Severe Respiratory Syncytial Virus Bronchiolitis Research Articles

Admission to the intensive care unit for respiratory syncytial virus bronchiolitis: a national survey before palivizumab use.

Preterm infants, especially those with chronic lung disease (CLD), are considered more susceptible to severe respiratory illness from respiratory syncytial virus (RSV) infection than healthy term infants, and are therefore targeted for prophylactic administration of immune globulins. The impact of this practice on the more severe cases of bronchiolitis (i.e., pediatric intensive care unit [PICU] admission, mechanical ventilation, mortality) has not been reported to date. The aim of this study was to evaluate PICU admissions, need for mechanical ventilation, and mortality attributable to RSV bronchiolitis in Israel before the introduction of RSV prophylaxis to the country. Prospective survey of 11 PICUs in Israel during the RSV season (November 2000-March 2001). All patients admitted to the PICU because of bronchiolitis, and the subgroups who needed mechanical ventilation or who died, were analyzed for known risk factors, namely, prematurity, CLD, and chronic oxygen dependence. A total of 105 patients with RSV bronchiolitis met the inclusion criteria, of whom 33 were mechanically ventilated. Most of the patients (84% total admission, 88% ventilated) were born after 32 weeks' gestation, and 89% and 88%, respectively, did not have CLD. Only 16% and 9%, respectively, met any of the American Academy of Pediatrics criteria for RSV prophylaxis, such that 84% of the whole sample and 91% of the ventilated patients were not candidates for RSV prophylaxis. Five patients died, 2 of them with cyanotic heart disease. Most of the infants with severe RSV bronchiolitis were born at term and did not have CLD. The great majority of patients admitted to the PICU for bronchiolitis were not candidates for RSV prophylaxis. Administration of RSV prophylaxis to the predefined high-risk population could be expected to yield no significant change in PICU admissions or number of infants needing mechanical ventilation. New risk-stratified guidelines for RSV prophylaxis are needed.

Moderate local and systemic respiratory syncytial virus-specific T-cell responses upon mild or subclinical RSV infection.

Respiratory syncytial virus (RSV) infections are a major cause of severe respiratory disease in infants. It has been shown that there is an increased frequency of childhood wheezing in ex-bronchiolitic preteen children. This was postulated to be mediated by a vigorous virus-specific Th2 response influencing the further development of the immune system. Little is known about the possible role of the immune response to clinically mild RSV infections in this respect. We have studied the RSV-specific cellular immune response in infants with a laboratory-confirmed RSV upper respiratory tract infection (URTI; n = 13, mean age 12 months, range 2-22 months) in comparison with infants with non-RSV mediated URTI (n = 9, mean age 9.3 months, range 4-18 months) or infants with severe RSV bronchiolitis (n = 11, mean age 2.3 months, range 1-6 months). RSV-specific cytokine-producing cells were enumerated using the ELISPOT method in peripheral blood mononuclear cells and nasal brush T-cells, collected during the acute and convalescent phase of the infection. Mixed Th1 (IFN-gamma) and Th2 (IL-4 and IL-13) responses were detected in all three groups. Frequencies of RSV-specific T-cells were lower in both URTI groups than in the RSV bronchiolitis group, and not significantly different between the RSV URTI and the non-RSV URTI group. The absence of vigorous virus-specific Th2 responses upon mild RSV infection does not support the hypothesis that these infections influence the development of the immune system and that they predispose for the development of atopic disease.

The Complex Relationship between Respiratory Syncytial Virus and Allergy in Lung Disease

Epidemiologic studies suggest a strong link between severe respiratory syncytial virus (RSV)-induced bronchiolitis in infancy and allergic disease; however, the mechanisms determining this relationship are currently unknown. In this review article, we summarize data from human clinical studies that explore the association between RSV infection and allergy, some that suggest that RSV bronchiolitis requiring hospitalization leads to an increased incidence of the allergic phenotype and others that suggest that pre-existing allergy is a risk factor for severe RSV bronchiolitis. We also review the published murine models that combine RSV infection and allergic sensitization that attempt to explain the complex relationship between these two factors in regard to lung immunopathology and physiologic dysfunction.

Human Metapneumovirus in Severe Respiratory Syncytial Virus Bronchiolitis

Reverse transcription-polymerase chain reaction was used to detect segments of the M (matrix), N (nucleoprotein), and F (fusion) genes of human metapneumovirus in bronchoalveolar fluid from 30 infants with severe respiratory syncytial virus bronchiolitis. Seventy percent of them were coinfected with metapneumovirus. Such coinfection might be a factor influencing the severity of bronchiolitis.

Association of severe respiratory syncytial virus bronchiolitis with interleukin-4 and interleukin-4 receptor alpha polymorphisms.

