Patient characteristics
We identified 104 patients who developed AE-IIPs for the first time and visited our hospital between April 2009 and July 2020. Among the patients with AE-IIPs, 33 patients who received PMX-DHP were included in this study. The patient characteristics are shown in Table 1. All patients were Japanese, and the median age was 71 years (range, 54–86 years). There were 31 men (93.34%) and 30 smokers (90.91%). Twenty-seven patients (81.82%) were diagnosed with IPF and other patients had clinical INSIP or UCIP prior to the development of AE-IIPs. Eleven patients (33.33%) received anti-fibrotic agents (nintedanib, seven patients; pirfenidone, four patients). Nine patients received corticosteroids prior to the development of AE. Among the patients who received corticosteroid, seven received immunosuppressants concurrently. Moreover, among the patients who received PMX-DHP, 18 patients survived for > 30 days after the initiation of PMX-DHP treatment (long survival group) and 15 patients survived for < 30 days (non-long survival group) (Figure. 1). There were no significant differences in the patient characteristics, including age, sex, smoking history, prior treatment for baseline IIPs, gender, age, and physiology (GAP) index for the severity of interstitial pneumonia 1–6 months before the development of AE, and diffusing capacity. In contrast, median forced vital capacity (FVC) was significantly higher in the survival group than in the non-survival group.
Table 1
Patient’s characteristics
| Total N = 33 | Survival ≥ 30 days N = 18 | Survival < 30 days N = 15 | p-value |
Age | 71 (54–86) | 71 (54–80) | 71 (62–86) | 0.7221 |
Sex, male | 31 (93.34%) | 16 (88.9%) | 15 (100%) | 0.1116 |
Smoking history, yes | 30 (90.91%) | 18 (93.33%) | 14 (93.33%) | 0.6546 |
IPF, yes | 27 (81.82%) | 15 (83.33%) | 12 (80.00%) | 0.8051 |
Pre-antifibrotic agents administration, yes | 11 (33.33%) | 5 (27.78%) | 6 (40%) | 0.4586 |
Baseline FVC, % | 73.77 (40.21-121.47) n = 30 | 86.11 (62.55-112.26) n = 16 | 62.15 (40.21-121.47) n = 14 | 0.0125 |
Baseline VC, % | 74.80 (38.00-12.22) n = 30 | 85.92 (67.77–120.00) n = 16 | 63.92 (38.00-122.22) n = 14 | 0.0215 |
Baseline DLco, % | 29.55 (11.12–64.66) n = 22 | 30.62 (19.22–64.66) n = 10 | 24.25 (11.22–45.34) n = 12 | 0.3356 |
Baseline GAP index, over 6, % | 9 (37.50%) n = 24 | 3 (27.27%) n = 11 | 6 (46.15%) n = 13 | 0.3412 |
Baseline modified GAP index I/II/III | 4/11/9 n = 24 | 3/5/6 n = 11 | 1/6/6 n = 13 | 0.3800 |
Clinical AE types Idiopathic/Inf-trigger/Non-inf-trigger | 12/10/11 | 3/8/7 | 9/2/4 | 0.0229 |
HRCT pattern Diffuse/Multi/Peripheral | 17/11/5 | 7/7/4 | 10/4/1 | 0.2214 |
Abbreviations: AE: Acute exacerbation, DLco: diffusing capacity of the lung Carbon monoxide, FVC: Forced vital capacity, HRCT: high resolution computed tomography, IPF: Idiopathic pulmonary fibrosis, VC: Vital capacity. |
Table 2
The difference in treatment for acute exacerbation of interstitial pneumonias between survival over and within 30 days
| Total N = 33 | Survival ≥ 30 days N = 18 | Survival < 30 days N = 15 | p-value |
