Donna Curtis

Hospitalized children with 2009 pandemic influenza A (H1N1): comparison to seasonal influenza and risk factors for admission to the ICU.

Background Limited data are available describing the clinical presentation and risk factors for admission to the intensive care unit for children with 2009 H1N1 infection. Methods We conducted a retrospective chart review of all hospitalized children with 2009 influenza A (H1N1) and 2008–09 seasonal influenza at The Childrens Hospital, Denver, Colorado. Results Of the 307 children identified with 2009 H1N1 infections, the median age was 6 years, 61% were male, and 66% had underlying medical conditions. Eighty children (26%) were admitted to the ICU. Thirty-two (40%) of the ICU patients required intubation and 17 (53%) of the intubated patients developed acute respiratory distress syndrome (ARDS). Four patients required extracorporeal membrane oxygenation. Eight (3%) of the hospitalized children died. Admission to the ICU was significantly associated with older age and underlying neurological condition. Compared to the 90 children admitted during the 2008–09 season, children admitted with 2009 H1N1 influenza were significantly older, had a shorter length of hospitalization, more use of antivirals, and a higher incidence of ARDS. Conclusions Compared to the 2008–09 season, hospitalized children with 2009 H1N1 influenza were much older and had more severe respiratory disease. Among children hospitalized with 2009 H1N1 influenza, risk factors for admission to the ICU included older age and having an underlying neurological condition. Children under the age of 2 hospitalized with 2009 H1N1 influenza were significantly less likely to require ICU care compared to older hospitalized children.

Pediatric Neurological Complications of 2009 Pandemic Influenza A (H1N1)

OBJECTIVE To analyze the spectrum of neurological manifestations in children hospitalized with pandemic influenza A H1N1 virus of 2009 (pH1N1). DESIGN Retrospective case series of children hospitalized from May 1, 2009, through November 30, 2009. SETTING Tertiary-care childrens hospital in Colorado. PATIENTS All hospitalized patients with pH1N1 with neurological consult or diagnosis, lumbar puncture, electroencephalogram, or neuroimaging were selected as suspected cases. These were systematically reviewed and selected for final analysis if confirmed by pre-established definitions as a neurological complication. RESULTS Of 307 children with pH1N1, 59 were selected as having suspected cases of neurological complications. Twenty-three children were confirmed to have a neurological complication. Of these 23, 15 (65%) required intensive care monitoring. The median length of stay was 4 days. Seventeen (74%) had a preexisting neurological diagnosis. The most common manifestation was seizure with underlying neurological disease (in 62% of cases) followed by encephalopathy with or without neuroimaging changes (in 26% of cases). Results from a lumbar puncture showed elevated protein levels in 3 of 6 patients but no significant pleocytosis. Seven of the 9 electroencephalograms showed diffuse slowing, and findings from magnetic resonance imaging were abnormal in 5 of 6 children. Deaths occurred in 13% of patients, and short-term disability in 22%. CONCLUSIONS Children infected with pH1N1 presented with a wide spectrum of neurological manifestations, which occurred primarily in individuals with preexisting neurological conditions. These individuals had a severe disease course, evidenced by need for intensive care services and relatively high rates of mortality or neurological disability. Children with underlying neurological conditions should be particularly targeted for influenza prevention and aggressive supportive treatment at the onset of influenzalike symptoms.

Vaccine strain varicella-zoster virus-induced central nervous system vasculopathy as the presenting feature of DOCK8 deficiency.

