jtd-2024-2142


Highlight box

Key findings

• The serum immunoglobulin (Ig) A level is an independent prognostic predictor of survival in patients with idiopathic pulmonary fibrosis (IPF).

What is known and what is new?

• The prognostic value of serum IgA and monocyte counts in peripheral blood has been demonstrated in previous studies; however, the relationship between serum IgA and monocyte counts has not been evaluated. The mechanism by which high serum IgA levels suggest poor survival in patients with IPF has not yet been clarified.

• Serum platelet-derived growth factor levels tended to be higher in patients with IPF and high serum IgA levels, suggesting potential involvement of fibrogenic cytokines in IPF. Serum IgA was not correlated with interleukin-10 and tended to be with monocyte counts.

What is the implication, and what should change now?

• High serum IgA levels were associated with poor survival of patients with IPF, suggesting the potential beneficial effects of prompt treatment with antifibrotic drugs.


Introduction

Background

Idiopathic pulmonary fibrosis (IPF) is a lung disease of unknown etiology (1). The prognosis for IPF is poor. The most important cause of death in IPF is an acute exacerbation (AE) (2), which was first reported by Kondoh et al. (3). Prognostic factors for IPF have been examined in many studies (4-8). Our previous studies showed that the percent predicted value of forced vital capacity (%FVC), modified Medical Research Council (mMRC) score, and bronchoalveolar lavage (BAL) lymphocyte count are significant prognostic factors for IPF (9).

Rationale and knowledge gap

The importance of serum immunoglobulin (Ig) A in IPF has been previously reported (10). Klooster et al. reported significant prognostic value for IPF (10). The prognosis of patients with IPF with serum IgA levels of >285 mg/dL was significantly worse than that of patients with lower IgA levels, although this has not been confirmed by other studies. We have also shown that anti-myxovirus resistant protein 1 (MX1) autoantibody is a significant poor prognostic factor (11). Further, not IgG and IgM antibodies, but IgA antibodies were associated with survival and occurrence of AE after adjustment for severity of IPF. Hence, we hypothesized that IgA might have pathophysiological value in pulmonary fibrosis and could be a prognostic factor in patients with IPF. Furthermore, high serum IgA levels are also important in predicting the survival of patients with chronic liver disease (12).

We recently showed that serum levels of platelet-derived growth factor (PDGF), one of the fibrogenic cytokines (9) have significant prognostic value in patients with IPF. Serum levels of interleukin (IL)-10 are higher in patients with IPF than in healthy volunteers (9), and IL-10 is associated with transforming growth factor (TGF)-β induction and the IgA class switch (13). Monocyte counts in the peripheral blood are also important predictors of survival in patients with IPF (14).

Objective

This study aimed to clarify the predictive value of serum IgA levels for prognosis and occurrence of AE. Furthermore, the study evaluated the pathophysiological role of IgA by focusing on serum cytokine levels and peripheral monocyte counts. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2142/rc).


Methods

Study design and patient enrolment

This was a retrospective single-center study. Ninety-four patients with IPF were identified in database of interstitial lung diseases at the NHO Kinki Chuo Chest Medical Center between 2004 and 2009 according to the 2011 American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) guidelines for IPF (4). Computed tomography (CT) findings were evaluated by Dr. Akira according to the guideline and multidisciplinary discussion (MDD) was performed by institutional MDD team including T.A. and T.K. (15). Two patients with AE at the time of IPF diagnosis were excluded. Serum samples obtained at the time of diagnosis were available for 71 of the 92 patients. The diagnosis of IPF in 71 patients was re-confirmed according to the updated ATS/ERS/JRS/ALAT guidelines for IPF in 2022 (1). Surgical lung biopsy (SLB) was performed on 36 out of the 71 patients. CT pattern of IPF patients clinically diagnosed without SLB was usual interstitial pneumonia pattern (1).

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the NHO Kinki Chuo Chest Medical Center Institutional Review Board (approval number Rin2022-048). All the participants provided written informed consent for inclusion of their data in this study.

Diagnosis of AE in IPF

AE of IPF was diagnosed according to diagnostic criteria of the JRS (16) as follows: (I) AE within 1 month of the chronic clinical course of IPF, and the following three conditions should be satisfied: (i) progressively worsening dyspnea, (ii) newly appeared ground-glass opacities evident on high-resolution CT scans superimposed on a background reticular or honeycomb pattern, and (iii) a reduction of resting PaO2 by more than 10 Torr compared to previous measurements under the same conditions; and (II) exclusion of obvious causes of acutely impaired respiratory function, such as infection, pneumothorax, cancer, pulmonary embolism, and congestive cardiac failure.

