Indian Journal of Rheumatology

ORIGINAL ARTICLE
Year
: 2022  |  Volume : 17  |  Issue : 1  |  Page : 24--29

A comparative study to assess vascular health in previously diagnosed patients of kawasaki disease


Malabika Maity1, Debadatta Mukhopadhyay2, Tapas Sabui3, Rakesh Mondal1, Jiban Krishna De4,  
1 Department of Pediatrics, Medical College and Hospital, Kolkata, West Bengal, India
2 Department of Pediatrics, Diamond Harbour Government Medical College and Hospital, Kolkata, West Bengal, India
3 Department of Pediatrics, RG Kar Medical College and Hospital, Kolkata, West Bengal, India
4 Department of Radiodiagnosis, NRS Medical College and Hospital, Kolkata, West Bengal, India

Correspondence Address:
Dr. Malabika Maity
Flat No. 11B, DDA Flats, Sarai Jullena, New Delhi - 110 025
India

Abstract

Background: Kawasaki disease, the commonest cause of multisystem vasculitis in children, was believed initially as a one-time disease. Long-term follow-up reveals that endothelial dysfunction persists in post-Kawasaki disease patients with and without coronary lesions and predisposes to atherosclerosis. Aims and Objectives: To establish the endothelial dysfunction and to correlate it with premature atherosclerosis in Kawasaki disease patients. Settings and Design: Prospective comparative study. Materials and Methods: Thirty patients of Kawasaki disease (age, 6 months to 20 years) were compared to the age matched control population and evaluated 2 times (1st F/U and 2nd F/U) at an interval of 6 months. USG Doppler was used to measure intimal thickness of carotid arteries CAD-IT, flow character and Resistive Index of anterior ATA-RI and posterior tibial arteries PTA-RI. Echocardiography was used to detect perivascular hyperintensity, dilatation and aneurysm of coronary arteries. Ongoing inflammation was documented by C- reactive protein (CRP) level. Coronary involvement (dilatation, small, medium, giant CAA) was determined by the z-scores adjusted to patients' body surface area (BSA) (AHA guidelines 2017). Statistical analysis used: Mean, paired t-test, GEE model, Odds ratio. Results: Significantly elevated CRP levels were observed in both the 1st follow up (p=0.0005) and 2nd follow up (p=0.000001) compared to control value. A significant rise (p<0.05) in total cholesterol, triglyceride levels, ATA-RI, PTA-RI and CAD-IT were seen. Seven patients developed coronary aneurysm of which three had persistent lesion. Conclusions: Kawasaki disease is not a one -time disease. Persistent endothelial dysfunction continues. CRP, total cholesterol, triglyceride, and USG doppler of coronary, carotids as well as peripheral arteries were found abnormal in follow up. So, these patients need to be followed up for a long period.



How to cite this article:
Maity M, Mukhopadhyay D, Sabui T, Mondal R, De JK. A comparative study to assess vascular health in previously diagnosed patients of kawasaki disease.Indian J Rheumatol 2022;17:24-29


How to cite this URL:
Maity M, Mukhopadhyay D, Sabui T, Mondal R, De JK. A comparative study to assess vascular health in previously diagnosed patients of kawasaki disease. Indian J Rheumatol [serial online] 2022 [cited 2022 Oct 4 ];17:24-29
Available from: https://www.indianjrheumatol.com/text.asp?2022/17/1/24/336277


Full Text



 Introduction



Although Kawasaki disease (KD) is considered a one-time disease, the recent experience speaks against this belief. KD has been detected in increasing numbers in India in the recent past. There is a sustained increase in newly detected cases replacing Henoch–Schonlein purpura as the most common vasculitic disorder in children.[1],[2] KD is now considered the number one cause of acquired heart disease in children in the developed world. In its acute phase, severe arteritis induces morphological changes in coronary arteries. It was believed initially that this change was transient. However, in the long term, follow-up (F/U) has revealed that the endothelial dysfunction persists and subclinical low-grade inflammation continues unabated in peripheral vessels in post-KD patients.[2] Damaged vessel wall predisposes to atherosclerosis. The risk for the development of atherosclerosis in adults is also increased in the long run and evidenced by increased thickness of the intima-medial portion of the carotid artery. Carotid Doppler ultrasound can detect structural and functional arterial abnormalities in the carotid arteries as well as hemodynamic alterations.

