Kawasaki disease (KD) is an acute inflammatory process mainly affecting children and characterized by multi-system vascular involvement.1 These patients experience a broad spectrum of clinical manifestations, including skin lesions, eyes, and neurological systems.2 Besides, numerous studies have shown that KD patients suffer from cardiovascular complications as the major causes of morbidity and mortality among these groups of patients.3,4 The major concerns lie in determining coronary artery abnormalities. However, other vascular abnormalities involved in systemic vascular physiology are gaining great clinical interest, including increased carotid artery intima-media thickness, reduced distensibility of arteries, and increased stiffness of central and peripheral arteries.5,6 Histopathological studies demonstrated the presence of aneurysm sites at other locations, predominantly affecting small to medium-sized vascular territories such as brachial, renal, femoral, and iliac arteries.7 The arterial function was investigated in several studies by various methods, including evaluation of coronary flow reserve with angiography, intracoronary flow velocity by transthoracic echocardiography, magnetic resonance imaging, and positron emission tomography.8,9

Nailfold capillaroscopy was a non-invasive diagnostic method for microvasculature evaluation in various rheumatologic disorders.10,11 Distinct morphologic patterns on nailfold capillary changes reveal specific capillaroscopic patterns, possibly reflecting an underlying autoimmune inflammatory disease. This technique is helpful for microvascular analysis in several diseases such as Juvenile systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, Behçet's disease, and familial Mediterranean fever.11,12 Although capillaroscopy is considered a safe and feasible diagnostic tool, little information exists regarding the application of this technique to assess microvascular function among the pediatric population diagnosed with KD. Therefore, the present study aimed to determine the utility of nailfold capillaroscopy in KD patients.

Thirty-one KD patients were identified, including 21 males (67.7%) and nine females (32.3%). The mean age of the patients and control group were not significantly different (3.39±1.59 vs. 4.58±2.91, respectively) (P=0.09). The male to female ratio was 2.1–1 in KD group. Most KD patients (71%) presented with typical clinical features of Kawasaki. Coronary involvement was identified in 13 KD patients (41.9%). The frequency of different coronary artery abnormalities as evaluated by a transthoracic echocardiogram is summarized in Table 1.

The nailfold capillaroscopy was conducted on both the KD and control groups. The abnormal capillaroscopic diameter was identified in 21 patients from KD group and four patients in the control group (Table 2). The most common abnormality in the evaluation of capillaries diameter was irregular dilatation (Fig. 1) seen in 11 (35.4%) KD patients and 4 (13.3%) in the control group. The normal capillary architecture distortions were commonly seen in KD group (n=8). On the other hand, there were no findings of architectural capillary abnormality in the control group (P=0.003). About half of KD patients had a reduction in capillary density (Fig. 2), while no similar abnormality was observed in the control group (P<0.001). There was no significant difference between KD patients and the control group in terms of morphology variations (P=0.4). Moreover, a positive correlation was observed between coronary involvement and abnormal capillaroscopic results (r=0.65, P<0.03).

Fig. 1.

The increased diameter in the irregular dilatation in the nail fold capillaroscopy on a 2.5 years old Kawasaki patient.

(0.04MB).

Fig. 2.

Abnormal morphology and loss of density of capillary vessels in a 14 months Kawaski patient with coronary involvement.

(0.08MB).

The sensitivity, specificity, PPV, and NPV of abnormal capillaroscopy patterns for KD were calculated. The results indicate that the sensitivity and specificity of a capillaroscopy for diagnosis of KD were 84.0% (95%CI: 63.9–95.5%) and 72.2% (95%CI: 54.8–85.8%), respectively. The PPV and NPV of capillaroscopy for KD were 67.7% (95%CI: 48.6–83.3) and 86.7% (95%CI: 69.3–96.2), respectively. The positive and negative likelihood ratios were 3.02 (95%CI: 1.74–5.26) and 0.22 (95%CI: 0.09–0.56), respectively.

Microcirculation is highly important to normal physiological processes, including tissue oxygenation, hemostasis, tissue repair, and nutritional exchange. Microcirculation assessment is vital in analyzing microvascular abnormalities in many rheumatologic disorders. Recently, nailfold capillaroscopy has been widely used to identify microcirculation damage since it gives precise information about capillaries’ conditions.11,14–16 However, limited data exist regarding the utility of this technique among pediatric patients with KD. The evaluations were done after IVIG treatment because Kawasaki disease is the acute vasculitis with the hypothesis of unstable alternations in the vasculature, especially the microvascular in the acute phase. The stabilization of capillaroscopy changes might be more in the sub-acute phase after IVIG treatment. In the present study, our findings suggest that nailfold capillaroscopy could detect morphological alterations in the microcirculation compared with the control group.