Clinical findings at time of diagnosis of IPF

Clinical findings, including age, sex, body mass index (BMI), smoking status, mMRC score (17), pulmonary function test results, and laboratory test results at the time of IPF diagnosis were obtained retrospectively from the medical records. Pulmonary function tests, including FVC and diffusing capacity of carbon monoxide (DLco), were performed using a Chestac 8080 spirometer (Chest, Tokyo, Japan). BAL fluid was obtained using a bronchoscope, as previously described (18).

Measurement of serum cytokines: PDGF and IL-10

We measured the serum levels of PDGF-BB homodimer and IL-10 in patients with IPF using the Bio-Plex Suspension Array System with the Bio-Plex Pro Human Cytokine Group Panel (Bio-Rad Laboratories Inc., Hercules, CA, USA), respectively, according to the manufacturer’s instructions (19). We have previously demonstrated the significance of PDGF in predicting survival in patients with IPF (9).

Statistical analysis

Continuous variables are presented as medians and interquartile ranges (IQRs), and categorical variables are presented as numbers and percentages. Continuous variables in the two groups were compared using the Mann-Whitney U test. Categorical variables were compared using Fisher’s exact test. Serum IgA levels were categorized as high or low with an upper limit of 400 mg/dL, as specified by a clinical testing company (BML, Inc., Shibuya-ku, Tokyo, Japan). Clinical parameters were compared between patients with high and low serum IgA levels using the Mann-Whitney U test. Monocyte counts in the peripheral blood were categorized using a cutoff of 600/µL, based on a previous report by Kreuter et al. (14). The significance of each clinical parameter as a predictor of survival and AE incidence was determined using univariate Cox proportional hazard regression analyses. The predictive value of each parameter with P<0.10 and serum IgA level, was adjusted for %FVC, generally one of the most important predictors of survival or AE occurrence, age, gender, and BMI, using multivariate Cox proportional hazard regression analysis. Survival curves were described using Kaplan-Meier method, and the log-rank test was used to compare the curves.

All statistical analyses were performed using SPSS for Macintosh v.29 (IBM Corp., Armonk, NY, USA). Statistical significance was set at P<0.05.


Results

Patient demographics and serum levels of IgA, peripheral monocyte counts, and cytokines

Fifty-nine of the 71 patients with IPF were males and of these 62 had a smoking history (Table 1). The median patient age was 67 (IQR 61–72) years. The median %FVC and %DLco were 76.5% and 51.1%, respectively. Shortness of breath, indicated by an mMRC score of ≥2, was observed in 23 patients. The median serum IgA level was 307 (IQR 232–408) mg/dL and the IgA level in 18 patients was >400 mg/dL. Monocyte counts in the peripheral blood were >600/µL in 8 patients. Median serum levels (IQR) of PDGF and IL-10 were 158 (64–466) and 0.42 (0.13–1.08) pg/mL, respectively.

Table 1

Patient demographics (n=71)

Parameters Value
Gender, male/female 59/12
Age, years 67 (61–72)
Smoking, NS/ES or CS 9/62
Comorbidities
   Diabetes mellitus, yes/no 10/61
   Cerebral infarction, yes/no 5/66
   Hypertension, yes/no 14/57
   Coronary diseases, yes/no 8/63
Diagnosis of IPF, clinical/SLB 35 (50.7)/36 (49.3)
BMI, kg/m2 24.8 (23.3–26.3)
mMRC, <2/≥2 48/23
%FVC*, % 76.5 (64.5–90.5)
%DLco**, % 51.1 (37.7–62.4)
KL-6*, ×100 U/mL 8.50 (5.87–12.02)
SP-D**, ×10 ng/mL 17.8 (10.9–30.5)
PDGF, ×100 pg/mL 1.58 (0.64–4.66)
IL-10, pg/mL 0.42 (0.13–1.08)
IgG, ×100 mg/dL 16.43 (14.10–19.07)
IgA, mg/dL 307 (232–408)
IgA, ≤400/>400 mg/dL 53/18
WBC, ×100/μL 66 (53–76)
Monocyte, ×100/μL 3.88 (3.29–4.71)
Monocyte, ≤600/>600/μL 63/8
Neutrophils in BAL*, % 2.3 (0.8–6.0)
Lymphocytes in BAL*, % 7.3 (3.4–12.4)
Pirfenidone, yes/no 10/61
Corticosteroids, yes/no 33/38
Corticosteroid before AE, yes/no 15/56
Occurrence of acute exacerbation, yes/no 23/48
Last observation: dead/alive 32/39
Observation period, days 1,289 (516–1,879)