It can be hypothesized that patients diagnosed with KD will develop premature endothelial dysfunction due to an ongoing inflammatory pathology. KD is also associated with important abnormalities in lipid metabolism. Hence, surveillance of this population is necessary to monitor lipid levels and their relation to the future development of coronary endothelial dysfunction. This ongoing inflammation can be identified through an elevated C-reactive protein (CRP), which reflects a long-term status.[3] Thus, the present study aimed to assess the effect of persistent inflammation in developing endothelial dysfunction among KD patients. In addition, the current research intends to identify the progression of endothelial dysfunction in the study population.

 Materials and Methods



A longitudinal repeated-measures study was conducted in the department of pediatrics in a tertiary care hospital in Eastern India during a span of 2 years (2015–2016). Diagnosed cases of KD aged between 5 and 20 years without any other disorder of lipid metabolism were studied. A total of 30 cases (16 males and 14 females) were compared to 30 age-matched control population (nonsick patients admitted for other minor reasons). Following baseline data collection at the time of recruitment, two samples were collected at an interval of 6 months, that is, 3 months after diagnosis (1st F/U) and 9 months after diagnosis (2nd F/U). Ultrasonography (USG) Doppler machine of PHILIPS (model) (Philips iE33 ultrasound, Philips India Limited, Gurgaon, Haryana, India) with L12-3 (frequency 12–3 MHZ), C5-2 probe (frequency 5-2 MHZ), was used to measure intima-medial thickness of carotid arteries (CAD-IT), flow character and resistive index (RI), and Doppler waveforms of anterior (ATA-RI) and posterior tibial arteries (PTAs-RI). These measurements were recorded with the help of a radiologist. RI was defined as (S – D)/S where S is the height of systolic peak and D is the height of end-diastolic trough and calculated by (PSV – EDV)/PSV, where PSV is peak systolic velocity and EDV is end-diastolic velocity. CAD-IT was measured at the level of the carotid point at the junction between the sternocleidomastoid muscle and the thyroid cartilage. Echocardiography (Philips with S8-3, S12-4 probes) was done with the help of a pediatric cardiologist to assess perivascular hyperintensity, dilatation, and aneurysm of coronary arteries. Coronary involvement (dilatation, small, medium, giant CAA) was determined by the z-scores adjusted to patients' body surface area (AHA guidelines 2017):[4]

No involvement: Always <2Dilation only: 2 to <2.5; or if initially <2, a decrease in z-score during F/U ≥1Small aneurysm: ≥2.5 to <5Medium aneurysm: ≥5 to <10, and absolute dimension <8 mmLarge or giant aneurysm: ≥10, or absolute dimension ≥8 mm.

Ongoing inflammation was assessed by CRP level. Lipid profile estimation included measurement of total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL) level. They were measured by an autoanalyzer Cobas 6000. The data obtained were analyzed at each time point by paired t-test to assess any significant difference. In order to understand the independent effect of the study variables and also to note whether the effect of these variables changes because of the presence of KD, a generalized estimating equations (GEE) model was developed to account for the effect of temporal trend and sparse outcome in control group. All the variables in the model were time dependent, except the diagnosis of KD. Interaction terms of the variables, that is, CRP (as measure of inflammation) and lipid profile parameters such as TG, TC, and HDL, with diagnosis of KD, were included in the model to identify the effects of these parameters nested within the effect of KD. The GEE model built was found to be statistically fit and the results had sufficient power (a power of 82.3% detected with two-tailed 95% confidence in post hoc test) to arrive at a statistically valid conclusion. The P values were considered significant when <0.05.

