Intravenous immune globulin plus corticosteroids in refractory Kawasaki disease.

BACKGROUND: The aim of the present study was to investigate the efficacy of i.v. immune globulin (IVIG) therapy combined with corticosteroids for additional treatment of acute Kawasaki disease (KD) unresponsive to initial IVIG treatment. METHODS: In 50 prospective KD patients, six IVIG non-responders without clinical improvement within 24-48 h after completion of initial IVIG, received 2 g/kg IVIG concurrently with 2 mg/kg i.v. prednisolone sodium succinate (PSL) until normalization of C-reactive protein level. Treatment was then changed to oral PSL, which was tapered over time. Clinical and coronary artery lesion (CAL) outcomes were compared with those of 13 IVIG non-responders who received additional heterogeneous therapies in 125 retrospective KD patients. In addition, the scoring system of Kobayashi et al. for prediction of non-responsiveness to initial IVIG treatment was retrospectively verified in 175 KD subjects, consisting of 50 prospective and 125 retrospective patients in order to evaluate the efficacy of the re-treatment regimen. RESULTS: Incidence of CAL in the study patients was lower than in the control patients, although differences were not significant both in the acute stage (within 1 month: 1/6, 16.7% vs 7/13, 53.8%; P= 0.177) and in the convalescent stage (after 1 month: 0/6, 0.0% vs 4/13, 30.8%; P= 0.255). According to the non-responder prediction system, the scores of six study and 13 control patients before initial IVIG treatment were similar (7.2 ± 1.9 vs 5.3 ± 3.1; P= 0.200). No serious adverse effects related to each treatment were noted in patients of either group. CONCLUSIONS: Additional IVIG combined with concurrent PSL appears to be safe and worth evaluation for the treatment of acute KD unresponsive to initial IVIG treatment.

[Incidence of community-acquired pneumonia and pneumococcal pneumonia, among children in Chiba City, Japan].

Population-based studies on community-acquired pneumonia (CAP) are rare in Japan. Among 984 Chiba City children admitted with CAP to 19 local hospitals in 2005, 854 were younger than 5 years old. The annual CAP incidence among children < 5 years old was 19.7 per 1,000. Five, 4 of whom were under 5 years old, had pneumococcus isolated from blood. The incidence of CAP with pneumococcal bacteremia was 9.21 per 100,000 among those < 5 years old.

Quantitative measurements of Hemophilus influenzae type b capsular polysaccharide antibodies in Japanese children.

BACKGROUND: Hemophilus influenzae type b (Hib) infection has a high morbidity and mortality rate in children. The frequency of natural immunity against Hib in Japanese children is not known, and Hib vaccine has not yet been introduced in Japan. METHODS: Anti-capsular polysaccharide-specific IgG (anti-CP) antibody titers were examined in serum samples from 100 children and 107 young adults who were not vaccinated against Hib, in serum samples from eight patients with Hib systemic infection and in 10 commercially available human immune globulin preparations on enzyme-linked immunosorbent assay. RESULTS: A total of 44% (44/100) of Japanese children and all patients with Hib systemic infection in the acute phase did not have the minimum protective level of anti-CP antibodies (>0.15 microg/mL). The rate of natural Hib immunity was lowest in children under 1 year of age and gradually increased with age. Only 3.74% (4/107) of Japanese young adults did not have the minimum protective level of anti-CP antibodies. Analysis of 10 commercially available human immune globulin preparations indicated an average level of 28.25 microg anti-CP antibody/mL immune globulin (range 14.96-44.17 microg/mL). CONCLUSIONS: Approximately half of Japanese children are not protected against Hib infection. Therefore, Hib vaccine should immediately be included as part of the routine immunization program in Japan. It was also found that all tested commercially available immune globulin preparations had high anti-CP titers. Well-controlled clinical trials of i.v. immune globulin administration for prevention and treatment of Hib systemic infection are needed in Japan.

