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PEDIATRIC
RHEUMATOLOGY FOR THE GENERAL
PEDIATRICIAN
KAWASAKI DISEASE IN THE THIRD MILLINEUM:
A SYNDROME STILL AT
RISK TO BE UNRECOGNISED OR UNDERDIAGNOSED
FERNANDA FALCINI,
GIOVAN BATTISTA CALABRI, GABRIELE SIMONINI, ALBERTO VIERUCCI
Department of Paediatrics,
Rheumatology Unit, University of Florence, Cardiology Unit, A Meyer Children's
Hospital, Firenze Italy
Key word: Kawasaki disease
Running
head: Kawasaki disease in the third century
Correspondence
to:
Falcini
Fernanda, MD
Dipartimento
di Pediatria, Via Luca Giordano 13, 50132 Firenze, Italy
E-mail
falcini@unifi.it
Phone
+39 -055-5662913
FAX
+39-055-5662916
ABSTRACT
Kawasaki
Disease (KD) is a febrile systemic vasculitis complicated by coronary and peripheral
arterial aneurysms in 20% to 35% of untreated patients. It is reported as the commonest cause of
acquired heart disease in children in developed countries and may be a risk for
adult ischemic heart disease. Prompt diagnosis is critical and the early administration of intravenous
gammaglobulin (IVIG) dramatically reduces the rate of coronary abnormalities to
less than 5% of patients. Despite the numerous
efforts there is still no diagnostic test available for KD, and the diagnosis
is based on clinical criteria after the exclusion of other diseases presenting
with high unexplicable persistent fever.
Since several
conditions may mimic KD, the syndrome may be either unrecognised or under
recognised, with high risk of coronary alterations. Although
KD has been reported all over the world, it is overexpressed among Asian
populations, especially Japanese. In the future, a role of the genetic predisposition to KD will be
elucidated in order to recognise patients at risk to develop the disease and
the coronary complications. A challenge
for pediatricians facing children with high persistent fever is represented by
atypical onset or incomplete cases of KD who are at high risk to develop
coronary aneurysms (CAA) since they do not receive the appropriate treatment or
they do not receive it timely. Most of
CAA occurring during the acute phase of the disease regress within several
years; however, recent studies show that abnormal vascular wall morphology and
vascular dysfunction may persist at the site of regressed alterations despite
normal angiographic findings. In adult life premature atherosclerosis may
develop in these patients, with a risk for myocardial infarction. Smoking,
dietary fat and additional risk factors for atherosclerosis should be avoided,
and a long term follow-up into adult life by cardiologists is advisable.
No recent guidelines are available regarding
sports in children who suffered from KD; stress testings may need to be
performed even in absence of CAA, and strenuous athletics may need to be
discouraged.
This review will focus on the approach to the diagnosis and treatment of
KD; in particular, it should help pediatricians to recognise KD early in the
disease course in order to prevent coronary alterations, even in atypical and
incomplete cases, by early appropriate therapy.
INTRODUCTION
In 1967 Tomisuku Kawasaki described
in Japan the first 50 patients affected with a disease characterised by high
fever, cervical lymphoadenopathy, conjunctival injection, red tongue, fissured
lips, erythema and swelling of hands and feet followed by periungueal digital
peeling. The association of these clinical manifestations, initially called
mucocutaneous lymph node syndrome (1), is now recognised as Kawasaki disease
(KD), the most common systemic vasculitis in childhood after Henoch-Schoenlein
purpura (2).
After the first descriptions, it became evident that patients with KD are at risk to develop coronary involvement if they do not receive the appropriate treatment with intravenous high dose gammaglobulin (IVIG) and aspirin (3-5). In fact, KD is a systemic vasculitis complicated by coronary and peripheral arterial aneurysms in 20% to 35% of untreated patients, and by myocardial infarction (5). It is now reported as the most common cause of acquired heart disease in children living in developed countries (2) and may be a risk for adult ischemic heart disease (6, 7, 8). Prompt diagnosis is critical and the early administration of IVIG dramatically reduces the rate of coronary abnormalities to less than 5% of patients (4, 5). Despite the numerous efforts there is still no diagnostic test available for KD, and the diagnosis is based on clinical criteria after the exclusion of other diseases presenting with high persistent fever (9).
