Facilitators and barriers to the training and maintenance of young persons' advisory groups (YPAGs).

INTRODUCTION: Increasing demands from public and private healthcare coupled with national initiatives in patient-oriented research has led to an increase in avenues to allow patients to be directly involved in research. In particular, the push towards participation of children and youth has resulted in the formation of pediatric patient advisory groups with broad partnerships and consultation requests across the globe. However, there is a lack of evidence to examine the challenges in formation and training of young persons' advisory groups (YPAGs) and management processes required thereafter. PURPOSE AND OBJECTIVES: This study's purpose is to document YPAG formation and training protocols around the world, highlight common strengths, and evaluate pitfalls and challenges. The results from this study will subsequently inform the development of standardized training protocols for children and youth to be piloted globally. METHODS: In this study, 17 select YPAG team leaders from 7 countries were surveyed to determine current training techniques used within existing groups. 17 youth representatives and 16 team leaders were then interviewed to gather further qualitative data on facilitators and barriers that aid or prevent successful initiation and maintenance of these groups. Qualitative interview data was coded and analyzed using NVivo by two independent reviewers (SYC, VWLT). Any inconsistencies in thematic analysis was confirmed by a third reviewer (JB). RESULTS: The most common training topics include consent and assent (64.71%), clinical trials (64.71%), and patient safety (70.59%). There are significant discrepancies to the amount of training received by each team. Most YPAGs out of the 17 groups receive no formal training (58.82%) while training sessions in the remaining 7 groups vary in both duration and frequency. Collectively, meetings ranged from 15  minutes to 6  hours long, with the majority of team meetings being 2-3  hours long (58.82%). The most common training facilitators are a positive relationship with a local hospital (82.35%) and access to a dedicated team coordinator (64.71%). 70.59% of team leaders identified a lack of access to appropriate educational materials available as a drawback to the impact of their YPAG, making this the greatest common barrier. CONCLUSION: Bringing children and youth to the forefront of paediatric trials and clinical research facilitates appropriate patient representation in subsequent research decision-making. There is an urgency to create and implement standardized protocols for the training of children and youth, especially in preparation for national and international research consultations. This low barrier framework may be of special interest to lower-middle-income countries who wish to encourage community participation in healthcare.

Primary immunodeficiency diseases: a practical guide for clinicians.

Primary immunodeficiency diseases (PIDs) are genetically determined disorders of the immune system resulting in greatly enhanced susceptibility to infectious disease, autoimmunity and malignancy. While individual PIDs are rare, as a group, it is estimated that between 1:2000 and 1:10 000 live births are affected by a PID. Moreover, PIDs can present at any age from birth to adulthood, posing a considerable challenge for the practising physician to know when and how to work-up a patient for a possible immune defect. In this review, we outline the basic organisation of the human immune system and the types of infections that occur when elements of the immune system are dysfunctional. Importantly, we provide practical guidelines for identifying patients who should be referred for assessment of possible immunodeficiency and an overview of screening investigations and effective therapeutic options available for these patients.

Severe periodontitis in a 5-year-old girl with hyperimmunoglobulin E syndrome.

The hyperimmunoglobulin E syndrome (HIES) is a multisystem disorder that affects the: (1) dentition; (2) skeleton; (3) connective tissues; and (4) immune system. Little is known about periodontal manifestations of the syndrome. The purpose of this report was to describe a 5-year-old girl with suspected autosomal-recessive HIES syndrome who revealed profusely bleeding and painful gingiva and generalized aggressive periodontitis. A polymerase chain reaction (PCR)-based microbiological examination detected Porphyromonas gingivalis, Tannerella forsythia, Prevotella nigrescens, Treponema denticola, Eikenella corrodens, and Campylobacter rectus in the deep periodontitis lesions. The extraction of all deciduous teeth due to a poor prognosis and risk of systemic infection led to resolution of the oral inflammation. Long-term follow-up is required to determine the periodontal prognosis of the erupting permanent teeth.

Biased immunoglobulin G (IgG) subclass production in a case of hyper-IgM syndrome.

Hyper-immunoglobulin M (IgM) syndrome (HIGM) is a rare heterogeneous primary immune deficiency. We describe a patient with HIGM characterized by skewed production of serum IgG subclasses and normal somatic hypermutation. This case may represent a subgroup of HIGM type 4 that is characterized by a biased switching to the V-region proximal constant regions.

Postpericardiotomy syndrome: no evidence for a viral etiology.

