Mark H. Sawyer

Updated Guidance for Palivizumab Prophylaxis Among Infants and Young Children at Increased Risk of Hospitalization for Respiratory Syncytial Virus Infection

Palivizumab was licensed in June 1998 by the Food and Drug Administration for the reduction of serious lower respiratory tract infection caused by respiratory syncytial virus (RSV) in children at increased risk of severe disease. Since that time, the American Academy of Pediatrics has updated its guidance for the use of palivizumab 4 times as additional data became available to provide a better understanding of infants and young children at greatest risk of hospitalization attributable to RSV infection. The updated recommendations in this policy statement reflect new information regarding the seasonality of RSV circulation, palivizumab pharmacokinetics, the changing incidence of bronchiolitis hospitalizations, the effect of gestational age and other risk factors on RSV hospitalization rates, the mortality of children hospitalized with RSV infection, the effect of prophylaxis on wheezing, and palivizumab-resistant RSV isolates. This policy statement updates and replaces the recommendations found in the 2012 Red Book.

Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features.

Background: Acute disseminated encephalomyelitis (ADEM) is a central nervous system demyelinating disease that usually follows an apparently benign infection in otherwise healthy young persons. The epidemiology, infectious antecedents and pathogenesis of ADEM are poorly characterized, and some ADEM patients are subsequently diagnosed with multiple sclerosis (MS). Methods: We retrospectively (1991–1998) and prospectively (1998–2000) studied all persons aged < 20 years diagnosed with ADEM from the 3 principal pediatric hospitals in San Diego County, CA, during 1991–2000. Acute neurologic abnormalities and imaging evidence of demyelination were required for study inclusion. Epidemiologic variables, risk factors, clinical course, laboratory and radiographic findings, neuropathology and treatment data were analyzed. Interleukin (IL)-12, interferon-γ(IFN-γ) and IL-10 were assayed in blinded manner on cerebrospinal fluid (CSF) obtained prospectively from a subset of ADEM cases and compared with CSF from patients with enteroviral (EV) meningoencephalitis confirmed by polymerase chain reaction (PCR) and controls without pleocytosis. Results: Data were analyzed on 42 children and adolescents diagnosed with ADEM during 1991–2000, and CSF IL-12, IFN-γ and IL-10 levels were compared among ADEM (n = 14), EV meningoencephalitis (n = 14) and controls without pleocytosis (n = 28). Overall incidence of ADEM was 0.4/100,000/year; incidence quadrupled during 1998–2000 compared with earlier years. No gender, age stratum, ethnic group or geographic area was disproportionately affected. A total of 4 (9.5%) patients initially diagnosed with ADEM were subsequently diagnosed with MS after multiple episodes of demyelination. Although most children eventually recovered, 2 died, including 1 of the 3 ultimately diagnosed with MS. Magnetic resonance imaging was required for diagnosis among 74% of patients; computerized tomography findings were usually normal. Patients with EV had significantly higher mean CSF IFN-γ (P = 0.005) and IL-10 (P = 0.05) than patients with ADEM and controls without CSF pleocytosis. CSF from ADEM patients had CSF cytokine values statistically similar to those of 3 patients subsequently diagnosed with MS. Conclusions: ADEM is a potentially severe demyelinating disorder likely to be increasingly diagnosed as more magnetic resonance imaging studies are performed on patients with acute encephalopathy. Further characterization of the central nervous system inflammatory response will be needed to understand ADEM pathogenesis, to improve diagnostic and treatment strategies and to distinguish ADEM from MS.

Human Bocavirus: Prevalence and Clinical Spectrum at a Children's Hospital

Abstract Background. Molecular methods of pathogen discovery have recently led to the description of several new respiratory viruses. Human bocavirus (HBoV), a proposed member of the family Parvoviridae, is one of the most recently described respiratory viruses. Initial reports indicate that HBoV is a common cause of respiratory tract infection in children. Methods. A total of 1474 nasal scraping specimens collected over a 20-month period were screened by polymerase chain reaction for the presence of HBoV nucleic acid. Positive results were confirmed with a second polymerase chain reaction assay from a different genomic region. The medical records of patients with positive results were reviewed for demographic and clinical data. Results. HBoV DNA was identified in 82 samples (5.6%). The peak rate of HBoV infection occurred during the period of March through May in both 2004 and 2005. Sixty-three percent of infected patients were <12 months of age. The most common symptoms were cough, rhinorrhea, and fever. Other symptoms of interest included diarrhea and a “paroxysmal” cough that was clinically suspected to be caused by Bordetella pertussis. Conclusions. HBoV DNA is commonly present in children with upper and lower respiratory tract infections. The presence of a pertussis-like cough and diarrhea in association with HBoV infection merits further investigation.

Diagnosis of enteroviral central nervous system infection by polymerase chain reaction during a large community outbreak.