Since several conditions may mimic KD,
particularly toxic shock syndrome, staphylococcal scalded skin syndrome,
infection with parvovirus, Epstein-Barr virus, cytomegalovirus, adenovirus,
enterovirus, and rickettsiae, the syndrome may be either unrecognised or under
recognised. In these cases IVIG are not administered or they are given more
than ten days after the onset of fever with high risk of coronary damage (5,
10).
Some cases of KD have been resistant to the first
infusion of gammaglobulin and benefit from a second and third infusion (11,
12). In these patients other diseases such as polyarteritis nodosa, systemic
onset juvenile idiopathic arthritis and malignancy have to be excluded. Moreover, several patients with severe KD do
not respond to IVIG and require either corticosteroids (13, 14) or
immunosuppressive drugs (14, 15). However, the role of steroids in KD is still
controversial.
EPIDEMIOLOGY
Although KD has been reported all over the world, the
disease is overexpressed among Asian populations, especially Japanese. Nationwide
epidemiological surveys indicate that the number of KD patients has gradually
increased in Japan since the last 1960s, with three epidemics in 1979, 1982, and 1986. Hospital surveillance
data suggest that the incidence of KD in Japan has risen by over 50% between
1987 and 1998. The annual attack rates are 120 to 150 cases per 100,000
children under 5 years, with 6000-8000 new cases annually (16). In US
Caucasians the attack rate is 4 to 15 cases per 100,000 (17). In Europe the
annual reported incidence ranges from 3 to 8 per 100,000 children under 5 years
(18). A recent analysis of hospital admission data in England shows that the
incidence of KD among English children has increased between 1991 and 2000
(19). It is possible that this reflects
an increase in recognition rather than incidence. In Italy the epidemiology of
KD is not fully known, since only few data from single Pediatric Units are
available (20).
CLINICAL
MANIFESTATIONS
The typical manifestations of KD are high fever
lasting more than 5 days without reasonable explanation and unresponsive to
antibiotics plus i) bilateral non
exudative conjunctivitis; ii) polymorphous exanthemata; iii) bilateral non
suppurative cervical lymphoadenopathy (at least one lymph node larger than 1.5
cm); iv) mucous membrane changes (i.e. injected or fissured lips, redness of
pharynx, strawberry-like tongue) (Figure 1) and v) extremity changes (e.g. erythema of palms and soles, edema of the hands and feet, periungueal digital
peeling (Figure 2). Fever of five days duration plus four of the five remaining criteria or the presence of fever and
coronary artery aneurysms (CAA) detected on 2D- echocardiogram with three
additional criteria are needed for the diagnosis of complete KD (Table 1).
Patients with high fever and fewer of the required
clinical findings are labelled "incomplete" cases. It has been reported that
infants can present CAA without developing the classic diagnostic criteria,
supporting the evidence that the disease is often under recognised or
misdiagnosed (21). The management of
less typical presentations of KD is controversial and guidelines are lacking.
Other patients can display an atypical onset of the
disease, such as acute surgical symptoms, meningeal irritation, joint
involvement, or lymphoadenopathy not responding to the appropriate antibiotic
therapy. These presentations often delay the diagnosis (22-25). These cases are
defined "atypical". Over time several "incomplete" or "atypical" KD patients
develop the lacking prerequisite clinical criteria, therefore confirming the
diagnosis. Cervical lymph nodes enlargement, a diagnostic criterion for KD, in
a few patients may be the only clinical manifestation associated with a
prolonged fever. Tashiro et al. performed an ultrasonographic evaluation of
cervical lymph nodes in KD patients and found different features in comparison
to bacterial lymphadenitis; the authors concluded that echocardiography could
identify KD at an early stage of the disease (26).
The eye findings in KD could play a role in the
earlier diagnosis and treatment; the presence of iridocyclitis and
conjunctivitis can provide additional support to the diagnosis in patients with
incomplete KD. Ocular evaluation should be included as a part of the work-up of
any suspected patient. Burns et. al reported asymptomatic anterior uveitis in
approximately three quarters of children with KD (27). It is usually mild and bilateral, sometimes
associated with keratic precipitates, and resolves within 2-8 weeks without any
sequelae. Slit-lamp examination may be useful in helping to differentiate KD
from diseases that closely mimic the condition, such as streptococcal and
staphylococcal toxin-mediated diseases and drug reactions.
