James Gaensbauer

Neuroinvasive Arboviral Disease in the United States: 2003 to 2012

OBJECTIVE: To describe the epidemiologic and clinical syndromes associated with pediatric neuroinvasive arboviral infections among children in the United States from 2003 through 2012. METHODS: We reviewed data reported by state health departments to ArboNET, the national arboviral surveillance system, for 2003 through 2012. Children (<18 years) with neuroinvasive arboviral infections (eg, meningitis, encephalitis, or acute flaccid paralysis) were included. Demographic, clinical syndrome, outcome, geographic, and temporal data were analyzed for all cases. RESULTS: During the study period, 1217 cases and 22 deaths due to pediatric neuroinvasive arboviral infection were reported from the 48 contiguous states. La Crosse virus (665 cases; 55%) and West Nile virus (505 cases; 41%) were the most common etiologies identified. Although less common, Eastern equine encephalitis virus (30 cases; 2%) resulted in 10 pediatric deaths. La Crosse virus primarily affected younger children, whereas West Nile virus was more common in older children and adolescents. West Nile virus disease cases occurred throughout the country, whereas La Crosse and the other arboviruses were more focally distributed. CONCLUSIONS: Neuroinvasive arboviral infections were an important cause of pediatric disease from 2003 through 2012. Differences in the epidemiology and clinical disease result from complex interactions among virus, vector, host, and the environment. Decreasing the morbidity and mortality from these agents depends on vector control, personal protection to reduce mosquito and tick bites, and blood donor screening. Effective surveillance is critical to inform clinicians and public health officials about the epidemiologic features of these diseases and to direct prevention efforts.

Humoral and intestinal immunity induced by new schedules of bivalent oral poliovirus vaccine and one or two doses of inactivated poliovirus vaccine in Latin American infants: an open-label randomised controlled trial

BACKGROUND Replacement of the trivalent oral poliovirus vaccine (tOPV) with bivalent types 1 and 3 oral poliovirus vaccine (bOPV) and global introduction of inactivated poliovirus vaccine (IPV) are major steps in the polio endgame strategy. In this study, we assessed humoral and intestinal immunity in Latin American infants after three doses of bOPV combined with zero, one, or two doses of IPV. METHODS This open-label randomised controlled multicentre trial was part of a larger study. 6-week-old full-term infants due for their first polio vaccinations, who were healthy on physical examination, with no obvious medical conditions and no known chronic medical disorders, were enrolled from four investigational sites in Colombia, Dominican Republic, Guatemala, and Panama. The infants were randomly assigned by permuted block randomisation (through the use of a computer-generated list, block size 36) to nine groups, of which five will be discussed in this report. These five groups were randomly assigned 1:1:1:1 to four permutations of schedule: groups 1 and 2 (control groups) received bOPV at 6, 10, and 14 weeks; group 3 (also a control group, which did not count as a permutation) received tOPV at 6, 10, and 14 weeks; group 4 received bOPV plus one dose of IPV at 14 weeks; and group 5 received bOPV plus two doses of IPV at 14 and 36 weeks. Infants in all groups were challenged with monovalent type 2 vaccine (mOPV2) at 18 weeks (groups 1, 3, and 4) or 40 weeks (groups 2 and 5). The primary objective was to assess the superiority of bOPV-IPV schedules over bOPV alone, as assessed by the primary endpoints of humoral immunity (neutralising antibodies-ie, seroconversion) to all three serotypes and intestinal immunity (faecal viral shedding post-challenge) to serotype 2, analysed in the per-protocol population. Serious and medically important adverse events were monitored for up to 6 months after the study vaccination. This study is registered with ClinicalTrials.gov, number NCT01831050, and has been completed. FINDINGS Between May 20, 2013, and Aug 15, 2013, 940 eligible infants were enrolled and randomly assigned to the five treatment groups (210 to group 1, 210 to group 2, 100 to group 3, 210 to group 4, and 210 to group 5). One infant in group 1 was not vaccinated because their parents withdrew consent after enrolment and randomisation, so 939 infants actually received the vaccinations. Three doses of bOPV or tOPV elicited type 1 and 3 seroconversion rates of at least 97·7%. Type 2 seroconversion occurred in 19 of 198 infants (9·6%, 95% CI 6·2-14·5) in the bOPV-only groups, 86 of 88 (97·7%, 92·1-99·4) in the tOPV-only group (p<0·0001 vs bOPV-only), and 156 of 194 (80·4%, 74·3-85·4) infants in the bOPV-one dose of IPV group (p<0·0001 vs bOPV-only). A further 20 of 193 (10%) infants in the latter group seroconverted 1 week after mOPV2 challenge, resulting in around 98% of infants being seropositive against type 2. After a bOPV-two IPV schedule, all 193 infants (100%, 98·0-100; p<0·0001 vs bOPV-only) seroconverted to type 2. IPV induced small but significant decreases in a composite serotype 2 viral shedding index after mOPV2 challenge. 21 serious adverse events were reported in 20 patients during the study, including two that were judged to be possibly related to the vaccines. Most of the serious adverse events (18 [86%] of 21) and 24 (80%) of the 30 important medical events reported were infections and infestations. No deaths occurred during the study. INTERPRETATION bOPV provided humoral protection similar to tOPV against polio serotypes 1 and 3. After one or two IPV doses in addition to bOPV, 80% and 100% of infants seroconverted, respectively, and the vaccination induced a degree of intestinal immunity against type 2 poliovirus. FUNDING Bill & Melinda Gates Foundation.

