Afebrile Kawasaki disease with coronary artery dilatation
Pediatrics International (2017) 59, 375–377 doi: 10.1111/ped.13214
Brief Report
Afebrile Kawasaki disease with coronary artery dilatation
Atsunori Yoshino,1,2,3 Risa Tanaka,1,† Tadamasa Takano1 and Tsutomu Oishi1,‡
1Department of Microbiology and Immunology, Saitama Children’s Medical Center, Saitama City and Departments of
2Pediatrics and 3Nephrology, Koshigaya Hospital, Dokkyo Medical University, Koshigaya, Saitama, JapanAbstract Herein we describe the cases of two afebrile patients who were thought to have Kawasaki disease (KD). Patient 1 was a 7-month-old-Japanese girl. She presented with bulbar conjunctival injection, diarrhea, skin ery- thema, and redness around the bacillus Calmette–Guerin (BCG) inoculation site. Thirteen days after the first symptoms, ultrasonic cardiogram (UCG) showed dilatations of the bilateral coronary arteries (CA). The dilata- tions had completely resolved 5 months later. Patient 2 was a 13-month-old Japanese boy. He first presented with bulbar conjunctival injection and redness around the BCG inoculation site. Twenty-two days after the first symptoms, UCG indicated bilateral and peripheral CA dilatations. The mild dilatations of the proximal CA remained. Although fever is the principal symptom of KD, some incomplete KD patients may be afebrile. Although it is difficult to diagnose these patients as having KD, redness at the BCG inoculation site may be a clue to the diagnosis.
Key words afebrile, bacillus Calmette–Guerin, coronary artery dilation, heat shock protein, Kawasaki disease.
Since Tomisaku Kawasaki first identified the disease in 1967, fever has been the most important symptom in Kawasaki disease (KD).1 Although fever is not required for a diagnosis of KD in the Japanese guidelines (Table 1), it is indispensable according to the American Heart Associa- tion guidelines.2,3 Recently, many pediatric physicians have found that there are patients with incomplete KD who do not fulfill the diagnostic criteria and, moreover, there have been two Japanese reports of afebrile KD with coronary artery dilatation.2–7 Unfortunately, the risk of CA abnormali- ties in incomplete KD is not lower than that in complete KD.6
In this report, we present two afebrile cases of suspected KD with CA dilatation. To the best of our knowledge, this is the first case report of afebrile KD in the English-language literature. This study was approved and registered by the Bioethics Committee of Dokkyo Medical University (accept no., hosp-k27012), and informed consent to publish was obtained from the parents of both patients.
Correspondence: Atsunori Yoshino, MD, PhD, Department of Nephrology, Dokkyo Medical University Koshigaya Hospital, 2-1-50 Minamikoshigaya, Koshigaya, Saitama 343-8555, Japan. Email: ayoshino@dokkyomed.ac.jp
† Present address: Department of Pediatrics, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan
‡ Present address: Department of Pediatrics, Akitsu-ryoikuen,
Higashimurayama, Tokyo, Japan
Received 26 June 2016; revised 26 November 2016; accepted
29 November 2016.
Case reports
Case 1
A 7-month-old Japanese girl developed intermittent bulbar conjunctival injection 11 days before presentation. Three days before consult, she had watery diarrhea seven to eight times a day, but no nausea or vomiting. Two days before, she devel- oped non-pruritic and indolent disseminated skin erythema and redness around a bacillus Calmette–Gu´erin (BCG) inoculation site. One day before, she visited the local pediatric clinic and was referred to Saitama Children’s Medical Center because of high C-reactive protein (CRP, 9.19 mg/dL), platelet count
(PLT) 100.9 9 104/lL, and total white blood cell count (WBC) 12 900/lL.
When the patient visited the outpatient clinic, she had bul- bar conjunctival injection and slight redness around the BCG inoculation site. Her temper was very good. Her mother had checked her axillary temperature more than twice per day since the first appearance of symptoms, but she did not have a fever (<37.2°C) during this episode. In addition, her mother also said that she never felt fever when she touched and held her daughter.