Atypical cases of KD are common (up to 10% of the
total) and the diagnosis should be considered even without the full complement
of diagnostic criteria. The risk of coronary damage is high if IVIG is not
administered or is given after ten days from disease onset. In a large study
from Hsieh et al., no differences were found in the age distribution, sex, and
rate of coronary artery involvement between typical and atypical Kawasaki
disease. At follow-up, patients with coronary arterial lesions had a prognosis
as good as those with typical KD if they had received IVIG on time (28).
According to these observations, atypical cases may be considered part of KD
and likely occur via the same pathogenesis, but have incomplete clinical
manifestations.
KD is rare in neonates (29), but if it occurs, it may
follow a rapid and severe course (30). Infants may often present as atypical
cases and commonly experience very severe inflammatory changes, especially
vasculitic signs. In several cases, despite aggressive treatment with IVIG,
aspirin, corticosteroids and antithrombotics, fatal outcome has been reported
(30, 31).
Digital peeling, a useful diagnostic hint, usually
occurs 10-15 days from the onset of typical fever even in children who had
received IVIG. A long- term follow-up of patients with KD has reported
recurrent episodes of skin peeling for several years after the disease
recovery. This event does not signal a recurrence of the disease and does not
require expensive re-treatment with IVIG. It has been reported only in patients
with complete KD and its significance and mechanisms are still unknown. It may
be also be
Since the clinical criteria of KD present
sequentially, and often the interval between the appearance of fever and the
development of all clinical manifestations may be longer than 1 to 2 weeks, it
often is a diagnostic dilemma for the clinician. Other causes of the
non-specific symptoms can be difficult to exclude. In these patients KD should
be suspected in the presence of high fever of unknown origin lasting more than
4 to 5 days, and IVIG should be administered even before diagnostic criteria
are satisfied. A sign that could help physicians in the diagnosis, even though
it is not included in the diagnostic criteria, is the irritability present in
the majority of children with KD that can be related to aseptic meningitis (2).
Recently, Brogan et al reported the appearance of erythema and induration at
sites of BCG immunizations as a useful early diagnostic sign. (34).
Other minor criteria in KD include: arthritis that
usually develops in the convalescent phase, urethritis, aseptic meningitis,
pneumonitis, otitis media and gastroenteritis. Jaundice and hydrops of
gallbladder are relatively uncommon, and abdominal ultrasound may be helpful in
detecting this complication. Though unusual, this acute phase complication may
support the diagnosis of atypical or incomplete KD (23). Neurological
manifestations,
such as febrile seizures or encephalopathy, may be the presenting
features of the disease (24).
ETIOLOGY
Despite numerous studies, the cause of KD remains unclear. The role of an infectious trigger, inducing the disease in a genetically susceptible host, is still strongly suggested by the epidemiology of the disease in Japanese and North American epidemics that resembles the spread of viral or bacterial infections. The role of one or more superantigens, capable of stimulating large numbers of T-cells, produced by certain strains of Staphylococcus or Streptococcus has been discussed in the aetiology of KD with no general consensus. A recent report from Leung et al. that studied the prevalence of superantigen secreting bacteria in children with KD did not find a significant difference between patients and controls with other febrile illnesses (35). However, future studies should further examine the potential role of Vβ2-stimulatory superantigens in KD. The role of climate, ethnicity and socio-economic status has been recently discussed (36), and a different disease outcome according to the patient ethnic group has been suggested (36,37).
Since KD is overrepresented in Japan
and among Americans of Japanese descent, a genetic predisposition needs to be
better investigated.
Pro-inflammatory
cytokines, including TNF-α, play a pivotal role in the pathogenesis of
coronary alterations (38) and the cytokine response to an inflammatory stimulus
is influenced by genetic polymorphisms (39). In the future, genotyping might
identify children at higher risk to develop coronary alterations, who therefore
require a closer monitoring and a more aggressive therapy in order to prevent
cardiac injury (40).