To the Editor: In contrast to autosomal dominant forms of hyper-IgE syndrome resulting from mutations in the STAT3 gene, autosomal recessive dedicator of cytokinesis 8 (DOCK8) deficiency, results in susceptibility to cutaneous viral infections, eosinophilia, and allergic disease. CNS manifestations have been reported in patients with DOCK8 deficiency, but progressive multifocal leukoencephalopathy caused by JC virus has been considered the only known viral etiology to date (1, 2). A 6 year-old boy with atopy and recurrent peripheral blood eosinophilia developed acute intermittent vomiting, diarrhea, headache, and dizziness. Magnetic resonance imaging (MRI) of the brain was normal. One day later, he began giggling inappropriately, experienced left leg paresthesias, urinary incontinence, and fell upon attempting to stand. Repeat MRI with axial diffusion-weighted images revealed multiple areas of acute infarction in areas supplied by both anterior cerebral arteries, a branch of the anterior cerebral artery, the right posterior cerebral artery, and the left middle cerebral artery (Figure 1A). A complete blood count revealed a total eosinophil count of 2,160/μL, but no other abnormalities. He was treated with acetylsalicylic acid and intravenous methylprednisolone followed by oral prednisolone, 2 mg/kg for 3 days after which prednisolone was maintained at 1 mg/kg daily. Figure 1 Manifestation of vaccine strain varicella zoster virus-induced central nervous system vasculopathy On presentation to us one month later, he had developed paresthesias of his hands. Neurological examination showed only mild weakness in the hands. Computed tomography angiogram revealed diffuse vasculopathy. Subsequent 3-dimensional time of flight magnetic resonance angiographic imaging of the circle of Willis revealed vascular narrowing and post-stenotic dilatation (Figure 1B). Post-contrast T1W black blood arterial wall imaging illustrated avid enhancement and thickening of the distal supraclinoid internal carotid arterial walls bilaterally (Figure 1C). Cerebral spinal fluid (CSF) was obtained. While awaiting results of testing for viral CNS infections, the patient was treated with acyclovir, 30 mg/kg intravenous daily, and maintained on oral prednisolone, 2 mg/kg/day. The CSF at the time of diagnosis of vasculopathy contained 21 mononuclear cells and no red blood cells; protein was 39 mg/dL and glucose was 72 mg/dL. Quantitative PCR (Focus Diagnostics Reference Laboratory, Cypress, CA) amplified 7,116 copies of VZV DNA/mL in the CSF. To determine the VZV genotype, Forster Resonance Energy Transfer PCR was used to identify specific VZV DNA sequence polymorphisms within VZV open reading frames 38, 54, and 62, which distinguishes vaccine VZV from wild-type virus (Online Supplement Table 1) (3). This confirmed Oka varicella vaccine strain in the CSF. The CSF also contained anti-VZV IgG antibodies, but no antibodies to HSV-1 or HSV-2, enterovirus, cytomegalovirus, or Epstein-Barr virus were detected and the respective PCR analysis were similarly negative. The serum to CSF ratio of anti-VZV IgG antibody was markedly decreased (ratio 2.3) compared to albumin (ratio 149). Two weeks after treatment with acyclovir, the neurologic examination was completely normal, the CSF was acellular, and PCR was negative for VZV DNA. The patient received routine immunizations including VZV vaccination at 12 months of age. He had 3 episodes of vesicular rashes at ages 3, 4, and 5 years, which always occurred after completing a course of oral corticosteroids. The first rash tested positive for HSV. The second rash was identical. The third rash at age 5 years with vesicles on the lower thigh was diagnosed clinically as zoster. All rashes resolved on oral acyclovir. Past history included early-onset atopic dermatitis, food allergies often with anaphylaxis, biopsy-confirmed eosinophilic esophagitis, asthma and recurrent upper respiratory tract infections. Peripheral blood eosinophilia peaked at 9,000 eosinophils/μL and serum IgE at 472 IU/mL. During flares of respiratory or skin disease, he