Impaired haemophilus influenzae type b transplacental antibody transmission and declining antibody avidity through the first year of life represent potential vulnerabilities for HIV-exposed but -uninfected infants.

ABSTRACT To determine whether immune function is impaired among HIV-exposed but -uninfected (HEU) infants born to HIV-infected mothers and to identify potential vulnerabilities to vaccine-preventable infection, we characterized the mother-to-infant placental transfer of Haemophilus influenzae type b-specific IgG (Hib-IgG) and its levels and avidity after vaccination in Ugandan HEU infants and in HIV-unexposed U.S. infants. Hib-IgG was measured by enzyme-linked immunosorbent assay in 57 Ugandan HIV-infected mothers prenatally and in their vaccinated HEU infants and 14 HIV-unexposed U.S. infants at birth and 12, 24, and 48 weeks of age. Antibody avidity at birth and 48 weeks of age was determined with 1 M ammonium thiocyanate. A median of 43% of maternal Hib-IgG was transferred to HEU infants. Although its level was lower in HEU infants than in U.S. infants at birth (P < 0.001), Hib-IgG was present at protective levels (>1.0 μg/ml) at birth in 90% of HEU infants and all U.S. infants. HEU infants had robust Hib-IgG responses to a primary vaccination. Although Hib-IgG levels declined from 24 to 48 weeks of age in HEU infants, they were higher than those in U.S. infants (P = 0.002). Antibody avidity, comparable at birth, declined by 48 weeks of age in both populations. Early vaccination of HEU infants may limit an initial vulnerability to Hib disease resulting from impaired transplacental antibody transfer. While initial Hib vaccine responses appeared adequate, the confluence of lower antibody avidity and declining Hib-IgG levels in HEU infants by 12 months support Hib booster vaccination at 1 year. Potential immunologic impairments of HEU infants should be considered in the development of vaccine platforms for populations with high maternal HIV prevalence.

Herpes PCR Testing and Empiric Acyclovir Use Beyond the Neonatal Period

BACKGROUND: Diagnostic strategies based on empirical testing and treatment to identify herpes simplex virus (HSV) infection in neonates may not be appropriate for older children in whom the most common presentation of severe infection is encephalitis, a rare and clinically recognizable condition. METHODS: Use of acyclovir in infants and children in 6 common non-HSV infection–related diagnosis-related groups was characterized between 1999 and 2012 at 15 US pediatric hospitals by using the Pediatric Health Information System database. Characteristics of non-neonatal patients at 1 institution tested for HSV encephalitis over a 6.5-year period were then analyzed to identify factors associated with potentially unnecessary testing and treatment. RESULTS: Acyclovir use increased from 7.6% to 15.6% (P < .001) from 1999 to 2012. Much of this increase came in infants 30 to 60 days of age (82.7% increase, P < .001) and in patients with milder disease severity (44.8% increase, P < .001). Length of stay was increased by 2 days for children treated with acyclovir (P < .001). At our institution, 1394 HSV cerebrospinal fluid polymerase chain reactions were performed in children >30 days old, with only 3 positive results (0.22%). Comparison of the 3 subjects with positive testing and 55 with negative testing revealed that all cases, but only 4% (95% confidence interval 1.2%–14.0%) of noncases had clinical characteristics typical of HSV encephalitis. CONCLUSIONS: Strategies for diagnosis and empirical treatment of suspected HSV encephalitis beyond the neonatal period have trended toward the approach common for neonates without evidence of an increase in disease incidence. This may result in increased medical costs and risk to patients.