LABORATORY FINDINGS
Laboratory findings are not specific of KD and are
shared by other acute inflammatory febrile diseases. Early in the course of
illness all parameters of inflammation are increased, namely erythrocyte
sedimentation rate (ESR), C-reactive protein (CRP), white blood cell (WBC) and
neutrophil counts. Platelet (PTL) count is normal in the acute phase and
markedly increases at the end of the second week reaching as high as
1,000,000/mm3. Occasionally a low
platelet count may be detected in the acute phase, as well as neutropenia. A
moderate-high increase of serum concentration of liver enzymes may occur in the
early stage, unrelated to aspirin administration. Urinalysis may show
leukocytes and erythrocytes but no bacteria. CSF contains increased numbers of
WBC, mainly lymphocytes, as expression of aseptic meningitis.
Lipid profile alterations occur in the early phase
including decreased levels of high-density lipoprotein (HDL), and cholesterol,
and increased levels of tryglicerides. Several authors report the persistence
of low HDL levels over
months to years, and after the acute phase, and hypothesise a
correlation with CAA (2)
CARDIAC INVESTIGATIONS
All children with typical or suspected KD have to be closely monitored
by electrocardiogram (EKG) and two-dimensional echocardiography (2D-echo). The
EKG may reveal arrhythmia, myocardial dysfunction and ischemia. 2D-echo is
useful in detecting coronary artery dilation and aneurysms. Ultrasound may
reveal aneurysms and other changes in peripheral arteries.
Cardiac monitoring includes 2D-echo at onset and six
to eight weeks after onset of the disease. However, in order to detect possible
coronary alteration not observed at the first evaluation, a third 2D-echo study
at 14 days has also been suggested. In patients with CAA, close followup by
echocardiography is mandatory in order to evaluate the size of aneurysms and to
detect the formation of thrombus.
EKG and 2D-echo studies need to be tailored to single
patient depending on the size of CAA (9).
Children with giant aneurysms (diameter
greater than 8 mm) require stress testing to define myocardial function.
Because of the risk of coronary stenosis in these patients, coronary
angiography is also recommended (42). Cardiac monitoring reveals that about 50%
of mild CAA normalise within two years, while 5-year follow-up
shows a complete regression of all CAA. Unfortunately, giant aneurysms
persist in most patients over time and may evolve in severe stenosis,
myocardial infarction, and even death (43). The mortality rate has completely
changed after the introduction of IVIG, and in Japan it is reported as low as
0.14 %.
THERAPY
The current treatment in any patient with definite or
suspected KD includes aspirin and IVIG. The use of these drugs together for KD
has unequivocally reduced the occurrence of CAA. The prevalence of coronary
artery abnormalities is dependent on IVIG dose but independent from that of aspirin
(44). The optimal dose of IVIG is 2 g/Kg given as a single infusion over 8-12
hours. In infants with cardiac compromise a single infusion in divided doses
over several days may be more appropriate.
IVIG should be administered as soon as the disease is
suspected and if all possible within the first 10 days from the onset of fever.
However, in the presence of persistent signs of inflammation, IVIG may have to
be given in patients who are diagnosed later than 10 days from onset. In most
children the fever drops either during IVIG infusion or few hours after. In
those children who do not respond to the initial infusion of gammaglobulin
and present persistent fever or disease recrudescence, a second and
third cycle may be required (11, 12, 14).
In the small group of non-responders to IVIG,
corticosteroids may be considered, even though their use is still controversial
(14, 45, and 46). Pulse methylprednisolone has been reported to be effective in
KD refractory to initial gammaglobulin treatment (47).
A long-term low dose aspirin treatment is required in
children with coronary alterations. The therapy should be continued until
normalisation of aneurysms is noted. Life-long low dose aspirin therapy may be
advisable if these cardiac changes persist. In children with aspirin intolerance,
another
antiplatelet agent may be used to prevent the formation of thrombi such
as dypiridamole (2-3 mg/Kg) (42).
In patients with giant aneurysms the addition of warfarin to aspirin has been suggested, but there is no general agreement on this subject. As the early phase of warfarin administration is sometimes associated with a paradoxical prothrombotic state, intravenous heparin is advisable for a short period (48).
Nonetheless, as reported by a recent
multicenter collaborative study performed in Japan, even with the use of prompt
IVIG treatment, coronary disease is common in a minority of KD patients
(49-51). Oki et. al found a prevalence of cardiac sequelae due to KD of 10.2%
one month after onset, and of 4.2% after one year (52).