Data are presented as n, n (%) or median (IQR). *, n=70; **, n=69, n=71 for the other parameters. AE, acute exacerbation; BAL, bronchoalveolar lavage; BMI, body mass index; CS, current smoker; ES, ex-smoker; IPF, idiopathic pulmonary fibrosis; IQR, interquartile range; Ig, immunoglobulin; IL-10, interleukin-10; KL-6, Krebs von den Lungen-6; mMRC, modified Medical Research Council score for shortness of breath; NS, non-smoker; PDGF, platelet-derived growth factor; SLB, surgical lung biopsy; SP-D, surfactant protein-D; WBC, white blood cell; %DLco, percent predicted value of diffusing capacity of carbon monoxide; %FVC, percent predicted value of forced vital capacity.

Outcomes according to serum IgA levels and peripheral monocyte counts

Patients with high IgA levels (>400 mg/dL) tended to die frequently during the observation period compared with that with low IgA levels (≤400 mg/dL) (P=0.054, Table 2). Patients with high monocyte counts (>600/µL) experienced AE significantly more frequently than that with low monocyte counts (≤600/µL) (P=0.01, Table 2).

Table 2

Relationship between outcomes and, IgA and monocyte count

Parameters High Low P value*
IgA >400 mg/dL (n=18) ≤400 mg/dL (n=53)
   Dead/alive 12/6 20/33 0.054
   AE, yes/no 8/10 15/38 0.45
Monocyte >600/μL (n=8) ≤600/μL (n=63)
   Dead/alive 5/3 27/36 0.25
   AE, yes/no 6/2 17/46 0.01

*, Fisher’s exact test was performed. AE, acute exacerbation, IgA, immunoglobulin A.

Survival according to serum IgA levels and peripheral monocyte counts

Survival of patients with IPF with IgA >400 mg/dL was worse than that in patients with IgA ≤400 mg/dL (Log-rank test, P=0.007) (Figure 1A). There was no significant difference in survival between patients with high and low monocyte counts (Figure 1B).

Figure 1 Survival curves of patients with IPF. (A) Patients with high IgA levels (>400 mg/dL, n=18, solid line) have significantly worse survival than those with low IgA levels (≤400 mg/dL, n=53, dotted line) (Log-rank test, P=0.007). (B) No significant difference in survival rates is observed between patients having IPF with high monocyte counts (>600/μL, n=8, solid line) and those with low monocyte counts (≤600/μL, n=63, dotted line) (Log-rank test, P=0.38). IgA, immunoglobulin A; IPF, idiopathic pulmonary fibrosis.

Prognostic analysis by Cox proportional hazard regression analysis

Univariate analysis revealed that mMRC, %FVC, %DLco, fraction of neutrophils in the BAL fluid (%), Krebs von den Lungen (KL)-6, and surfactant protein (SP)-D were significant prognostic factors (Table 3). Serum IgA [hazard ratio (HR), 1.003; 95% confidence interval (CI): 1.001–1.006, P=0.02] and IgG levels (HR, 1.058; 95% CI: 1.001–1.118, P=0.048) and serum IgA levels of >400 mg/dL (HR, 2.620; 95% CI: 1.262–5.438, P=0.01) also significantly predicted survival. However, monocyte counts or monocyte counts of >600/µL were not significant prognostic factors.