The patient was admitted to the ward. Axillary temperature was 37.0°C. On blood examination, WBC was 14 300/lL with 54% polymorphs; PLT, 94.9 9 104/lL; erythrocyte sedimenta-
tion rate (ESR), 125 mm/h; and CRP, 9.43 mg/dL. Blood and
stool cultures were negative for any organisms, and chest radiography was normal. Electrocardiogram (ECG) showed a slight down-sloping ST segment only at the precordial lead (V1). Although she did not have a fever, KD was suspected.
376 A Yoshino et al.
Table 1 Diagnostic guideline for KD in Japan (2) (5th revised edition, February 2002, excerpt)
This is a disease of unknown etiology that primarily develops in infants and young children under 5 years of age. The symptoms can be classified into two categories: principal symptoms and other significant symptoms or findings.
A. Principal symptoms
1. Fever persisting for 5 days (including patients in whom fever has subsided before the fifth day in response
to treatment)
2. Bilateral conjunctival congestion
3. Oral cavity: reddening of lips, strawberry tongue, diffuse injection of oral and pharyngeal mucosa
4. Polymorphous exanthema
5. Changes of peripheral extremities: (acute stage) reddening of peripheral digitus or palms or soles and indurative edema; (convalescent stage) membranous desquamation
from fingertips
6. Acute non-purulent cervical lymphadenopathy
For the confirmation of diagnosis of KD, patients need to present with at least five of the listed six principal
symptoms. Patients presenting with four of the six principal symptoms, however, can be diagnosed with KD when they have coronary aneurysm or dilatation on 2-D echocardiography or coronary angiography.
B. Other significant symptoms or findings
The following symptoms and findings should be considered in the clinical evaluation of suspected KD.
1. Cardiovascular: auscultation (heart murmur, gallop rhythm, and distant heart sounds), ECG changes
(prolonged PR/QT intervals, abnormal Q wave, low-voltage QRS complexes, ST-T changes, and arrhythmias), chest
X-ray findings (cardiomegaly), 2-D echo findings (pericardial effusion and coronary aneurysms), aneurysm of peripheral arteries other than coronary (axillary), and angina pectoris or myocardial infarction
2. Gastrointestinal tract: diarrhea, vomiting, abdominal pain, enlargement of gallbladder, paralytic ileus, mild jaundice, and increasing of serum transaminase
3. Blood: leukocytosis with shift to the left, thrombocytosis, increasing of ESR, positive CRP, hypoalbuminemia, increasing of a2-globulin, and mild anemia
4. Urine: proteinuria and pyuria
5. Skin: redness and crust formation at the site of BCG inoculation, small pustules, and transverse wrinkles of the finger nails
6. Respiratory: cough, rhinorrhea, and abnormal shadow on chest X-ray
7. Joint: pain and swelling
8. Neurological: CSF pleocytosis, convulsion, consciousness disturbance, facial palsy, paralysis of the extremities.
BCG, bacillus Calmette–Gu´erin; CRP, C-reactive protein; CSF, cerebrospinal fluid; ECG, electrocardiogram; ESR, erythrocyte sedimentation rate; KD, Kawasaki disease.
Hence, we gave her 5 mg/kg/day aspirin. Ultrasonic cardio- gram (UCG) performed 2 days after admission showed dilata- tion of the bilateral CA of 3.9 mm and 4.3 mm in diameter (at right coronary artery [RCA] 1 and left coronary artery [LCA] 5; Z scores 7.4 and 8.0, respectively). On the third day after admission, bulbar conjunctival injection resolved. On the fourth hospital day, we treated her with 2 g/kg i.v. immunoglobulin (IVIG), 40 mg/kg/day aspirin, and 5 mg/kg/
day ticlopidine hydrochloride because CRP remained elevated. On the seventh day, CRP and WBC were decreased (0.7 mg/ dL and 9200/lL, respectively). On the ninth day, ECG showed a slightly upsloping ST segment on II, III, and aVf, and a downsloping ST segment on V1 and V2, which disappeared
3 weeks later. There was no elevation of cardiac enzymes. On the tenth day, the redness around the BCG inoculation site dis- appeared; there had also been no finger desquamation through- out the course of the disease. CA diameter increased to
4.1 mm (1) and 4.6 mm (5) on the ninth day (Z scores of 8.0 and 8.9, respectively). Five months later, RCA 1 was 2 mm and LCA 5 was 2.7 mm in diameter.
