Marian E. Melish

The Treatment of Kawasaki Syndrome with Intravenous Gamma Globulin

We compared the efficacy of intravenous gamma globulin plus aspirin with that of aspirin alone in reducing the frequency of coronary-artery abnormalities in children with acute Kawasaki syndrome in a multicenter, randomized trial. Children randomly assigned to the gamma globulin group received intravenous gamma globulin, 400 mg per kilogram of body weight per day, for four consecutive days; both treatment groups received aspirin, 100 mg per kilogram per day, through the 14th day of illness, then 3 to 5 mg per kilogram per day. Two-dimensional echocardiograms were interpreted blindly and independently by two or more readers. Two weeks after enrollment, coronary-artery abnormalities were present in 18 of 78 children (23 percent) in the aspirin group, as compared with 6 of 75 (8 percent) in the gamma globulin group (P = 0.01). Seven weeks after enrollment, abnormalities were present in 14 of 79 children (18 percent) in the aspirin group and in 3 of 79 (4 percent) in the gamma globulin group (P = 0.005). No child had serious adverse effects from receiving gamma globulin. We conclude that high-dose intravenous gamma globulin is safe and effective in reducing the prevalence of coronary-artery abnormalities when administered early in the course of Kawasaki syndrome.

A Single Intravenous Infusion of Gamma Globulin as Compared with Four Infusions in the Treatment of Acute Kawasaki Syndrome

BACKGROUND Treatment of acute Kawasaki syndrome with a four-day course of intravenous gamma globulin, together with aspirin, has been demonstrated to be safe and effective in preventing coronary-artery lesions and reducing systemic inflammation. We hypothesized that therapy with a single, very high dose of gamma globulin would be at least as effective as the standard regimen. METHODS We conducted a multicenter, randomized, controlled trial involving 549 children with acute Kawasaki syndrome. The children were assigned to receive gamma globulin either as a single infusion of 2 g per kilogram of body weight over 10 hours or as daily infusions of 400 mg per kilogram for four consecutive days. Both treatment groups received aspirin (100 mg per kilogram per day through the 14th day of illness, then 3 to 5 mg per kilogram per day). RESULTS The relative prevalence of coronary abnormalities, adjusted for age and sex, among patients treated with the four-day regimen, as compared with those treated with the single-infusion regimen, was 1.94 (95 percent confidence limits, 1.01 and 3.71) two weeks after enrollment and 1.84 (95 percent confidence limits, 0.89 and 3.82) seven weeks after enrollment. Children treated with the single-infusion regimen had lower mean temperatures while hospitalized (day 2, P less than 0.001; day 3, P = 0.004), as well as a shorter mean duration of fever (P = 0.028). Furthermore, in the single-infusion group the laboratory indexes of acute inflammation moved more rapidly toward normal, including the adjusted serum albumin level (P = 0.004), alpha 1-antitrypsin level (P = 0.007), and C-reactive protein level (P = 0.017). Lower IgG levels on day 4 were associated with a higher prevalence of coronary lesions (P = 0.005) and with a greater degree of systemic inflammation. The two groups had a similar incidence of adverse effects (including new or worsening congestive heart failure in nine children), which occurred in 2.7 percent of the children overall. All the adverse effects were transient. CONCLUSIONS In children with acute Kawasaki disease, a single large dose of intravenous gamma globulin is more effective than the conventional regimen of four smaller daily doses and is equally safe.

The staphylococcal scalded-skin syndrome.

Abstract A syndrome of dermatologic response to infection with phage Group 2 coagulase-positive staphylococci with reactions ranging from bullous impetigo to generalized scarlatiniform rash without exfoliation to generalized exfoliative disease was observed in 17 children. Staphylococci isolated from these patients, as well as two additional Group 2 organisms, produced exfoliation in newborn mice. The experimental lesion progressed from the development of a Nikolsky sign to bullous formation and then widespread exfoliation. Histologic sections were characterized by a cleavage plane within the epidermis at the stratum granulosum. Among 36 strains, the capacity to produce exfoliation was unique to staphylococci of phage Group 2. The disease produced in newborn mice reproduces the scalded-skin syndrome. Staphylococci may be recovered from involved animals. Thus Kochs postulates are fulfilled, and staphylococci of phage Group 2 are established as the etiologic agent of this syndrome.

