Immunogenicity and Safety of a Measles-Mumps-Rubella Vaccine Administered as a First Dose to Children Aged 12 to 15 Months: A Phase III, Randomized, Noninferiority, Lot-to-Lot Consistency Study.

BACKGROUND: MMR II (M-M-R II [Merck & Co, Inc.]) is currently the only measles, mumps, and rubella (MMR) vaccine licensed in the United States. A second MMR vaccine would mitigate the potential risk of vaccine supply shortage or delay. In this study, we assessed the immunogenicity and safety of another MMR vaccine (MMR-RIT [Priorix, GlaxoSmithKline]) compared with those of the MMR II in 12- to 15-month-old children who received it as a first dose. METHODS: In this phase III, observer-blinded, noninferiority, lot-to-lot consistency clinical trial (ClinicalTrials.gov identifier NCT01702428), 5003 healthy children were randomly assigned to receive 1 dose of MMR-RIT (1 of 3 production lots) or MMR II along with other age-recommended routine vaccines. We evaluated the immunogenicity of all vaccines in terms of antibody concentrations (by using an enzyme-linked immunosorbent assay or electrochemiluminescence assay) and/or seroresponse rates 43 days after vaccination. We also assessed the reactogenicity and safety of the vaccines. RESULTS: Immunoresponses after vaccination with MMR-RIT were robust and noninferior to those after vaccination with the MMR II. Immunogenicity of the 3 production lots of MMR-RIT was consistent; more than 97% of the children had a seroresponse to MMR components. The coadministered vaccines elicited similar immunoresponses in the MMR-RIT and MMR II groups. Both MMR vaccines resulted in comparable reactogenicity profiles, and no safety concerns were detected. CONCLUSIONS: If licensed, the MMR-RIT could provide a valid option for the prevention of measles, mumps, and rubella in children in the United States and would reduce potential risks of a vaccine shortage.

Idiopathic T cell lymphopenia identified in New York State Newborn Screening.

Quantification of T-cell receptor excision circles (TRECs) for newborn screening for SCID has advanced the diagnosis of severe combined immune deficiency (SCID). However, it has led to the identification of infants with T cell lymphopenia without known cause. The clinical characteristics, appropriate laboratory monitoring, and outcomes of patients remain unclear. We performed a retrospective review of clinical and laboratory studies for 26 infants collected from 7 New York State referral centers from 2010 to 2016 with low TRECs (mean, 70copies/µl) and subnormal CD3 counts (mean, 1150/cubicmm). Over time absolute CD3 counts increased in 17 and decreased in 9; 22 (85%) have done well clinically regardless of absolute T cell values. Additional infants with TCL will continue to be identified in newborn screening panels. While most patients seem to do well clinically, parameters for diagnosis and monitoring have yet to be formalized, and additional information needs to be collected, causes and outcomes reported.

Lot-to-lot consistency, safety and immunogenicity of 3 lots of Haemophilus influenzae type b conjugate vaccine: results from a phase III randomized, multicenter study in infants.

BACKGROUND: Vaccination against Haemophilus influenzae type b (Hib) is included in routine pediatric immunization schedule in the United States. Previous vaccine shortages have created the need for additional options for Hib vaccination. METHODS: This phase III, randomized, multi-centered study (NCT01000974) evaluated the safety and immunogenicity of a monovalent tetanus toxoid-conjugate Hib vaccine (Hib-TT) compared to a monovalent (Hib-TT control) and a combination Hib-TT vaccine. We hierarchically assessed lot-to-lot consistency of 3 Hib-TT lots and non-inferiority of Hib-TT to Hib-TT control. We co-administered routine pediatric vaccines with Hib-TT vaccines at 2, 4, 6months (primary vaccination) and 15-18months of age (booster vaccination). We recorded adverse events (AEs) for 4 (solicited) and 31days (unsolicited) post-vaccination and serious AEs (SAEs) throughout the study. RESULTS: Of 4009 enrolled children, 3086 completed booster phase. Lot-to-lot consistency was not demonstrated. The study met statistical criteria for non-inferiority of Hib-TT to Hib-TT control in terms of immune responses to Hib and co-administered vaccines' antigens, but not in terms of participants achieving post-primary vaccination anti-PRP levels ≥1µg/mL. Because of the hierarchical nature of the objectives, non-inferiority could not be established. In all groups, 92.5-96.7% and 99.6-100% of participants achieved anti-PRP levels ≥0.15µg/mL, while 78.3-89.8% and 97.9-99.1% had anti-PRP levels ≥1µg/mL, post-primary and post-booster vaccination, respectively. Immune responses to co-administered vaccines and reported incidence of AEs were comparable among groups. We recorded SAEs for 107/2963 (3.6%), 24/520 (4.6%), and 21/520 (4.0%) children post-primary vaccination, and 29/2337 (1.2%), 4/435 (0.9%), and 2/400 (0.5%) children post-booster vaccination with Hib-TT, Hib-TT control and combination Hib-TT vaccine, respectively; 6/5330 (0.1%) SAEs in the Hib-TT groups were considered vaccine-related. CONCLUSION: Hib-TT induced seroprotective antibody concentrations in the majority of participants and was well-tolerated when co-administered with routine pediatric vaccines according to a 3+1 schedule.