The association of variants of genes encoding interleukin (IL)-4 and the IL-4 receptor alpha chain (IL-4Ralpha) with respiratory syncytial virus (RSV) bronchiolitis was examined in hospitalized infants. Polymorphisms in IL-4 (C-590T) and IL-4Ralpha (I50V and Q551R) were genotyped by restriction fragment-length polymorphism analysis. Control subjects included parents of the hospitalized children (for the transmission/disequilibrium test), and a random population sample (for the case-control study). Results were also analyzed in a combination of these 2 tests, using Fisher's method. The IL-4 590T allele was found more frequently among children hospitalized with RSV than expected in the case-control (odds ratio [OR], 1.43; P=.04) and combination (OR, 1.41; P=.02) tests. Among children who were >6 months old when they were hospitalized, compared with the control group or with the <6 months old who were hospitalized for RSV infection, higher frequencies of both the IL-4 590T allele and the IL-4Ralpha R551 allele were found. These results indicate that gain-of-function variants of T helper type 2 cytokine genes may play a role in increasing the severity of RSV disease, which appears more pronounced after the first half-year of life.

Age at first viral infection determines the pattern of T cell-mediated disease during reinfection in adulthood.

Infants experiencing severe respiratory syncytial virus (RSV) bronchiolitis have an increased frequency of wheeze and asthma in later childhood. Since most severe RSV infections occur between the 8th and 24th postnatal week, we examined whether age at first infection determines the balance of cytokine production and lung pathology during subsequent rechallenge. Primary RSV infection in newborn mice followed the same viral kinetics as in adults but was associated with reduced and delayed IFN-γ responses. To study rechallenge, mice were infected at 1 day or 1, 4, or 8 weeks of age and reinfected at 12 weeks. Neonatal priming produced more severe weight loss and increased inflammatory cell recruitment (including T helper 2 cells and eosinophils) during reinfection, whereas delayed priming led to enhanced interferon γ production and less severe disease during reinfection. These results show the crucial importance of age at first infection in determining the outcome of reinfection and suggest that the environment of the neonatal lung is a major determinant of cytokine production and disease patterns in later life. Thus, simply delaying RSV infection beyond infancy might reduce subsequent respiratory morbidity in later childhood.

RSV bronchiolitis and risk of wheeze and allergic sensitisation in the first year of life.

Severe respiratory syncytial virus (RSV) infection has been hypothesised to be a risk factor for the development of allergy and asthma, but epidemiological studies in older children have been inconclusive. The current study hypothesises that the effect of RSV bronchiolitis might be most prominent during the first year after bronchiolitis. Forty-two infants had experienced RSV bronchiolitis severe enough to cause hospitalisation. For each child with RSV infection, two controls were acquired from a birth cohort and matched for date of birth and sex. All the children were followed prospectively and underwent a follow-up examination at a mean age of 1 yr, which included physical examination, and serum immunoglobulin (Ig) E tests for common food and inhaled allergens. Risk factors for the development of recurrent wheezing and IgE antibodies were analysed for the whole group of 126 children. A positive test for IgE antibodies was noted in 14 of 42 (33%) RSV children and in 2 of 84 (2.3%) children in the control group. RSV bronchiolitis was the most important risk factor for allergic sensitisation. Likewise, 13 children (15.5%) of the RSV group and three (3.6%) children of the control group suffered from recurrent wheezing, and RSV bronchiolitis posed a considerable risk for recurrent wheezing. Severe respiratory syncytial virus bronchiolitis during the first year of life is an important risk factor for the development of recurrent wheezing and sensitisation to common allergens during the subsequent year.

Early Ribavarin Treatment of Bronchiolitis: Effect on Long-term Respiratory Morbidity

The mortality rate from respiratory syncytial virus (RSV) bronchiolitis has significantly reduced over the last decade. A major concern now is the long-term respiratory morbidity following RSV bronchiolitis. In this prospective study, we randomly assigned 49 previously healthy infants with severe RSV bronchiolitis, early in the course of illness (< 5 days duration), to receive either conservative treatment (n = 21) or additional ribavirin treatment (n = 24). Both groups were closely matched for age and clinical characteristics. During a prospective, closely monitored, 1-year follow-up period, the group treated with ribavirin had significantly fewer episodes (2.7 +/- 2.3 episodes vs 6.4 +/- 4.2 episodes per patient per year) and reduced severity of reactive airway disease (0.08 episodes vs 1.09 episodes of moderate-to-severe illness per patient per year) and respiratory illness-related hospitalization (25 hospital days vs 90 hospital days per 100 patients per year). Early ribavirin treatment of RSV bronchiolitis in previously healthy infants resulted in reduction of incidence and severity of reactive airway disease as well as respiratory illness-related hospitalization.

Enhanced IL-4 responses in children with a history of respiratory syncytial virus bronchiolitis in infancy.