mPSL pulse therapy | 33 (100%) | 18 (100%) | 15 (100%) | 0.9999 |
IVCY | 18 (54.55%) | 10 (55.56%) | 8 (53.33%) | 0.8984 |
Immunosuppressant | 15 (45.45%) | 8 (44.44%) | 7 (46.67%) | 0.8984 |
rhTM | 13 (39.39%) | 7 (38.89%) | 6 (40.00%) | 0.9481 |
Antibiotics | 33 (100%) | 18 (100%) | 15 (100%) | 0.9999 |
PMX-DHP within 48 h | 21 (63.64%) | 14 (77.78%) | 7 (46.67%) | 0.0627 |
Abbreviations: IVCY: Intravenous cyclophosphamide, mPSL: methylprednisolone, PMX-DHP: Polimyxin B immobilized fiber column direct hemoperfusion, rhTM: recombinant human thrombomodulin |
Table 3
The difference in serum markers associated with interstitial pneumonia between Survival and Non-survival groups
| Total N = 33 | Survival ≥ 30 days N = 18 | Survival < 30 days N = 15 | p-value |
Serum markers at the PMX-DHP initiated day KL-6. IU/L | 1060 (303–5250) | 1009 (303–3528) | 1439 (712–5250) | 0.5986 |
SP-D, ng/mL | 384 (62-1680) | 369 (62-1450) | 477 (168–1680) | 0.2397 |
LDH, IU/L | 391 (175–652) | 390 (193–652) | 395 (175–633) | 0.9984 |
WBC, /µL | 12550 (5500–17900) | 12550 (5500–16800) | 12400 (8700–17200) | 0.3452 |
Neutrophil, /µL | 10827 (1210–16400) | 10624 (1210–14610) | 11040 (6960–16400) | 0.1770 |
Lymphocyte, /µL | 1377 (75-2064) | 930 (75-2064) | 1044 (116–2032) | 0.9582 |
CRP, mg/dL | 9.65 (0.87–28.55) | 8.25 (0.87–28.55) | 10.11 (3.65–18.02) | 0.7443 |
Platelet, /µL | 22.2 (3.8–47.6) | 21.9 (3.8–47.6) | 22.5 (10.8–46.8) | 0.5270 |
D-dimer, ng/mL | 3.45 (1.2–72.8) | 2.9 (1.2–41.1) | 5.0 (2.1–72.8) | 0.2070 |
Serum markers after 7 days from PMX-DHP initiated day KL-6, IU/L | 1363 (388–4473) | 1183 (415–2672) | 1814 (388–4473) | 0.0708 |
SP-D, ng/mL | 377 (70-1630) | 205.5 (70-1410.6) | 700.5 (252–1630) | 0.0518 |
LDH, IU/L | 341 (174–768) | 283 (174–589) | 406 (212–768) | 0.0033 |
WBC, /µL | 12900 (5000–26300) | 12200 (5000–17400) | 15200 (8500–26300) | 0.0156 |
Neutrophil, /µL | 10522 (2754–22500) | 9804 (2754–17100) | 14034 (7826–22500) | 0.0065 |
Lymphocyte, /µL | 878 (112–2599) | 1250 (112–2599) | 488 (113–1995) | 0.0313 |
CRP, mg/dL | 1.8 (0.11–24.24) | 1.2 (0.11–14.29) | 3.65 (0.13–24.24) | 0.1615 |
Platelet, /µL | 19.8 (4.5–47.6) | 19.2 (5.1–47.6) | 20.2 (4.5–38.5) | 0.4148 |
D-dimer, ng/mL | 3.8 (1.1–16.9) | 3.25 (1.1–8.5) | 4.9 (1.6–16.9) | 0.0164 |
ΔSerum markers between 7 days and PMX-DHP initiated day KL-6, IU/L | 197 (-1727-2173) | 148 (-1314-985) | 282 (-1727-2173) | 0.8759 |
SP-D, ng/mL | -27 (-767-648) | -64.5 (-767-806) | 108 (-601-648) | 0.2504 |
LDH, IU/L | -52 (-296-403) | -71 (-276–59) | 45 (-296-403) | 0.0124 |
WBC, /µL | 1100 (-7900-11200) | 800 (-7900-7800) | 2900 (-4300-11200) | 0.0769 |
Neutrophil, /µL | 1112 (-7452-11858) | 1112 (-7452-5520) | 2601 (-3856-11858) | 0.0886 |
Lymphocyte, /µL | -65.5 (-1330-1636) | 37 (-784-1636) | -330 (-1330-751) | 0.0318 |
CRP, mg/dL | -6.4 (-27.5-8.1) | -6.42 (27.55–7.44) | -5.08 (-17.92-8.11) | 0.2187 |
Platelet, /µL | -1.3 (-13.5-24.8) | -1.3 (-13.5-24.8) | -2.3 (-9.4-11.1) | 0.9403 |
D-dimer, ng/mL | 0.5 (-10.6-59.9) | 1.8 (-3.4-13.8) | 0.2 (-10.6-59.9) | 0.6021 |
