Coronary risks after high-dose gamma-globulin in children with Kawasaki disease.

OBJECTIVES: The goals of the present study were to develop a predictive coronary risk scoring system after intravenous gamma-globulin (IVGG) therapy of any dose for the different preparations currently used in the treatment of children with Kawasaki disease and to determine the predictive value of the system. The previously reported scoring systems were based on treatment with high-dose IVGG therapy at limited doses and were determined using investigative methods. METHODS: Four hundred and fifty-one patients were randomized into one of three groups and received either i.v. polyethylene glycol-treated human immunoglobulin at a dose of either 200 (n = 147) or 400 mg/kg per day (n = 152) or freeze-dried sulfonated human immunoglobulin at 200 mg/kg per day (n = 152) for 5 consecutive days. We documented 31 cases of coronary abnormalities (CA). Univariate and multivariate logistic regression was performed using 49 clinical variables and the resulting predictive model was validated. RESULTS: The duration of fever (odds (I day)/odds (- 5 days)= 0.158; 95% confidence interval (CI) 0.0385-0.648), hemoglobin (odds (Q1 = 10.3)/odds (Q3 = 11.6) = 3.97; 95% CI 1.92-8.20), IgG (odds (Q1 = 1,900)/odds (Q3=2,658)=2.72, 95% CI 1.18-6.25) and IgA (odds (Q1 =72)/odds (Q3= 160) = 0.415; 95% CI 0.253-0.680) levels after completion of gamma-globulin infusion were independent predictors. The model is quasi-cross validated and has acceptable sensitivity and selectivity. The estimated risk and observed occurrence of CA coincide. CONCLUSIONS: Determinants of the risk of CA after IVGG therapy are a longer duration of fever, a lower IgG level, a higher IgA level and a lower hemoglobin level after IVGG infusion. This model is applicable for IVGG doses from 1 to 2 g/kg and for at least two different gamma-globulin preparations.

Specific deposition of passively transferred monoclonal antibodies against herpes simplex virus type 1 in rat brain infected with the virus.

The kinetics of human monoclonal antibody (anti-gB) to herpes simplex virus type 1 (HSV-1) were investigated after intravenous injection of anti-gB into an HSV-1 encephalitis animal model. Immunohistochemical study revealed specific deposition of passively transferred anti-gB in the hippocampus and thalamus of the infected rat brain, and it bound to the same neurons in which HSV-1 antigen was positively stained. To examine the macroscopic distribution of anti-gB in the infected brain, we undertook an 125I-labeled anti-gB injection study, and the same distribution of 125I-labeled anti-gB deposition was observed by brain semimicroautoradiography as in the immunohistochemical study. These results suggest that anti-gB easily permeates the capillary wall and is deposited in the inflammatory site where HSV-1-specific antigen is detectable. The use of radioisotope-labeled anti-gB injection and external brain imaging could lead to a noninvasive diagnostic tool for the early detection of HSV-1 antigen in cases of suspected HSV-1 encephalitis.

Interferon production during the course of Mycoplasma pneumoniae infection.

In patients infected with Mycoplasma pneumoniae the development of interferon (IFN) was studied in nasopharyngeal secretions and sera. The production of IFN-gamma by lymphocytes was also investigated in response to M. pneumoniae antigen and mumps virus antigen. IFN-alpha was detected in 25 (61.0%) of 41 nasopharyngeal secretion samples and in 25 (59.5%) of 42 serum samples within 6 days after the onset of illness. IFN-alpha was significantly higher in nasopharyngeal secretions than in sera and a significant correlation was observed between the two. In most of the patients lymphocytes produced a larger amount of IFN-gamma in the convalescent stage than in the acute stage, when lymphocytes were stimulated with M. pneumoniae antigen. In some patients, however, lymphocytes did not produce IFN-gamma during the course of illness. Such lymphocytes, negative for IFN-gamma production in response to M. pneumoniae, produced IFN-gamma after the depletion of macrophages, and readdition of macrophages suppressed the production of IFN-gamma by lymphocytes. When lymphocytes were stimulated with heterogeneous antigen (mumps virus), they produced no IFN or a small amount of IFN in the acute stage of M. pneumoniae infection, and IFN production increased in the convalescent stage. Different mechanisms seem to work for homogeneous and heterogeneous antigens in the suppression of IFN production in M. pneumoniae infection.