FLORENCE DATA
Our
experience on KD began in 1980 when the first two children in our region of
Tuscany, Italy were recognised with the typical manifestations of the disease.
Since 1980 another 157 patients have been observed. In our cohort the male to female ratio is 1.8 to 1 (101 M, 58 F),
with a median age at diagnosis of 29 months. The majority of cases occurred in
children younger than 5 years, with the youngest patient aged 51 days and the
oldest 24 years. The seasonal
distribution shows that 48 cases occurred in autumn, 46 in
winter, 39 in spring and 26 in summer. Patients have been followed for a mean period of 3 years (range, 3 - 216 months).
One hundred and twenty-one out of 159 patients (76.1%) fulfilled the criteria for diagnosis, while 38 (23.9%) had typical high fever and coronary aneurysm detected on 2D-echocardiogram plus two other clinical criteria. Eight children (5.1%), 5 boys and 3 girls, had an atypical onset of KD: acute gastrointestinal symptoms resulting in surgical intervention in two, aseptic meningitis was seen in four, and isolated lymphadenopathy not responding to wide spectrum antibiotics in two. All these patients fulfilled the criteria for KD later during the disease course.
The majority of our cases, 139 out of 159 (87.3%), received aspirin (50-80 mg/Kg/day during the acute phase of the disease, and 3-5 mg/Kg/day thereafter). IVIGs was administered (400 mg/Kg/day for 5 days, 18 patients, and 2 g/Kg in a single infusion, 121 patients) from day one to day 51 from the onset of fever (mean day 8). All children who did not receive IVIG therapy were diagnosed before the introduction of gammaglobulin in the standard treatment of KD. Five patients received two cycles of IVIG for the persistence of high fever and severe coronary damage, and all had a prompt amelioration of both systemic features and coronary dilatation. None of our patients required steroids for the control of the disease.
Echocardiographic evaluation of the coronary arteries has been performed in all patients at presentation, and at 2, 4 and 8 weeks after the onset of clinical symptoms, and follow-up at 6 to 12 months. Patients with coronary abnormalities were followed up to the echocardiogram normalisation; patients with normal echocardiograms at 2-month follow-up did not present alterations at subsequent evaluations.
Coronary artery abnormalities, including ectasia (lumen diameter > 2.5 mm in a child < 5 years), and aneurysms (lumen diameter at least 3.5 mm in a child < 5 years and 4 mm in a child ≥5 years) were observed in 30 (18.8%) out of 159 children; 21 were males and 9 females, with 2 children, one infant of 4 month and 1 boy aged 5 years, developing giant aneurysms (lumen diameter > 8 mm).
Mean fever duration, ESR and CRP values in patients with CAA were not different from the whole group, whilst baseline hemoglobin levels were lower with CAA than in patients not developing coronary alterations. IVIG had been administered in 28 out of 30 patients with coronary abnormalities. The day of administration of IVIG was not different in the children with coronary abnormalities than in the whole group. Other cardiac complications were pericardial effusion detected in 21 patients, and ECG conduction alterations in 10 patients.
The disease course was typical in the majority of our children and the outcome was favorable. Only a four month old infant had a fatal outcome as he developed cardiac arrest and myocardial infarction seven weeks after the onset of fever. 2D-echocardiogram revealed giant aneurysms in both coronary arteries. In this baby KD was not initially suspected and IVIG was only administered at admission in the Intensive Care Unit, 40 days from fever onset. In most of the patients coronary abnormalities normalised in a period ranging from 6 months to 1 year; only in 8 patients did they last more than one year, and in 4 the lesions were permanent, even though the lumen diameter of the aneurysm decreased.
CONTROVERSY AND CHALLENGES
Despite the numerous efforts to improve the early diagnosis, KD remains a disease at risk to be under recognised or misdiagnosed with other febrile illnesses in young children. Since no diagnostic tests are available, the diagnosis of KD is still based on clinical criteria. The atypical onset and the incomplete cases represent a major challenge for pediatricians.
Even though the early administration of IVIG has dramatically reduced the rate of coronary abnormalities to less than 5 %, KD is still the most common cause of acquired heart disease in children living in UK and the USA, and represents a risk for adult ischemic heart disease. Moreover, a considerable proportion of children with acute KD do not respond to standard therapy with IVIG, and 10% - 30 % of children have fever for 72 hours or more after the initial therapy with IVIG. At onset it is impossible to distinguish IVIG responders from non-responders, as both may have similar demographic and clinical characteristics, initial cardiac involvement, and overall outcomes (49-53).