Evaluation of recent New Vaccine Surveillance Network data regarding respiratory syncytial virus hospitalization rates in US preterm infants.

In July 2014, the Committee on Infectious Diseases (COID) updated their guidance on the use of palivizumab, recommending against use in preterm infants 29 to 35 weeks' gestational age (wGA). A primary data source cited to support this significant change was the low respiratory syncytial virus (RSV) hospitalization rate observed in the subpopulation of preterm (<37 wGA) infants evaluated from 2000 to 2005 through the New Vaccine Surveillance Network (NVSN). Here we critically appraise the preterm infant data from the NVSN in the context of data regarding the use of palivizumab in this same time period. Data from the NVSN, an analysis of Florida Medicaid data, and a national survey of US in-hospital palivizumab administration demonstrated that during 2001 to 2007, palivizumab was administered to 59% to 83% of preterm infants born at <32 wGA and 21% to 27% of all preterm infants (<37 wGA). When the NVSN data regarding incidence of RSV hospitalization in preterm infant subgroups were evaluated as a function of chronologic age, preterm infants <32 wGA showed a paradoxical increase in RSV hospitalization with older age, with the highest risk of RSV hospitalization occurring at 18 to 23 months of age. This pattern is most consistent with a reduction in RSV hospitalizations in <32 wGA infants in the first 12 to 18 months of life due to high palivizumab use at these young ages. The NVSN data were not designed to and cannot accurately describe RSV disease burden in preterm infants given the small size of the analyzed subpopulation and the high use of palivizumab during the study period.

Valganciclovir for symptomatic congenital cytomegalovirus disease.

BACKGROUND: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). CONCLUSIONS: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).

Partial palivizumab prophylaxis and increased risk of hospitalization due to respiratory syncytial virus in a Medicaid population: a retrospective cohort analysis.

BACKGROUND: Infection with respiratory syncytial virus (RSV) is common among young children insured through Medicaid in the United States. Complete and timely dosing with palivizumab is associated with lower risk of RSV-related hospitalizations, but up to 60% of infants who receive palivizumab in Medicaid population do not receive full prophylaxis. The purpose of this study was to evaluate the association of partial palivizumab prophylaxis with the risk of RSV hospitalization among high-risk Medicaid-insured infants. METHODS: Claims data from 12 states during 6 RSV seasons (October 1st to April 30th in the first year of life in 2003-2009) were analyzed. Inclusion criteria were birth hospital discharge before October 1st, continuous insurance eligibility from birth through April 30th, ≥ one palivizumab administration from August 1st to end of season, and high-risk status (≤34 weeks gestational age or chronic lung disease of prematurity [CLDP] or hemodynamically significant congenital heart disease [CHD]). Fully prophylaxed infants received the first palivizumab dose by November 30th with no gaps >35 days up to the first RSV-related hospitalization or end of follow-up. All other infants were categorized as partially prophylaxed. RESULTS: Of the 8,443 high-risk infants evaluated, 67% (5,615) received partial prophylaxis. Partially prophylaxed infants were more likely to have RSV-related hospitalization than fully prophylaxed infants (11.7% versus 7.9%, p< 0.001). RSV-related hospitalization rates ranged from 8.5% to 24.8% in premature, CHD, and CLDP infants with partial prophylaxis. After adjusting for potential confounders, logistic regression showed that partially prophylaxed infants had a 21% greater odds of hospitalization compared with fully prophylaxed infants (odds ratio 1.21, 95% confidence interval 1.09-1.34). CONCLUSIONS: RSV-related hospitalization rates were significantly higher in high-risk Medicaid infants with partial palivizumab prophylaxis compared with fully prophylaxed infants. These findings suggest that reduced and/or delayed dosing is less effective.

Newborn screening for SCID in New York State: experience from the first two years.