[Pediatric pneumonia, pleural effusion, and pericarditis following cat scratch disease and serological cross-reactions among Bartonella henselae and Rickettsia japonica determined by indirect fluorescence antibodies].

Cat scratch disease is associated with a variety of systemic manifestations. We report a pediatric case associated with pneumonia, pleural effusion, and pericarditis. A 3-year-old boy developed prolonged fever unresponsive to antibiotic treatment, including azithromycin and minocycline. Although the fever resolved with corticosteroid treatment, Bartonella henselae IgG titer was positive in indirect fluorescence antibodies, as was Rickettsia japonica IgG titer. Both titers were significantly reduced by serum absorption with B. henselae antigens, and we observed a serological cross-reaction between B. henselae and R. japonica.

[Clinical effects of piperacillin and tazobactam/piperacillin on Haemophilus influenzae lower respiratory tract infection in pediatric patients].

OBJECTIVE: The prevalence of beta-lactamase-nonproducing ampicillin-resistant (BLNAR) Haemophilus influenzae (H. influenzae) has been increasing in recent years. Piperacillin (PIPC) is one of a few beta-lactams possessing good activity against BLNAR H. influenzae. We studied clinical efficacy of piperacillin and its beta-lactamase inhibitor, tazobactam/piperacillin (TAZ/PIPC) in children with lower respiratory tract infection caused by H. influenzae including resistance strains. METHODS: Subjects were 20 children with lower respiratory tract infection caused by H. influenzae treated with PIPC 100mg/kg/day (7 cases) or TAZ/PIPC 125mg/kg/day (13 cases). We selected cases from which resistant H. influenzae strains might be detected. Patients received prior antimicrobial therapy within two weeks before admission, or with underlying diseases. We examined patient profiles, clinical efficacy, susceptibilities for 6 beta-lactam antibiotics [PIPC, TAZ/PIPC, ampicillin (ABPC), cefotaxime (CTX), ceftriaxone (CTRX), and meropenem (MEPM)] and analyzed 6 genotype patterns of beta-lactam resistant genes by PCR. RESULTS: Efficacy was 7/7 in patients in PIPC group and 12/13 in patients in TAZ/PIPC group. Diminished efficacy was seen in only one case complicated with severe RSV infection. The susceptibility of all strains but one beta-lactamase producing, ABPC resistant (BLP) strain to PIPC and of all to TAZ/ PIPC was below 0.25 microg/mL. The genotype of the 15 strains isolated from the sputum on administration was as follows; beta-lactamase nonproducing, ABPC-susceptible (gBLNAS) strains were 4, gBLP strain was 1, beta-lactamase nonproducing, and ABPC-resistant (gLow-BLNAR) strains were 2, beta-lactamase nonproducing, ABPC resistant (gBLNAR) strains were 8. CONCLUSION: PIPC and TAZ/PIPC were useful against lower respiratory tract infection caused by H. influenzae including BLNAR in children.

Serotypes of Haemophilus influenzae strains isolated from pediatric patients with respiratory tract infections.

Capsular serotypes of 122 respiratory Haemophilus influenzae strains were identified utilizing antigenic examinations (Slide Agglutination Test [SAT] and counter immuno-electrophoresis [CIE]), and PCR method. Results of the two methods were compared to find disagreement. Clinical and bacteriological characteristics of encapsulated strains were analyzed. By utilizing PCR assay, 3 (2.5%) serotype b, 1 (0.8%) serotype f and 118 (96.7%) non-typeable strains were found among 122 tested strains. Discrepancy between the results of antigenic examinations and PCR assay was found in one strain. That strain gave positive results by antigenic tests with capsular type c antiserum but it was determined to be capsular type f by PCR. No serotype b- strain was detected. All the encapsulated strains displayed biotype I. All the serotype b strains produced beta-lactamase, but none of those was sulbactam/ampicillin and amoxicillin/clavulanic acid resistant. The serotype f strain was beta-lactamase non-producing ampicillin susceptible. The patients suffered from respiratory infections due to encapsulated strains displayed safe clinical manifestations and good clinical responses to antibiotic treatments using beta-lactams. In pre-vaccination era, PCR is considered to be a useful method for determination of serotypes of respiratory H. influenzae, which may contribute to reducing a possibility of clonal transmission of serotype b strains among children community, which is one of the potential risk factors for pediatric invasive infections.