Impact of influenza virus infection as a cause of pediatric hospitalization.

From winter 1989 to spring 1990, a severe epidemic caused by influenza A (H3N2) and B viruses developed in Japan. During the epidemic (December 1989 to February 1990), 244 children were admitted to the pediatric ward of Nippon Kokan Hospital: 53 (21.7%) were hospitalized with influenza virus infection, 22 (9.0%) with rotavirus gastroenteritis, and 17 (7.0%) with respiratory syncytial virus infection. Among those with influenza, 24 had type A and 29 had type B. Most were young healthy children without underlying illnesses (mean age, 4.8 +/- 3.4 years). The impact of the influenza epidemic on pediatric hospitalization is probably much greater than generally thought when a severe epidemic occurs.

[Pharmacokinetics and clinical efficacy of flomoxef in neonates].

Clinical pharmacology and efficacy of flomoxef (FMOX) in neonates were investigated. And the following results were obtained. 1. Mean serum concentrations of FMOX at 30 minutes after administration were 24.3 micrograms/ml, 47.6 micrograms/ml, and 85.8 micrograms/ml at doses of 10 mg/kg, 20 mg/kg, and 40 mg/kg administered, respectively. 2. Mean serum half-lives of FMOX were 3.4 hours in 0-3 day-old neonates, and 2.6 hours in 4 day-old or older subjects. 3. A dose response was evident among different dose groups given 10 mg/kg, 20 mg/kg, and 40 mg/kg. 4. Urinary recovery rates of FMOX in the first 6 hours after administration ranged between 12.8 and 51.1%. 5. FMOX was effective in 7 out of 8 cases in which causative pathogens were identified. 6. Diarrhea was observed in 1 case as a side effect of the drug, but the symptom was relieved soon after the completion of the treatment. There was no case in which any abnormal laboratory results were observed. 7. FMOX has a broad spectrum of activities against Gram-positive and Gram-negative aerobes and anaerobes. It is stable against most of beta-lactamases. It was demonstrated to be highly effective in our study, and yet without any serious side effects. FMOX is therefore considered to be one of the useful agents of the first choice for the treatment of bacterial infections such as sepsis and urinary tract infections in neonates and infants.

Interferon-gamma production closely related to antibody production in lymphocyte cultures stimulated with mumps virus.

Enzyme-linked immunosorbent assay (ELISA) antibody to mumps virus and virus specific interferon (IFN)-gamma production were investigated in lymphocyte cultures stimulated with mumps virus before and after immunization with live mumps vaccine. Synthesis of immunoglobulin (Ig) M but not Ig G was enhanced after vaccination. Spontaneous production of mumps ELISA antibodies in lymphocyte culture increased after vaccination and substantially higher levels of antibodies were produced when lymphocytes were stimulated with mumps virus after vaccination. The production of mumps ELISA antibodies was closely related to IFN-gamma production (r = 0.326, p less than 0.01) but not to IFN-alpha production (r = 0.084, p greater than 0.05).

The head circumference growth curve for Japanese children between 0-4 years of age: comparison with Caucasian children and correlation with stature.

Controversy exists regarding possible international and interracial differences in head circumferences of children. We undertook the present study in order to see if there was a difference in head circumference between Japanese and Caucasian children. The subjects consisted of a total of 42,392 Japanese children between 0 and 4 years of age surveyed from 1940 to 1980, and these data were compared with those of American and British children. We conclude that there is a significant ethnic difference in head circumference, as large as one channel of usual percentiles, between Japanese and Caucasian children. The results indicate that smaller head circumference in Japanese children primarily reflects smaller stature of the Japanese.

Vascular abnormalities in congenital cutis laxa--report of two cases.