PURPOSE: To describe the process and assess outcomes for the first 2 years of newborn screening for severe combined immunodeficiency (SCID NBS) in New York State (NYS). METHODS: The NYS algorithm utilizes a first-tier molecular screen for TRECs (T-cell receptor excision circles), the absence of which is indicative of increased risk of immunodeficiency. RESULTS: During the first 2 years, 485,912 infants were screened for SCID. Repeat specimens were requested from 561 premature and 746 non-premature infants with low or borderline TRECs. A total of 531 infants were referred for diagnostic evaluation leading to identification of 10 infants with SCID and 87 with a clinically significant non-SCID abnormality based on flow cytometry or CBC results (positive predictive value 20.3 %). Nine infants were diagnosed with typical SCID and one with leaky SCID. SCID diagnoses included two patients with adenosine deaminase deficiency, three patients with typical and one with leaky IL2RG-related SCID, one patient with IL7Rα-related SCID, and three cases of typical SCID, etiology unknown. TRECs were undetectable in eight of the nine babies with typical SCID. Infants with other non-SCID conditions included 27 patients with a syndrome that included T-cell impairment, 18 of which had DiGeorge syndrome. Seventeen infants had T-cell impairment secondary to another clinically significant condition, and 13 were classified as 'other'. Among 30 infants classified as idiopathic T-cell lymphopenia, 11 have since resolved, and the remainder continues to be followed. One infant with undetectable TRECs had normal follow-up studies. Molecular studies revealed the presence of two changes in the infant's DNA. CONCLUSIONS: Overall, ten infants with SCID were identified during the first 2 years of screening in NYS, yielding an incidence of approximately 1 in 48,500 live births, which is consistent with the incidence observed by other states screening for SCID. The incidence of any clinically significant laboratory abnormality was approximately 1 in 5,000; both estimates are higher than estimates prior to the onset of newborn screening for SCID. Improvements to the NYS algorithm included the addition of a borderline category that reduced the proportion of infants referred for flow cytometric analysis, without decreasing sensitivity. We identified a large number of infants with abnormal TRECs and subsequent idiopathic T-cell lymphopenia. Long-term follow-up studies are needed to determine the prognosis and optimal treatment for this group of patients, some of whom may present with previously unrecognized, transient lymphopenia of infancy.

Cost utility of palivizumab prophylaxis among pre-term infants in the United States: a national policy perspective.

OBJECTIVE: The cost-effectiveness of palivizumab has previously been reported among certain guideline-eligible, high-risk premature infants in Medicaid. Because guideline authorities base decisions on a national perspective, the economic model of palivizumab was adapted to include all infants, that is, public and privately insured patients (60% of palivizumab use is public, 40% is private). METHODS: This study examined four groups of premature infants without chronic lung disease of prematurity or congenital heart disease: (1) <32 weeks gestational age (wGA) and ≤ 6 months chronologic age (CA); (2) 32-34 wGA, ≤ 3 months CA, with 2009 American Academy of Pediatrics (AAP) risk factors (RFs); (3) 32-35 wGA, ≤ 6 months CA, with 2006 AAP RFs; and (4) 32-35 wGA, ≤ 6 months CA, with ≤ 1 RF. An average estimate was used between public and private payors for (1) background rates of respiratory syncytial virus hospitalization (RSV-H), (2) direct medical costs associated with RSV-H, and (3) cost of palivizumab. Incremental cost-effectiveness ratios (ICERs) are reported in cost per quality-adjusted life-year (QALY) gained. Sensitivity analyses were performed. RESULTS: Palivizumab saved costs and improved QALYs among infants <32 wGA. Palivizumab was cost-effective in infants 32-34 wGA with 2009 AAP RFs ($44,774 per QALY) and in infants 32-35 wGA with 2006 AAP RFs ($79,477 per QALY). The ICER for infants 32-35 wGA with ≤ 1 RF was $464,476 per QALY. Influential variables in the sensitivity analysis included background rate of RSV-H and cost and efficacy of palivizumab. LIMITATIONS: The results are not generalizable to populations outside of the US. The model did not examine all RFs. The wholesale acquisition cost was used as a payment benchmark; actual price paid by end providers varies. CONCLUSIONS: From a national policy perspective, palivizumab remained cost-effective for publically and commercially insured, guideline-eligible, high-risk premature infants. Palivizumab was not cost-effective in infants of 32-35 wGA with ≤ 1 RF.

Cost-effectiveness analysis of palivizumab among pre-term infant populations covered by Medicaid in the United States.