was treated with oral corticosteroids intermittently for 3 to 5 days, a few times annually. The frequency of such treatment increased and between ages 5½ and 6, he was treated with oral corticosteroids 1 to 2 times monthly during the prior 6 months. Conventional comparative genomic hybridization array analysis revealed a large deletion of exons 1 to 13 in a single allele of the DOCK8 gene. PCR analysis of genomic DNA and DOCK8 gene sequencing identified a single base pair mutation on the opposite allele at exon 12, resulting in a frame shift and premature stop codon: c.1266delC, p.Y423TfsX18, based upon reference sequence NM_00193536.1, isoform 3 (Figure 2A). Western Blot analysis confirmed lack of DOCK8 protein expression (Figure 2B). Parental testing demonstrated that the large exon deletion was inherited from the mother while the point mutation was inherited from the father. Immunological findings are summarized in Supplemental Table 2. Figure 2 DOCK8 molecular analyses The neurological symptoms and signs, imaging and CSF abnormalities, virological studies, and response to antiviral treatment were all features characteristically seen in VZV vasculopathy (4). Evidence of both focal and diffuse CNS disease was corroborated by widespread infarction produced by stenosis of multiple large cerebral arteries. The CSF examination revealed a pleocytosis as found in two-thirds of patients with VZV vasculopathy and both VZV DNA and anti-VZV IgG antibody with reduced serum/CSF ratios of anti-VZV IgG antibody were detected, indicative of intrathecal synthesis of anti-VZV IgG. Analysis of VZV DNA in CSF revealed that the VZV genotype was vaccine strain, demonstrating, for the first time, that VZV reactivation after vaccination in childhood can result in VZV vasculopathy. Although the underlying immunological consequences of DOCK8 deficiency remain to be fully elucidated, multiple immune system abnormalities may account for enhanced susceptibility to viral infection including impaired dendritic cell migration affecting T cell priming, lymphopenia, defective CD8 T cell activation and expansion, decreased production of the anti-viral cytokines IFN-γ and TNF-α, impaired T cell survival, decreased NK cell cytotoxicity, and antibody abnormalities (5-9). Germinal center formation and survival of germinal center B cells are impaired in DOCK8 deficiency, leading to defective long-lived antibody production (8). Responses to protein or polysaccharide-conjugated vaccines are often variable while responses to previously encountered viruses such as HSV and VZV have been normal as demonstrated here for VZV antibodies in serum and CSF. As in some other young patients with DOCK8 deficiency, this patient tended toward the milder spectrum of the disease with a relatively limited history of cutaneous infections, absence of severe systemic infections other than chronic mild otitis, and the modestly elevated serum IgE level. Instead, eosinophilia and moderate-severe eczema, asthma, and food sensitivities predominated. To control these conditions, courses of oral corticosteroids were administered with increased frequency over time. Interestingly, each of the 3 episodes of cutaneous viral infections with HSV or VZV was preceded by a course of oral corticosteroids. It is possible corticosteroids alone enabled the activation of vaccine strain VZV infection. More likely, the use of oral corticosteroids to gain disease control reduced the patient’s “immunologic threshold” and together resulted in reactivation of vaccine strain VZV and subsequent vasculopathy. In summary, a young patient with significant atopic disease and widespread infarction produced by stenosis of multiple large cerebral arteries was shown to express novel mutations on both alleles of the DOCK8 gene. For the first time, VZV vasculopathy was shown to be due to the vaccine strain. This case highlights the importance of considering the possibility of DOCK8 deficiency in the context of severe allergic disease and the potential risks for CNS infection including VZV vaccine-related vasculopathy.