Table 3

Univariate and multivariate Cox proportional hazard regression analysis to evaluated prognostic factors

Parameters HR 95% CI P value
Univariate analysis
   Gender (male vs. female) 0.988 0.405–2.410 0.98
   Age, years 1.023 0.977–1.072 0.33
   Smoking (CS or ES vs. NS) 0.877 0.337–2.283 0.79
   Diagnosis of IPF (clinical vs. SLB) 1.474 0.732–2.967 0.28
   BMI, kg/m2 0.957 0.855–1.071 0.44
   mMRC (≥2 vs. <2) 4.946 2.441–10.021 <0.001
   %FVC*, % 0.950 0.930–0.970 <0.001
   %DLco**, % 0.961 0.939–0.983 0.001
   Neutrophils in BAL*, % 1.093 1.020–1.172 0.01
   Lymphocytes in BAL*, % 0.962 0.913–1.014 0.15
   PDGF, ×100 pg/μL 1.089 0.977–1.213 0.12
   IL-10, pg/mL 0.763 0.404–1.440 0.40
   KL-6*, ×100 U/mL 1.056 1.019–1.095 0.003
   SP-D*, ×10 ng/mL 1.020 1.005–1.036 0.009
   IgG, ×100 mg/dL 1.058 1.001–1.118 0.048
   IgA, mg/dL 1.003 1.001–1.006 0.02
   IgA, >400 mg/dL 2.620 1.262–5.438 0.01
   WBC, ×100/μL 1.003 0.987–1.019 0.75
   Monocyte, ×100/μL 1.098 0.863–1.398 0.45
   Monocyte, >600/μL 1.528 0.585–3.988 0.39
Significance of biomarkers adjusted by multivariate analysis#
   IgA, mg/dL 1.003 1.001–1.006 0.04
   IgA, >400 mg/dL 2.206 1.048–4.644 0.04
   mMRC (≥2 vs. <2) 2.578 1.234–5.389 0.01

Prognostic significance of each parameter was evaluated by univariate Cox proportional hazard regression analysis. #, parameters with P value <0.10 by univariate analysis were adjusted with %FVC, age, gender, and body mass index by multivariate analysis with stepwise selection procedure. IgG, %DLco, neutrophils in BAL, KL-6, and SP-D, were not significant prognostic factors. *, n=70, **, n=69, n=71 for the other parameters. BAL, bronchoalveolar lavage; BMI, body mass index; CI, confidence interval; CS, current smoker; ES, ex-smoker; HR, hazard ratio; IL-10, interleukin-10; Ig, immunoglobulin; IPF, idiopathic pulmonary fibrosis; KL-6, Krebs von den Lungen-6; mMRC, modified Medical Research Council score for shortness of breath; NS, non-smoker; PDGF, platelet-derived growth factor; SP-D, surfactant protein-D; SLB, surgical lung biopsy; WBC, white blood cell; %FVC, percent predicted value of forced vital capacity; %DLco, percent predicted value of diffusing capacity of carbon monoxide.

When significant prognostic factors, in the univariate analysis, except for the pulmonary function test were adjusted for %FVC, age, gender, and BMI by multivariate analysis with stepwise selection procedure, IgA (HR, 1.003; 95% CI: 1.001–1.006, P=0.04) and IgA levels >400 mg/dL (HR, 2.206; 95% CI: 1.048–4.644, P=0.04) were significant predictors of poor survival.

Additionally, neither IgA, monocyte counts, nor high monocyte counts >600/µL were significant prognostic factors for patients with lower IgA by univariate analysis (Table 4).

Table 4

Prognostic factors in IPF patients with low IgA (≤400 mg/dL)

Parameters HR 95% CI P value
Univariate analysis
   IgA, mg/dL 0.996 0.990–1.003 0.28
   Monocyte, ×100/μL 1.182 0.901–1.550 0.23
   Monocyte, >600/μL 1.689 0.559–5.101 0.35

Multivariate analysis with stepwise selection procedure using age, gender, body mass index, and percent predicted value of forced vital capacity revealed that all 3 parameters were not significant prognostic factors. CI, confidence interval; HR, hazard ratio; IPF, idiopathic pulmonary fibrosis; Ig, immunoglobulin.

Occurrence of AE according to serum IgA levels and peripheral monocyte counts

AE tended to occur earlier in patients with IgA >400 mg/dL than in those with IgA ≤400 mg/dL (Log-rank test, P=0.08) (Figure 2A). Patients having IPF with high monocyte counts (>600/µL) experienced AE significantly earlier than those with lower monocyte counts (≤600/µL) (Log-rank test, P=0.02) (Figure 2B).

Figure 2 Incidence of AE in patients with IPF. (A) Patients with high IgA levels (>400 mg/dL, n=18, solid line) tend to have a higher incidence of AE than those with low IgA levels (≤400 mg/dL, n=53, dotted line) (Log-rank test, P=0.08). (B) The incidence of AE in patients with IPF with high monocyte counts (>600/μL, n=8, solid line) is significantly higher than that of patients with low monocyte counts (≤600/μL, n=63, dotted line) (Log-rank test, P=0.02). AE, acute exacerbation; IgA, immunoglobulin A; IPF, idiopathic pulmonary fibrosis.

