The KD parent symposium 2020 highlighted the most recent advancements in Kawasaki disease research, led by the world’s leading researchers in this field. You can find the full video of the symposium here.
Here are some important take home messages:
Professor Michael Levin: New Horizons in Kawasaki
The exact cause of KD is unknown.
Delayed diagnosis and treatment is one of the most important factors in children with KD suffering coronary artery damage.
Diagnosis is not easy as many clinical features of KD are shared with other diseases
Gene ‘’signature”, based on 13 genes has been found to accurately diagnose and distinguish the disease from other causes of fever.
A 13 gene KD kit is underway and could help improve diagnosis.
Late Cardiovascular Sequelae
Patients after Kawasaki disease can have coronary aneurysms (a dilatation in the wall of an artery supplying blood to a specific area), which often can cause in complications as thrombosis (clotting of the blood in a part of the circulatory system) or stenosis (abnormal narrowing) leading to myocardial infarction (damaged heart muscle).
Patients with coronary aneurysms after Kawasaki disease are at increased risk and require long-term follow-up by cardiologists knowledgeable about management issues in this patient population.
1. Patients with LARGE coronary aneurysms after Kawasaki disease are at high risk for cardiovascular complications and will require life-long surveillance by cardiologists knowledgeable about management issues in this patient population.
2. Patients with REGRESSED (returned to an original state) aneurysms after Kawasaki disease remain at increased risk for thrombosis and other adverse outcomes, and should also be followed closely.
Management of sequelae of
Kawasaki disease in adults
Late manifestations of Kawasaki disease (KD) in young adults include:
1. Cardiomyopathy: Diseases of the heart muscle, where the walls of the heart chambers have become stretched, thickened, or stiff.
2. Ischemia: An inadequate blood supply to an organ or part of the body, especially the heart muscles
3. Infarction: Death of tissue resulting from a failure of blood supply, commonly due to obstruction of a blood vessel by a blood clot or narrowing of the blood-vessel channel.
KD poses special management challenges for the adult cardiologist who must recognize the unique features of the cardiovascular lesions in this growing population of patients.
In the article signed by John Gordon and Jane Burns have been presented the results of the observations made on a population of 140 adult KD patients enrolled in the San Diego Adult KD Collaborative Study.
Coronary artery aneurysms (a bulge in a blood vessel caused by a weakness in the blood vessel wall) resulting from KD in childhood are associated with a high risk of thrombosis (clotting of blood within an artery or vein so that the blood flow is reduced or impeded) and stenosis (abnormal narrowing) at the inlet or outlet of the aneurysm. These aneurysms are often highly calcified and may contain a large thrombus burden that may obscure the true size of the aneurysm.
All patients with important coronary artery damage as a result of Kawasaki disease (KD) in childhood should be in follow up care with an adult cardiologist knowledgeable about the unique challenges in managing this patient population.
Understanding KD lesions: Once the normal arterial wall architecture has been damaged during the acute, inflammatory phase of KD, the affected segment will always have abnormal characteristics.
The pathologic changes in these lesions can include both:
1. rapid production of myofibroblasts (cells of wound healing), and,
2. layering of thrombus (blood clot) along the wall of the aneurysm (bulge in a blood vessel caused by a weakness in the blood vessel wall)
These processes, alone or in concert, contribute to progressive stenosis (abnormal narrowing) of the vessel lumen.
Intravascular ultrasound studies have documented the abnormal composition of the arterial wall, which cannot dilate under conditions of increased oxygen demand.
Thus, even though the lumen appears normal by angiography, the calcified wall acts as a functional stenosis (abnormal narrowing).
The highest complication rate is among patients with large aneurysms affecting both the left and right coronary arteries. This is a group that requires frequent monitoring and therapies to prevent thrombosis.
Gordon JB, Burns JC. Management of sequelae of Kawasaki disease in adults. Global cardiology science & practice. 2017 Oct 31;2017(3).
Management of Kawasaki disease Lesions
A. MEDICAL management
The consequences of arterial wall damage can manifest in various ways.
One final common pathway is complete thrombosis (blood clot in a blood vessel) of the aneurysm (a bulge in a blood vessel) with development of collaterals (side branch).
This scenario is most often seen when the acute phase of KD occurred at a very young age, which seems to favour the development of collaterals. These patients have essentially performed an “auto-bypass” with the growth of collaterals to supply territories at risk. Their potential for ischemia should be evaluated by stress echocardiography repeated at intervals to ensure timely recognition of changes in myocardial perfusion.
However, many of these patients will do well and are not candidates for interventions or bypass surgery.
