Robert C. Welliver

The Release of Leukotrienes in the Respiratory Tract during Infection with Respiratory Syncytial Virus: Role in Obstructive Airway Disease

ABSTRACT: Samples of nasopharyngeal secretions from a group of 73 infants with bronchiolitis or upper respiratory illness alone during infection with respiratory syncytial virus were analyzed for leukotriene C4 (LTC4) content using a reverse-phase high-pressure liquid chromatography assay with confirmation by radioimmunoassay. Titers of respiratory syncytial virus (RSV)-specific IgE in nasopharyngeal secretion (NPS) specimens were determined using an enzyme-linked immunosorbent assay. The highest concentrations of LTC4 were found in the first 3 to 8 days after the onset of illness, and LTC4 was detectable in progressively lower concentrations in samples obtained up to 28 days after the onset of illness. LTC4 was detected in samples of NPS obtained in the acute phase of illness from 67% of infants with bronchiolitis due to RSV and in 33% of samples of NPS obtained during the same interval from infants with upper respiratory illness alone (p < 0.025). Concentrations of LTC4 in children with bronchiolitis were 5-fold higher (1271 pg/ml) then the mean concentration of LTC4 in children with upper respiratory illness (224 pg/ml, p < 0.02). LTC4 was detected in 83% of the children developing an RSV-IgE response and in 24% of subjects not developing an RSV-IgE response (p < 0.001). Quantities of LTC4 measured in NPS were directly correlated with the magnitude of the RSV-IgE response in secretions (r = 0.33, p < 0.02). These studies lend support to previous investigations suggesting that severe bronchiolitis due to RSV results from IgE-mediated hypersensitivity reactions to viral antigens, with release of chemical mediators of airway obstruction. Their implications should be considered in new approaches to therapy of RSV bronchiolitis.

Role of parainfluenza virus-specific IgE in pathogenesis of croup and wheezing subsequent to infection

In order to determine the role of parainfluenza virus-specific IgE antibody production and release of histamine in the pathogenesis of lower respiratory disease caused by parainfluenza virus infection, we studied 84 infants and children at the time of parainfluenza virus infection. Parainfluenza virus-IgE antibody was detected in samples of nasopharyngeal secretions by means of an enzyme-linked immunosorbent assay, and histamine content of nasopharyngeal secretions was determined by a fluorometric technique. Virus-specific IgE responses appeared earlier and were of greater magnitude in patients with croup, wheezing, and croup with wheezing caused by parainfluenza virus infection than in patients with parainfluenza virus-induced upper respiratory illness. Histamine was detectable in nasopharyngeal secretions of patients with parainfluenza virus-related croup significantly more often than in patients with upper respiratory illness caused by parainfluenza virus. These observations suggest a role for immunologic mechanisms in the pathogenesis of severe forms of respiratory illness caused by parainfluenza virus infection.

Eosinophilia at the time of respiratory syncytial virus bronchiolitis predicts childhood reactive airway disease.

Objective. Bronchiolitis in infancy is viewed as a risk factor for childhood asthma, but factors predicting which infants will have persistent wheezing have not been identified. In addition, the nature of the association between the 2 conditions is uncertain. We wished to determine whether eosinophil counts at the time of acute bronchiolitis predicted the presence of wheezing in later childhood. Methods. We retrospectively identified infants hospitalized with bronchiolitis, determined peripheral blood eosinophil counts at the time of bronchiolitis, and then contacted their families when they had reached 7 years of age. Results. Eosinophil counts at the time of bronchiolitis were greater in subjects who would have wheezing at 7 years of age (median: 98 cells/mm3) than in infants who would have no recurrent wheezing (median: 0 cells/mm3) or transient wheezing only up to 3 years of age (median: 0 cells/mm3). When the effects of family history of asthma, gender, and passive exposure to cigarette smoke were examined, only eosinophilia at the time of bronchiolitis demonstrated a statistically significant relationship to the presence of wheezing at 7 years of age. Conclusions. Eosinophilia at the time of bronchiolitis generally predicts the development of wheezing persisting into later childhood. Therefore, the association of bronchiolitis and childhood asthma seems more likely to be attributable to an immunologic anomaly that precedes the development of, or is induced by, bronchiolitis rather than to structural damage to the airway as a result of bronchiolitis.