Clinical and epidemiologic characteristics of patients referred for evaluation of possible Kawasaki disease

Study objectives (1) To determine those diseases that most often mimic Kawasaki disease (KD) in the United States. (2) To examine the physical findings and laboratory studies that influenced experienced clinicians to exclude the diagnosis of KD. (3) To compare epidemiologic features of patients with KD and patients referred for evaluation of possible KD in whom alternative diagnoses were established. Design: Case comparison study. Setting: Seven pediatric tertiary care centers. Patients: Consecutive sample of 280 patients with KD and 42 comparison patients examined within the first 14 days after onset of fever. Measurements and main results: (1) Infectious diseases, particularly measles and group A β-hemolytic streptococcal infection, most closely mimicked KD and accounted for 35 (83%) of 42 patients in the comparison group. (2) The standard diagnostic clinical criteria for KD were fulfilled in 18 (46%) of 39 patients in whom other diagnoses were established. (3) Patients with KD were significantly less likely to have exudative conjunctivitis or pharyngitis, generalized adenopathy, and discrete intraoral lesions, and more likely to have a perineal distribution of their rash. The patients with KD were also more likely to have anemia and elevated erythrocyte sedimentation rate; leukocyte count 3 /mm 3 and platelet count 3 /mm 3 were significantly less prevalent in patients with KD. (4) Residence within 200 yards of a body of water was more common among KD patients. Conclusions: (1) Measles and streptococcal infection should be excluded in patients examined for possible KD. (2) Laboratory studies that may be useful in discriminating patients with KD from those with alternative diagnoses include hemoglobin concentration, erthyrocyte sedimentation rate, and serum alanine aminotransferase activity. (3) Residence near a body of water may be a risk factor for the development of KD.

Association of Kawasaki disease with tropospheric wind patterns.

The causal agent of Kawasaki disease (KD) remains unknown after more than 40 years of intensive research. The number of cases continues to rise in many parts of the world and KD is the most common cause of acquired heart disease in childhood in developed countries. Analyses of the three major KD epidemics in Japan, major non-epidemic interannual fluctuations of KD cases in Japan and San Diego, and the seasonal variation of KD in Japan, Hawaii, and San Diego, reveals a consistent pattern wherein KD cases are often linked to large-scale wind currents originating in central Asia and traversing the north Pacific. Results suggest that the environmental trigger for KD could be wind-borne. Efforts to isolate the causative agent of KD should focus on the microbiology of aerosols.

Kawasaki Syndrome in Hawaii

Objective: To describe the incidence and epidemiology of Kawasaki syndrome (KS) in Hawaii. Methods: Retrospective analysis of the State Inpatient Database for Hawaii residents hospitalized with KS during 1996 through 2001. Results: During 1996 through 2001, 267 persons younger than 18 years of age living in Hawaii were hospitalized with KS; 226 (84.6%) were younger than 5 years of age. The average annual incidence for KS was 45.2 per 100,000 children younger than 5 years of age. The incidence was higher for children younger than 1 year of age than for those 1–4 years of age (74.3 and 37.5 per 100,000). The KS incidence for Asian and Pacific Islander children and for White children was 70.9 and 35.3 per 100,000, respectively. Incidence was highest among Japanese American children living in Hawaii (197.7 per 100,000). Honolulu County had the most KS patients (85.0%) and the highest incidence (53.1 per 100,000) among Hawaii counties. For children younger than 5 years of age hospitalized with KS, the median length of stay was 2 days, and the median hospital charge was

Clinical and Imaging Findings in an Infant With Zika Embryopathy

9379. Conclusion: During 1996 through 2001, the annual incidence rate for KS among children younger than 5 years of age in Hawaii was the highest in the United States. The incidence among Japanese American children in Hawaii was higher than that among other racial groups in the state and when compared with children living in Japan.

Elevated levels of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 during the acute phase of Kawasaki disease.