 Results and Analysis



We collected the data from the cases as well as the controls and analyzed them accordingly. CRP level was measured to detect ongoing inflammation. The maximum and minimum CRP values observed were 333 mg/L and 3 mg/L, respectively (mean value 56.6 ± 82.4 mg/dl) at 1st F/U and 100 mg/L and 2 mg/L, respectively (mean value 27.4 ± 27 mg/dL) at 2nd F/U in respect to the CRP value in control population, as shown in [Table 1].{Table 1}

Even after 3 months at the first F/U and 9 months at the second F/U, CRP levels remained significantly elevated (P < 0.001 at both the F/U) despite adequate initial treatment with immunoglobulin therapy.

The lipid profile was abnormal. Maximum and minimum TC levels were 270 mg/dL and 110 mg/dL, respectively (mean 155.8 ± 40 mg/dl) (1st F/U) and 180 mg/dL and 110 mg/dL, respectively (mean 145.3 ± 21.4 mg/dl) (2nd F/U). The mean TG values were 112 ± 19 mg/dL and 112 ± 17.4 mg/dL in the 1st and 2nd F/U, respectively. The highest and lowest HDL values observed were 68 mg/dL and 35 mg/dL (mean 48.9 ± 10 mg/dl) (1st F/U) and 65 mg/dL and 38 mg/dL (mean 49.1 ± 8.3 mg/dL) (2nd F/U), respectively. TC and TG levels were significantly high in cases compared to that of the control population (TC: P = 0.02 and 0.09 at 1st and 2nd F/U, respectively; TG: P < 0.05 in both F/U). However, no significant alteration was observed in the case of HDL levels. The mean values for TC, TG, and HDL in the control group are provided in [Table 1].

Echocardiography was used to detect cardiac as well as coronary artery abnormalities. Out of 30 patients, 11 patients at the 1st F/U and 15 patients at the 2nd F/U revealed no abnormal findings. Perivascular hyperintensity/glistening (G) without coronary artery dilatation (D) or coronary aneurysm (A/CAA) was seen in 11 and 8 patients in the 1st F/U and 2nd F/U, respectively. In the 1st F/U, one patient had perivascular hyperintensity as well as dilated coronary artery and in the 2nd F/U, four patients had similar findings. Coronary aneurysm in addition to perivascular hyperintensity and coronary dilation developed in seven patients in the 1st F/U, but aneurysm persisted only in three cases in the 2nd F/U. One patient (2 years/male) responded completely to therapy and echocardiography was almost normal at the 2nd F/U. The z-score values are shown in [Table 2].{Table 2}

According to the findings of the USG Doppler, CAD-IT was significantly increased only in the 2nd F/U (P = 0.67 and 0.005 in the 1st and 2nd F/U, respectively). RI in both anterior and PTAs was significant in both the F/Us compared to that of the control population (ATA-RI: P = 0.01 and <0.001; PTA-RI: P < 0.001 and 0.001 in the 1st and 2nd F/U, respectively). These findings are summarized in [Table 1]. In our study, we found monophasic flow in tibial arteries in four patients in Doppler USG [Figure 1]a, whereas the rest of the patients and control population had triphasic flow ([Figure 1]b.{Figure 1}

[Table 3] summarizes the GEE model depicting relationship between inflammation in KD and development of endothelial dysfunction. Higher levels of CRP and TG were identified to be important risk factors. On the other hand, effect of KD was statistically significant with an adjusted odds ratio of 1.93 (95% confidence interval: 1.84–2.10). The effect of raised CRP in the presence of KD has been represented by the interaction term, which was statistically significant, implying a higher risk of development of endothelial dysfunction due to higher CRP level among those suffering from KD.{Table 3}

 Discussion



In our study, we found significantly elevated CRP levels even after 3 months at the 1st F/U and 9 months at the 2nd F/U, despite adequate initial immunoglobulin therapy. In literature, it has been observed that persistently high CRP levels after the convalescent phase indicated smoldering vasculitis with alteration of arterial function.[3],[4],[5] Milani et al. also showed a significant elevation of CRP in KD patients with coronary artery lesion (CAL) compared to controls and other KD groups with normal coronary arteries or with regressed aneurysms, suggesting that the presence of aneurysms is associated with persistent systemic inflammation years after disease onset.[6] Our study is also in line with them.