OBJECTIVE: Medicaid infants are at high risk of severe respiratory syncytial virus (RSV) disease. The study objective was to estimate the cost-effectiveness of palivizumab in a Medicaid population. METHODS: A societal cost-utility analysis was conducted of prophylaxis with palivizumab vs no prophylaxis among four groups of premature infants: (1) <32 weeks gestational age (wGA) and ≤ 6 months chronologic age (CA); (2) 32-34 wGA, ≤ 3 months CA with 2009 American Academy of Pediatrics (AAP) risk factors (RF); (3) 32-35 wGA, ≤ 6 months CA with 2006 AAP RF; and (4) 32-35 wGA, ≤ 6 months CA with ≤ 1 RF. Full dosing of palivizumab was assumed throughout the RSV season (consistent with the FDA-approved label). All costs were in 2010 US dollars. The societal public payer spend for palivizumab was estimated using Medicaid reimbursement methodologies for the top 10 palivizumab-using states in 2010 minus mandatory manufacturer rebates. This study reports the incremental cost-effectiveness ratios (ICERs) in cost per quality-adjusted life-year (QALY) gained. Sensitivity and probabilistic analyses were also conducted. RESULTS: Palivizumab saved costs and improved QALYs among infants <32 wGA. Palivizumab was cost-effective in infants 32-34 wGA with 2009 AAP RF ($16,037 per QALY) and in infants 32-35 wGA with 2006 AAP RF ($38,244 per QALY). The ICER for infants 32-35 wGA with ≤ 1 RF was $281,892 per QALY. Influential variables in the sensitivity analysis included the background rate of RSV hospitalization, the cost of palivizumab, and the efficacy of palivizumab. KEY LIMITATIONS: These results are not generalizable to commercially insured infants or infants outside of the US. CONCLUSIONS: This is the first cost-utility analysis of palivizumab in a Medicaid population. Palivizumab, when dosed consistent with the FDA-approved labeling, was either cost-saving or cost-effective among current guideline-eligible infants in the Medicaid population. Palivizumab did not demonstrate cost-effectiveness in 32-35 wGA infants with ≤ 1 RF.

Oral acyclovir suppression and neurodevelopment after neonatal herpes.

BACKGROUND: Poor neurodevelopmental outcomes and recurrences of cutaneous lesions remain unacceptably frequent among survivors of neonatal herpes simplex virus (HSV) disease. METHODS: We enrolled neonates with HSV disease in two parallel, identical, double-blind, placebo-controlled studies. Neonates with central nervous system (CNS) involvement were enrolled in one study, and neonates with skin, eye, and mouth involvement only were enrolled in the other. After completing a regimen of 14 to 21 days of parenteral acyclovir, the infants were randomly assigned to immediate acyclovir suppression (300 mg per square meter of body-surface area per dose orally, three times daily for 6 months) or placebo. Cutaneous recurrences were treated with open-label episodic therapy. RESULTS: A total of 74 neonates were enrolled--45 with CNS involvement and 29 with skin, eye, and mouth disease. The Mental Development Index of the Bayley Scales of Infant Development (in which scores range from 50 to 150, with a mean of 100 and with higher scores indicating better neurodevelopmental outcomes) was assessed in 28 of the 45 infants with CNS involvement (62%) at 12 months of age. After adjustment for covariates, infants with CNS involvement who had been randomly assigned to acyclovir suppression had significantly higher mean Bayley mental-development scores at 12 months than did infants randomly assigned to placebo (88.24 vs. 68.12, P=0.046). Overall, there was a trend toward more neutropenia in the acyclovir group than in the placebo group (P=0.09). CONCLUSIONS: Infants surviving neonatal HSV disease with CNS involvement had improved neurodevelopmental outcomes when they received suppressive therapy with oral acyclovir for 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; CASG 103 and CASG 104 ClinicalTrials.gov numbers, NCT00031460 and NCT00031447, respectively.).

Incidence of invasive community-onset Staphylococcus aureus infections in children in Central New York.

We determined the incidence of invasive community-onset Staphylococcus aureus infections, clinical characteristics, and antibiotic susceptibilities in 128 hospitalized children in central New York. The prevalence of invasive S aureus infections in our institution remained <1% between 1996 and 2006, although the proportion of methicillin-resistant S aureus infections significantly increased.

Dipylidium caninum mimicking recurrent enterobius vermicularis (pinworm) infection.

Pinworm infection is a very common diagnosis in young children that is not always confirmed through laboratory evaluation before empiric therapy is prescribed. This article describes a toddler who was treated several times for pinworms because small white worms were seen in her perianal area. Laboratory analysis of parasite material found in her diaper later confirmed a diagnosis of dipylidiasis. Because the signs of dipylidiasis and pinworm infection overlap and the treatments for these parasitic infections are different, the laboratory should clinically confirm suspected persistent or recurrent pinworms.

Methemoglobinemia revisited: an important complication after transesophageal echocardiography.

Methemoglobinemia induced by the use of benzocaine-containing topical anesthetics is a rare, but potentially lethal complication after transesophageal echocardiography (TEE). We report a patient who developed methemoglobinemia after TEE. A review of the literature was performed and the majority of cases of benzocaine-induced methemoglobinemia reported thus far have occurred in patients undergoing TEE, endotracheal intubation, esophagogastroduodenoscopy, and bronchoscopy. All of these procedures have become more frequent than before, and there is a need to reemphasize the potential problem and to reconsider the need for further use of topical anesthetics.

Head lice.

Head lice infestation is associated with little morbidity but causes a high level of anxiety among parents of school-aged children. This statement attempts to clarify issues of diagnosis and treatment of head lice and makes recommendations for dealing with head lice in the school setting.