Two cases of Japanese girls with congenital cutis laxa associated with cardiovascular abnormalities are described. Case 1: A 12-year-old girl has been under our observation from the age of 6 months. Cardioangiogram revealed dilatation of the ascending aorta, meandering of the descending aorta and the coronary arteries, coiling of the carotid and innominate (brachiocephalic) arteries, and hypoplasia of the pulmonary arteries. Case 2: A 2.8/12-year-old girl died after our follow-up from the age of 3 months. The cause of death was congestive heart failure secondary to peripheral stenosis of the pulmonary arteries. In both cases, skin biopsy revealed a decreased number of elastic fibers and an increased amount of acidic mucopolysaccharides. The same histological features were observed in the pulmonary arteries and other arteries as well. Electron microscopic findings were diffuse thinning of elastic fibers and reduced elastic content. The high blood level of elastase (167.8 micrograms/l) in case 1 may cast a light on the unknown etiology of the disease.

[Pharmacokinetics and clinical safety of aztreonam in neonates].

Clinical pharmacology and safety of aztreonam (AZT) in the neonatal period were investigated. The results obtained are summarized as follows. 1. Serum concentrations of AZT at 30 minutes after administration of 10 mg/kg were 22.1-32.2 micrograms/ml and those of 20 mg/kg 22.5-75.9 micrograms/ml. 2. Serum half-lives of AZT were 3.5-6.6 hours in 0-3 day-old neonates, and 2.0-4.0 hours in neonates 4 day-old or older. 3. A dose response was evident between the 10 mg/kg administration group and the 20 mg/kg group. 4. Urinary recovery rates of AZT in the first 6 hours after administration ranged between 17.8 and 69.9%. 5. No clinical side effects were observed in the administration of AZT alone (6 cases), or in combination with ampicillin (9 cases). Thrombocytosis was observed in 1 case as an abnormal laboratory finding, but it returned to normal within 1 week after the completion of AZT administration. 6. AZT had a potent antimicrobial activity against Gram-negative aerobes and hardly induced beta-lactamase. Furthermore, side effects were not observed in this study. Therefore, AZT is considered to be useful for the treatment of urinary tract infections and other serious infections caused by Gram-negative pathogens even in the neonatal period.

Increased activities of cytosol aminopeptidase and lactate dehydrogenase in serum originate from lymphocytes in necrotizing lymphadenitis.

In three pediatric patients with necrotizing lymphadenitis, cytosol aminopeptidase activity (c-AP; EC 3.4.11.1) in serum was markedly increased to 509, 417, and 191 U/L, respectively (normal range 25-60 U/L). Lactate dehydrogenase (LD; EC 1.1.1.27) was also increased, with LD-3 predominating. The increased concentrations of c-AP and LD presumably originated from the destruction of infected, activated lymphocytes, especially T lymphocytes. Necrotizing lymphadenitis is probably caused by a lymphocytotropic virus.

Evaluation of live trivalent vaccine of measles AIK-C strain, mumps Hoshino strain and rubella Takahashi strain, by virus-specific interferon-gamma production and antibody response.

A trivalent measles-mumps-rubella live virus vaccine, containing measles AIK-C strain, mumps Hoshino strain, and rubella Takahashi strain, was evaluated in 229 children, aged 1 to 5 years. The vaccine induced a high seroconversion rate: 221 (98.7%) out of 224 subjects initially seronegative for measles virus, 167 (93.3%) out of 179 initially seronegative for mumps virus, and 212 (99.1%) out of 214 initially seronegative for rubella virus. It also induced a sufficient cellular immunity against each of the three viruses in over 90% of the subjects, as judged by virus-specific interferon-gamma (IFN-gamma) production. Virus-specific IFN-gamma production was observed 10 days after vaccination by stimulation with measles virus and rubella virus and 14 days after vaccination by stimulation with mumps virus. Mumps-virus-specific IFN-gamma production was observed in 7 out of 12 recipients without seroconversion for mumps virus. And measles-virus-specific IFN-gamma production was demonstrated in one out of three recipients without seroconversion for measles virus. A significant correlation was observed between the serum antibody and IFN-gamma production six weeks after vaccination for measles virus (r = 0.201, P less than 0.01) and for mumps virus (r = 0.174, P less than 0.05) but not for rubella virus (r = -0.045, P less than 0.05). The incidence of febrile reactions of greater than or equal to 37.5 C was quite low, 14.4%, and that of greater than or equal to 39 C occurred in only 1.3% of the recipients. These results suggested that the trivalent vaccine induced sufficient humoral and cellular immunity and yet resulted in no more untoward reaction than observed from the measles vaccine alone.

