PMC8335158_01
Course of disease after admission. ABPC/SBT, ampicillin/sulbactam; CRP, C-reactive protein; sIL2-R, soluble interleukin-2 receptor; BNP, B-type natriuretic peptide.
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The laboratory measures from hospitalization to diagnosis are shown in Table 1; the patient's course of disease following hospitalization is shown in Figure 1. On the patient's fifth day of illness, she developed bilateral bulbar conjunctival congestion, anterior chest erythema, and right palm erythema, in addition to exacerbation of lip reddening; the patient thus fulfilled all six Japanese criteria for Kawasaki disease (Supplementary Figure 1). Furthermore, the serum levels of inflammation markers (e.g., C-reactive protein, procalcitonin, ferritin, and soluble interleukin-2 receptor; Figure 1) also decreased relatively rapidly from a peak on the 5th day of illness. No symptom recurrence was noted; inflammatory reaction markers (e.g., C-reactive protein; Figure 1) also decreased relatively rapidly.
Echocardiography findings on the 6th day of illness: (A) M-mode (left ventricular ejection fraction, 50.2%), (B) mild mitral regurgitation by 4-chamber view, (C) right coronary artery (seg1: 3.0 mm, Z score+1.6), Z score was calculated by "Z score calculator of coronary arterial diameter" (http://raise.umin.jp/zsp/calculator/), (D) left coronary artery (seg5: 3.0 mm, Z score+0.9, seg6: 2.7 mm, Z score+1.3, seg11: 2.6 mm, Z score+1.5). Ao, aorta; RCA, right coronary artery; LAD, left anterior descending artery.
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On the 6th day of illness, however, she exhibited reduced left ventricular systolic function (ejection fraction 50.2%) and enhanced left ventricular end-diastolic diameter (Figure 2A), as well as pericardial effusion, mild mitral regurgitation (Figure 2B), and mild tricuspid regurgitation. No coronary artery dilation was evident (Figures 2C,D). Moreover, she exhibited ST-T elevations (Supplementary Figure 2) and was diagnosed with acute myocarditis, following observations of elevated serum troponin I level (0.256 ng/mL) and elevated blood B-type natriuretic peptide level (211 pg/mL) in blood tests.
Dynamic changes in cytokines according to changes in clinical symptoms. Febrile period shown in dark gray; duration of myocarditis shown in light gray.   indicates IVIG+PSL+ASA start timing. Dots represent blood draw timings. (A) Cytokines with peak titers before treatment initiation. (B) Cytokines with rapid reductions following fever resolution. (C) Cytokines that persisted at high titers for an extended period following fever resolution, which then decreased with amelioration of myocarditis. ASA, aspirin; IVIG, intravenous immunoglobulin; PSL, prednisolone; IL, interleukin; MIP, macrophage inflammatory protein; IFN, interferon; MCP, monocyte chemoattractant protein; MIG, monokine induced by interferon-gamma; IP, interferon-gamma-induced protein; TNF, tumor necrosis factor; HGF, hepatocyte growth factor; G-CSF, granulocyte colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor.
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We investigated changes in these 71 markers during the patient's course of disease (Supplementary Figure 3). Cytokine changes were striking, such that temporal cytokine kinetics exhibited five patterns: (1) a peak before treatment initiation on the 5th day of illness (Figure 3A: interleukin (IL)-2, interferon-lambda3 et al.); (2) elevation until the 5th day of illness, followed by rapid reduction on the 6th day of illness after treatment initiation and concomitant fever resolution (Figure 3B: IL-6, IL-10, IL-17, IL-8, CCL20); (3) persistence of high titers for several days after fever resolution, followed by a reduction in titers after resolution of myocarditis (Figure 3C: IL-1 receptor antagonist (Ra), CXCL9, CXCL11, CCL2, interferon-gamma, IL-1beta, IL-18, CXCL10, and tumor necrosis factor-alpha et al.); (4) low titers in the acute phase, followed by elevation (CCL17 and SCGF-beta); and (5) no change [CCL11, CCL15, CCL23, IL-3, IL-4, IL-5, IL-12(p70)].