Abbreviations: CRP: C-related peptide, KL-6: Krebs von den Lungen-6, LDH: lactate dehydrogenase, PMX-DHP: polymyxin B-immobilized fiber column-direct hemoperfusion, SP-D: Surfactant Protein-D, WBC: white blood cell. |
Characteristics of acute exacerbation
We previously reported differences in survival among the clinical AE-IIP types, including idiopathic, infection-triggered, and non-infection-triggered AE-IIPs, and evaluated the difference in survival among these categories in the current study. Twelve patients were considered to have idiopathic AE-IIPs, 11 were suspected with infection-triggered AE-IIPs, and five were diagnosed with non-infection-triggered AE-IIPs. Proportions of patients with these three categories of AE-IIPs were significantly different between the survival and non-survival groups.
Subsequently, we compared the treatment for AE-IIPs between the two groups. All patients received methylprednisolone and antibiotics. Eighteen patients (54.55%) received immunosuppressants, including cyclophosphamide, tacrolimus, or cyclosporine. However, there was no significant difference in the frequency of receiving immunosuppressants between the survival and non-survival groups. Then, the duration since the development of AE-IIPs to the initiation of PMX-DHP treatment was evaluated. PMX-DHP treatment was initiated within 48 h of the development of AE-IIPs in 21 patients (63.64%). The proportion of patients who received PMX-DHP treatment within 48 h tended to be higher in the survival group than in the non-survival group (p = 0.0627).
Serum markers and oxygenation associated with AE-IIPs
We evaluated the serum markers associated with IIPs, including serum levels of KL-6, SP-D, LDH, CRP, and D-dimer and counts of WBCs, neutrophils, lymphocytes, and platelet, prior to the development of AE-IIPs, on the day of initiation of PMX-DHP treatment, and 7 days after the initiation of PMX-DHP treatment and compared these markers between the survival and non-survival groups (Table. 3 and Supplementary Table 1). Then, the changes in clinical parameters differences, particularly LDH and lymphocyte, between first day and 7 were shown in Fig. 2A and 2B. There were no significant differences in all marker levels/counts prior to the development of AE-IIPs and on the first day of the PMX-DHP treatment. In contrast, 7 days after the initiation of PMX-DHP treatment, serum LDH levels, WBC, neutrophil, and lymphocyte counts, and D-dimer levels differed significantly between the non-survival and survival groups. Serum KL-6 and SP-D levels tended to be higher in the non-survival group than in the survival group. Moreover, we analyzed the difference in the changes in serum marker levels/counts between baseline and the first day of PMX-DHP treatment and between the first day of PMX-DHP treatment and 7 days after the initiation of PMX-DHP. Although there were no significant differences in the serum marker levels/counts between baseline and the first day of PMX-DHP treatment, the changes in LDH levels (ΔLDH) and lymphocyte counts (ΔLymphocyte) differed significantly between the two groups.