Safety, immunogenicity and shedding of LAIV4 in HIV-infected and uninfected children.

OBJECTIVES HIV-infected children have poor responses to inactivated influenza vaccines. Live vaccines (LAIVs) are highly efficacious in children, but they are not used in HIV-infected children du e to limited information. We investigated the safety, immunogenicity and viral shedding of LAIV4 in HIV-infected compared with uninfected children. DESIGN Forty-six HIV-infected and 56 uninfected children 2 to 25 years old, who had been previously vaccinated against influenza, consented to receive a single dose of LAIV4. All grade adverse events (AEs) were recorded in the first month post-vaccination and serious AEs (SAEs) throughout the influenza season. Nasopharyngeal swabs for influenza PCR and IgA ELISA and blood for hemagglutination inhibition antibody (HAI) measurements were collected at entry, 2-5, 7-10 and 21-28 days post-vaccination. RESULTS The HIV-infected subjects had median CD4+ cells of 649 cells/μL and plasma HIV RNA of 20 copies/mL. AEs were similar in the two groups. There were no vaccine-related SAEs. Shedding of ≥1 vaccine virus was detected in 67% HIV-infected and 50% uninfected participants (p=0.14). HAI titers did not appreciably change, but mucosal IgA antibodies significantly increased post-vaccination in both groups. High baseline HAI and IgA antibody concentrations were associated with decreased viral shedding in controls, but not in HIV-infected subjects. Similar proportions of HIV-infected vaccinees and controls reported influenza-like illnesses (12% and 6%) throughout the season. CONCLUSIONS LAIV4 was equally safe and immunogenic and caused similar viral shedding in HIV-infected and uninfected children. A correlate of protection against vaccine viral shedding was not identified in HIV-infected participants, although both circulating and mucosal antibodies correlated with protection in controls.

Characterization of Functional Antibody and Memory B-Cell Responses to pH1N1 Monovalent Vaccine in HIV-Infected Children and Youth

Objectives We investigated immune determinants of antibody responses and B-cell memory to pH1N1 vaccine in HIV-infected children. Methods Ninety subjects 4 to <25 years of age received two double doses of pH1N1 vaccine. Serum and cells were frozen at baseline, after each vaccination, and at 28 weeks post-immunization. Hemagglutination inhibition (HAI) titers, avidity indices (AI), B-cell subsets, and pH1N1 IgG and IgA antigen secreting cells (ASC) were measured at baseline and after each vaccination. Neutralizing antibodies and pH1N1-specific Th1, Th2 and Tfh cytokines were measured at baseline and post-dose 1. Results At entry, 26 (29%) subjects had pH1N1 protective HAI titers (≥1:40). pH1N1-specific HAI, neutralizing titers, AI, IgG ASC, IL-2 and IL-4 increased in response to vaccination (p<0.05), but IgA ASC, IL-5, IL-13, IL-21, IFNγ and B-cell subsets did not change. Subjects with baseline HAI ≥1:40 had significantly greater increases in IgG ASC and AI after immunization compared with those with HAI <1:40. Neutralizing titers and AI after vaccination increased with older age. High pH1N1 HAI responses were associated with increased IgG ASC, IFNγ, IL-2, microneutralizion titers, and AI. Microneutralization titers after vaccination increased with high IgG ASC and IL-2 responses. IgG ASC also increased with high IFNγ responses. CD4% and viral load did not predict the immune responses post-vaccination, but the B-cell distribution did. Notably, vaccine immunogenicity increased with high CD19+CD21+CD27+% resting memory, high CD19+CD10+CD27+% immature activated, low CD19+CD21-CD27-CD20-% tissue-like, low CD19+CD21-CD27-CD20-% transitional and low CD19+CD38+HLADR+% activated B-cell subsets. Conclusions HIV-infected children on HAART mount a broad B-cell memory response to pH1N1 vaccine, which was higher for subjects with baseline HAI≥1:40 and increased with age, presumably due to prior exposure to pH1N1 or to other influenza vaccination/infection. The response to the vaccine was dependent on B-cell subset distribution, but not on CD4 counts or viral load. Trial Registration ClinicalTrials.gov NCT00992836

Enterovirus D68 in Critically Ill Children: A Comparison With Pandemic H1N1 Influenza.