BACKGROUND: Postpericardiotomy syndrome has been considered a disorder induced by viral infection. This conclusion is based on serologic criterions, but these may be unreliable following either cardiopulmonary bypass or transfusion therapy. Previous studies have not verified the proposed etiology either by isolation of viruses, or by detection of their genome. We sought, therefore, to clarify the role, if any, of viruses in this syndrome. METHODS AND RESULTS: We studied prospectively 149 children aged from 6 months to 16 years who were undergoing open heart surgery. Blood samples were collected from all prior to operation, and again 7 to 10 days post-operatively, and 47 were sampled at the time of development of symptoms of pericardial involvement. Serums were analyzed for the presence of IgM and IgG antibodies to cytomegalovirus, herpes simplex virus, and Epstein-Barr virus. The polymerase chain reaction was used for amplification when assessing the genome of the enteroviruses. Cultures for viruses were established on samples of stool, urine, and throat swabs collected 7 days post-operatively, and at the time of postpericardial symptoms. Pericardial fluid obtained from 5 patients with the syndrome was cultured for viruses, and tested for enterovirus genome. On the basis of clinical and echocardiographic findings, 34 children were determined to have definite evidence of the syndrome, 13 were considered to have possible evidence, and the results from these patients were compared to those from patients with no pericardial symptoms, the latter being matched for age and transfusion status. We isolated viruses from one or more sites in five patients with definite evidence (16%), from one (9%) of those with possible evidence, and from seven (19%) of the controls. All serums and pericardial samples were negative for enterovirus genome. IgM antibodies were found in only 5 patients, three with symptoms of pericardial involvement and two without. Rates of seroconversion to IgG for the viruses were lower in the patients with symptoms of pericardial involvement compared to controls, but were strongly influenced by transfusion status. CONCLUSION: Our study has provided no evidence to support a viral etiology for the postpericardiotomy syndrome.

Systemic capillary leak syndrome in a child.

A child with idiopathic systemic capillary leak syndrome had four episodes between 3 and 3 years 9 months of age, all characterized by the sudden onset of hypovolemic shock without any obvious triggering factor. Between the attacks she is well and free of symptoms. Early establishment of intravenous access facilitates volume replacement during the acute episodes.

Humoral immunity in DiGeorge syndrome.

OBJECTIVE: To assess humoral immunity after immunization and natural infection in patients with clinical manifestations of the DiGeorge anomalad. DESIGN: Retrospective review of cases. SETTING: Ambulatory immunology clinic of a tertiary care teaching hospital. PATIENTS: The 13 patients had a symptom complex including congenital heart disease, characteristic facies of the DiGeorge anomalad, possible hypocalcemia, and thymic hypoplasia or aplasia. Molecular and cytogenic studies of 12 patients demonstrated that all had 22q11 microdeletions. METHODS: Serial studies included lymphocyte population enumeration by flow cytometry, lymphocyte proliferation assays with the mitogens phytohemagglutinin and pokeweed mitogen and Staphylococcus aureus, and immunoglobulin quantitation. Specific antibody studies included virus neutralization assays for poliovirus antibodies, and enzyme-linked immunosorbent assay for diphtheria, tetanus, measles, rubella, varicella-zoster virus (VZV), and cytomegalovirus (CMV) antibodies. Avidity of rubella, VZV, and CMV antibodies was tested by enzyme-linked immunosorbent assay modified to include a mild protein denaturant in the first wash after incubation with sera. RESULTS: All patients had a CD3+ cell count greater than 0.500 x 10(9)/L and a CD4+ cell count greater than 0.350 x 10(9)/L). One patient had low proliferation responses to S. aureus, and one to phytohemagglutinin and pokeweed mitogen. Immunoglobulin levels, compared with those in age-related control subjects, were normal except that two patients had transient, borderline low IgG levels and two had elevated IgA levels. Specific antibody tests showed (No. of patients with positive results/No. tested) the following: diphtheria (13/13); tetanus (13/13); poliomyelitis caused by polio virus type 1 (5/9), type 2 (9/9), and type 3 (8/9); measles (11/13); rubella (11/13); and infection with VZV (5/5) and CMV (7/13). There were no significant differences in antibody avidity results between patients and control subjects for rubella (mean avidity index, 83.5 +/- 8.79 vs 85 +/- 17.6), VZV (81.6 +/- 3.98 vs 65.1 +/- 12.38), or CMV (69.3 +/- 22.31 vs 73.3 +/- 12.46). CONCLUSIONS: Patients with "partial" DiGeorge anomalad, defined by clinical and immunologic criteria, can be immunized and for the most part can generate good antibody responses.

Cranial neuropathy, polyneuropathy and thrombocytopenia with Epstein-Barr virus infection.