Pediatric Invasive Pneumococcal Disease in Guatemala City: Importance of Serotype 2.

Introduction: To inform estimations of the potential impact of recently introduced pneumococcal conjugate vaccine (PCV), we report results of 11 years of pre-PCV surveillance for invasive pneumococcal disease (IPD) among children in Guatemala City. Methods: Cases of IPD in children younger than 5 years were identified by active surveillance at 3 referral hospitals in Guatemala City from October 1996 through 2007. Clinical and demographic data were obtained, and isolates of Streptococcus pneumoniae from normally sterile sites were serotyped using latex agglutination and confirmed by Quellung reaction. Results: Four hundred fifty-two cases of IPD were identified with a case fatality rate of 21%. Meningitis was the most common cause of death (77% of all deaths) and occurred more often in infancy (median age 5 months) than other clinical syndromes. Of the 137 isolates serotyped, type 1 (26 cases, 17%), type 2 (25 cases, 16%) and type 5 (18 cases, 12%) were the most common. Serotype 2 was associated with a higher case fatality rate (28%), higher rate of meningitis (68%) and occurred in younger infants (median age, 3.5 months) than other common serotypes. Recently introduced PCV13 includes 73% of observed serotypes in the study. Conclusion: Infants with IPD presented at a young age. Serotype 2, rarely reported as a significant cause of IPD and not included in available PCVs, was a common cause of disease in this population. PCV13 introduction in Guatemala, begun in 2013, may not have as great an impact in disease reduction as has been observed in other countries.

Analysis of the pediatric health information system database as a surveillance tool for travel-associated infectious diseases.

The Pediatric Health Information System (PHIS) database collects admission, diagnostic, and treatment data among 44 childrens hospitals across the United States (U.S.) and presents an opportunity for travel-associated infectious disease (TAID) surveillance. We calculated cumulative incidence rates among children admitted to 16 PHIS hospitals for dengue, malaria, and typhoid, and pooled TAID using discharge codes from 1999 to 2012. We compared incidence rates before, during, and after the 2007-2009 economic recession. Among 16 PHIS hospitals during the study period (1999-2012), incidence of dengue and pooled TAID (malaria, dengue, typhoid fever) increased significantly, and rates of malaria and typhoid trended upward. Admissions for dengue and pooled TAIDs increased significantly among 16 childrens hospitals across the United States from 1999 to 2012. The PHIS database may provide a useful surveillance tool for TAIDs among children in the United States.

Procalcitonin: a marker of infection not subverted by treatment with interleukin-6 receptor inhibition.

To the Editors: We report the case of a 21-year-old female who developed a serious bacterial infection while receiving the anti-interleukin-6 (IL-6) receptor monoclonal antibody tocilizumab and in whom the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) responses were blunted by her immunosuppressive therapy. Serum procalcitonin (PCT), however, remained a useful marker of the acute infection and her subsequent clinical improvement, suggesting an important role for PCT in the diagnosis of serious infection in patients receiving tocilizumab. A 21-year-old female with juvenile idiopathic arthritis and chronic abdominal pain presented to the emergency department with fever, abdominal pain, vomiting and diarrhea 1 day after her biweekly infusion of tocilizumab. Physical examination was unrevealing, and routine laboratory testing showed a white blood cell count of 8300/mm with 70% neutrophils, CRP <0.5 mg/dL (normal <1.0 mg/dL) and an ESR of 3 mm/hr, and she was discharged. She returned 1 day later with worsened abdominal pain and was hospitalized. Abdominal computed tomography and pelvic inflammatory disease testing were negative. On hospital day 2, acute otitis media was noted, and she developed a generalized erythrodermal rash with bullous sloughing consistent clinically and on subsequent biopsy with staphylococcal scalded-skin syndrome associated with the acute otitis media. She was treated with ampicillin-sulbactam and slowly improved. She was discharged completely recovered after 8 days of hospitalization on oral amoxicillin-clavulanic acid. Blood testing throughout showed persistently low ESR and CRP (Table 1). Given the suspected inhibition of these markers by tocilizumab, a serum procalcitonin test was ordered on hospital day 5 and retrospectively performed on 3 prior frozen serum samples, including 1 taken at the time of her initial Emergency Department presentation. The initial PCT of 15.96 ng/mL (normal 0.0–0.5 ng/mL) was highly suggestive of bacterial infection, and subsequent values showed a clear trend toward normalization, reaching 0.54 ng/mL by day 5 after exposure to antistaphylococcal therapy. Procalcitonin, a 116 amino acid peptide precursor to calcitonin, is transcribed by the calcitonin-related polypeptide alpha gene on chromosome 11. In the setting of bacterial infection, PCT is released in large quantities in to the circulation from a wide range of differentiated parenchymal tissues, particularly fat cells. PCT release is driven in vivo primarily by the proinflammatory cytokines tumor necrosis factor-α and IL-1ß. IL-6 is a critical mediator of inflammation and plays a central role in the induction of acute phase reactants in the liver, including CRP and fibrinogen, the primary driver of elevated ESR. Other cytokines, notably IL-1 and tumor necrosis factor-α, which can also elevate CRP and ESR, appear to do so through stimulation of IL-6. Although IL-6 can stimulate PCT release in vitro, in vivo it is not essential and elevation of IL-6 can occur without a rise in PCT, as demonstrated in a study of 360 febrile children with proven viral infections. Little published information exists demonstrating the effects of biological immunosuppressant agents on the PCT compared with other acute phase reactants. Tocilizumab is a mouse derived, humanized monoclonal antibody directed against the IL-6 receptor. Given the central role of IL-6 in CRP and ESR elevation, and the distinct alternate pathways of procalcitonin release, an IL-6 inhibitor should blunt the response to CRP and ESR while allowing PCT to elevate in response to severe bacterial infection, as was demonstrated in this case. In patients undergoing therapy with IL-6 receptor inhibitors, PCT may be the preferred surrogate marker of bacterial infection.