Innate Immune Responses in Respiratory Syncytial Virus Infections

Respiratory syncytial virus (RSV) is the most important viral respiratory pathogen of early life. Studies of the immune response in general (and the innate response in particular) to this agent are of interest for a number of reasons. First, severe forms of illness may be a result of enhanced immunologic responsiveness to viral constituents at the time of infection. Secondly, the immune response to RSV may consist principally of innate immune responses at the time of maximum severity of illness. Third, RSV infection in infancy may be linked via immune mechanisms to the development of childhood wheezing. Finally there are no meaningfully effective forms of therapy for RSV infection, and elucidation of the immune response may suggest new therapeutic approaches. This review will summarize our current knowledge of innate immune responses to RSV infection. Specifically we will review early interactions of the virus with surfactant proteins and Toll-like receptors, chemokine release from infected cells, cytokine release from activated inflammatory cells, activation of neuroimmune pathways, generation of dendritic cells, the release of soluble mediators of airway obstruction, and genetic polymorphisms associated with RSV-related illness.

Respiratory Syncytial Virus-Specific IgE Responses following Infection: Evidence for a Predominantly Mucosal Response

ABSTRACT: In order to determine whether IgE production occurs predominantly at mucosal or systemic sites, we studied the production of respiratory syncytial virus (RSV)- specific antibody in serum and nasopharyngeal secretions (NPS) from 41 patients with RSV infection using an enzyme- linked immunosorbent assay. RSV-IgE was found in higher titer in samples of NPS than in simultaneously obtained serum specimens at all phases of illness. Despite the excess dilution incurred in the collection process, RSVIgE was frequently detected in NPS specimens while it was undetectable in serum. In 20 selected subjects, ratios of RSV antibody in NPSrserum were 2.00 for RSV-IgE, 2.42 for RSV-IgA, and 0.01 for RSV-IgG. Also the geometric mean value of ratios of RSV-IgE:RSV-IgG was 1.74 in NPS and 0.05 in serum, while the geometric mean value of ratios of RSV-IgA:RSV-IgG were 1.85 in NPS and 0.09 in serum. These data suggest that IgE production occurs predominantly at mucosal surfaces.

RESPIRATORY SYNCYTIAL VIRUS IMMUNOGLOBULIN AS PROPHYLAXIS AGAINST RESPIRATORY SYNCYTIAL VIRUS IN CHILDREN WITH CONGENITAL HEART DISEASE. • 662

Respiratory Syncytial Virus (RSV) lower respiratory tract infection produces significant morbidity and mortality in young children with congenital heart disease (CHD). Respiratory Syncytial Virus Immunoglobulin (RSVIG) is effective in preventing severe RSV illness in high-risk preterm infants. A 3 year prospective multicenter blinded study was undertaken to determine safety and efficacy of RSVIG as RSV prophylaxis in CHD. Children <48 months were randomized to an infusion group (I) receiving 750 mg/kg RSVIG monthly over the RSV season, or to a control group (C) receiving no RSVIG. Weekly phone surveillance, monthly visits and evaluation of RSV respiratory illness was performed by blinded personnel. Study children included 202 (I) and 214 (C). P=NS for (I) vs (C) for the following variables: mean age [9.3 mo. (I), 10.7 mo. (C)]; gender; crowding; smoke exposure and cardiac severity score but more children with cyanotic CHD were randomized to receive RSVIG [78/202 (I) vs 47/214 (C), p=0.001]. Reduction in RSV hospitalization, ICU admission and mechanical ventilation rates were not statistically significant when the entire group was analyzed. However, in infants <6 months of age at study entry, RSVIG reduced hospitalization by 57% (p=0.01). In acyanotic CHD RSVIG recipients, a trend towards reduced hospital rates and days was also observed[18% (I) vs 10% (C), p=0.06]. Surgically-related severe events (SSE) were more frequent in cyanotic CHD [22/78 (I) vs 4/47 (C), p=0.01] as were surgically-related fatalities [5 (I) vs 0 (C)]. We conclude that RSVIG is safe and should be effective in decreasing serious RSV illness in children <6 months of age with acyanotic CHD. While the increased SSE and surgically-related fatalities appeared to be unrelated to RSVIG administration, children with cyanotic CHD should not be given RSVIG until the cause for this finding has been determined.