Neurological involvement is an uncommon complication of Epstein-Barr virus infection, and the long incubation period may complicate the diagnosis. A 15-year-old boy is described with Epstein-Barr virus infection complicated by prolonged life-threatening thrombocytopenia, cranial neuropathy and peripheral sensorimotor neuropathy. The abnormal platelet count was unresponsive to multiple-drug therapy and splenectomy, but normalized 13 months after presentation. Neurological recovery was slow; the patient continues to have a mild peripheral sensorimotor neuropathy three years after the onset of the illness. Infection with Epstein-Barr virus should be considered in patients with acute neurological problems associated with thrombocytopenia. Measurement of antibodies to individual Epstein-Barr virus proteins facilitates the diagnosis of Epstein-Barr virus infection.

Occurrence of chickenpox during pregnancy in women seropositive for varicella-zoster virus.

In a group of 21 women counseled after exposure to chickenpox during pregnancy, 4 developed varicella despite initial studies showing that preinfection sera were varicella-zoster virus (VZV)-seropositive by fluorescent anti-membrane antibody, latex agglutination, ELISA, and VZV glycoprotein immunoblot assay. Further investigations showed that 2 of the 4 had low-titer (1/100), low-avidity, VZV-reactive IgG3 antibodies by ELISAs of preinfection sera. After chickenpox, these women developed primary-like serologic responses to VZV. Two women with high-titer (1/1600, 1/3200), high-avidity, IgG1 antibodies showed anamnestic serologic responses after reinfection. The criteria of protective VZV immunity remain ill-defined.

Varicella-zoster virus antibody avidity and IgG-subclass patterns in children with recurrent chickenpox.

The normal immune response after primary varicella-zoster virus (VZV) infection includes IgG subclass evolution to predominantly IgG1-type antibodies, and maturation from low to high avidity antibodies which are maintained for life. Twenty-three healthy and apparently immunocompetent children with a history of 2-5 episodes of chickenpox were studied after repeat disease. Serial sera were tested for VZV-IgG subclass patterns and VZV IgG and G-subclass antibody avidity by urea elution enzyme linked immunoassay (ELISA). Of 11 patients studied within 8 weeks of repeat chickenpox (Early Group), mean antibody avidity was significantly lower (31.3 +/- 26.81) than control (65.1 +/- 12.38) (P < .001). Seven had low avidity antibody (< 30 percent) and an abundance of IgG3 which was a pattern like primary chickenpox, and 2/11 had high avidity antibody characteristic of anamnestic responses. Early Group patients and 12 others studied over 8 weeks after repeat disease (Late Group) showed avidity maturation and attrition of IgG subclass antibodies other than IgG1. At least nine children failed to show VZV-specific secondary (memory) immune responses early in the course of repeat disease. It is possible that failure to maintain or evoke a secondary immune response could explain their susceptibility to repeat chickenpox.

Production of factors with B-cell growth and differentiation activities by peripheral blood mononuclear cells from patients with hypogammaglobulinemia.

BACKGROUND: The maturation of normal B lymphocytes proceeds through a growth phase and a differentiation phase. These two phases appear to be under the influence of mediators released by immune cells, B-cell growth factor(s), which induce proliferation of B cells; and B-cell differentiation factor(s), which induce B-cell differentiation. METHODS: We analyzed the ability of peripheral blood mononuclear cells from patients with hypogammaglobulinemia to produce B-cell growth factor and B-cell differentiation factor activity in comparison with normal peripheral blood mononuclear cells. RESULTS: Of 27 patients tested, 26 had normal production of B-cell growth factor activity. A quantitative but not absolute defect in B-cell growth factor production was demonstrable in one boy with hypogammaglobulinemia. Interleukin-2 and interleukin-4 levels, as determined antigenically in these supernatants, had a similar distribution pattern from patients' or from control peripheral blood mononuclear cells; that is, undetectable levels of interleukin-2 were produced by cells from 4 of 16 patients tested and from 4 of 13 control subjects, and undetectable levels of interleukin-4 produced by cells from 6 of 16 patients and 4 of 13 control subjects. B-cell differentiation factor activity was absent in only one child tested but present in all other patients. Two patients had quantitatively low secretion of B-cell differentiation factor, but all others were within normal range. The two patients with quantitatively depressed B-cell differentiation factor activity had normal levels of B-cell growth factor activity, interleukin-2, and interleukin-4 produced from their cells. CONCLUSION: Peripheral blood mononuclear cells from the majority of patients with hypogammaglobulinemia appear to have the capacity to produce B-cell growth factors and B-cell differentiation factor activity in vitro.

The influence of recombinant mediators on in vitro IgG subclass secretion by peripheral blood mononuclear cells from patients with hypogammaglobulinemia and from normal donors.