Case 2
A 13-month-old Japanese boy visited the pediatric physician 22 days before admission to hospital for bulbar conjunctival injection and redness around a BCG inoculation site. Axillary temperature was 37.4°C only once at this time; after that, he never had a fever in this clinic. His mother also continued checking his axillary temperature more than twice per day, but it remained lower than 37.0°C. His doctor carried out blood
tests 2 days later because of persistent symptoms. On exami- nation, WBC was 13 400/lL; PLT, 41.8 9 104/lL; and CRP,
0.63 mg/dL. The doctor referred him to us 6 days after presentation due to suspicion of KD.
At the first visit to the outpatient clinic, he had slight red- ness of his lips and hands. Axillary temperature was 36.8°C. WBC was 18 900/lL; PLT, 45.0 9 104/lL; and CRP,
0.75 mg/dL. ECG showed slightly deep, but not pathological
Q waves at II, III, aVf (0.4, 0.8 and 0.7 mm, respectively). UCG showed a normal CA and a small pericardial effusion. We diagnosed incomplete KD and treated the patient with aspirin (60 mg/day, 5 mg/kg/day). On his second visit 14 days
before admission, WBC was 14 800/lL; PLT, 41.7 9 104/lL;
and CRP, 0.45 mg/dL. The second UCG on this admission day, however, showed bilateral CA dilatations: RCA 1 mea- sured 3.8 mm in diameter and LCA 5 was 4.5 mm (Z scores of 5.8 and 7.2, respectively). ECG showed pathological deep Q waves at III, aVf (1.2 and 1.0 mm; 30% and 55% depth of QRS complex, respectively), which disappeared 4 days later. Consequently, he was admitted to the ward.
On the first hospital day, redness of the lips, hands, and around the BCG inoculation site had already disappeared. Blood tests indicated mild inflammation (WBC, 13200/lL;
PLT, 44.2 9 104/lL; CRP, 0.44 mg/dL), but no elevation of
cardiac enzymes. Blood and stool cultures were negative for any organisms. Aspirin dosage was increased to 450 mg/day (40 mg/kg/day) and he was started on 50 mg/day (4 mg/kg/ day) cyclosporin and 50 mg/day ticlopidine hydrochloride. We adjusted the dosage of the cyclosporin to maintain a trough blood range from 60 to 100 ng/mL. On the 21st day, WBC
was 10 500/lL; PLT, 46.4 9 104/lL; and CRP, 0.02 mg/dL.
On the 26th day, the diameters of RCA 1 and LCA 5 were 3.7 mm and 3.8 mm, respectively (Z scores of 5.6 and 5.3, respectively). Five months later, cyclosporin was
This is a disease of unknown etiology that primarily develops in infants and young children under 5 years of age. The symptoms can be classified into two categories: principal symptoms and other significant symptoms or findings.
A. Principal symptoms
1. Fever persisting for 5 days (including patients in whom fever has subsided before the fifth day in response
to treatment)
2. Bilateral conjunctival congestion
3. Oral cavity: reddening of lips, strawberry tongue, diffuse injection of oral and pharyngeal mucosa
4. Polymorphous exanthema
5. Changes of peripheral extremities: (acute stage) reddening of peripheral digitus or palms or soles and indurative edema; (convalescent stage) membranous desquamation
from fingertips
6. Acute non-purulent cervical lymphadenopathy
For the confirmation of diagnosis of KD, patients need to present with at least five of the listed six principal
symptoms. Patients presenting with four of the six principal symptoms, however, can be diagnosed with KD when they have coronary aneurysm or dilatation on 2-D echocardiography or coronary angiography.
B. Other significant symptoms or findings
The following symptoms and findings should be considered in the clinical evaluation of suspected KD.