Recent Zika virus (ZIKV) outbreaks have been associated with an increased incidence of neonatal microcephaly. Subsequently, tropism for the brain was established in human fetal brain tissue. We present the first congenital ZIKV infection in the United States, confirmed by high ZIKV immunoglobulin M antibody titers in serum and cerebrospinal fluid. The phenotypic characteristics of the patient fall within fetal brain disruption sequence, suggesting impaired brain development in the second half of gestation. Brain imaging revealed an almost agyric brain with diffuse parenchymal calcifications, hydrocephalus ex vacuo, and cerebellar hypoplasia. Ophthalmologic examination revealed macular pigment stippling and optic nerve atrophy. Liver, lungs, heart, and bone marrow were not affected. The patient had progressive neurologic deterioration in the first month of life. The discovery of ZIKV infection in human fetal brain tissue along with serologic confirmation proves the vertical transmission of ZIKV. Therefore, ZIKV has joined the group of congenital infections.

A revised decision analysis of strategies in the management of febrile children at risk for occult bacteremia

ABSTRACT Kawasaki disease (KD) is an acute, self-limiting, multisystem vasculitis of unknown etiology affecting infants and young children. Unless treated promptly with high-dose intravenous gamma globulin and aspirin, patients frequently develop coronary aneurysms. Previously, matrix metalloproteinase 9 (MMP-9), which is secreted complexed to tissue inhibitor of metalloproteinase 1 (TIMP-1), has been implicated in abdominal aortic aneurysm formation. Since the clinical and pathological features of KD include inflammation and weakening of blood vessels, we analyzed acute- and convalescent-phase paired plasma or serum samples from 31 KD patients, 7 patients who did not completely meet the criteria for KD, and 26 non-KD controls (9 febrile and 17 afebrile patients) for pro-MMP-9 (92 kDa) enzyme activity by gelatin zymography and for active MMP-9 (83 kDa), pro-MMP-9, and TIMP-1 protein levels by enzyme-linked immunosorbent assay. Statistical analysis was performed by using Student t tests, linear regression, and the Wilcoxon rank-sum test. Markedly elevated pro-MMP-9 enzymatic activity, pro-MMP-9 protein levels, and TIMP-1 protein levels were found during the acute phase of illness in patients with clinically established KD and in patients who were suspected of having KD but did not meet all of the criteria. There was no significant difference in active MMP-9 levels. Furthermore, pro-MMP-9 and TIMP-1 protein levels were significantly elevated among KD patients, compared to those of febrile and afebrile non-KD controls. The significantly elevated pro-MMP-9 enzyme and protein levels during the acute phase of KD may reflect vascular remodeling or an inflammatory response to a microbial agent, suggesting a pathophysiological role for MMP-9 in coronary aneurysm formation.

Prevalence of Antibodies to Zika Virus in Mothers from Hawaii Who Delivered Babies with and without Microcephaly between 2009-2012

Two decision analysis reports published in 1991 concluded that the strategy of routine blood culture and empiric antibiotics was the superior strategy for febrile children at risk for occult bacteremia. This report describes a decision analysis of treatment strategies for these children considering the following changes that have occurred since then: (1) Hemophilus influenzae B incidence is low because of widespread vaccine use; (2) the emergence of resistant Streptococcus pneumoniae may affect the clinical effectiveness of empiric antibiotics in the future; and (3) the negative consequences of unnecessary antibiotic treatment have yet to be well defined. A decision analysis approach, modifying the original assumptions, was carried out. Sensitivity analyses were conducted on all assumption variables. Strategies employing empiric antibiotics were found to have the best outcomes, assuming low negative treatment consequences. If a high level of negative treatment consequences is assumed, strategies using a white blood cell count (WBC) are superior. If a very high level of negative treatment consequences is assumed, the strategy of no tests and no empiric antibiotic treatment is usually superior, unless the frequency of bacteremia is 10% or higher and empiric antibiotic efficacy is high, in which case a WBC strategy is superior. This information can be used to select a treatment strategy based largely on the estimation of the negative consequences of treatment.