Enteroviruses are common causes of localized and systemic infection in patients of all ages and are the most frequent cause of epidemic aseptic meningitis in the United States. We have developed a polymerase chain reaction (PCR) assay of cerebrospinal fluid (CSF) for rapid diagnosis of enteroviral meningitis. This assay was applied to 257 CSF specimens during a large community outbreak of enterovirus disease; 109 (97%) of 112 enterovirus culture-positive CSF samples contained enterovirus RNA. In addition 35 (66%) of 53 samples from patients with suspected central nervous system disease with negative or no CSF viral cultures were positive by enterovirus PCR. The enterovirus PCR detected 13 different enterovirus serotypes. PCR results are available within 24 hours compared with a mean of 6.8 days for enterovirus culture. The clinical characteristics of 141 patients with enterovirus central nervous system disease are presented. This study demonstrates the usefulness of enterovirus PCR for the rapid diagnosis of enterovirus central nervous system disease and the potential for PCR tests to shorten hospitalization.

Successful treatment of Balamuthia amoebic encephalitis: presentation of 2 cases.

Case histories are presented of 2 individuals (a 5-year-old girl and 64-year-old man) who developed encephalitis caused by the free-living amoeba Balamuthia mandrillaris. Both individuals survived after diagnosis and initiation of effective antimicrobial therapy. Immunostaining for Balamuthia-specific antibody levels identified the causative agent of the infections. Antimicrobial therapy with flucytosine, pentamidine, fluconazole, sulfadiazine, and a macrolide antibiotic (azithromycin or clarithromycin) was initiated. Phenothiazines (thioridazine and trifluoperazine) were also used. Both patients recovered, and there was no evidence of recrudescence of the disease at 2 and 6 years after onset of symptoms. Awareness of Balamuthia as the causative agent of encephalitis and early initiation of antimicrobial therapy were critical to the recovery of both patients. Although optimal antimicrobial therapy for Balamuthia amoebic encephalitis has yet to be determined, the antimicrobials used in these 2 cases effectively controlled the disease. These 2 individuals are the only known survivors of this otherwise fatal type of amoebic encephalitis.

Cytomegalovirus Infection and Bronchopulmonary Dysplasia in Premature Infants

During a five-year period, 32 preterm infants weighing less than 2000 g were diagnosed as having postnatally acquired cytomegalovirus (CMV) infection in a neonatal intensive care unit. These CMV-infected infants were matched with 32 uninfected controls for gestational age, birth weight, and birth date; the two groups did not differ in Apgar scores or the incidence of respiratory distress syndrome and patent ductus arteriosus. Roentgenographic evidence of bronchopulmonary dysplasia (BPD) developed in 24 (75%) of 32 CMV-infected infants, an incidence significantly greater than that observed in control infants (12/32; 38%). Infants with acquired CMV infection required more respiratory support and longer hospitalization than uninfected controls. This association between acquired CMV infection in premature infants and the development of chronic lung disease provides further evidence that vigorous efforts to prevent CMV infection in hospitalized neonates is warranted.

Interferon-γ Release Assays for Diagnosis of Tuberculosis Infection and Disease in Children

Tuberculosis (TB) remains an important problem among children in the United States and throughout the world. Although diagnosis and treatment of infection with Mycobacterium tuberculosis (also referred to as latent tuberculosis infection [LTBI] or TB infection) remain the lynchpins of TB prevention, there is no diagnostic reference standard for LTBI. The tuberculin skin test (TST) has many limitations, including difficulty in administration and interpretation, the need for a return visit by the patient, and false-positive results caused by significant cross-reaction with Mycobacterium bovis–bacille Calmette-Guérin (BCG) vaccines and many nontuberculous mycobacteria. Interferon-γ release assays (IGRAs) are blood tests that measure ex vivo T-lymphocyte release of interferon-γ after stimulation by antigens specific for M tuberculosis. Because these antigens are not found on M bovis–BCG or most nontuberculous mycobacteria, IGRAs are more specific tests than the TST, yielding fewer false-positive results. However, IGRAs have little advantage over the TST in sensitivity, and both methods have reduced sensitivity in immunocompromised children, including children with severe TB disease. Both methods have a higher positive predictive value when applied to children with risk factors for LTBI. Unfortunately, neither method distinguishes between TB infection and TB disease. The objective of this technical report is to review what IGRAs are most useful for: (1) increasing test specificity in children who have received a BCG vaccine and may have a false-positive TST result; (2) using with the TST to increase sensitivity for finding LTBI in patients at high risk of developing progression from LTBI to disease; and (3) helping to diagnose TB disease.