Predictors of AE by Cox proportional hazard regression analysis

Univariate analysis revealed that mMRC, %FVC, %DLco, fraction of neutrophils in the BAL fluid (%), KL-6, SP-D, and IgG were significant predictors of AE (Table 5). A monocyte count of >600/µL also significantly predicted the occurrence of AE (HR, 2.994; 95% CI: 1.167–7.682, P=0.02). However, serum IgA and IgA levels of >400 mg/dL were not significant predictors of AE. Neither serum IgA nor monocyte count could significantly predict AE after adjusting for %FVC, age, gender, and BMI. However, monocyte counts (HR, 1.382; 95% CI: 1.013–1.884, P=0.04) and a monocyte count of >600/µL (HR, 3.219; 95% CI: 1.043–9.937, P=0.04) were significant predictors of AE occurrence for patients with serum IgA levels of ≤400 mg/dL after adjusting for %FVC, age, gender, and BMI (Table 6).

Table 5

Univariate and multivariate Cox proportional hazard regression analysis to evaluated predictive factors of occurrence of AE in IPF

Parameters HR 95% CI P value
Univariate analysis
   Gender (male vs. female) 1.074 0.364–3.166 0.90
   Age, years 1.042 0.983–1.104 0.17
   Smoking (CS or ES vs. NS) 0.738 0.249–2.182 0.58
   Diagnosis of IPF (clinical vs. SLB) 1.583 0.689–3.633 0.28
   BMI, kg/m2 1.011 0.884–1.156 0.87
   mMRC, ≥2 vs. <2 4.786 2.024–11.316 <0.001
   %FVC*, % 0.955 0.932–0.978 <0.001
   %DLco**, % 0.971 0.946–0.996 0.03
   Neutrophils in BAL*, % 1.086 1.009–1.168 0.03
   Lymphocytes in BAL*, % 0.997 0.949–1.047 0.90
   PDGF, ×100 pg/mL 1.127 0.998–1.273 0.054
   IL-10, pg/mL 0.910 0.447–1.853 0.80
   KL-6*, ×100 U/mL 1.064 1.024–1.106 0.002
   SP-D*, ×10 ng/mL 1.017 1.001–1.034 0.04
   IgG, ×100 mg/dL 1.081 1.017–1.148 0.01
   IgA, mg/dL 1.002 0.999–1.005 0.22
   IgA, >400 mg/dL 2.128 0.887–5.105 0.09
   WBC, ×100/μL 1.010 0.993–1.027 0.26
   Monocyte, ×100/μL 1.257 0.971–1.628 0.08
   Monocyte, >600/μL 2.994 1.167–7.682 0.02
Significance of biomarkers adjusted by multivariate analysis#
   PDGF, ×100 pg/mL 1.185 1.040–1.351 0.01
   mMRC, ≥2 vs. <2 2.562 1.018–6.450 0.046

Significance of each parameter as predictive factors for AE was evaluated by univariate Cox proportional hazard regression analysis. #, parameters with P value <0.10 by univariate analysis were adjusted with %FVC, age, gender, BMI by multivariate analysis with stepwise selection procedure. IgA, IgA (>400 mg/dL), IgG, neutrophils in BAL KL-6, SP-D, and monocyte, and monocyte (>600/μL) was not significant predictors of occurrence of AE in IPF. *, n=70; **, n=69, n=71 for the other parameters. AE, acute exacerbation; BAL, bronchoalveolar lavage; BMI, body mass index; CI, confidence interval; CS, current smoker; ES, ex-smoker; HR, hazard ratio; Ig, immunoglobulin; IPF, idiopathic pulmonary fibrosis; IL-10, interleukin-10; KL-6, Krebs von den Lungen-6; mMRC, modified Medical Research Council score for shortness of breath; NS, non-smoker; PDGF, platelet-derived growth factor; SLB, surgical lung biopsy; SP-D, surfactant protein-D; WBC, white blood cell; %FVC, percent predicted value of forced vital capacity; %DLco, percent predicted value of diffusing capacity of carbon monoxide.