Objective: In 2014, the Unites States experienced an outbreak of enterovirus D68 associated with severe respiratory illness. The clinical characteristics associated with severe illness from enterovirus D68 during this outbreak compared with those associated with the 2009 H1N1 influenza virus outbreak are unknown. Design and Setting: In this retrospective cohort study, we characterized the clinical features of children with enterovirus D68 admitted to the PICU between August 1, 2014, and November 1, 2014, and compared them with critically ill children infected with H1N1 influenza during the pandemic admitted between May 1, 2009, and January 31, 2010. Patients: PICU patients. Interventions: None. Measurements and Main Results: Ninety-seven severely ill children with enterovirus D68 infections were compared with 68 children infected with H1N1 influenza during the 2009 pandemic. Children with enterovirus D68 were more likely to have asthma (62% vs 23%; p < 0.001) and present with reactive airway disease exacerbations, with greater receipt of albuterol (94% vs 49%) and steroids (89% vs 40%; p < 0.0001 for both). Although more children with enterovirus D68 were admitted to the ICU compared with those with H1N1 influenza, they had a shorter hospital length of stay (4 vs 7 d; p < 0.0001), with lower intubation rates (7% vs 44%), vasopressor use (3% vs 32%), acute respiratory distress syndrome (3% vs 24%), shock (0% vs 16%), and death (0% vs 12%; p < 0.05 for all). Compared with children with other enteroviruses and rhinoviruses, children with enterovirus D68 were more likely to have a history of asthma (64% vs 45%) or multiple prior wheezing episodes (54% vs 34%; p < 0.01 for both). Conclusions: Critically ill children with enterovirus D68 were more likely to present with reactive airway disease exacerbations, whereas children with H1N1 influenza were more likely to present with pneumonia. Compared with the pandemic H1N1 influenza outbreak, the enterovirus D68 outbreak resulted in more children requiring admission to the ICU, but was associated with less severe outcomes.

A comparison of H1N1 influenza among pediatric inpatients in the pandemic and post pandemic era.

BACKGROUND The novel influenza A H1N1 (A[H1N1]pdm09) strain emerged in 2009, contributing to significant morbidity and mortality. It is not known whether illness associated with A(H1N1) pdm09 in the post-pandemic era exhibits a similar disease profile. OBJECTIVE The objectives of this study were to compare the burden of disease of A(H1N1) pdm09 influenza from the 2009 pandemic year to the post-pandemic years (2010-2014), and to explore potential reasons for any differences. STUDY DESIGN We conducted a retrospective cohort study of inpatients admitted to Childrens Hospital Colorado with a positive respiratory specimen for influenza from May-December, 2009 and December, 2010-April, 2014. Univariate and multivariate analyses were conducted to compare the demographics and clinical characteristics of patients with H1N1 during the two periods. RESULTS There were 388 inpatients with influenza A(H1N1) pdm09 in 2009, and 117 during the post-pandemic years. Ninety-four percent of all H1N1 during the post-pandemic era was observed during the 2013-2014 influenza season. Patients with A(H1N1) pdm09 during the post-pandemic year were less likely to have an underlying medical condition (P<0.01). Patients admitted to the ICU during the post-pandemic year had a lower median age (5 vs 8 years, P=0.01) and a lower proportion of patients were intubated, had mental status changes, and ARDS compared with the pandemic years, (P<0.01 for all), with decreased mortality (P=0.02). CONCLUSION Patients with influenza A(H1N1) pdm09 during the post-pandemic years appeared to have less severe disease than patients with A(H1N1) pdm09 during the pandemic year. The reasons for this difference are likely multifactorial.

Antibody responses to influenza a H1N1 vaccine compared to the circulating strain in influenza vaccine recipients during the 2013/2014 season in North America

