B Cell Disorders in Children: Part II.

PURPOSE OF REVIEW: B cell disorders result in decreased levels or function of immunoglobulins in an individual. Genetic mutations have been reported in a variety of B cell disorders. This review, in follow-up to a previous review, describes some rare B cell disorders as well as their known underlying genetic etiologies. RECENT FINDINGS: Genetic studies identify and permit precise classification of an increasing number of B cell disorders, leading to a greater understanding of B cell development and function. The B cell disorders are rare diseases. While clinicians are most familiar with X-linked agammaglobulinemia and so-called common variable immunodeficiency (CVID), there are many causes of hypogammaglobulinemia. Genetic testing provides a specific diagnosis, offers useful information for genetic counseling, and can identify previously unrecognized B cell disorders.

Demographic and Risk-Factor Differences between Users and Non-Users of Unscheduled Healthcare among Pediatric Outpatients with Persistent Asthma.

This study assesses differences between users and non-users of unscheduled healthcare for persistent childhood asthma, with regard to select demographic and risk factors. The objectives are to provide important healthcare utilization information and a foundation for future research on self-management effectiveness (SME), informed by a recently developed "holistic framework" for measuring SME in childhood asthma. An 18-month retrospective chart review was conducted on 59 pediatric outpatients with persistent asthma-mild, moderate, or severe, to obtain data on various demographic and risk factors, and healthcare use for each child. The study examined five types of "unscheduled" healthcare use. Users had non-zero encounters (at least one) in any of the five types; non-users had zero encounters (not even one) in all five types. Differences between users and non-users were assessed using contingency table and logistic regression analysis. There were 25 users and 34 non-users of unscheduled healthcare. Each severity category contained users and non-users. The only statistically significant finding was that the mild persistent category had fewer users than severe persistent (p < 0.05). There were no significant differences between users and non-users for any other demographic or risk factor examined. After adjusting for asthma severity, there were no other significant differences between users and non-users of unscheduled healthcare. This is a crucial finding which suggests that something else is driving unscheduled healthcare use in these children, given there were users and non-users in each asthma severity category. These results provide impetus for future research on the role of other aspects of the "holistic framework" in explaining differences in uses of unscheduled healthcare in persistent childhood asthma.

G and P types of circulating rotavirus strains in the United States during 1996-2005: nine years of prevaccine data.

BACKGROUND: Rotavirus vaccine was recommended for routine use among US infants in 2006. To provide prevaccine data, we conducted strain surveillance for 9 consecutive seasons during 1996-2005. METHODS: Using reverse-transcriptase polymerase chain reaction genotyping and nucleotide sequencing, we determined P/G genotypes of >3100 rotavirus strains collected in up to 12 cities each year from different US regions. RESULTS: The most prevalent strain globally, P[8] G1, was the most prevalent each year in the United States (overall, 78.5% of strains; range, 60.0%-93.9%), and 9.2% of the samples were P[4] G2, 3.6% were P[8] G9, 1.7% were P[8] G3, and 0.8% were P[8] G4. Genotype P[6] G9, which emerged in 1995, was detected continuously for several seasons (from 1996-1997 to 2000-2001, 0.2%-5.4%) but was not identified in the subsequent 4 seasons. Single or a few detections of rare genotypes (eg, P[6] G12, P[9] G6, and P[9] G3) were observed during several rotavirus seasons at frequencies of 0.5%-1.7% and, overall, comprised 0.6% of all the samples from the entire surveillance period. Several globally common strains in addition to G1, especially G2 and G9, circulated at high prevalence (33%-62%) in some cities during certain years. CONCLUSIONS: Almost 85% of strains during 1996-2005 had either a G or P antigen that is present in both RotaTeq (Merck) and Rotarix (GlaxoSmithKline). Monitoring of strains after introduction of rotavirus vaccines is important.

Isolation and characterization of a new simian rotavirus, YK-1.

BACKGROUND: To effectively analyze the requirements for protection to rotavirus infection, a reliable animal model that reasonably mimics infection and disease in humans is needed. A requirement for an effective animal model is the availability of appropriate rotavirus stocks for challenge. RESULTS: A new simian rotavirus, designated YK-1, was isolated from a 2-year-old immunodeficient pigtailed macaque with chronic diarrhea. YK-1 was distinguishable by electropherotype from the other simian rotavirus strains, SA11 and RRV. One variant of YK-1, clone 311, which was isolated after adaptation and plaque purification in cell cultures, displayed an unusual RNA electropherotype with an abnormally migrating gene 11 segment. Sequence analysis demonstrated a genetic rearrangement that involved a partial duplication of the gene 11 ORF encoding NSP5. YK-1 was identified as a Group A rotavirus belonging to subgroup 1. To further characterize the YK-1 strain, the genes encoding VP4, VP7, and NSP4 were sequenced. Analysis of VP4 and VP7 gene fragments suggests that this strain is a G3P3 rotavirus and is closely related to the simian rotavirus strain RRV. Serotype analysis also identified YK-1 as a G3 rotavirus. The NSP4 genotype of YK-1 is C, the same genotype as RRV. CONCLUSION: This newly isolated rotavirus, YK-1, is being used to establish a nonhuman primate model for studying the infectivity, immunity, and pathogenesis of rotavirus and for evaluating candidate rotavirus vaccines.

Serotype diversity and reassortment between human and animal rotavirus strains: implications for rotavirus vaccine programs.

