Kawasaki disease is an acute, systemic vasculitis involving small and medium arteries, typically affecting children under 5 years of age. Since the first report of KD disease in 1976, the incidence has been rising. The incidence reported recently in Japan is 306/100,0005, while in Beijing in 2000 and 2004 was 40.9/100,000 and 55.1/100,000, respectively 6. In 2014, the incidence was 116.6/100,000 in Japan5. In developed countries, KD has become the most common cause of acquired heart disease1, replacing rheumatic heart disease. The international diagnostic criteria include fever lasting for more than five days along with at least four of the following signs: erythema of the lips and oral mucosa, bilateral nonexudative conjunctivitis, polymorphous skin rash, changes in the extremities, and unilateral cervical lymphadenopathy. The clinical features can present at different times, making the diagnosis more challenging at an early stage. The most serious cardiac complications include coronary aneurysm, pericardial effusion, left ventricular enlargement and mitral insufficiency. Demonstration of coronary abnormalities at echocardiography confirms the diagnosis, even if clinical criteria are not complete.
Due to the use of IVIG, the incidence of coronary artery complications in KD has decreased from 20% to about 5%, but there are still about 0.1% of pediatric patients with giant coronary artery aneurysm (GCAA)5, mainly in the middle right coronary artery and the anterior descending left coronary artery, leading to a high incidence of cardiovascular events, mortality and poor prognosis7. Immune activation, inflammatory factors, nuclear factor-κB, matrix metalloproteinase, vascular endothelial injury and many other factors are involved in the pathogenesis of KD. Aspirin combined with IVIG is the main treatment of KD, which can effectively alleviate the clinical symptoms of KD and reduce the risk of coronary artery injury caused by KD. In recent years, the use of glucocorticoids and tumor necrosis factor-α blockers in selected cases of KD, has further improved the prognosis of this disease.
The most striking feature of the KD case-report described here was the very early onset of the coronary artery damage. Symptoms of KD can be unspecific at an early stage, or the clinical picture can be incomplete. In very young infants KD can be easily misdiagnosed as sepsis, urinary infection or no non-specific inflammatory disease. This subgroup of infants (< 6 months of age) more frequently presents with an atypical or incomplete presentation, in comparison to older children; and fever can be low-grade or sometimes absent2,8.
The risk of coronary dilatations and aneurism seems to be increased in younger children (< 6 months) compared with older KD patients9. In younger children mortality is higher compared with older children10–11. It remains unclear whether the major severity of KD in young infants is the consequence of the diagnostic difficulties and consequently delayed diagnosis or whether it is secondary to specific age-related factors.
Cardiac changes (particularly coronary artery dilatation and aneurisms) generally require time to develop and are typically identified during the second week of the disease1. Studies have reported that the time range of CAA reaching the maximum diameter in children with Kawasaki disease is 11 days to 87 days, and the median is 35 days (n = 195)12. Our case presented with an exceptional early onset of coronary dilatation (3 days of illness) suggesting the need of maintaining a very high index of suspicion of KD in a young infant and to perform a precocious cardiac evaluation, even in the absence of a complete clinical picture.
Despite the description of a higher risk of coronary abnormalities and cardiac risks in younger infants with KD, it’s not clear whether the effect of a younger age influences also the timing of onset of coronary damage. In the study by Salgado et al13 not only coronary dilation was more common but also was diagnosed earlier in the course of the disease in younger than in older infants. Similar results are described in the study by Moreno et al14, where a higher baseline z-score and z-max and a higher prevalence of dilatations and aneurysms were already present at first echo in the youngest infants (< 6 months) compared to older children.
Timely treatment of KD with IVIG (within seven days), can significantly reduce the risk of coronary artery aneurysms. Our patient was treated with IVIG on day 4 of fever, however there was recurrence of symptoms requiring further treatment. At present, the mechanism of gamma globulin resistance is not completely clear, and it is hypothesized to be related to genetic factors, in particular to the polymorphism of Fcγ receptor15. In our patient, after early infusion of the second dose of gamma globulin combined with glucocorticoid, symptoms were relieved and there was no evidence of cardiac complications. The use of steroids along with IVIG as initial treatment of high-risk KD is still controversial. Results from a meta-analysis found that a combination of steroids with standard-dose IVIG as an initial treatment in high-risk KD patients reduced the rate of coronary artery abnormalities16 with data coming mostly from Japan, however it is not clear whether this treatment choice should be applied in high-risk populations outside of Japan. According to the AHA guidelines, steroids and other treatments (anti-TNF alpha) remain a second line choice, in cases of IVIG resistance. We treated our patient with a second dose of IVIG along with steroids (2 mg/kg) with a full clinical response. Recent studies have also found that the incidence of coronary artery lesions (CAL) varies significantly depending on the timing of IVIG treatment, suggesting that early use of IVIG is an effective method to inhibit systemic inflammation and prevent CAL17.
Aspirin has anti-inflammatory and antiplatelet effects, and it is a coadjuvant therapy in KD. The time and dose of aspirin are currently controversial. In the acute phase of Kawasaki disease, the United States guidelines advocate a high dose (80–100mg/Kg/day) regimen1, while in Japan and Western European countries medium doses (30–50 mg Kg/day) are used4, which is subsequently reduced to a low dose (3–5 mg/Kg/day) regimen. Recent studies have shown that compared with low-dose aspirin, medium and high doses of aspirin have no advantages in preventing CAL18–19. In our case we selected a medium-dose aspirin regimen. The lack of improvement of the thrombosis at 2 weeks follow-up and the parallel increase in liver enzymes convinced us to review our choice of anticoagulant drugs. Warfarin is currently recognized as a safe anticoagulant for the prevention and treatment of coronary artery thrombosis. It has the advantages of good oral absorption, fast onset, long half-life, and simple schedule (once a day)20. However, its therapeutic window is narrow, with the risk of adverse reactions such as bleeding, therefore it should be prescribed and monitored cautiously. In clinical practice, dose adjustment should be carried out in combination with the monitoring of the thrombosis and the severity of coronary artery lesions. Studies have shown that warfarin has a positive effect on the prognosis of coronary artery lesions and thrombosis in children with Kawasaki disease complicated with CAA21, although the risk of thrombosis remain significant (14% in patients treated with warfarin)21.
In conclusion this case-report suggests that coronary artery damage can appear very early in the course of KD and reminds clinicians to perform cardiac ultrasound examination at an early stage in cases of suspected KD. If cardiac damage is confirmed, prompt treatment with IVIG should be initiated and close follow-up is necessary, especially in young infants.