BACKGROUND Influenza strain A/California/07/2009 H1N1 (H1N1-09) reemerged in 2013/2014 as the predominant cause of illness. We sought to determine if antigenic drift may have contributed to the decreased responses to influenza vaccine. METHODS Fifty adults who received trivalent inactivated influenza vaccine (IIV3) and 56 children who received live attenuated quadrivalent influenza vaccine (LAIV4) had hemagglutination inhibition (HAI) and microneutralizing (MN) antibodies measured in plasma against H1N1-09 and H1N1 2013/2014 (H1N1-14) influenza. Partial sequencing of the hemagglutinin gene (nt 280-780) was performed on 38 clinical isolates and the vaccine prototype. RESULTS In IIV3 recipients, HAI and MN titers against H1N1-14 were significantly lower than against H1N1-09 (p<0.0001 and 0.04, respectively). In LAIV4 recipients, only MN titers were significantly lower (p=0.02) for H1N1-09 compared with H1N1-14. A combined analysis showed significantly lower HAI and MN titers for H1N1-14 compared with H1N1-09 (p=0. 016 and 0.008, respectively). All 38 clinical isolates encoded the HA gene K166Q non-synonymous substitution; other non-synonymous substitutions were observed in <10% of the clinical isolates. CONCLUSIONS 2013/2014 IIV3 and LAIV4 recipients had consistently lower MN antibody titers against H1N1-14 compared with H1N1-09. The HA K166Q mutation, located in a neutralizing epitope, probably contributed to these findings.

Enterovirus D-68 in Critically-ill Children: a Comparison to Pandemic H1N1 Influenza

OBJECTIVE In 2014, the Unites States experienced an outbreak of enterovirus D68 associated with severe respiratory illness. The clinical characteristics associated with severe illness from enterovirus D68 during this outbreak compared with those associated with the 2009 H1N1 influenza virus outbreak are unknown. DESIGN AND SETTING In this retrospective cohort study, we characterized the clinical features of children with enterovirus D68 admitted to the PICU between August 1, 2014, and November 1, 2014, and compared them with critically ill children infected with H1N1 influenza during the pandemic admitted between May 1, 2009, and January 31, 2010. PATIENTS PICU patients. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Ninety-seven severely ill children with enterovirus D68 infections were compared with 68 children infected with H1N1 influenza during the 2009 pandemic. Children with enterovirus D68 were more likely to have asthma (62% vs 23%; p < 0.001) and present with reactive airway disease exacerbations, with greater receipt of albuterol (94% vs 49%) and steroids (89% vs 40%; p < 0.0001 for both). Although more children with enterovirus D68 were admitted to the ICU compared with those with H1N1 influenza, they had a shorter hospital length of stay (4 vs 7 d; p < 0.0001), with lower intubation rates (7% vs 44%), vasopressor use (3% vs 32%), acute respiratory distress syndrome (3% vs 24%), shock (0% vs 16%), and death (0% vs 12%; p < 0.05 for all). Compared with children with other enteroviruses and rhinoviruses, children with enterovirus D68 were more likely to have a history of asthma (64% vs 45%) or multiple prior wheezing episodes (54% vs 34%; p < 0.01 for both). CONCLUSIONS Critically ill children with enterovirus D68 were more likely to present with reactive airway disease exacerbations, whereas children with H1N1 influenza were more likely to present with pneumonia. Compared with the pandemic H1N1 influenza outbreak, the enterovirus D68 outbreak resulted in more children requiring admission to the ICU, but was associated with less severe outcomes.

11452009 H1N1 Compared to Post-pandemic H1N1 Influenza Among Pediatric Inpatients

Pediatric Inpatients Suchitra Rao, MB, BS; Joshua Williams, MD; Maureen Cunningham, MD; Donna Curtis, MD, MPH; Dayanand Bagdure, MD; Mary Glode, MD, FIDSA; Samuel R. Dominguez, MD, PhD; Pediatrics (Infectious Diseases), University of Colorado School of Medicine, Aurora, CO; Pediatrics, University of Colorado School of Medicine, Aurora, CO; Pediatric Infectious Disease, University of Colorado Denver School of Medicine, Aurora, CO; Pediatric Critical Care, University of Maryland, Baltimore, MD; Pediatric Infectious Diseases, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO; Department of Infectious Disease, Children’s Hospital Colorado/University of Colorado School of Medicine, Aurora, CO