Vaccine-Strain Varicella Virus Transmitted to a Term Infant Following Maternal Postpartum Vaccination.

Varicella is a highly contagious disease caused by Varicella-zoster virus (VZV). The American College of Obstetricians and Gynecologists (ACOG) adopted the routine administration of varicella vaccine to varicella non-immune mothers postpartum before leaving the facility per the Advisory Committee in Immunization Practices (ACIP) recommendation of Varicella prevention. While the vaccine is well-tolerated, a live attenuated vaccine has the potential to cause clinical symptoms and complications, including rash. Secondary transmission of the vaccine virus from healthy persons is rare. Only 13 confirmed cases of secondary transmission from 11 immunocompetent vaccine recipients have been reported. We report the confirmed case of extensive neonatal varicella disease in a neonate after exposure to a vaccine varicella rash that developed after maternal postpartum vaccination.

Acute Adult-Onset Kawasaki Disease Complicated by Coronary Artery Aneurysms, Thrombosis, and ST-Segment Elevation Myocardial Infarction.

A 21-year-old man who had an initial misdiagnosis of chest wall cellulitis and sepsis presented to the emergency department with chest pain. Electrocardiogram demonstrated ST-segment elevation in the inferior leads. Cardiac catheterization identified diffuse aneurysmal dilation and thrombosis of the distal right coronary artery. Clinical signs were consistent with acute Kawasaki disease. (Level of Difficulty: Intermediate.).

A real-time and high-throughput neutralization test based on SARS-CoV-2 pseudovirus containing monomeric infrared fluorescent protein as reporter.

Neutralizing antibodies to SARS-CoV-2 have been shown to correlate with protection in animals and humans, disease severity, survival, and vaccine efficacy. With the ongoing large-scale vaccination in different countries and continuous surge of new variants of global concerns, a convenient, cost-effective and high-throughput neutralization test is urgently needed. Conventional SARS-CoV-2 neutralization test is tedious, time-consuming and requires a biosafety level 3 laboratory. Despite recent reports of neutralizations using different pseudoviruses with a luciferase or green fluorescent protein reporter, the laborious steps, inter-assay variability or high background limit their high-throughput potential. In this study we generated lentivirus-based pseudoviruses containing a monomeric infrared fluorescent protein reporter to develop neutralization assays. Similar tropism, infection kinetics and mechanism of entry through receptor-mediated endocytosis were found in the three pseudoviruses generated. Compared with pseudovirus D614, pseudovirus with D614G mutation had decreased shedding and higher density of S1 protein present on particles. The 50% neutralization titers to pseudoviruses D614 or D614G correlated with the plaque reduction neutralization titers to live SARS-CoV-2. The turn-around time of 48-72 h, minimal autofluorescence, one-step image quantification, expandable to 384-well, sequential readouts and dual quantifications by flow cytometry support its high-throughput and versatile applications at a non-reference and biosafety level 2 laboratory, in particular for assessing the neutralization sensitivity of new variants by sera from natural infection or different vaccinations during our fight against the pandemic.

Elevated Levels of Pentraxin 3 Correlate With Neutrophilia and Coronary Artery Dilation During Acute Kawasaki Disease.

Kawasaki disease (KD) is the leading cause of acquired pediatric heart disease in the developed world as 25-30% of untreated patients and at least 5% of treated patients will develop irreversible coronary artery lesions (CAL). Pentraxin-3 (PTX-3) has been well-studied in inflammatory diseases, particularly in cardiovascular diseases associated with vascular endothelial dysfunction. We hypothesized that PTX-3 plays an important role in the development of KD-associated CAL and investigated the circulating levels of PTX-3 in the serum of KD patients. Children with acute KD were followed from diagnosis through normalization of the clinical parameters of inflammation (convalescent phase). Serum samples were obtained and echocardiograms were conducted at several phases of the illness: acute [prior to intravenous immunoglobulin (IVIG) treatment], sub-acute (5-10 days after IVIG treatment), and convalescent (1-4 months after KD diagnosis). Seventy children were included in the final cohort of the study, of whom 26 (37%) presented with CAL and 18 (26%) developed IVIG resistance. The patients included in this study came from diverse ethnic backgrounds, mostly with mixed ancestry/ ethnicity. Significantly increased PTX-3 levels were observed during the acute phase of KD compared to the sub-acute and the convalescent phases. The PTX-3 levels during acute KD were significantly higher among KD patients with CAL compared to patients with normal coronary arteries (NCA). Also, the PTX-3 levels were significantly higher in patients with IVIG resistance. Furthermore, the PTX-3 levels were significantly higher in IVIG-resistant KD patients with CAL as compared to the NCA group. Moreover, the PTX-3 levels were significantly correlated to coronary artery z-score during acute KD and to neutrophil counts throughout KD progression regardless of coronary artery z-score. Elevated PTX-3 levels correlated to elevated neutrophil counts, a known source of PTX-3 in acute inflammation and an important player in the development of KD vasculitis. We, therefore, suggest PTX-3 as a novel factor in the development of KD-associated CAL and propose neutrophil-derived PTX-3 as contributing to KD vascular dysfunction.