Table 6

Univariate and multivariate Cox proportional hazard regression analysis to predict occurrence of AE in patients with low IgA (≤400 mg/dL)

Parameters HR 95% CI P value
Univariate analysis
   IgA, mg/dL 0.998 0.991–1.006 0.68
   Monocyte, ×100/μL 1.383 1.025–1.868 0.03
   Monocyte, >600/μL 4.090 1.358–12.321 0.01
Significance of biomarkers adjusted by multivariate analysis#
   Monocyte, ×100/μL 1.382 1.013–1.884 0.04
   Monocyte, >600/μL 3.219 1.043–9.937 0.04

#, predictive factors were examined by multivariate Cox proportional hazard regression analysis with stepwise selection procedure using age, gender, body mass index, and percent predicted value of forced vital capacity. AE, acute exacerbation; CI, confidence interval; HR, hazard ratio; Ig, immunoglobulin.

Correlation between serum IgA and other parameters including cytokine levels and monocyte counts

Serum IgA was significantly negatively correlated with white blood cell (WBC) counts but was positively correlated with IgG levels (P=0.007 and 0.009, respectively) and tended to be negatively correlated with monocyte counts in the peripheral blood (P=0.06) (Spearman’s rank correlation) (Table 7). Serum SP-D levels were significantly higher, and serum PDGF levels tended to be higher in patients with high IgA levels than in those with low IgA levels (P=0.048 and 0.09, respectively, Mann-Whitney U test) (Table 8). Peripheral WBC counts were significantly lower in patients with high IgA levels than in those with low IgA levels (P=0.008, Mann-Whitney U test) (Table 8).

Table 7

Correlation between IgA or monocyte counts, and other parameters#

Parameters IgA Monocytes
Rho P value Rho P value
BMI, kg/m2 0.018 0.88 0.031 0.80
mMRC (≥2 vs. <2) 0.084 0.48 0.001 0.99
%FVC*, % −0.136 0.26 0.047 0.70
%DLco**, % −0.088 0.47 −0.182 0.14
Neutrophils in BAL*, % 0.074 0.54 −0.105 0.39
Lymphocytes in BAL*, % −0.162 0.18 −0.015 0.90
PDGF, ×100 pg/mL 0.169 0.17 0.050 0.68
IL-10, pg/mL −0.018 0.88 −0.060 0.62
KL-6*, ×100 U/mL 0.016 0.89 −0.017 0.89
SP-D*, ×10 ng/mL 0.176 0.15 −0.070 0.89
IgG, ×100 mg/dL 0.310 0.009 −0.077 0.52
WBC, ×100/μL −0.318 0.007 0.664 <0.001
Monocyte, ×100/μL −0.226 0.06 NA NA

#, Spearman’s rank correlation; *, n=70; **, n=69, n=71 for the other parameters. BAL, bronchoalveolar lavage; BMI, body mass index; Ig, immunoglobulin; IL-10, interleukin-10; KL-6, Krebs von den Lungen-6; mMRC, modified Medical Research Council score for shortness of breath; NA, not applicable; PDGF, platelet-derived growth factor; SP-D, surfactant protein-D; WBC, white blood cell; %FVC, percent predicted value of forced vital capacity; %DLco, percent predicted value of diffusing capacity of carbon monoxide.

Table 8

Difference in clinical parameters according to high and low serum IgA

Parameters IgA >400 mg/dL (n=18) IgA ≤400 mg/dL (n=53) P value
BMI, kg/m2 24.7 (20.1–26.2)* 24.9 (23.3–26.4)# 0.54
Corticosteroid before AE, yes/no 6/12 10/43 0.21
Corticosteroid for whole period, yes/no 12/6 21/32 0.06
mMRC, ≥2/<2 10/8 38/15 0.25
%FVC*, % 69.0 (63.7–82.9)* 81.3 (65.4–95.0)§ 0.18
%DLco**, % 45.3 (34.1–55.0)* 53.3 (37.5–69.6) 0.12
Neutrophils in BAL*, % 4.4 (0.7–10.3)* 2.2 (0.8–4.4)§ 0.21
Lymphocytes in BAL*, % 6.5 (3.4–13.3)* 8.0 (3.4–12.4)§ 0.83
PDGF, ×100 pg/mL 3.66 (0.81–6.24)** 1.34 (0.58–4.44)§ 0.09
IL-10, pg/mL 0.29 (0.42–1.06)** 0.365 (0.067–1.080)§ 0.44
KL-6*, ×100 U/mL 8.16 (5.98–20.20)** 8.50 (5.77–11.65)# 0.30
SP-D*, ×10 ng/mL 23.6 (13.2–39.4)** 16.5 (9.9–26.0)§ 0.048
IgG, ×100 mg/dL 17.43 (16.42–21.02)* 15.77 (13.53–18.67)# 0.054
WBC, ×100/μL 53.0 (46.5–64.7)* 68.0 (56.0–79.0)# 0.008
Monocyte, ×100/μL 3.57 (2.87–4.59)* 4.00 (3.42–4.71)# 0.22
Monocyte, >600/≤600/μL 2/16 6/47 >0.99