[Pharmacokinetics and clinical studies on cefsulodin in neonates].

Pharmacokinetics and clinical studies on cefsulodin (CFS) were conducted in neonates. 1. MIC's of CFS, sulbenicillin and gentamicin (GM) were determined using 7 strains of Pseudomonas aeruginosa clinically isolated from neonates and maintained as stock cultures. CFS was found to be nearly as active as GM. 2. When CFS 20 mg/kg was administered to a 12-day-old neonate by intravenous bolus injection, serum concentrations were 8.7 micrograms/ml before administration and 51.7 micrograms/ml at 30 minutes, 44.4 micrograms/ml at 1 hour, 38.6 micrograms/ml at 2 hours and 11.1 micrograms/ml at 6 hours after administration. The half-life was 2.5 hours. 3. CFS was administered alone or combination with other drugs to 3 neonates. The drug was clinically effective in 2 cases and slightly effective in another. Bacteriologically, one case was rated as decreased, another as replaced, and the remaining one as unchanged. 4. Neither side effects nor abnormal laboratory values attributable to CFS were found.

[Effects of transfer factor on chronic hepatitis B in childhood].

Nine children, 1 to 13 years of age, with HBeAg positive chronic hepatitis B received transfer factor (T.F.) monotherapy for 3 to 17 months, and were monitored by check-ups every six months from serum HBeAg, anti-HBe and GPT. In 12 months, 4 subjects became HBeAg negative and had normal serum GPT. In 22 to 48 months, 6 of the nine subjects had negative HBeAg and normal GPT, 2 had positive HBeAg and high GPT values. The remaining 1 subject who was observed for six months after T.F. therapy remained HBeAg positive with a high GPT values. No side effects were observed. These preliminary observations may indicate beneficial effects of T.F. on the natural course of chronic hepatitis B in childhood, though the ultimate effects awaits longer and well controlled clinical trials.

[Pharmacokinetic and clinical studies on cefmenoxime in neonates and premature infants].

Pharmacokinetic and clinical studies on cefmenoxime (CMX) in neonates and premature infants were conducted. The results are summarized as follows. 1. Intravenous administration of CMX at 20 mg/kg, via bolus injection or 1-hour drip infusion, produced at sufficiently high blood concentration. As it is the case with other cephem antibiotics, the half-life varied with age and tended to become shorter with aging. 2. There were intergroup differences in urinary recovery of the drug, but urinary concentrations were generally high. 3. In the clinical evaluation, 12 out of 15 cases which were evaluable for efficacy were rated "excellent" or "good". 4. Side effects were evaluated in 27 cases. A bleeding tendency was found in 1 case, eosinophilia in 1 case, elevated GOT in 1 case, and positive PIVKA II in 4 cases. It is, therefore, concluded that CMX is a highly useful drug for the treatment of bacterial infections in neonates and premature infants.

[Conversion of acute leukemia from a T-lymphoid to a myeloid phenotype].

A 7-year-old girl with an acute leukemia was reported whose blasts showed conversion from a T-lymphoid to a myeloid phenotype. At the onset of the disease, the blasts were negative for peroxidase and displayed FAB L1 morphology. Surface marker analysis revealed only CD7 antigen. Although complete remission was achieved, an extramedullary relapse was identified as having a several subcutaneous tumors 15 months later. Tumor cells showed the same marker expression as that of the blasts at the onset. After short term culture without an addition of any differentiation stimulators, the blast cells expressed CD2, CD3, CD4, CD8, and CD25 antigens. The karyotype was 46, XX, t(12; 21) (p11; q22). The intensive chemotherapy and radiation therapy were carried out, however, a hematological relapse occurred 12 months later. At this time, the blasts were strongly positive for peroxidase and expressed HLA-DR and CD33 antigens with disappearance of the CD7 antigen. Chromosome analysis revealed the additional abnormalities (del (7) (p15), -17, +der (17) t (17;?) (p13;?].

[A T-cell type non-Hodgkin's lymphoma with a near-triploid karyotype].