Mapping the Trends of Kawasaki Disease in Hawai'i from 1996 to 2018.

Kawasaki disease is a systemic vasculitis of unknown etiology and is the leading cause of acquired heart disease in children in the developed world. Historically, Hawai'i has had the highest incidence of Kawasaki disease in the United States, likely due to the population's unique ancestral composition. To analyze the epidemiology, demographics and spatiotemporal distribution of Kawasaki disease in Hawai'i, a retrospective chart review was conducted utilizing data from Kapi'olani Medical Center for Women and Children encompassing the period of 1996-2018. A total of 858 patients were analyzed with 877 episodes of Kawasaki disease. On average, 37 episodes of Kawasaki disease were diagnosed annually over the 23-year period. The annual incidence was 32 per 100 000 children <5 years of age. Asian children (66.1%) accounted for the majority of cases, followed by Native Hawaiians and Other Pacific Islanders (16.6%). Unlike Japan and the continental United States, there was no characteristic seasonal pattern in the distribution of Kawasaki disease in Hawai'i, which may be attributed to its tropical climate or the recent changes in global weather patterns. Local geographical differences in the incidence of Kawasaki disease demonstrated that the Windward (Eastern) coast of O'ahu had a higher rate, while the Leeward (Western) coast displayed a lower incidence rate. This could be explained by variations in ethnic composition and weather patterns of certain areas. Future studies could provide geographical weather data and statistical analysis to determine what environmental triggers are correlated with Kawasaki disease trends in the State of Hawai'i.

The Importance of Echocardiogram during the Second Week of Illness in Children with Kawasaki Disease.

OBJECTIVE: To determine the timing of peak coronary artery dilation and the characteristics of patients who present with new-onset coronary artery dilation during the acute phase of Kawasaki disease with an initial normal echocardiogram. STUDY DESIGN: This retrospective study analyzed 231 children hospitalized for Kawasaki disease in Hawai'i over a period of 7 years. Clinical and echocardiographic data were collected to calculate the timing of peak z score, and study subjects were compared based on the timing of coronary dilation. RESULTS: Peak coronary artery dilation was observed on average at 11.5 days from the onset of fever (median 8, IQR 7-13 days). Among study subjects with normal z scores in both coronary arteries during the initial encounter and echocardiogram (n = 164), 16 (10%) developed coronary artery dilation or aneurysm at the second echocardiogram, and 5 (3%) continued to have coronary artery dilation or aneurysm at the convalescent phase. CONCLUSIONS: A repeat echocardiogram during the second week of illness (day 7-14 from fever onset) in patients with normal initial echocardiogram could identify new-onset coronary artery dilation or aneurysm and could be useful in the timely adjustment of antithrombotic or anti-inflammatory therapies.

Study design and rationale to assess Doxycycline Efficacy in preventing coronary Artery Lesions in children with Kawasaki disease (DEAL trial) - A phase II clinical trial.

BACKGROUND: Kawasaki disease (KD) is the most common acquired heart disease in children of the developed world, and triggers progressive coronary artery lesions (CAL) in 30% of cases if left untreated. Despite standard anti-inflammatory treatment for KD, CAL (dilation or aneurysm) still occurs in 5-10% of children, increasing their risk for fatal coronary artery complications. CAL is mediated by enhanced matrix metalloproteinase activity and elastin breakdown induced by the inflammatory process in the coronary artery wall. Doxycycline is an effective inhibitor of matrix metalloproteinases, and has been shown to reduce elastin breakdown and CAL in a mouse model of KD, but has not been evaluated in patients. OBJECTIVE: We aim to evaluate the efficacy of doxycycline in the prevention of CAL in children during the acute phase of KD. DESIGN: This is a phase II prospective, randomized, double-blinded, clinical trial in two steps. In Step 1, any child older than 1month with the diagnosis of KD will be included. Children with KD will be included in Step 2 if they develop coronary artery dilation (z-score≥2.5) within 20days from the onset of fever. Study subjects in Step 2 will be randomized to receive a 3-week course of doxycycline or placebo. EVALUATION: The efficacy of a 3-week doxycycline course during the acute phase of KD will be evaluated by measuring the decline in coronary artery z-scores from baseline with doxycycline treatment compared to placebo. CLINICAL TRIAL REGISTRATION: This study was registered on clinicaltrials.gov (NCT01917721).