Value of washed sputum gram stain smear and culture for management of lower respiratory tract infections in children.

To date, the technique of washed sputum examinations has not been widely used in the clinical management of lower respiratory tract infections in children. A total of 224 sputum samples from 125 pediatric patients with lower respiratory tract infections were collected for washed sputum Gram stain smears and cultures. The results with these methods were compared to find correlation rates. The value of washed sputum cultures was assessed by examining the clinical responses of the patients who received antibiotic therapies instituted on the basis of the sputum culture results. Isolation rates of Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Staphylococcus aureus were 22.4%, 9.4%, 4.9%, and 0.4%, respectively. For the prediction of H. influenzae, S. pneumoniae, and M. catarrhalis, the sensitivities of the washed sputum Gram stain smears compared with the culture method were 86.0%, 81.0%, and 90.9%, respectively. The specificities of the washed sputum Gram stain smear technique were 94.8%, 97.5%, and 98.1%, respectively. Overall, the sensitivity and specificity of the washed sputum Gram stain smear method were 85.5% and 87.2%, respectively. S. aureus was isolated from only one specimen; and washed sputum Gram stain smear estimation was correlated with the culture result. On the basis of the washed sputum culture results, appropriate antibiotic therapies were instituted for 93.3% of the patients with acute lower respiratory tract infections. This study suggests that the techniques of washed sputum Gram stain smear and culture are valuable and should be encouraged in clinical practice for the management of lower respiratory tract infections in children.

Bcl6 is a transcriptional repressor for the IL-18 gene.

Bcl6 functions as a sequence-specific transcriptional repressor, and Bcl6-deficient (Bcl6(-/-)) mice have been reported to display Th2-type inflammatory diseases in multiple organs. Since IL-18 is a potent stimulator of Th2 cells, we examined the expression of IL-18 mRNA in bone marrow-derived macrophages from Bcl6(-/-) mice after LPS stimulation. Here we show that the expression was strikingly up-regulated after stimulation. The expression was also up-regulated in RAW264 cells, a murine macrophage cell line, by transfection with the dominant negative type of Bcl6 gene. We identified a putative Bcl6-binding DNA sequence (IL-18BS) upstream of exon 1 of the murine IL-18 gene and three IL-18BSs in the promoter region of human IL-18 gene. Binding of Bcl6 in nuclear protein from resting RAW264 cells to murine IL-18BS was detected by gel retardation assay and chromatin immunoprecipitation assay. The binding activity was diminished gradually in RAW264 cells after LPS stimulation. However, the amount of Bcl6 protein in these cells was constant over the period examined, suggesting the functional modification of Bcl6 protein after stimulation. Furthermore, murine IL-18BS was required for Bcl6 to repress the expression of the luciferase reporter gene under control of the IL-18 promoter. Taken together, Bcl6 is a key regulator of IL-18 production by macrophages.

Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells.

After immunization with T cell-dependent antigens, the high-affinity B cells selected in germinal centers differentiate into memory B cells or long-lived antibody-forming cells. However, a role for germinal centers in development of these B lineage cells is still controversial. We show here that Bcl6-deficient B cells, which cannot develop germinal centers, differentiated into IgM and IgG1 memory B cells in the spleen but barely differentiated into long-lived IgG1 antibody-forming cells in the bone marrow. Mutation in the V-heavy gene was null in these memory B cells. Therefore, Bcl6 and germinal center formation are essential for somatic hypermutation, and generation of memory B cells can occur independently of germinal center formation, somatic hypermutation, and Ig class switching.