Medical management with low dose aspirin and a statin to maintain vascular health are reasonable therapies in this patient population.
These patients are not candidates for systemic anticoagulation unless there are aneurysms that have not thrombosed.
Anti-coagulation with warfarin or enoxaparin coupled with anti-platelet therapy with aspirin forms the mainstay of therapy for patients with LARGE aneurysms. The use of statins to promote endothelial cell health is also reasonable.
B. Catheter-based interventions
For young adults with a known history of aneurysms following acute KD, monitoring of lesions should be guided by principles established for atherosclerotic disease. Patients should be followed non-invasively with a combination of CT angiography and stress echocardiograms.
Invasive catheterization should be reserved for those patients in whom an intervention is contemplated.
C. SURGICAL interventions
The use of arterial bypass grafting in adults post-KD has met with mixed success.
Gordon JB, Burns JC. Management of sequelae of Kawasaki disease in adults. Global cardiology science & practice. 2017 Oct 31;2017(3).
Prevalence of Kawasaki Disease in Young Adults with Suspected Myocardial Ischemia
Up to 25% of patients with untreated Kawasaki disease (KD) and 5% of those treated with intravenous immunoglobulin will develop coronary artery aneurysms (abnormal dilatation of the coronary arteries). The aneurism can persist without symptoms until later in life when myocardial ischemia can occur. (Myocardial ischemia occurs when blood flow to the heart is reduced, preventing the heart muscle from receiving enough oxygen).
Dr Lori and collab. collected data from 261 young adult patients in San Diego who have been investigated for presumed myocardial ischemia, wanting to see how many of them had a history of KD. The method of investigation was coronary angiography (a type of X-ray used to check blood vessels) which can detect coronary artery aneurysms often with calcification (a build-up of calcium in arteries) suggesting a history of KD.
In their study 16 patients from 261 had coronary aneurysms.
5% of young adults who undergo coronary angiography to evaluate symptoms for myocardial ischemia may have KD as the underlying cause.
Cardiologists should be aware of patients who have coronary changes from KD, whose treatment should differ from patients who have coronary artery disease from other causes, like atherosclerosis (deposition of fatty material on their inner walls).
Kawasaki disease (KD) is an inflammation of the blood vessels of unknown origin that occurs in young children. KD can be difficult to recognize, and many cases go undiagnosed.
Approximately 25% of children with untreated KD (and 5% of those treated with intravenous immunoglobulin) will develop coronary aneurysms (abnormal dilatation of the coronary arteries). As children with coronary aneurysms caused by KD grow older, they are at an increased risk for myocardial infarction (damaged heart muscle) and other adverse events.
Optimal treatment of KD vasculopathy (disease affecting blood vessels) differs in several ways from treatment of typical atherosclerosis:
1. Acutely, patients with KD who present with myocardial infarction often have a significant thrombus burden in their aneurysmal segments. In the setting of a large thrombus (a blood clot formed in the vascular system of the body and impeding blood flow), the true diameter of the aneurysmal segment may not be fully appreciated, and further investigation like intravascular ultrasound is needed.
2. In Subacute (intermediate between acute and chronic) settings, coronary computed tomography angiography may help to identify the presence and size of aneurysms, as well as the presence of thrombus (blood clot), calcifications (build-up of calcium in arteries), and stenoses (narrowing or restriction of a blood vessel that reduces blood flow).
3. Long-term therapy with systemic anticoagulation (treatment with anticoagulant drugs to reduce the risk of the formation of blood clots), often in addition to antiplatelet agents (medicines that prevent blood clots from forming), is frequently indicated for patients with large coronary aneurysms.
Adult life after KD
KD usually presents in children under five years old. Children with KD may require life-long treatment, however, since the acute phase of KD is self-limited, KD diagnosis is often missed. Consequently, individuals reach adulthood unaware of their KD history and face multiple cardiac complications. In the US and Japan alone, more than 14,000 new cases of KD are detected each year, yet no official guidelines exist to assist cardiologists in treating patients with a KD history.
Once an individual’s normal arterial wall architecture has been damaged during the acute, inflammatory phase of KD, the affected segment will always have abnormal characteristics. Characteristics resulting from KD earlier in life can contribute to pathological cardiovascular conditions known as cardiovascular sequelae in adulthood. Growing numbers of young adults are presenting to cardiologists cardiovascular sequelae resulting from KD, including…
Cardiomyopathy (a disease of the heart muscle making it harder for the heart to pump blood around the body).
Myocardial ischemia (insufficient blood supply to the heart tissue).
Myocardial infarction (heart attack).
Proliferation of myofibroblasts.
