Genetic epistasis between killer immunoglobulin-like receptors and human leukocyte antigens in Kawasaki disease susceptibility.

Kawasaki disease (KD) is a pediatric acute multisystemic vasculitis complicated by development of coronary artery lesions. The breakthrough theory on KD etiopathogenesis points to pathogens/environmental factors triggered by northeastern wind coming from China. Natural Killer cells and T lymphocytes express the inhibitory/activating Killer Immunoglobulin-like Receptors (KIR) to elicit an immune response against pathogens by binding to human leukocyte antigens (HLA) class I epitopes. We first report on the role of KIR/HLA genetic epistasis in a sample of 100 Italian KD children. We genotyped KIR, HLA-A, HLA-B and HLA-C polymorphisms, and compared KD data with those from 270 Italian healthy donors. The HLA-A*11 ligand for KIR2DS2/2DS4/3DL2 was a KD susceptibility marker by itself (odds ratio (OR)=3.85, confidence interval (CI)=1.55-9.53, P=0.004). Although no epistasis between HLA-A*11 and KIR2DS2/S4 emerged, HLA-A*11 also engages KIR3DL2, a framework gene encoding for a pathogen sensor of CpG-oligodeoxynucleotides (CpG-ODN), and KD blood mononuclear cells are actually prone to pathogen CpG-ODN activation in the acute phase. Moreover, carriers of KIR2DS2/HLA-C1 and KIR2DL2/HLA-C1 were more frequent among KD, in keeping with data demonstrating the involvement of these HLA/KIR couples in autoimmune endothelial damage. The highest KD risk factor was observed among carriers of KIR2DL2 and two or more HLA ligands (OR=10.24, CI=1.87-56.28; P=0.007).

Clinical characteristics and cardiac outcome of acute rheumatic fever in Italy in the last 15 years.

OBJECTIVE: To analyze clinical characteristics, cardiac outcome and response to therapy of an Italian pediatric population affected with acute rheumatic fever (ARF) in the last 15 years. METHODS: 135 patients with ARF (aged 2-14.9 years, mean 8.4+/-2.5 years) diagnosed from 1992 to 2006 at the Pediatric Rheumatology Centre of the University of Milan (Italy) were retrospectively reviewed. All patients underwent physical examination, laboratory evaluation, electrocardiogram and echocardiography. Patients were divided into 2 groups: group 1 - patients with complete adherence to updated Jones criteria (107 patients), and group 2 - exceptions (28 patients). Echocardiographic criteria were used to confirm the presence of carditis and to evaluate severity of mitral (MR) and aortic regurgitation (AR) at diagnosis and after treatment with steroids or acetylsalicylic acid (ASA)/non-steroidal anti-inflammatory drugs (NSAIDs). RESULTS: We observed a persistence of ARF in the last 15 years (mean 9 new cases/year with a peak of 19 cases in 2000). Carditis and arthritis were the main major criteria observed (102/135 and 71/135 patients respectively), then chorea (29/135), erythema marginatum (8/135) and subcutaneous nodules (1/135). Arthritis and chorea resolved completely with various therapies. At the last follow-up (> or =5 years) in group 1, loss of MR was observed in 46% steroid-treated (26/56 cases) and in 39% ASA/NSAID-treated (7/18 cases) patients and loss of AR in 59% steroid-treated (22/38) and 2/7 ASA/NSAID-treated patients (p>0.05). CONCLUSION: Incidence of ARF is clinically important currently in the area of northern Italy. Non-suppurative complications of streptococcal pharyngitis should be considered when deciding therapy in a pediatric patient that presents with sore throat.

[Diagnostic and therapeutic criteria of arterial hypertension in childhood]. / Criteri diagnostici e terapeutici dell'ipertensione arteriosa in età pediatrica.

Arterial hypertension (AH), either primary or secondary, is an important issue in childhood for its short- and long-term cardiovascular morbidity. Renal diseases are the most frequent causes of AH in children, but essential hypertension can also be detected early in life. It is important for blood pressure (BP) to be checked regularly (at least once every 5 years) in healthy children and adolescents and every year in those belonging to at-risk categories (family history of AH, low birth weight, obesity, etc). In children, AH is defined as BP recorded in three non-consecutive measurements with an appropriate device and cuff size > or = 95th centile for age, gender and height. Ambulatory BP monitoring is a valuable diagnostic tool and once AH is confirmed, a specific primary cause should always be ruled out (renovascular, cardiac, vascular, endocrine, pharmacologic, other). In case of border-line or significant AH (between 90th and 99th centile) a non-pharmacological treatment should be considered, whereas severe hypertension (>99th centile for height and age) will require pharmacological treatment (Diuretics, Angiotensin Converting Enzyme Inhibitors, Angiotensin Receptor Blockers, beta - and Calcium blockers).