We found that TC and TG levels in the serum of KD patients were significantly high compared to those of controls. High TC and TG levels are important risk factors for atherosclerosis on inflamed endothelium caused by ongoing vasculitis. Chen et al. observed similar changes.[7] They suggested that increase of blood TG, together with hypercoagulation in KD, indicates the necessity to control blood lipid levels as well as anticoagulation therapy, such as the use of statins to prevent premature atherosclerosis. However, Mitani et al. showed that there were no differences between patients with KD 10 years after the onset and the control subjects about concerning TC and HDL-cholesterol levels.[8] In epidemiological studies of children, it has been documented that subtle adverse lipoprotein levels at late teen years predicted future dyslipidemia in young adulthood.[9] Takahashi et al. concluded that subjects with a history of KD present a risk factor for atherosclerosis later in life.[10] Iranian and Indian studies suggest that children with a history of KD are more prone to changes in their lipid profile, especially in the level of TG s and HDL, which may lead to premature atherosclerosis.[11],[12] Therefore, the literature is in favor of routine estimation of lipid profile and periodic control of lipid values in these groups of patients.

Severe endothelial dysfunction is common among patients with coronary artery aneurysms.[13],[14] Abnormalities of systemic endothelial function persist many years after the resolution of acute KD, even in patients without detectable early coronary involvement. Even in patients without coronary aneurysm formation in the acute phase, mild carotid intimal thickening can be detected in some of them.[15] One retrospective study showed the development of coronary artery stenoses in the majority of children with giant coronary aneurysms over the long term particularly in patients <6 months of age who were at high risk.[16] Hence, evaluation of coronary arteries for any detectable lesion and proper therapy are necessary to arrest coronary artery remodeling after KD. High-resolution transthoracic 2D echocardiography should be added to the F/U protocol of KD because of its noninvasiveness and reproducibility. Japanese guidelines also discuss the lifetime F/U for cardiovascular risk assessment and counseling every 3–5 years for KD patients who never had CA enlargement or had the only transient CA ectasia.[17]

Doppler USG of carotid arteries showed significant CAD-IT in long-term F/U, indicating postinflammatory changes. We observed high CAD-IT, suggestive of the development of postinflammatory arteriosclerotic remodeling.[18] KD with CALs eventually leads to the development of postinflammatory arteriosclerotic remodeling characterized by luxuriant intimal proliferation and neo-angiogenesis.[19] KD complicated by giant or medium-sized CAA has a trend toward continued increased CAD-IT and suggestion of more severe impact on the arterial wall.[20],[21],[22] IT has been noted in both affected coronary arteries and systemic arteries. The children are predisposed to premature atherosclerosis who have both altered lipid profiles and increased CAD-IT.[23] Results in some studies suggest that children with KD may continue to have increased CAD-IT as compared with healthy control subjects even after several years of the acute episode.[24],[25],[26],[27],[28] Children who have KD may need to be followed up into adulthood for adverse coronary events and prevention of cardiovascular risk factors.[28],[29]

In our study, we found monophasic arterial flow in tibial arteries in four patients and statistically significant RI in all patients compared to the controls using Doppler USG, indicating increased arterial stiffness in tibial arteries. Our finding is similar to that of other studies where arterial stiffness determined by pulse wave velocity in patients with KD was high, regardless of antecedent CAL, relative to controls.[30] Our observation needs to be confirmed further by a larger study with a long F/U.

Implications of the study

The present study highlights the importance of the measurement of CRP as a useful tool to detect ongoing vasculitis. Patients with KD have to be followed up for a long time as they are at high risk to develop atherosclerosis. Measurement of RI in anterior and PTAs by USG Doppler can be used to detect ongoing endothelial dysfunction in a setting of limited resource, where a device like EndoPAT (FDA-approved device to detect endothelial function noninvasively) is too costly to procure.

 Conclusion



KD is not a one-time disease. Persistent endothelial dysfunction continues. CRP, TC, TG, and USG Doppler of coronary, carotids, as well as peripheral arteries were found abnormal in F/U. Hence, these patients need to be followed up for a long period.

Acknowledgment

We acknowledge the staffs of Biochemistry and Radiology Departments in our institute for their support.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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