Inability of the CA to dilate in times where myocardial oxygen demand is greater due to the arterial wall’s abnormal composition and calcification.
Propensity to develop aneurisms in systemic arteries (arteries carrying blood from the heart to the body), and patients may present with symptoms of ischemia including weakness in a limb or extremity. These aneurisms have a high propensity to clot, sometimes completely, though many patients do well and can manage this symptom with low-dose aspirin and statins, avoiding bypass surgery.
The management of cardiovascular sequelae conditions is different from atherosclerotic heart disease but there is little awareness in the adult cardiology community regarding the special challenges posed by cardiovascular sequelae of KD. For example, coronary artery aneurisms which can cause insufficient BP and myocardial ischemia in patients with KD history are associated with high risk of thrombosis (clotting) and stenosis (blocking or narrowing) at aneurism. These aneurisms are often highly calcified. In healthy individuals, narrowing of blood vessels can be treated with acetylcholine which induces vasodilation, however, in patients with cardiovascular sequelae from KD, the endothelium of the coronary artery demonstrates paradoxical vasoconstriction in response to this treatment, and thus treatment with acetylcholine is ineffective.
It is therefore crucial for cardiologists to be able to make retrospective KD diagnosis with their adult patients. Cardiologists should, therefore, be familiar with KD signs and symptoms. It is also advised that doctors question the patient's parents about KD-compatible illness. Imaging studies such as magnetic resonance can also be useful. The detection of calcification of the arterial wall at places of former aneurysms is a sign of KD antecedent. However, since the KD etiology remains unknown, no specific test can be conducted for a retrospective KD diagnosis.
KD disease remains enigmatic. To improve the care of patients with antecedent KD, more systematic studies are necessary to collect data about patient histories and outcomes. This will allow the formulation of a hypothesis about the appropriate care and their test under clinical studies.
Research by Dr. J. Burns, UC San Diego School of Medicine
Managing Adults With a History of Kawasaki Disease
1. If the adult DID NOT HAVE any coronary artery changes in childhood during the initial illness:
A. A one-time computed tomography (CT) calcium score is recommended to look for calcium deposition in the arterial wall. CT calcium score can assess coronary artery abnormalities with low radiation. The CT calcium score should be done at least 10 years after the acute disease.
B. An echocardiogram is recommended to evaluate wall motion, valve function, and aortic root internal diameter, which may be clues to more significant initial injury than was previously suspected. If these screening tests are normal, patients can be reassured.
No data is currently available regarding long-term outcomes. For young adults in their 20s and 30s, re-evaluation in 10 years is reasonable. No pharmacologic therapy is recommended.
2. Adults with initial ABNORMAL echocardiograms showing transient coronary dilation (enlargement of the coronary arteries), ectasia (distention), or aneurysms (a dilatation in the wall of an artery supplying blood to a specific area), patients should have the following investigations:
(1) coronary artery CT angiogram and calcium score as a baseline. If normal, then repeated studies are not indicated unless clinical status changes. Cardiac magnetic resonance angiography is another option for imaging the coronary arteries.
(2) Stress echocardiogram should be performed on all patients with persistent structural ABNORMALITIES of the coronary arteries. These patients should be followed at least annually by a cardiologist with repeat testing dictated by symptoms and functional status.
(3). If there is evidence for inducible ischemia, invasive angiography is indicated. (Inducible ischemia is a disease that occurs due to the restricted flow of the oxygen-rich blood to different parts of the body. Inducible ischemia mentions that the heart is receiving low oxygen levels and demanding more, causing pressure on the surrounding muscular regions. Inducible ischemia occurs when the artery becomes narrow for a short period)
(4) Aggressive management of traditional cardiovascular risk factors.
(5) Medical therapy: For patients with large aneurysms (>8mm), retrospective data from Japan strongly supports the use of systemic anticoagulation (treatment with anticoagulant drugs to reduce the risk of the formation of blood clots) in combination with antiplatelet therapy (drugs that decrease platelet aggregation and inhibit thrombus formation in the arterial circulation).
The combination of warfarin (international normalized ratio 2.0–3.0) and aspirin (81 mg/day) is traditional. There is very limited experience with the newer oral anticoagulants (direct thrombin inhibitors and factor Xa inhibitors) but these would seem to be reasonable alternatives.
(a) For patients with smaller aneurysms or remodelling of larger aneurysms, antiplatelet therapy is recommended. Aspirin (81 mg) or clopidogrel have traditionally been used.
(b) Statin therapy has theoretical benefits for patients with Kawasaki disease vasculopathy (disease affecting blood vessels) and they are recommended.