Acute Demyelinating Lesion of the Upper Thoracic Spine Complicating Kawasaki Disease

We present the first reported case of a child with Kawasaki disease (KD) complicated by meningoencephalitis and an acute focal demyelinating lesion. Neurologic outcome in this patient was excellent without any persistent neurologic deficits. We also review the neurologic complications associated with KD.

Inactivated polio vaccines from three different manufacturers have equivalent safety and immunogenicity when given as 1 or 2 additional doses after bivalent OPV: Results from a randomized controlled trial in Latin America

Highlights • Since April 2016 type 2 polio immunization is only possible with inactivated polio vaccines (IPV).• Global IPV supply is currently under pressure, being supplied by only four manufacturers.• We previously confirmed the effectiveness of mixed bOPV and IPV schedules from one manufacturer.• We compared intestinal and humoral immunity of IPV from 3 WHO prequalified manufacturers.• All three WHO prequalified IPV were similarly immunogenic when 1 or 2 doses were given with bOPV.

Enteropathogen Identification by Multiplex PCR in Guatemalan Children with Acute, Non-bloody Diarrhea

Abstract Background Diarrhea is a leading cause of morbidity and mortality in children in low and middle income countries (LMICs). Assessing diarrhea etiology in LMICs is of great importance in order to better develop both therapeutic and public health strategies, but is hampered by the complexity of potential diarrheal pathogens, and diverse methodology needed for pathogen identification Methods Subjects 6 to 35 months old with acute, moderate severity, non-bloody diarrhea were enrolled in a diarrheal treatment trial, conducted at one rural (N = 172) and two urban sites (N = 144) in Guatemala. Diarrheal pathogens were determined in stool by multiplex PCR (FilmArray GI® Biofire) which allows simultaneous identification of 23 bacterial, viral, parasitic pathogens. Descriptive statistics on demographics, pathogen load, and differences in pathogen occurrence by site were performed; differences were assessed with t-test and chi2 test Results Nearly all (96.8%) subjects had pathogens identified, and most had multiple potential pathogens identified (mean pathogen count: 2.7 urban and 4.8 rural; P < 0.001 (Figure 1). Notable pathogen differences were observed between rural and urban populations. Bacteria (particularly E.coli pathotypes and Campylobacter) and protozoa (particularly giardia) were more common in the rural population (Figure2). Viral pathogens were either similar or more common (norovirus; P = 0.04) in the urban population; rotavirus was uncommon in both sites (10 rural and 12 urban cases). A similar pattern of pathogen evolution with patient age was noted in both settings, with a decrease in the relative number of viral and increase in parasitic pathogens (Figure 3). Important demographic and socioeconomic differences between rural and urban were noted: rural subjects had poorer nutritional status, underdeveloped water and sanitation facilities and more domestic animal exposure Conclusion Acute diarrheal episodes in Guatemalan children were associated with a complex spectrum of pathogens when determined by multiplex PCR, with distinct patterns in rural and urban populations. Future studies to precisely determine diarrheal etiologies in LMICs will need to incorporate controls to sort causative organisms from those colonizing the intestine. Disclosures All authors: No reported disclosures.