Patients with hypogammaglobulinemia have recurrent infections and fail to produce protective antibodies. In order for B cells to mature into antibody producing cells, several other cell types such as macrophages and helper T lymphocytes must be involved. They secrete several mediators such as interleukin-1 (IL-1), IL-4, IL-5, IL-6 and interferon-gamma (IFN-gamma). These factors, as recombinant mediators, were tested to assess their ability to correct the immunoglobulin production defect in vitro from pokeweed mitogen (PWM) stimulated cultures of peripheral blood mononuclear cells (PBMC) from 11 patients with hypogammaglobulinemia, and from 10 normals as controls. In general, PBMC from hypogammaglobulinemic patients secreted very little Ig in cultures, and no mediator induced a statistically significant increase in the secretion of any IgG subclass. When assessed on an individual basis, one patient demonstrated a variable pattern of increase in total IgG, IgG1, and IgG3, secretion induced by various mediators, to within one standard deviation of the average secretion of normal PBMC cultured in PWM. In the case of the normal cells, IL-4, IL-6 and IL-1 plus IL-4 were able to increase IgG2 secretion in culture with PWM. No increase in secretion of IgG1, IgG3 and IgG4 or total IgG was demonstrable however. Hence, although there is variability in responsiveness amongst the patients, there does not appear to be any one of these recombinant mediators which will correct the defect.(ABSTRACT TRUNCATED AT 250 WORDS)

Reye syndrome associated with subclinical varicella zoster virus and influenza A infection.

An association is reported between Reye syndrome and varicella zoster virus (VZV) infection in a 10-year-old boy who had serologic evidence of coinfection with VZV and influenza A H3N2, and exposure to salicylates. He developed VZV reinfection without skin lesions after family exposure and influenza A was community-acquired. Recent chickenpox contact should initiate VZV serologic studies in Reye syndrome patients, regardless of the chickenpox history or evidence of infection with other viruses.

Ataxia-telangiectasia in a child with vaccine-associated paralytic poliomyelitis.

Vaccine-acquired poliomyelitis developed in a nonimmunized 10-month-old boy. At age 4 years, ataxia-telangiectasia was recognized. We conclude that the occurrence of vaccine-related poliomyelitis warrants a detailed assessment of immunity, and that, in patients with ataxia-telangiectasia, the use of live vaccines may be hazardous, even in those with apparently normal immunity.

Severe combined immune deficiency presenting with cyclic hematopoiesis.

At age 2 months a male infant presented with a cyclic clinical syndrome every 14-21 days that included pharyngeal aphthous ulcers, high fever, lymphadenopathy, pallor, and malaise. Serial blood studies indicated cycling of all blood cell elements, compatible with a diagnosis of cyclic hematopoiesis (CH). He also manifested a progressively severe immune deficiency, not described before in human CH. When first studied at age 5 months, he was hypogammaglobulinaemic with normal B lymphocyte numbers. By 6.5 months, he was agammaglobulinaemic. At age 8 months, he developed severe pneumocystis carinii pneumonia, and studies showed a state of severe combined immune deficiency. The patient received a bone marrow transplant from his HLA-identical sister with no preconditioning therapy. Subsequently, normal immune function developed and the cyclic hematopoiesis resolved. The majority of lymphocytes is of donor origin. Persistence of erythrocytes and neutrophils of recipient origin suggests that the hematopoietic stem cells were not abnormal. We speculate that this patient had a primary deficiency of a differentiation factor affecting maturation of lymphoid and myeloid progenitor cells.

Epstein-Barr virus shedding in breast milk.

One hundred healthy women already donating to the Children's Hospital Breast Milk bank consented to provide a sample of breast milk for this study. Using a DNA-DNA hybridization dot-blot assay Epstein-Barr virus (EBV) genome (Bam HIW region) was detected in cells shed into breast milk of 46 out of 100 women studied and in 60 out of 132 (46%) of samples donated overall. The prevalence of EBV shedding increased postnatally to a peak of 74% (26/35 positive samples) between 3 and 12 weeks postdelivery. Women delivering prematurely had an initially lower prevalence of shedding with only six out of 30 (20%) positive samples in the first week after delivery, compared to 16 out of 35 (46%) for women delivering at term. Of the 18 women donating more than one sample, 13 showed consistently positive (n = 8) or negative (n = 5) results, and the remaining five had intermittent shedding detected. Only seven out of 42 (17%) breast milk samples studied were EBV-IgG antibody positive, and none showed IgM or IgA-EBV antibodies. Further studies and prospective followup of infants are needed to confirm that breast milk is a significant source for early EBV infection of infants, as indicated by serologic studies.