Our findings indicated that various morphological changes could be identified by using capillaroscopy among patients with KD, including irregular dilatation of capillaries, reduction in capillary density, and architectural capillary abnormality. Among our KD patients, the most frequent capillaroscopic findings were decreased capillary density (45.2%) and irregular dilatation of capillaries (35.4%). In patients with systemic sclerosis, the capillaroscopic patterns are characterized by a progressive capillary loss microvasculature function and have been associated with higher disease activity.17 Ingegnoli et al.18 evaluated microvascular damage among 123 cases diagnosed with systemic lupus erythematosus using nailfold capillaroscopy, and their findings indicated that about 35.8% of cases were found to have capillary abnormalities (including elongated loops, dilatation of the efferent side, increased tortuosity, and branching), while, 28.5% of the patients had shown normal pattern. The bed nails’ capillary abnormalities (including elongated loops, dilatation of the efferent side, increased tortuosity, branching, and loss of density) are determined in connective tissue disorders such as systemic lupus erythematosus,18,19 Dermatomyositis,20 scleroderma,17 and the others cause of vasculitis and vasculopathy as a chronic process of vascular inflammation.

On the contrary, Kawasaki disease is an acute vasculitis accompanied by an acute inflammation process with similar abnormalities, regardless of probable different mechanisms. Oxidative stress has a major role in endothelial dysfunction in Kawasaki disease's acute and sub-acute phases. In addition, the CRP level, fever duration, and cytokines of inflammations lead to endothelial injuries accompanied by oxidative stress directly or indirectly.21,22 So, the mechanisms of acute alternations in bed nail capillaries may differ from the chronic capillaroscopy in the other connective tissue disorders. Although, further evaluations should be involved.

This study observed a significant positive correlation between abnormal capillary changes and coronary artery involvement in sub-acute phases of Kawasaki disease after IVIG treatments. Similarly, Huang et al.23 reported that coronary artery involvement significantly correlates with changes in peripheral microcirculation, especially in the sub-acute phase. In IVIG-resistance Kawasaki disease, the IL6 and IL10 cytokines mildly decrease, and IL4 and TNFα cytokines increase with more coronary involvement.24 On the other hand, cytokine elevations and more inflammations accompanied by more oxidative stress lead to endothelial dysfunctions.25 Indeed, oxidative stress lead to RBC hemostasis dysfunctions, platelet activation, apoptosis inhibition, and ultimately thrombocytosis causes clot formations in microvascular.26 Microvascular involvements in KD such as conjunctival injections, extremities edema, and erythema in the acute phase of KD may be prodromal to medium-sized vascular involvement such as coronary vasculitis in the sub-acute phase.27 Similarly, the microvascular involvements prodromal to coronary involvements may occur in the heart muscle.28 Thus, early evaluations of microvascular involvements may change the treatment strategies to aggressive treatment in the early phase other than IVIG, such as corticosteroids and anti-TNF.29,30 Capillaroscopy may predict the early microvascular involvements, consequently improving the outcome with aggressive and urgent treatments. However, further research should be involved.

The present study had several limitations. Our study's relatively small sample size may have reduced the power to detect a significant correlation between capillaroscopic findings and other disease manifestations. Moreover, this study lacks a prospective follow-up to determine factors associated with alteration in capillaroscopic features. Therefore, the results of the present study should be interpreted in the context of its limitations.

In conclusion, the findings of this study indicate that capillary alterations can be seen in KD, although it is not specific to this disease. So, nail fold capillaroscopy can be helpful in detecting the capillary alternations in KD patients. Accurate coronary artery involvement diagnosis in KD patients is the most important component in evaluating and managing this disorder. Currently, echocardiography is the initial step in evaluating coronary complications in KD. Nailfold capillaroscopy is a feasible noninvasive diagnostic method to evaluate peripheral endothelial dysfunction that could indirectly help predict coronary arterial anomalies in KD patients, along with echocardiography. Nevertheless, Capillaroscopy cannot replace echocardiography, but it might be a complementary part of the diagnostic approach. Further studies are warranted to validate this finding and provide enough evidence on using capillaroscopy to detect coronary involvement among KD patients.

B.S. and N.R. performed data gathering and drafting of the manuscript.

S.R., and F.T. contributed to the conception and design of the study, and clinical expertise.

R.A., and S.N. analyzed and interpreted the clinical data, and clinical expertise.

E.A. performed echocardiography and contributed to interpretation of the clinical data.

V.Z. provided the concept the survey, interpretation of the clinical data, oversaw the project and critical revision of the final draft of manuscript, primary responsibility for the paper.

All authors read and approved the final version of the manuscript.

The authors have no conflicts of interest to declare.