Clinical and Imaging Findings in an Infant With Zika Embryopathy.

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.

Appendicitis as the presenting manifestation of Kawasaki disease.

In cases of Kawasaki's disease (KD) presenting as acute surgical abdomen, rarely has the presence of acute appendicitis been found. We report two cases of histologically confirmed acute appendicitis in the presence of KD and a review of the literature as it pertains to acute abdomen and atypical presentations 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.

Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease.

OBJECTIVE: To investigate the safety, tolerability, and pharmacokinetics of the anti-tumor necrosis factor-alpha monoclonal antibody infliximab in subjects with intravenous immunoglobulin (IVIG)-resistant Kawasaki disease (KD). STUDY DESIGN: We conducted a multicenter, randomized, prospective trial of second IVIG infusion (2 g/kg) versus infliximab (5 mg/kg) in 24 children with acute KD and fever after initial treatment with IVIG. Primary outcome measures were the safety, tolerability, and pharmacokinetics of infliximab. Secondary outcome measures were duration of fever and changes in markers of inflammation. RESULTS: Study drug infusions were associated with cessation of fever within 24 hours in 11 of 12 subjects treated with infliximab and in 8 of 12 subjects retreated with IVIG. No infusion reactions or serious adverse events were attributed to either study drug. No significant differences were observed between treatment groups in the change from baseline for laboratory variables, fever, or echocardiographic assessment of coronary arteries. CONCLUSIONS: Both infliximab and a second IVIG infusion were safe and well tolerated in the subjects with KD who were resistant to standard IVIG treatment. The optimal management of patients resistant to IVIG remains to be determined.

Infliximab treatment for refractory Kawasaki syndrome.

OBJECTIVE: To evaluate the use of tumor necrosis factor (TNF)-alpha blockade for treatment of patients with Kawasaki syndrome (KS) who fail to become afebrile or who experience persistent arthritis after treatment with intravenous gamma globulin (IVIG) and high-dose aspirin. STUDY DESIGN: Cases were retrospectively collected from clinicians throughout the United States who had used infliximab, a chimeric murine/human immunoglobulin (Ig)G1 monoclonal antibody that binds specifically to human TNF-alpha-1, for patients with KS who had either persistent arthritis or persistent or recrudescent fever > or =48 hours following infusion of 2 g/kg of IVIG. RESULTS: Response to therapy with cessation of fever occurred in 13 of 16 patients. C-reactive protein (CRP) level was elevated in all but one patient before infliximab infusion, and the level was lower following infusion in all 10 patients in whom it was re-measured within 48 hours of treatment. There were no infusion reactions to infliximab and no complications attributed to infliximab administration in any of the patients. CONCLUSION: The success of TNF-alpha blockade in this small series of patients suggests a central role of TNF-alpha in KS pathogenesis. Controlled, randomized clinical trials are warranted to determine the role of anti-TNF-alpha therapy in KS.

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

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.

TT virus: preferential distribution in CD19(+) peripheral blood mononuclear cells and lack of viral integration.

In order to determine whether peripheral blood mononuclear cells (PBMC) contain proviral DNA or double-stranded replicative forms of TT virus (TTV) and to define which cell subset harbors TTV, we analyzed 126 PBMC DNA samples by PCR, using the NG059/NG061/NG063 and the T801/T935 primer sets. TTV sequences were detected in nearly 20% (25/126) of PBMC DNA samples. Analysis of PBMC subsets revealed that TTV was preferentially distributed in CD19(+) cells. TTV DNA was also detected in CD3(+)/CD19(+) double-depleted cells but was undetectable in CD3(+) cells. After degradation of single-stranded DNA using mung bean nuclease (MBN), TTV could not be detected in previously TTV-positive PBMC DNA samples nor in DNA from CD19(+) cells, CD3(+)-depleted, and CD3(+)/CD19(+) double-depleted cells, indicating the lack of TTV DNA integration and the absence of viral double-stranded replicative intermediates in PBMC or PBMC subset cells. Our data indicate that PBMC and PBMC subsets are not the major sites of TTV replication.