The development of rotavirus vaccines that are based on heterotypic or serotype-specific immunity has prompted many countries to establish programs to assess the disease burden associated with rotavirus infection and the distribution of rotavirus strains. Strain surveillance helps to determine whether the most prevalent local strains are likely to be covered by the serotype antigens found in current vaccines. After introduction of a vaccine, this surveillance could detect which strains might not be covered by the vaccine. Almost 2 decades ago, studies demonstrated that 4 globally common rotavirus serotypes (G1-G4) represent >90% of the rotavirus strains in circulation. Subsequently, these 4 serotypes were used in the development of reassortant vaccines predicated on serotype-specific immunity. More recently, the application of reverse-transcription polymerase chain reaction genotyping, nucleotide sequencing, and antigenic characterization methods has confirmed the importance of the 4 globally common types, but a much greater strain diversity has also been identified (we now recognize strains with at least 42 P-G combinations). These studies also identified globally (G9) or regionally (G5, G8, and P2A[6]) common serotype antigens not covered by the reassortant vaccines that have undergone efficacy trials. The enormous diversity and capacity of human rotaviruses for change suggest that rotavirus vaccines must provide good heterotypic protection to be optimally effective.

Prevalence and genetic diversity of human astroviruses in Mexican children with symptomatic and asymptomatic infections.

The prevalence and type diversity of human astroviruses (HAstV) in children with symptomatic and asymptomatic infections were determined in five localities of Mexico. HAstV were detected in 4.6 (24 of 522) and 2.6% (11 of 428) of children with and without diarrhea, respectively. Genotyping of the detected strains showed that at least seven (types 1 to 4 and 6 to 8) of the eight known HAstV types circulated in Mexico between October 1994 and March 1995. HAstV types 1 and 3 were the most prevalent in children with diarrhea, although they were not found in all localities studied. HAstV type 8 was found in Mexico City, Monterrey, and Mérida; in the last it was as prevalent (40%) as type 1 viruses, indicating that this astrovirus type is more common than previously recognized. A correlation between the HAstV infecting type and the presence or absence of diarrheic symptoms was not observed. Enteric adenoviruses were also studied, and they were found to be present in 2.3 (12 of 522) and 1.4% (6 of 428) of symptomatic and asymptomatic children, respectively.

Genetic variability among serotype G6 human rotaviruses: identification of a novel lineage isolated in Hungary.

Rotavirus serotype G6 has been demonstrated to be a rare cause of gastroenteritis in man. To date, only a few well characterized strains have been described from Italy, Australia, and the United States. Nucleotide sequencing of G6 VP7 genes shows that these strains belong to two distinct G6 lineages, one for strains of serotype P11[14],G6 (PA169-like strains) and one for strains of serotype P3[9],G6 (PA151-like strains). In this study, we sequenced the VP7 genes and VP8* gene fragments of human rotavirus G6 strains detected in Hungary. Phylogenetic analysis demonstrated that the VP7 genes of Hungarian G6 strains fell into three lineages, represented by a single PA169-like strain, three PA151-like strains, and two novel G6 strains, respectively. The amino acid sequence identity of VP7 was 97.2-100% within each lineage and 92-93.9% between any two lineages. The sequence analysis of VP8* revealed that the single PA169-like Hungarian G6 strain belonged to genotype P[14] and was phylogenetically closely related to P11[14],G6 strains characterized previously. In contrast, the VP8* of PA151-like Hungarian G6 strains clustered in accordance with their VP7 genes representing genetically distinguishable variants of genotype P[9]. This finding raises the possibility that Hungarian genotype P[9],G6 strains might have been generated through independent reassortment events. Serotype G6-specific primers for each human G6 lineage were also developed. The use of these primers in reverse-transcription polymerase chain reaction genotyping may help determine the epidemiological role of G6 strains in humans.

Diversity of rotavirus strains among children with acute diarrhea in China: 1998-2000 surveillance study.

As part of a national rotavirus surveillance activity, we collected fecal specimens from 3,177 children with acute diarrhea in 10 regions of China between April 1998 and April 2000 and screened them for rotavirus. Rotavirus was detected in 41% (n = 1,305) of specimens, and in these, G1 was the predominant serotype (72.6%), followed by G3 (14.2%), G2 (12.1%), G4 (2.5%), G9 (0.9%), and G untypeable (0.7%). Among 327 G-typed strains tested for P genotype, 14 different P-G combinations were identified, with the globally common strains P[8]G1, P[4]G2, P[8]G3, and P[8]G4 representing 75.6% of all typed rotavirus strains. Among the uncommon strains, 11 were P[6]G9, and others included P[6]G1, P[6]G3, and five novel P-G combinations (P[9]G1, P[4]G1, P[4]G3, P[4]G4, and P[8]G2). Our results indicate that while the common rotavirus strains remain predominant, the diversity of strains is much greater than was previously recognized.

Outbreaks of adult gastroenteritis traced to a single genotype of rotavirus.

Between November 1998 and December 2000, the Centers for Disease Control and Prevention screened samples from 263 outbreaks of gastroenteritis in the United States and identified 3 that were associated with rotavirus among adults. Rotaviruses from each outbreak were further characterized by reverse-transcription polymerase chain reaction. Surprisingly, all specimens were of serotype G2, a strain that is, as determined by high-stringency hybridization analysis, genetically distinct in all 11 gene segments from the other common rotavirus strains in circulation. The unusual coincidence of identification of only G2 strains in these 3 outbreaks of rotavirus gastroenteritis among adults is similar to results from other studies, in which G2 strains were found in association with more-severe disease in children than other rotavirus serotypes and in association with outbreaks of diarrhea among adults in Japan. Although rotavirus infections in adults are relatively uncommon, which indicates that good overall protective immunity exists, the predominance of G2 strains in outbreaks that have occurred in adults suggests that natural immunity to more common strains does not always provide adequate heterotypic immunity to G2 strains. For the rotavirus vaccines under development, special attention may need to be paid to protection against G2 strains.