Defective Regulation of Immune Responses in Croup Due to Parainfluenza Virus

ABSTRACT: In order to determine if defects in regulation of immune responses play a role in the pathogenesis of croup, we studied 37 infants and children with either croup or upper respiratory illness alone due to parainfluenza virus (PV). PV-specific IgE responses were determined by an enzyme-linked immunosorbent assay, cell-mediated immune responses to PV antigen were studied by in vitro lymphocyte transformation assays, and suppressor cell function was determined by addition of histamine to lymphocyte transformation assays. In comparison to patients with upper respiratory illness alone, patients with croup had increased production of PV-specific IgE antibody, increased lymphoproliferative responses to PV antigen, and diminished histamine-induced suppression of lymphocyte transformation responses to PV. These results suggest that a defect in suppressor function exists among croup patients. Similar defects have been demonstrated in bronchiolitis and atopic diseases, providing an immunologic link between the three illnesses.

Lactoferrin Reverses Respiratory Abnormalities in Respiratory Syncytial Virus (RSV) Infection of Mice

Lactoferrin Reverses Respiratory Abnormalities in Respiratory Syncytial Virus (RSV) Infection of Mice

Fusarium Osteomyelitis in a Patient With Pearson Syndrome: Case Report and Review of the Literature

Fusarium species are ubiquitous fungi causing a wide array of infections, including invasive disease in the immunosuppressed. We present a fusarium bone infection in a child with Pearson syndrome and review the literature. Ten cases of fusarium osteomyelitis were reported in the past 40 years, and we review the treatments.

ROLE OF VIRUL SPECIFIC Ige IN THE RELEASE OF LEUKOTRIENE C4 (LTC4) IN NASOPHARYNGEAL SECRETIONS (NPS) OF INPANTS WITH RESPIRATORY SUNCYTIAL VIRUS (RSV) INFECTION

Samples of NPS from groups of infants with bronchiolitis or upper respiratory illness alone during infection with RSV were analyzed for LTC4 content using a reverse-phase high-pressure liquid chromatography (HPLC) assay and confirmed by radioimmunoassay. Titers of RSV-specific IgE in NPS specimens were determined using an ELISA assay. LTC4 was present in 67% of samples obtained in the first week after the onset of illness and was detectable in progressively lower concentrations in samples obtained up to 27 days after the onset of illness, but not beyond. LTC4 was detectable in samples of NPS obtained in the acute phase of illness from 73% of infants with bronchiolitis due to RSV, and in about 30% of samples of NPS obtained during the same interval from infants with upper respiratory illness alone, significantly, however, quantities of LTC4 measured in NPS could be directly correlated with the magnitude of the peak RSV-IgE response in secretions (r=0.557, p<0.02). LTC4 was not detected in NPS specimens from any of the patients who did not develop an RSV-IgE response. These studies lend support to previous investigations suggesting that severe bronchiolitis due to RSV results from IgE-mediated hypersensitivity reactions to viral antigens, with release of chemical mediators of airway obstruction. Their implications should be considered in new approaches to therapy for RSV bronchiolitis.