Parameters were shown as number or median (IQR). Numerical parameters were compared by Fisher’s exact test. Continuous parameters were compared by Mann-Whitney U test. *, n=18; **, n=17; #, n=53; §, n=52; , n=51. AE, acute exacerbation; BMI, body mass index; Ig, immunoglobulin; IL-10, interleukin-10; KL-6, Krebs von den Lungen-6; IQR, interquartile range; mMRC, modified Medical Research Council score for shortness of breath; PDGF, platelet-derived growth factor; SP-D, surfactant protein-D; WBC, white blood cell; %FVC, percent predicted value of forced vital capacity; %DLco, percent predicted value of diffusing capacity of carbon monoxide.


Discussion

Key findings

In this study, we demonstrated the predictive value of serum IgA levels for the survival of patients with IPF. The predictive value of serum IgA levels was significant even after adjusting for %FVC, age, gender, and BMI. Patients with high serum IgA levels had significantly lower WBC counts and tended to have higher PDGF levels than those with low serum IgA levels.

Strengths and limitations

This study has some limitations that should be considered. First, this study was performed retrospectively at a single center, and the number of patients included in this study was limited. Second, we discussed the possibility that TGF-β levels might be indicated by IgA levels, although we have no data about TGF-β levels. Third, we supposed that IL-10 might be associated with the IgA class switch; however, no significant association was found in this study. Large-scale detailed studies are required to reach more definitive conclusions. Limited patients were treated with an antifibrotic drug, pirfenidone. This is because most subjects of this study were diagnosed before the approval of pirfenidone (16), and nintedanib also had not been approved. A claim database analysis revealed less than 10% of Japanese patients with IPF were treated with pirfenidone in 2009 (20).

Comparison with similar research

Although the pathophysiological role of IgA has not been sufficiently clarified, measuring IgA levels might be a useful molecular marker indicative of an increase in TGF-β production, which is known to be a potent fibrogenic cytokine associated with pulmonary fibrosis (19,21,22). Coffman et al. reported that the addition of TGF-β to cultures of lipopolysaccharide-stimulated murine B cells caused a 10-fold enhancement of IgA production (23). High levels of serum IgA might suggest high levels of TGF-β production in the lung. Although the results were not significant in our study, serum IgA levels may also be correlated with serum PDGF levels to some extent. Unfortunately, we did not have any data relative to TGF-β levels in this study. We assume that TGF-β might be elevated in patients with high PDGF levels because TGF-β is known to exert fibrotic activity coupled with PDGF (24,25). Although IL-10 is known to affect the class switch to IgA with TGF-β, we did not observe any significant correlation between serum IgA and serum IL-10 levels (13).

Explanations of findings

IgA may also induce pulmonary fibrosis directly. Arakawa et al. (26) reported that secretary IgA induced higher levels of IL-6, IL-8, monocyte chemoattractant protein-1, and granulocyte-macrophage colony-stimulating factor (26), which are associated with pulmonary fibrosis in humans induced by pulmonary fibroblasts (19). Further, IgA stimulates the lung fibroblast production of collagen and α-smooth muscle actin (26). Secretary IgA accumulates in the airspaces of patients with IPF and promotes production of vascular endothelial growth factor, TGF-β, and IL-8 from alveolar epithelial cells in vitro (27). Takada et al. suggested that IgA suppresses angiogenesis (28), which is associated with wound repair (29). We hypothesized that pulmonary fibrosis might be aggravated through the delay of chronic pulmonary injury caused by high IgA levels.