[Differentiated carcinoma of the thyroid in the young. Clinical and histopathologic aspects]. / Carcinoma differenziato della tiroide in età giovanile. Aspetti clinici ed istopatologici.

BACKGROUND: The surgical approach to Differentiated Thyroid Carcinoma (DTC) is controversial. Aim of this study is to evaluate the opportunity of total thyroidectomy as treatment of choice for DTC in children. METHODS: We examined the tumor features at diagnosis, the complications of surgery and the clinical outcome in a consecutive series of 33 young patients, (age range 7-19 yrs), who underwent total thyroidectomy for DTC as compared to a consecutive series of 181 adult patients operated for DTC (age range 20-64 yrs). RESULTS: Histopathological examination has shown that bilateral foci of the tumor and extrathyroidal extension, were present with similar frequency in both groups of patients (15 vs 18% and 39 vs 48% respectively); node metastases and distant metastases were more frequent in young patients than in adult patients. Complications of total thyroidectomy were not frequent with 6% of permanent hypoparathyroidism. No case of laryngeal nerve damage was observed. In 7/8 patients with lung metastases the radioiodine treatment was effective: in four patients we observed a complete remission of disease, and in three patients a partial response with a decrease of Tg levels and a reduction of the radioiodine uptake areas. CONCLUSIONS: Thyroid carcinoma is not less aggressive in children than in adults. Total thyroidectomy plus lymph node dissections appears to be the treatment of choice as routine surgical treatment of DTC in children. Radioiodine therapy gives good results for the treatment of lung metastases.

[Sudden infant death syndrome in Italy. A multidisciplinary approach]. / La sindrome della morte improvvisa del lattante in Italia. Un approccio multidisciplinare.

A Center for the Sudden Infant Death Syndrome has been established in 1981. Active research involves clinical prospective studies and basic research, mostly aimed at testing our cardiac theory for SIDS. The bereaved families enter in a follow-up program with specific psychological support. At risk babies are evaluated for cardio-respiratory abnormalities and repeatedly controlled. Parents of victims are in the process of forming a group with the objective to support and inform the families of new victims. This is the first attempt to approach systematically the SIDS problem in Italy.

[Cardiovascular abnormalities in Kawasaki disease. An Italian prospective study]. / Complicanze cardiovascolari in una popolazione pediatrica con malattia di Kawasaki. Uno studio prospettico.

We report a prospective study performed over a 9 year period in 96 children with Kawasaki disease (mean age 35 +/- 29 months), 84 of whom < 5 years of age. The male/female ratio was 1.5 (57/39). A total of 38 patients had cardiac involvement, including flattened T waves in the ECG (10 patients), pericardial effusion (6 patients), myocarditis (1 patient), and coronary artery aneurysms (25 patients; frequency of aneurysms: 26%). All patients were evaluated during the acute phase (first month) of the illness. The first echocardiographic examination was performed 15 days (range 4.30 days) from the appearance of fever, and coronary aneurysms were observed in 23 patients; in 2 patients, however, aneurysms appeared later (2 and 6 months). Aneurysms were small (< or = 4.5 mm) in 12, medium (4.5-7 mm) in 11, and large (> 7 mm) in 12 patients. Male sex (p = 0.02), age < 12 months (p = 0.005), ESR (p = 0.001), platelet count (p = 0.009), and pericardial effusion (p = 0.02) were significantly related to the presence of aneurysm. Among females, incidence of aneurysms was significantly higher in infants < 12 months than in older patients (60 vs 6%, p < 0.001). Intravenous immunoglobulin treatment was started early (within 10 days) in 61 patients and late (> 10 days) in 22. Compared to late treatment, early i.v. immunoglobulin treatment was associated with smaller aneurysms and higher regression rate (67 vs 28%, p < 0.05). No difference was observed concerning frequency and number of dilated vessels as related to therapeutical regimens. Total i.v. immunoglobulin dose (2 g/kg) was administered over 1-2 days in 26 patients (scheme I) or over 4-5 days in 58 (scheme II). Frequency of aneurysms was significantly lower in patients treated early (p = 0.02). No myocardial infarctions or deaths occurred at short- or long-term follow-up.