A 16 year-old boy of non-Hodgkin's lymphoma (NHL) was reported. Although Hodgkin's disease was suspected by the presence of Reed-Sternberg-like cells and lacunar cells histologically, a diagnosis of NHL was made because of atypism and monoclonality of the background's cells as well as the morphology of invasive cells in the bone marrow. The tumor cells expressed, CD2, CD3, CD4, CD5 and CD7 antigens, which corresponded to the phenotype of helper-inducer T-lymphocytes. In the analysis of their karyotypes, 16 out of 24 cells revealed normal karyotype, while all the rest showed near-triploidy. Common abnormality was identified as trisomies of No. 1, 3, 5, 16, 21 chromosomes, tetrasomies of No. 10, 19, 20 chromosomes, and 4q+, 7q+, 14p+. Multimodal chemotherapy was successful to induce the patient promptly into complete remission. He has been free from the disease for approximately 12 months. Thus far, triploid clones in hematopoietic malignancies have rarely been described. More importantly, the appearance of them in pediatric lymphoid neoplasms has not yet been reported.

Lack of linkage between height and weight and age at menarche during the secular shift in growth of Japanese children.

During the past century, Japanese children have shown a most dramatic secular trend toward earlier menarche and accelerated tempo of growth. In order to assess the inter-relationship between these dual secular trends, we analysed the data on height and weight measurements of Japanese children, collected by the Japanese Ministry of Education in the years from 1900 through 1986, with reference to various retrospective studies on the age of menarche among Japanese. Between 1950 and 1983, both the mean height and weight at menarche varied significantly but percentage of the mean height achieved at menarcheal age, as compared with the mature height, remained relatively stable at approximately 95%. The results indicate that the secular trend toward earlier menarche reflects largely, if not solely, the secular change in tempo of physical growth in Japanese children.

Outbreak of herpangina associated with Coxsackievirus B3 infection.

An outbreak of acute febrile illness was observed in summer, 1987, in a welfare home in which 31 healthy infants were accommodated. Within a 5-day period 25 infants (81%) acquired a febrile illness. Coxsackievirus B3 was isolated from 16 (64%) of 25 throat swabs. In the patients in whom viral culture was negative or not performed, 6 were serologically identified as having a coxsackievirus B3 infection. Among 22 patients identified as having a coxsackievirus B3 infection 7 had typical herpangina and the others had pharyngitis with or without a few small vesicles. Serum alpha-interferon was detected in all but 2 cases (one with proved infection and another with indefinite infection). Herpangina can be associated with coxsackievirus B3 as well as with the more frequently associated coxsackievirus Group A; this explosive type of outbreak might be transmitted by a small particle aerosol.

[Biphenotypic leukemia in childhood--analysis of 19 cases].

The leukemic cells of 19 patients (pts) out of 180 children with acute leukemia expressed both CD 19 (B 4) and CD 13 (MY 7) antigens. These biphenotypic leukemias (BiL) were divided into 3 groups on the basis of clinical features, antigen profiles and karyotypes. GroupI pts (N = 6) were infants under one year of age with high initial white blood cell (WBC) count over 200,000/microliters. The blasts of this group did not express CD 10 (J 5) antigen. In 4 of these pts, the blasts initially did not express CD 13 antigen, however, they became strongly positive after short-term culture without stimulation. Cytogenetic analysis revealed a breakpoint at 11 q 23. Group 11 pts (N = 6) were often school age and had a high WBC count over 100,000/microliters and CD 10 positive blasts. The blasts of 4 pts did not express CD 13 antigen until short-term culture. Cytogenetic marker was Ph1 chromosome. Group III pts (N = 7) were often preschool age and the WBC count was lower than that of other groups. The blasts expressed CD 10 antigen with normal karyotypes or various karyotype abnormalities. Prognosis of pts with BiL was more poor than that of CD 13- common ALL, and among 3 groups survival of Group I and II was significantly shorter than that of group III. This study suggests that childhood BiL represents heterogeneous leukemias. It is important to distinguish BiL in childhood acute leukemia and further divide into the groups in order to establish an adequate therapy for prognostically poor BiL.