In addition, we evaluated the PaO2/FiO2 ratio (P/F ratio) and alveolar-to-arterial oxygen difference (Aa-DO2) on the first day of PMX-DHP and 7 days after PMX-DHP initiation (Table 4). Then, the change in P/F ratio between first day and 7 was shown in Fig. 2C. At the initiation, although the P/F ratio tended to be higher in the non-survival group than in the survival group, there was no significant difference in Aa-DO2 between the two groups. The P/F ratio was significantly higher in the survival group than in the non-survival group at 7 days after the initiation of PMX-DHP (p = 0.0019). Aa-DO2 was also significantly higher in the non-survival group than in the survival group (p = 0.0032). Finally, we evaluated the differences in the two oxygenation markers (ΔP/F ratio and ΔAa-DO2) between 7 days after the initiation of PMX-DHP treatment and the first day. The ΔP/F ratio was significantly higher in the survival group than in the non-survival group at 7 days after the initiation of PMX-DHP treatment (p = 0.0235). ΔAa-DO2 value was significantly higher in the non-survival group than in the survival group (p = 0.0409).
Table 4
The difference in the change in PaO2/FiO2 ratio and alveolar-to-arterial difference for oxygen between survivor and non-survivor
| Total N = 33 | Survival ≥ 30 days N = 18 | Survival < 30 days N = 15 | p-value |
P/F ratio and Aa-DO2 at the PMX-DHP initiated day | | | | |
P/F ratio | 121.3 (42.6-325.9) | 155.6 (42.6-325.9) | 110.6 (54.2-179.5) | 0.0641 |
Aa-DO2 | 253.7 (31.8-622.3) | 296.5 (31.8-618.2) | 250.2 (140.2-622.3) | 0.9005 |
P/F ratio and Aa-DO2 after 7 days from PMX-DHP initiated day | | | | |
P/F ratio | 180.0 (72.7-470.5) | 229.3 (81.9-470.5) | 112.2 (72.7-260.1) | 0.0019 |
Aa-DO2 | 195.5 (14.1-599.9) | 98.9 (14.1-399.5) | 304.2 (83.9-599.9) | 0.0032 |
P/F ratio and Aa-DO2 between 7 days and PMX-DHP initiated day | | | | |
ΔP/F ratio | 28.5 (-41.5-265.8) | 57.6 (-34.3-265.8) | 18.3 (-41.5-139.3) | 0.0235 |
ΔAa-DO2 | -52.5 (-475.2-406.8) | -102.5 (-475.2-48.4) | 11.75 (-321.6-406.8) | 0.0409 |
Abbreviations: Aa-DO2: alveolar-arterial oxygen difference, P/F ratio: PaO2/FiO2 ratio, PMX-DHP: polymyxin B-immobilized fiber column-direct hemoperfusion |
Risk factors associated with early death in patients treated with
The results of multivariate analysis of risk factors for early death (death within 30 days from the PMX-DHP initiation) among PMX-DFP-treated patients are shown in Table 5. Multivariate analysis performed using three variables (ΔLDH, ΔLymphocyte, and ΔP/F ratio) indicated that ΔLDH (the difference between 7 days and 0 days from the initiation of PMX-DHP) was the only risk factor associated with early death (OR = 9.891, 95% CI = 1.366–71.639, p = 0.031).