Molecular Analysis of the Pyrimidine Deoxyribonucleoside Kinase Gene of Wild-type and Acyclovir-resistant Strains of Varicella-Zoster Virus

The pyrimidine deoxyribonucleoside kinase (dPK) genes from five wild-type and four acyclovir-resistant varicella-zoster virus (VZV) strains were studied. One of the acyclovir-resistant strains was isolated from a patient receiving chronic acyclovir therapy. Acyclovir-resistant strains expressed the 1.8 kb VZV dPK transcript but lacked dPK activity. To determine the basis for the lack of enzyme activity the dPK gene from each strain was cloned and its DNA sequence determined. The VZV dPK gene was found to be highly conserved among strains, with greater than 99% nucleotide and amino acid homology. Each acyclovir-resistant VZV strain differed from its wild-type parent in only a single amino acid. The dPK genes from the acyclovir-resistant strains contained either point mutations near the putative thymidine-binding site of the enzyme or ones that resulted in the premature termination of protein synthesis. Single point mutations were sufficient to render these strains dPK-negative and highly resistant to acyclovir. The molecular basis for acyclovir resistance at the dPK locus of VZV is similar to that previously noted to render herpes simplex viruses resistant to acyclovir.

Impact of Acute Rotavirus Gastroenteritis on Pediatric Outpatient Practices in the United States

Objectives: The objectives of this study were to determine the presenting symptoms, healthcare utilization, and lost time from work and day care associated with acute rotavirus gastroenteritis. Methods: During the winter to spring seasons of 2002–2003 or 2003–2004, children <36 months of age presenting with acute gastroenteritis to urban and suburban pediatric outpatient practices affiliated with 5 academic centers across the United States were enrolled in similarly designed studies. The case definition required ≥3 watery or looser-than-normal stools and/or forceful vomiting within a 24-hour period beginning ≤72 hours before presentation. Stool samples were tested for rotavirus antigen by standard commercial assays. Symptom frequencies for laboratory-confirmed rotavirus and nonrotavirus gastroenteritis were compared by Fishers exact test; the number of healthcare contacts and lost days from work or day care were compared with the median 2-sample test. Results: Stool specimens were obtained from 284 of 303 (94%) participants; 115 (40%) of tested specimens were positive for rotavirus (range, 31–50% across the 5 centers). Compared with participants with nonrotavirus gastroenteritis, children with rotavirus gastroenteritis were more likely to have 1) vomiting (83% versus 66%; P = 0.003), 2) combined diarrhea and vomiting (75% versus 50%; P < 0.001), and 3) fever (60% versus 43%; P = 0.010). More time from work was lost by parents/guardians of children with rotavirus than nonrotavirus gastroenteritis (median 2 versus 0 day; P = 0.007). More day care was missed by children with rotavirus than nonrotavirus gastroenteritis (median 3 versus 1 day; P = 0.002). Conclusions: In this multicenter study, rotavirus consistently caused a sizable proportion of cases of acute gastroenteritis seen in pediatric outpatient practices in the United States during the winter and spring. Rotavirus gastroenteritis was more frequently associated with vomiting, combined diarrhea and vomiting, fever and lost time from work and day care than nonrotavirus gastroenteritis.

The Complex Relationship of Realspace Events and Messages in Cyberspace: Case Study of Influenza and Pertussis Using Tweets

Background Surveillance plays a vital role in disease detection, but traditional methods of collecting patient data, reporting to health officials, and compiling reports are costly and time consuming. In recent years, syndromic surveillance tools have expanded and researchers are able to exploit the vast amount of data available in real time on the Internet at minimal cost. Many data sources for infoveillance exist, but this study focuses on status updates (tweets) from the Twitter microblogging website. Objective The aim of this study was to explore the interaction between cyberspace message activity, measured by keyword-specific tweets, and real world occurrences of influenza and pertussis. Tweets were aggregated by week and compared to weekly influenza-like illness (ILI) and weekly pertussis incidence. The potential effect of tweet type was analyzed by categorizing tweets into 4 categories: nonretweets, retweets, tweets with a URL Web address, and tweets without a URL Web address. Methods Tweets were collected within a 17-mile radius of 11 US cities chosen on the basis of population size and the availability of disease data. Influenza analysis involved all 11 cities. Pertussis analysis was based on the 2 cities nearest to the Washington State pertussis outbreak (Seattle, WA and Portland, OR). Tweet collection resulted in 161,821 flu, 6174 influenza, 160 pertussis, and 1167 whooping cough tweets. The correlation coefficients between tweets or subgroups of tweets and disease occurrence were calculated and trends were presented graphically. Results Correlations between weekly aggregated tweets and disease occurrence varied greatly, but were relatively strong in some areas. In general, correlation coefficients were stronger in the flu analysis compared to the pertussis analysis. Within each analysis, flu tweets were more strongly correlated with ILI rates than influenza tweets, and whooping cough tweets correlated more strongly with pertussis incidence than pertussis tweets. Nonretweets correlated more with disease occurrence than retweets, and tweets without a URL Web address correlated better with actual incidence than those with a URL Web address primarily for the flu tweets. Conclusions This study demonstrates that not only does keyword choice play an important role in how well tweets correlate with disease occurrence, but that the subgroup of tweets used for analysis is also important. This exploratory work shows potential in the use of tweets for infoveillance, but continued efforts are needed to further refine research methods in this field.