It has recently been proposed that pulmonary fibrosis is not associated with inflammation but may occur during recovery from epithelial apoptosis and injury (30). However, Xue et al. reported that the plasma concentrations of B-cell activating factor was significantly greater in patients with IPF than in normal controls, and that the percentage of antigen-producing plasmablasts in circulating B-cells was inversely correlated with the FVC (31). In particular, IgA-producing B cells in the lungs are a topic of interest in various lung diseases, including IPF (32). Lymphoid aggregates are occasionally observed in SLB specimens of IPF (33). Using immunohistochemistry of SLB specimens from patients with IPF, Heukels et al. reported that IgA-positive B cells were strongly expressed in germ cell centers (34). In addition, higher levels of autoreactive IgA were observed in patients with IPF than in healthy controls, and autoreactive IgA levels significantly correlated with a decline in the FVC. Hence, some patients with IPF might be categorized as having autoimmune lung diseases, autoreactive IgA might affect the onset of IPF, and in turn, autoantibodies may be associated with higher serum levels of IgA.

Serum levels of MX1 IgA antibody may be a predictor of survival and occurrence of AE in patients with IPF after adjusting for the Gender, Age, and Physiology stage (11). Solomon et al. also showed that IgA antibody against citrullinated protein antigens (IgA-ACPA) was present in >20% of patients with IPF and could predict poor survival (35). There is a strong correlation between IgA-ACPA levels and the number of ectopic lymphoid aggregates on histological examination of IPF. Although the pathophysiological role of these antibodies has not been clarified, their presence is consistent with the results reported by Heukels et al. (34).

We also examined the predictive role of peripheral monocyte counts in the prognosis and occurrence of AE. IgA is related to immunologic reactions, and the prognostic value of monocyte counts has been previously evaluated (14). Monocyte counts were significantly associated with the occurrence of AE but not with survival in the univariate analysis, although the multivariate analysis clarified that they were not associated with either event. However, for patients with low serum IgA levels (≤400 mg/dL), monocyte counts and high monocyte counts (>600/µL) were significant predictors of AE occurrence after the adjustment by other factors. Relationship between monocyte counts and occurrence of AE has been previously reported (36,37), and our results were consistent with the results. Pathophysiological link between monocytes and AE has not been clarified yet, hyperresponsiveness to trigger factors by increased monocyte counts was advocated (36).

Serum IgA levels significantly and inversely correlated with WBC and tended to with peripheral monocyte counts. M2-like monocyte-derived macrophages play crucial roles in pulmonary fibrosis (38). M2 macrophages secret IL-10 and TGF-β and might be associated with IgA class switching (39). Monomeric IgA induces IL-10 production in monocytes and monocyte-derived dendritic cells (40). Hence, we hypothesized that the monocyte count could be positively correlated with serum IgA levels. However, our results did not support this hypothesis. As for particulate matter (PM) 2.5 induced AE, a specific monocyte population is shown to have increased and affected the AE occurrence (41). Hence, IgA levels might be associated with counts of the specific monocyte population, not with total monocyte counts. Another explanation is that IgA and monocytes might independently and differently affect the progression of IPF; the former mainly affect the progression of chronic fibrosis and the latter the occurrence of acute lung injury, namely AE.


Conclusions

High serum IgA levels indicate poor survival in patients with IPF. IgA levels might suggest serum fibrogenic cytokine levels. Serum IgA levels might be associated with prognosis differently from peripheral monocyte counts. The pathophysiological role of IgA needs to be elucidated in future studies.


Acknowledgments

We are grateful for Dr. Masanori Akira for evaluating radiological findings of this study.


Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2142/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2142/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2142/prf

Funding: This work was partially supported by a JSPS KAKENHI grant (number JP17K09636) awarded to T.A. and a National Hospital Organization grant (H28-NHO [Kokyu]-2) awarded to T.A.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2142/coif). T.A. received lecture fees from Boehringer Ingelheim, Shionogi, AstraZeneca, and Sekisui Medical and funds from Sekisui Medical and Sysmex for activities not connected to the submitted work. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the NHO Kinki Chuo Chest Medical Center Institutional Review Board (approval number Rin2022-048). All the participants provided written informed consent for inclusion of their data in this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


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Cite this article as: Arai T, Hirose M, Hatsuda K, Kagawa T. Serum IgA levels and survival in patients with idiopathic pulmonary fibrosis: association with serum cytokine levels and peripheral monocyte counts. J Thorac Dis 2025;17(4):2038-2049. doi: 10.21037/jtd-2024-2142

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