Both paediatric and adult cardiologists will need to work together to bridge this knowledge gap and to ensure the continuation of quality, evidence-based care for our Kawasaki disease patients.
Pregnancy after KD
Due to the relatively recent discovery of KD and lack of awareness of the disease, research into the effects of the disease during and following pregnancy is scarce and sample sizes in studies are generally small. All cardiovascular sequelae of KD pose risks to the mother during pregnancy, labour and delivery, and medications used to manage these conditions may pose risks to the foetus.
In the most recent study of 10 women with a history of KD, only one experienced an obstetrical complication of post-partum haemorrhage, which was possibly related to premature re-institution of heparin therapy after delivery (1). This highlights the need for more studies into the management of KD and associated cardiovascular sequelae in order to develop evidence-based guidelines for obstetricians to support the mothers and babies affected by KD.
Two women in this study delivered infants that developed KD at two and five months. Both mothers were unaware of the genetic component to susceptibility to KD and were unfamiliar with the characteristic clinical signs of KD because they had no personal memory of their illness in childhood. This underscores the need to improve knowledge of the disease’s genetic risk in people with history of the disease.
The study also reviewed reports of the management, delivery method and outcomes in 52 Japanese women with a history of KD. Obstetrical complications were reported in 9.7% of the deliveries including premature rupture of membranes, preterm labor, and post-partum hemorrhage. Cardiovascular complications were also reported in 9.6% of the women. Of the 72 infants, 63 were delivered at term and were healthy; two infants were delivered prematurely at 33 weeks by caesarean section due to maternal distress; five additional infants were born prematurely; two additional infants had congenital abnormalities consisting of ventricular septal defect (hole in the heart) and agenesis of the corpus callosum.
Some patients with a remote history of Kawasaki disease (KD) develop coronary artery aneurysms (abnormal dilatation of the coronary arteries) with associated risks of late medical problems.
If a patient with a remote history of KD has aneurysms, the computed tomography (CT) coronary artery calcium (CAC) scoring detects late CAC. Therefore, CAC scanning may be a useful tool to screen patients with a remote history of KD or suspected KD and unknown coronary artery status for aneurysms.
Coronary calcification was not observed in subjects with a history of KD who had normal coronary arteries by echocardiography during the acute phase.
Coronary calcification, which may be severe, occurs late in patients with coronary aneurysms.
Dr Kahn and colab. performed CT calcium volume scoring in 166 subjects (median age 19.5 years) with a remote history of KD (median interval from KD to CT 15.1 years).
From these 166 patients based on echocardiography the coronary arteries were:
- normal in 100 patients
- transiently (temporarily) dilated in 23 patients
- persistently (continuously) dilated in 10 patients
- remodelled aneurysm in 9 patients or,
- aneurysm in 24 patients
All subjects with coronary arteries classified as normal, persistently dilated, or remodelled aneurysm had zero CAC.
For subjects with aneurysms, 19 of 24 (79%) patients had calcification. Of the 5 subjects with aneurysms and zero calcification, four of the five were imaged within 6 years of KD onset.
CT images from a 28 year old male with a history Kawasaki disease (KD) at age 14 and coronary aneurysms. (A) Image from CT calcium scan demonstrating coronary calcification of the right coronary artery (arrows). (B) Curved oblique images from CT angiogram demonstrating a large fusiform aneurysm (arrows) of the right coronary artery.
This data provides strong evidence that patients with normal coronary arteries acutely do not develop late coronary artery calcium within three decades of the onset of KD and supports the concept that these patients have no evidence of coronary artery abnormalities.
Patients with a history of KD and coronary artery aneurysms virtually always develop late coronary artery calcification. The degree of calcification did not correlate with the interval since acute KD; however, calcification is a process that is often not detected in the first decade after disease onset.
Kahn AM, Budoff MJ, Daniels LB, Oyamada J, Gordon JB, Burns JC. Usefulness of calcium scoring as a screening examination in patients with a history of Kawasaki disease. The American journal of cardiology. 2017 Apr 1;119(7):967-71.
Watch this space for key updates and publications.
Technology and Tools We saw this and hope more doctors will make use of technology and tools like VisualDx so fewer cases of KD go misdiagnosed. This shows how difficult it can be for doctors to diagnose. “It’s one of those conditions where, if you’re not thinking of it, you’ll miss it. Doctors will say, ‘It’s a virus. It’ll pass’, but it’s one of the few conditions where kids can die of a major heart attack”.
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Kawasaki Parent Symposium
To hear more about the history of Kawasaki Disease, ongoing research, and patient experience - click on the video!