There is still debate about the appropriate treatment of children who are unresponsive to the first treatment with IVIG. While there is general agreement that gammaglobulin significantly reduces the risk of cardiac complications compared with aspirin only as initial treatment, additional administration of IVIG do not appear to be highly effective against persistent or recurrent fever, even though they have be shown to be safe. In contrast, corticosteroids seem to be more effective in the control of fever when compared to IVIG. Previous studies suggested that children who received corticosteroids and aspirin as initial treatment may have an increased risk of developing CAA. Recently the use of corticosteroids is being revaluated as an optional therapy in non-responders to IVIG. A very intriguing topic is the role of different parameters on the risk of developing coronary disease. Although no definitive data have been obtained; determinants of the risk of coronary aneurysms have been considered longer duration of fever, lower IgG levels, higher IgA levels, and a lower hemoglobin value after IVIG infusion (52, 53).
Even after IVIG introduction, KD remains a disease with high morbidity. In a recent study from Nakamura et al., the mortality among persons with a history of Kawasaki disease and cardiac sequelae in Japan was higher than in normal population (6). An improved understanding of the etiology of this disease and a clearer definition of the possible predictors of coronary involvement are needed to better control coronary damage (51).
Therefore, pediatricians have to be
extremely cautious when facing young children with persistent high fever, red
lips and irritability. If KD is not recognised early, the child may not receive
the effective early therapy and may develop coronary alterations that in some
cases may be severe and irreversible, leading to myocardial infarction or giant
aneurysms. Conversely, if KD is diagnosed in a child with another disease, the
appropriate treatment for the unrecognised disease is delayed and costly
diagnostic and therapeutic interventions may be performed. The high-risk groups
for coronary artery disease are infants younger than 6 months of age, and older
children with very high platelet count, high ESR and fever lasting for more
than 2 weeks.
CONCLUSION
Pediatricians have to be very aware of KS when facing a child with persistent high fever of unknown origin, red lips and irritability. In many cases the diagnosis represents a diagnostic dilemma, in particular in neonates and older children. However, the high risk of coronary alterations obligates early and aggressive introduction of the appropriate treatment even in those patients who do not fulfill the diagnostic criteria. The atypical onset or incomplete cases of KD present a special and difficult challenge for pediatricians caring for children with high persistent fever. One clinical tip that could help in the diagnosis is the irritability present in the majority of children with KD.
It has been reported that
most of coronary aneurysms occurring during the acute phase of the disease
regress within several years. Yet
recent studies show that abnormal vascular wall morphology and vascular dysfunction may persist at the site of regressed alterations despite normal angiographic findings (54, 55). The long-term prognosis and natural history of KD remain uncertain. In adult life premature atherosclerosis may develop in these patients, with a risk for myocardial infarction. Smoking, dietary fat and additional risk factors for atherosclerosis should be avoided. Cardiologists should follow KD children with CAA well into adult life.
No recent guidelines are
available to use to counsel parents and children about sports in children who
suffered from KD. Lacking guidelines, it may be prudent to perform stress
testing even in absence of CAA and consider avoidance of strenuous athletics.
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Legends
Figure
1. The picture shows typical bilateral
conjunctivitis and red lips in a four-year old boy with Kawasaki Disease.
Figure
2. Digital peeling in a 18-moth old boy
with typical Kawasaki Disease.
TABLE 1
| KAWASAKI DISEASE: DIAGNOSTIC CRITERIA | |
| Fever | Duration of 5 days or more plus 4 of the following |
| 1. Conjunctivitis | Bulbar, non-suppurative, bilateral |
| 2. Lymphadenopathy | Cervical >1.5cm |
| 3. Rash | Polymorphous, non vesicles or crusts |
| 4. Changes of lips or oral mucosa | Red cracked lips; "strawberry tongue; diffuse erythema of oropharynx |
| 5. Changes of extremities | Initial stage: erythema and oedema of palms and soles
Convalescent stage: peeling of skin from fingertips |
Kawasaki
disease may be diagnosed with fewer than 4 of these features if coronary artery
aneurysms are detected