1. Cardiovascular: auscultation (heart murmur, gallop rhythm, and distant heart sounds), ECG changes
(prolonged PR/QT intervals, abnormal Q wave, low-voltage QRS complexes, ST-T changes, and arrhythmias), chest
X-ray findings (cardiomegaly), 2-D echo findings (pericardial effusion and coronary aneurysms), aneurysm of peripheral arteries other than coronary (axillary), and angina pectoris or myocardial infarction
2. Gastrointestinal tract: diarrhea, vomiting, abdominal pain, enlargement of gallbladder, paralytic ileus, mild jaundice, and increasing of serum transaminase
3. Blood: leukocytosis with shift to the left, thrombocytosis, increasing of ESR, positive CRP, hypoalbuminemia, increasing of a2-globulin, and mild anemia
4. Urine: proteinuria and pyuria
5. Skin: redness and crust formation at the site of BCG inoculation, small pustules, and transverse wrinkles of the finger nails
6. Respiratory: cough, rhinorrhea, and abnormal shadow on chest X-ray
7. Joint: pain and swelling
8. Neurological: CSF pleocytosis, convulsion, consciousness disturbance, facial palsy, paralysis of the extremities.
BCG, bacillus Calmette–Gu´erin; CRP, C-reactive protein; CSF, cerebrospinal fluid; ECG, electrocardiogram; ESR, erythrocyte sedimentation rate; KD, Kawasaki disease.
Hence, we gave her 5 mg/kg/day aspirin. Ultrasonic cardio- gram (UCG) performed 2 days after admission showed dilata- tion of the bilateral CA of 3.9 mm and 4.3 mm in diameter (at right coronary artery [RCA] 1 and left coronary artery [LCA] 5; Z scores 7.4 and 8.0, respectively). On the third day after admission, bulbar conjunctival injection resolved. On the fourth hospital day, we treated her with 2 g/kg i.v. immunoglobulin (IVIG), 40 mg/kg/day aspirin, and 5 mg/kg/
day ticlopidine hydrochloride because CRP remained elevated. On the seventh day, CRP and WBC were decreased (0.7 mg/ dL and 9200/lL, respectively). On the ninth day, ECG showed a slightly upsloping ST segment on II, III, and aVf, and a downsloping ST segment on V1 and V2, which disappeared
3 weeks later. There was no elevation of cardiac enzymes. On the tenth day, the redness around the BCG inoculation site dis- appeared; there had also been no finger desquamation through- out the course of the disease. CA diameter increased to
4.1 mm (1) and 4.6 mm (5) on the ninth day (Z scores of 8.0 and 8.9, respectively). Five months later, RCA 1 was 2 mm and LCA 5 was 2.7 mm in diameter.
Case 2
A 13-month-old Japanese boy visited the pediatric physician 22 days before admission to hospital for bulbar conjunctival injection and redness around a BCG inoculation site. Axillary temperature was 37.4°C only once at this time; after that, he never had a fever in this clinic. His mother also continued checking his axillary temperature more than twice per day, but it remained lower than 37.0°C. His doctor carried out blood
tests 2 days later because of persistent symptoms. On exami- nation, WBC was 13 400/lL; PLT, 41.8 9 104/lL; and CRP,
0.63 mg/dL. The doctor referred him to us 6 days after presentation due to suspicion of KD.
At the first visit to the outpatient clinic, he had slight red- ness of his lips and hands. Axillary temperature was 36.8°C. WBC was 18 900/lL; PLT, 45.0 9 104/lL; and CRP,
0.75 mg/dL. ECG showed slightly deep, but not pathological
Q waves at II, III, aVf (0.4, 0.8 and 0.7 mm, respectively). UCG showed a normal CA and a small pericardial effusion. We diagnosed incomplete KD and treated the patient with aspirin (60 mg/day, 5 mg/kg/day). On his second visit 14 days
before admission, WBC was 14 800/lL; PLT, 41.7 9 104/lL;
and CRP, 0.45 mg/dL. The second UCG on this admission day, however, showed bilateral CA dilatations: RCA 1 mea- sured 3.8 mm in diameter and LCA 5 was 4.5 mm (Z scores of 5.8 and 7.2, respectively). ECG showed pathological deep Q waves at III, aVf (1.2 and 1.0 mm; 30% and 55% depth of QRS complex, respectively), which disappeared 4 days later. Consequently, he was admitted to the ward.