The QT interval throughout the first 6 months of life: a prospective study.

A prospective electrocardiographic study was designed to establish baseline values for electrocardiographic measurements, with specific reference to the QT interval during infancy, and to test the "QT hypothesis" for the sudden infant death syndrome (SIDS). In this ongoing study, ECGs are recorded on the fourth day of life and in the second, fourth and sixth months. The state of health at 1 year is ascertained by a phone call. So far, 4205 newborns have been enrolled. The mean QTc (QT interval corrected for heart rate) was 397 +/- 18 msec (+/- SD) at the fourth day, 409 +/- 15 msec (p less than 0.0001) at the second month, and 406 +/- 15 msec at the fourth month; by the sixth month, it returned to 400 +/- 14 msec. In 88 newborns, the QTc increased by over 40 msec at the second month. Among the 2000 infants checked at 1 year, there have been three sudden and unexpected deaths. The QTc of one of the victims at the fourth day was 563 msec, which exceeded the mean by more than 9 standard deviations, while the QTc of the other SIDS victims exceeded the mean by more than 2 and 3 standard deviations. These results are consistent with the "QT hypothesis," but more data are necessary before any conclusion on the potential relationship between QT interval prolongation and SIDS can be drawn. This study provides definitive waking normal values for QT interval in infancy and indicates that the QT interval lengthens physiologically and temporarily during the first months of life. In some infants, this lengthening may transiently impair cardiac electrical stability.

Neonatal lupus: fetal myocarditis progressing to atrioventricular block in triplets.

We report a case of neonatal lupus syndrome (NLS) in an in vitro fertilization induced triplet pregnancy. Echocardiographic signs of myocarditis were evident at the 21st week of gestation (w.g.) in twin I, with a subsequent development of a complete atrioventricular (AV) block at the 25th w.g.; twin III also displayed echocardiographic signs of myocarditis at the same time. Treatment with dexamethasone (4mg/day) was started at the 25th w.g. A complete echocardiographic regression of the myocarditis signs was achieved, while AV block was unaffected. Caesarian section was performed at the 31.5 w.g. after a premature rupture of the membranes. Complete AV block was confirmed in twin I with a heart rate of 51 beats/min that required a pacemaker implant 40 days after. Twin III developed a first-degree AV block that switched to a periodic second-degree block later, while twin II displayed only liver enzyme abnormalities.

Prolongation of the QT interval and the sudden infant death syndrome.

BACKGROUND: The sudden infant death syndrome (SIDS) is multifactorial in origin, but its causes remain unknown. We previously proposed that prolongation of the QT interval on the electrocardiogram, possibly resulting from a developmental abnormality in cardiac sympathetic innervation, may increase the risk of life-threatening ventricular arrhythmias and contribute to this devastating disorder. We prospectively tested this hypothesis. METHODS: Between 1976 and 1994, we recorded electrocardiograms on the third or fourth day of life in 34,442 newborns and followed them prospectively for one year. The QT interval was analyzed with and without correction for the heart rate. RESULTS: One-year follow-up data were available for 33,034 of the infants. There were 34 deaths, of which 24 were due to SIDS. The infants who died of SIDS had a longer corrected QT interval (QTc) than did the survivors (mean [+/-SD], 435+/-45 vs. 400+/-20 msec, P<0.01) and the infants who died from causes other than SIDS (393+/-24 msec, P<0.05). Moreover, 12 of the 24 SIDS victims but none of the other infants had a prolonged QTc (defined as a QTc greater than 440 msec). When the absolute QT interval was determined for similar cardiac-cycle lengths, it was found that 12 of the 24 infants who died of SIDS had a QT value exceeding the 97.5th percentile for the study group as a whole. The odds ratio for SIDS in infants with a prolonged QTc was 41.3 (95 percent confidence interval, 17.3 to 98.4). CONCLUSIONS: Prolongation of the QT interval in the first week of life is strongly associated with SIDS. Neonatal electrocardiographic screening may permit the early identification of a substantial percentage of infants at risk for SIDS, and the institution of preventive measures may therefore be possible.