Case number 1
A 9-month-old Caucasian girl presented to our pediatric unit with fever, pallor, bilateral non-secreting conjunctivitis, and rash. Anamnestic records revealed that 12 days before she had remittent fever, which spontaneously resolved in 5 days. Fever started again after 3 days, associated with pharyngitis, and, later, with cervical adenopathy, diarrhea, and vomiting. She was treated with amoxicillin plus clavulanic acid and steroids, without defervescence. At admission, 9 days after fever onset, she showed fever, conjunctivitis, pharyngitis, generalized rash, and bilateral cervical adenopathy. Hematological parameters revealed: leukocytes, 18,000/mm3 with neutrophils of 8520/mm3, lymphocytes of 6250/mm3, and monocytes of 1930/mm3; hemoglobin, 9.1 g/dl; platelets, 318,000/mm3; and transaminases, albumin, natremia, and urine analysis in the normal range. Her C-reactive protein (CRP) was 2.31 mg/dl; her erythrocyte sedimentation rate (ESR) was 120.
An electrocardiogram (ECG) and echocardiography were normal, including coronary
Z-scores. IgM and IgG against Epstein–Barr virus, cytomegalovirus, and parvovirus were tested, and she showed positive IgM against parvovirus. This was confirmed at further testing after 10 days. She was treated with clarithromycin and obtained quick defervescence. A diagnosis of parvovirus infection with severe anemia was made. For this reason and because of the prompt defervescence, it was exclusively treated as a viral infection. During follow-up, further cardiologic evaluation was done because of the risk of pericarditis secondary to the parvovirus infection, and at day 26 after fever onset, CAL were documented, with: a proximal right coronary artery
Z-score of 6.02; left main coronary
Z-score of 5.72; and left anterior descending
Z-score of 5.78. Coronary artery
Z-scores are commonly used for decisions in KD management and decisions on treatment, even if
Z-scores show variations based on the
Z-scores formula used for larger coronary artery dimensions [
5]. However, the
Z-score value for CAL is useful for the follow-up of a patient and for testing the response to treatment.
The child was promptly treated with IVIG at the dosage of 2 g/kg plus acetylsalicylic acid (ASA) at the dosage of 5 mg/kg per day. Despite treatment, a further echocardiographic evaluation showed worsening of CAL: proximal right coronary artery Z-score of 5.93; left main coronary Z-score of 5.63; and left anterior descending Z-score of 5.39, which showed a saccular aneurysm of 2.9 mm of diameter (Z-score of 5.08).
A laboratory test did not show inflammation, but the girl was treated with three bolus doses of intravenously administered methylprednisolone at 30 mg/kg per dose. The
Z-score of CAL did not change. Informed consent by parents was obtained, and our patient was treated with anakinra at the dosage of 4 mg/kg per day. She showed a progressive improvement of CAL and after 25 days of anti-IL-1 treatment, her proximal right coronary artery
Z-score was 0.93, left main coronary
Z-score 4.02, and left anterior descending
Z-score 2.93. Treatment was continued for 2 months, at which point
Z-scores normalized (see Table
1).
Table 1
Coronary artery lesions (Z-scores) substantial improvement during anakinra treatment
Before IVIG | 3.5 | 5.93 | 3.6 | 5.63 | 3.1 | 5.40 |
Before anti-IL-1 | 3.5 | 5.93 | 3.6 | 5.63 | 3 | 5.39 |
T = 4 days after anti-IL-1 | 3.5 | 5.93 | 3.6 | 5.63 | 3 | 5.39 |
T = 25 days after anti-IL-1 | 1.8 | 0.93 | 3.05 | 4.02 | 2.22 | 2.93 |
T = 40 days after anti-IL-1 | 1.8 | 0.93 | 2.9 | 3.46 | 2.2 | 2.77 |
T = 71 days after anti-IL-1 | 1.6 | 0.27 | 2.5 | 2.19 | 1.8 | 1.43 |
The first diagnosis in this patient was a parvovirus-related infection, which explained the clinical manifestations and the clinical course of the disease. The diagnosis of KD was reached late; a control echocardiogram showed CAL. Mild CAL are described in systemic juvenile arthritis, in febrile diseases, and in infectious diseases such as Mediterranean spotted fever [
6]. Aneurysms, conversely, are typical of KD.
IVIG did not arrest the worsening of CAL, which were stabilized after three doses of methylprednisolone. However, our patient received IVIG 26 days after the fever started and this delay can explain the poor response. In fact, a delay in IVIG infusion is recognized as a risk factor for non-response to first-line treatment, as demonstrated in our population [
6,
7].
Case number 2
A 7-year-old Caucasian boy, the brother of Case number 1, presented fever (38 °C) and vomiting at the same time as his sister, which spontaneously resolved after 4 days. Four days later, he again had fever, abdominal pain, tachycardia, and tachypnea. He was admitted to our cardiologic unit. He showed pallor, tachypnea, stasis at the pulmonary bases, tachycardia (180 beats/minute), gallop rhythm, hypotension, and secondary anuria hepatomegaly with pain at palpation. Hematological tests evidenced: leukocytes of 24,680/mm3 with neutrophils of 19,744/mm3, lymphocytes of 3430/mm3, and monocytes of 960/mm3; hemoglobin, 10.4 g/dl; platelets, 632,000/mm3; CRP, 0.24 mg/dl; aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase (gamma-GT) in the normal range; creatine phosphokinase (CPK), 773 mg/dl; creatinine, 0.77 mg/dl; and blood urea nitrogen (BUN), 111 mg/dl. He had elevated myocardial necrotic enzymes (c-troponin T, 91.4 ng/l) and pro-brain natriuretic peptide (BNP) > 70,000.
An echocardiogram revealed that the left ventricle had a normal diameter (telediastolic diameter, 40 mm;
Z-score, 0.37) and generalized hypokinesia, with a severe reduction of the ejection fraction (EF) (20–25%); the left atrium was dilated (diameter, 35 mm;
Z-score, 3.3) and the mitral valve had a moderate insufficiency. The right ventricle had normal dimension; the tricuspid valve showed a moderate insufficiency. His suprahepatic veins were dilated. No pulmonary hypertension was documented. He received dopamine (5 gamma/kg per minute), dobutamine (7 gamma/kg per minute), furosemide (1 mg/kg) plus steroids (2 mg/kg). Clinical signs, echocardiographic parameters, and plasmatic enzymes showed a progressive but slow improvement. Sixteen days later, his EF was 45%; however, a persistent septal hypokinesia was documented. He continued to receive treatment with furosemide and enalapril. Specific serological tests were performed to exclude Epstein–Barr virus (for the skin rash, associated with fever and hepatic cholangitis) [
8] and coxsackie virus infection (for fever and myocarditis) [
9]. A nasal swab for influenza and parainfluenza virus was negative. However, the index case of the sister suggested we should run a serology test for anti-parvovirus, and we found increased IgM anti-parvovirus with low IgG.
A cardiologic follow-up revealed: a further EF improvement (50%); left ventricle was 38 mm (normal value: 32.7–45.5); Z-score, 0.15. His right atrium and ventricle were in the normal range for diameters and kinesis.