Table 5
The risk factors associated with early death (within 30 day) in patients who received PMX-DHP by multivariate analysis
| Odds ratio | 95% CI | p-value |
ΔLDH | 9.891 | 1.366–71.639 | 0.031 |
ΔLymphocyte | 1.000 | 0.998–1.001 | 0.539 |
ΔP/F ratio | 0.994 | 0.975–1.007 | 0.245 |
Abbreviations: LDH: lactate dehydrogenase, P/F ratio: PaO2/FiO2 ratio, PMX-DHP: polymyxin B-immobilized fiber column-direct hemoperfusion |
Cut-off values of markers
We calculated the cut-off values of ΔLDH, ΔLymphocyte, and ΔP/F ratio using Receiver operating characteristic (ROC) curve analysis. With regard to the cut-off values, AUCs for early death among PMX-DHP-treated patients with AE-IIPs were as follows: ΔLDH, 0.7521 (95% confidence interval [CI]: 0.784–0.962; p = 0.001); ΔLymphocyte, 0.693 (95% CI: 0.509–0.882; p = 0.068); ΔP/F ratio, 0.714 (95% CI: 0.525–0.904; p = 0.050); %FVC, 0.7950 (95% CI: 0.631–0.958; p = 0.006); and GAP index, 0.7610 (95% CI: 0.567–0.954; p = 0.033). The optimal cut-off values for death within 30 days since the initiation of PMX-DHP were as follows: ΔLDH, − 8 (IU/L) (Fig. 3A); ΔLymphocyte, − 323(/µL) (Fig. 3B); ΔP/F ratio, 140 (Fig. 3C); %FVC, 60.0 (Figure S1A); and GAP index, 6 (Figure S1B).
Prognostic differences
We analyzed the survival time from the initiation of PMX-DHP. The MST was 30 days (95% CI: 18.571–41.429) among the 33 patients who received PMX-DHP (Fig. 4A). Then, we compared prognosis according to the difference in ΔLDH, ΔLymphocyte, and ΔP/F ratio using the cut-off values of the three variables. The MST was significantly longer in patients with low ΔLDH ( < − 8 IU/L) than in patients with high ΔLDH ( > − 8 IU/L) (low: 52 days, 95% CI: 34.469–69.531; high: 51 days, 95% CI: 42.235–59.765, hazard ratio = 10.144, p = 0.0011, Fig. 4B). However, there was no significant difference in the MST between patients with low ( < − 323/µL) and high ΔLymphocyte ( > − 323/µL) (low: 29 days, 95% CI: 16.053–41.947, high: 52 days, 95% CI: 38.918–65.082, hazard ratio: 1.355, p = 0.244, Fig. 4C) and between patients with low (< 140) and high ΔP/F ratio (< 140) (low: 29 days, 95% CI: 18.887–39.113; high: 83 days, 95% CI: 21.410–144.590, hazard ratio = 2.630, p = 0.105, Fig. 4D). Moreover, with regard to FVC, the MST was significantly longer in patients with a high %FVC (> 60%) than that in patients with a low %FVC (< 60%), (> 60%: 46 days, 95% CI: 22.523–69.477; <60%: 11 days, 95% CI = 6.741–23.891, hazard ratio = 11.454, p = 0.0013, Figure S2A). With regard to GAP index, the MST was significantly longer in patients with a low GAP index (> 6) than that in patients with high GAP index (< 6) (low GAP index: MST: 51 days, 95% CI: 16.945–85.055; high GAP index: MST: 19 days, 95% CI: 5.449–32.551, hazard ratio = 5,199, p = 0.0233, Figure S2B). Although we compared the difference in the prognosis among the clinical AE-IIP types, including idiopathic, infection-triggered, and non-infection-triggered IIPs, there were no significant differences in survival among the three groups (hazard ratio = 3.315, p = 0.1911, idiopathic: MST: 39 days, 95% CI: 14.184–63.816, infection-triggered: MST: 60 days, 95% CI: 20.368–99.816, and non-infection-triggered: 19 days, 95% CI: 3.723–34.277, Figure S2C). Finally, we evaluated the difference in survival between patients who received PMX-DHP treatment within and after 48 h from the onset of AE-IIPs. The MST was significant longer in the patients who received PMX-DHP within 48 h than in those who received PMX-DHP after 48 h (within 48 h: MST: 25 days, 95% CI: 11.555–38.445; after 48 h: MST: 51 days, 95% CI : 42.235–59.765, hazard ratio = 4.914, p = 0.0027, Figure S2D).