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. 2021 Apr 12:12:624802.
doi: 10.3389/fimmu.2021.624802. eCollection 2021.

Increased Pentraxin 3 Levels Correlate With IVIG Responsiveness and Coronary Artery Aneurysm Formation in Kawasaki Disease

Toshiyuki Kitoh  1   2 , Tsuyoshi Ohara  1 , Taichiro Muto  2 , Akihisa Okumura  2 , Reizo Baba  2   3 , Yusuke Koizumi  4 , Yuka Yamagishi  4 , Hiroshige Mikamo  4 , Kenji Daigo  5 , Takao Hamakubo  5
Affiliations

Increased Pentraxin 3 Levels Correlate With IVIG Responsiveness and Coronary Artery Aneurysm Formation in Kawasaki Disease

Toshiyuki Kitoh et al. Front Immunol. .

Abstract

Kawasaki disease (KD) is a febrile disease of childhood characterized by systemic vasculitis that can lead to coronary artery lesions (CAL). This was a prospective cohort study to determine the levels of the pentraxin 3 (PTX3), soluble CD24-Subtype (Presepsin) and N-terminal pro-brain natriuretic peptide (NT-pro BNP) in consecutive KD patients. From January 2013 to March 2015, all patients with KD admitted to Aichi Medical University Hospital who provided consent had their plasma saved before IVIG administration. In total, 97 cases were registered. 22 cases of incomplete KD were excluded from the outcome analysis. The total 75 cases were used for statistical analyses. A PTX3 threshold of >7.92 ng/ml provided a specificity of 88.5 %, a sensitivity of 94.4 %, and a likelihood ratio as high as 15.92 for the diagnosis of KD compared with febrile non-KD controls. Although an echocardiographic diagnosis of CAL in the early course of the disease was confirmed in 24 cases, it was not in the remaining 51 cases. Neither NT-proBNP nor Presepsin had statistical significance for the prediction of the echocardiographic CAL diagnosis. Only PTX3 was significantly predictive of the echocardiographic CAL diagnosis (p=0.01). The PTX3 level was significantly higher in the intravenous immunoglobulin (IVIG) non-responders (45.9±7.45) than in the IVIG responders (17.0 ± 1.46 ng/ml) (p< 0.001). The PTX3 level also correlated with the number of IVIG treatment courses needed to resolve fever (R² =0.64). Persistent CAL (pCAL) formation was observed in three cases; one of aneurysm only and two aneurysms with dilatations. The patients with pCAL had significantly higher PTX3 levels (85 ± 8.4 ng/ml) than patients without pCAL (22 ± 2.2 ng/ml) (p< 0.0001). In terms of pCAL prediction, the area under the curve (AUC) of receiver operating characteristic ROC curve of PTX3 was 0.99, and it was significantly greater than that of Presepsin (0.67) or NT-proBNP (0.75). PTX3 is a soluble pattern recognition molecule that acts as a main component of the innate immune system. These data suggest that PTX3 can be utilized as a definitive biomarker for the prediction of IVIG resistance and subsequent CAL formation in patients with KD.

Keywords: Kawasaki disease; N-terminal pro-brain natriuretic peptide; coronary aneurysm; coronary artery abnormalities; intravenous immunoglobulin therapy; pentraxin 3; presepsin; systemic vasculitis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Plasma levels of PTX3, NT-proBNP and Presepsin during the disease course of KD. Unpaired Student t-test. Comparison of the level of PTX3 (A), NT-proBNP (B), and Presepsin (C) in healthy non-febrile controls, non-KD febrile controls, and KD. Between-group differences were determined using ANOVA and logical regression analysis. A: Circulating levels of PTX3 throughout KD. B: Circulating levels of NT-proBNP throughout KD. C: Circulating levels of Presepsin throughout KD. ns, not significant; *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.001. HC, healthy controls; Non-KD, non KD febrile disease; at the time of onset of KD or before IVIG (Pre-IVIG), after IVIG (Post-IVIG); Conv, convalescent.
Figure 2
Figure 2
Correlation curve showing the dose of IVIG needed to resolve KD versus PTX3, NT-proBNP and Presepsin levels. The plasma PTX3 (A), NT-proBNP (B) and Presepsin (C) levels are plotted against the dose of IVIG needed to resolve the KD. Zero indicates cases treated with aspirin only (non-IVIG). The PTX3 levels exhibited a significant correlation with IVIG doses required to resolve KD (y = 22.177 x - 4.2684, R² = 0.6402). ns, not significant; *p < 0.05, **p < 0.01, ***p < 0.005, ****p < 0.001.
Figure 3
Figure 3
AUC and predictive power of the biomarker candidate levels at the time of admission. (A) Unpaired Student t-test. Comparison of the PTX3 level in patients with or without pCAL. ****p < 0.001. (B) ROC curves comparing the sensitivity and specificity of certain variables and CAL formation; the AUC values of PTX3, NT-proBNP and Presepsin were respectively 0.9885±0.014 (95% confidence interval [CI]: 0.961 to 1.00, p = 0.005), 0.8563±0.054 (95% CI: 0.7513 to 0.9614, p = 0.039), and 0.6667± 0.148 (95% CI: 0.3765 to 0.9568, p = 0.33). The cut-off value of 69 ng/ml to predict subsequent CAL had a specificity of 1.00, sensitivity of 0.98, and a likelihood ratio of 49.0 PTX3, filled circles •; NT-proBNP, open circles ○; Presepsin, open triangles △.
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