On the first hospital day, redness of the lips, hands, and around the BCG inoculation site had already disappeared. Blood tests indicated mild inflammation (WBC, 13200/lL;
PLT, 44.2 9 104/lL; CRP, 0.44 mg/dL), but no elevation of
cardiac enzymes. Blood and stool cultures were negative for any organisms. Aspirin dosage was increased to 450 mg/day (40 mg/kg/day) and he was started on 50 mg/day (4 mg/kg/ day) cyclosporin and 50 mg/day ticlopidine hydrochloride. We adjusted the dosage of the cyclosporin to maintain a trough blood range from 60 to 100 ng/mL. On the 21st day, WBC
was 10 500/lL; PLT, 46.4 9 104/lL; and CRP, 0.02 mg/dL.
On the 26th day, the diameters of RCA 1 and LCA 5 were 3.7 mm and 3.8 mm, respectively (Z scores of 5.6 and 5.3, respectively). Five months later, cyclosporin was
Afebrile KD with CA dilatation 377
discontinued. Eight months later, dilatation of the proximal RCA and LCA remained. In addition, he no longer had finger desquamation.
In both patients, no antibodies against Epstein–Barr virus (EBV) were present at admission (anti-viral capsid antigen IgG, IgM, IgA antibodies; anti-early antigen diffuse–restricted complex IgG, IgM, IgA antibodies; and anti-EBV nuclear antigen antibody on immunofluorescent complement-fixation assays). Antibody tests against Yersinia pseudotuberculosis were also negative. Neither patient had neurological abnormalities, muscle pain, hypertension, or urinary abnormalities during observation, nor did they have liver dysfunction or pyuria throughout the course.
Discussion
We have often encountered incomplete KD and have had diffi- culties with this diagnosis. Sudo et al.8 reported that the mor- bidity rate of incomplete KD was 20.0% among their 23 263 diagnosed cases in a Japanese nationwide survey. They also noted that incomplete KD involves a significant degree of CA abnormalities (13.1%), similar to complete KD (8.8%).There are six diseases that can cause CA abnormalities: KD; chronic active EBV; Yersinia pseudotuberculosis infec- tion; systemic juvenile idiopathic arthritis; Takayasu disease; and juvenile polyarteritis nodosa (J-PAN). In both of the present patients, there were no anti-EBV antibodies or anti- Yersinia antibodies, they had negative stool cultures for all organisms, no prolonged inflammation, no arthritis manifesta- tions, no wall thickening of the large vessel wall and did not fulfill the criteria for J-PAN. Both patients had redness around the BCG inoculation sites, and we believed that we could exclude systemic juvenile idiopathic arthritis, Takayasu dis- ease and J-PAN due to this manifestation.
Uehara et al.9 reported redness or crust formation at a BCG inoculation site in 49.9% of 15 524 KD patients; among these patients, >70% who had BCG redness or crust formation were between the ages of 3 months and 2 years. This important symptom may be related to one of the causes of KD, heat shock protein (HSP). Sireci et al.10 noted that the CD4 and CD8 T-cell clones from KD patients had cross-reactivity between the speci- fic epitopes of mycobacterial HSP65 and human HSP63. There- fore, this is a very specific symptom in KD patients aged
≤2 years old. Although redness around the BCG inoculation site is not a principal symptom for the diagnosis of KD, we believe that it may need to be included in the principal symptoms in order to help identify afebrile incomplete KD patients.
In conclusion, although reported cases are rare, the acknowledgement of these afebrile illnesses may be very important for clinicians, because patients with such conditions may not be accurately diagnosed. Hence, we recommend that the assessment of CRP, WBC, and UCG should be performed in all patients with redness around a BCG inoculation site.
Acknowledgment
We thank Editage (www.editage.jp) for English-language edit- ing.Disclosure
The authors declare no conflict of interest.Author contributions
A.Y. and T.O. contributed to conception, design, data acquisi- tion, analysis and interpretation, drafted the manuscript, and critically revised the manuscript. R.T. and T.T. contributed to conception and data acquisition, and critically revised the manuscript. All authors read and approved the final manu- script.References
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