Infants who recover from respiratory syncytial virus (RSV)-induced bronchiolitis are at high risk of developing asthma and recurrent wheezing. It is not known whether severe RSV infection itself causes persistent effects or is a marker of a "wheezy" predisposition. To determine the long-term immunological correlates of infantile bronchiolitis, interleukin (IL)-4 and interferon (IFN)-gamma responses to a panel of antigens were studied in a well-characterised cohort of 7-8-yr-old children with a history of severe RSV bronchiolitis in infancy. Peripheral blood lymphocytes from 37 children who were hospitalised with RSV bronchiolitis in infancy and from 69 age-, sex- and location-matched controls were stimulated in vitro with RSV, house-dust mite, birch and cat antigens. Cellular proliferation, and enzyme-linked immunoSPOT IFN-gamma and IL-4 production were measured. IL-4 producing T-cells responding to RSV and cat antigens were significantly more frequent in exbronchiolitics. Other responses (including the IFN-gamma response to RSV) were equally strong in exbronchiolitics and controls. Respiratory syncytial virus infection primes memory T-cells that make interferon-gamma, but virus and aeroallergen-specific and interleukin-4 producing T-cells are also frequently primed in bronchiolitics. Respiratory syncytial virus bronchiolitis in infancy may increase the risk of allergic sensitisation by providing a local interleukin-4-rich environment, in which airborne allergens are first encountered.

Cytokines in severe respiratory syncytial virus bronchiolitis.

Bronchiolitis caused by respiratory syncytial virus (RSV) infection is an important cause of severe lung disease in infants, and increasing evidence suggests that it is immunologically mediated. Experiments in mice suggest that this may be due to differential T-cell activation producing either type 1 or type 2 cytokines. We investigated this hypothesis in man by studying 24 infants ventilated with severe RSV bronchiolitis and by measuring messenger RNA (mRNA) for interleukin-4 (IL-4) and interferon-gamma (IFN-gamma), by polymerase chain reaction, in nasopharyngeal aspirates (NPAs) and bronchoalveolar lavage (BAL) fluids. A semiquantitative assay was used to estimate concentrations of mRNA for these cytokines in comparison to mRNA of the constitutively expressed hypoxanthine guanine phosphoribosyl transferase gene. BAL from 18/24 infants showed polarization of cytokine production: 6 with only IFN-gamma mRNA, and 12 with only IL-4 mRNA. For the 6/24 infants in whom both IL-4 mRNA and IFN-gamma mRNA were detected in BAL fluid, each was present in low amounts, compared with those with mRNA for IL-4 or IFN-gamma alone. IL-4 and IFN-gamma mRNA were not detected in any of the NPAs.These findings provide the first direct evidence in infants that in RSV bronchiolitis there are divergent T-cell responses and suggest that more than one mechanism may be responsible for immune-mediated disease enhancement.

Immunological mechanisms of severe respiratory syncytial virus bronchiolitis.

Respiratory syncytial virus (RSV) bronchiolitis resulting in respiratory insufficiency is frequently encountered during the winter season in paediatric intensive care units. This review evaluates potential determinants described in severe RSV bronchiolitis with special attention to the role of immaturity of immune responses during infancy. Pre-existent cardiac or pulmonary compromises have been documented as clinical risk factors for severe RSV bronchiolitis. In addition to this group of infants with pre-morbidity, a large proportion of mechanically ventilated RSV bronchiolitis patients are previously healthy full-term infants or premature neonates without predisposing risk factors. In general, infants at this early age have maturation-related deficient cellular immunity. Several studies show an association between decreased cellular immunity and severe RSV bronchiolitis, indeed suggesting that a maturation-related defect of the cellular immune system facilitates severe RSV. In addition, low virus-specific antibody titres prior to RSV bronchiolitis have been shown to be a risk factor for severe RSV bronchiolitis. A low level of cellular and humoral immunity would explain that higher viral titres are found in infants with most severe illness. In conclusion, immaturity of the physiological functions in healthy pre-term infants and neonates, in particular the immune system, appears to be an important factor in the pathogenesis of RSV bronchiolitis resulting in mechanical ventilation.

DNase treatment for atelectasis in infants with severe respiratory syncytial virus bronchiolitis

Respiratory insufficiency due to respiratory syncytial virus (RSV) bronchiolitis is partly due to the abundance of thickened mucus and the inability to clear it from the airways. Mucus in RSV bronchiolitis contains necrotic inflammatory and epithelial cells. The viscoelastic properties of purulent airway secretions are largely due to the presence of highly polymerized deoxyribonucleic acid (DNA). Recombinant human deoxyribonuclease (rhDNase) is known to liquefy such mucus in patients with cystic fibrosis, whereas case reports described a beneficial effect in other respiratory disorders. The authors hypothesized that rhDNase would diminish atelectasis and mucus plugging in infants with severe RSV bronchiolitis. Two infants with RSV bronchiolitis with massive unilateral atelectasis in whom mechanical ventilation was imminent due to exhaustion, and three mechanically ventilated infants (two neonates, one with bronchopulmonary dysplasia) with RSV bronchiolitis with pneumonia received treatment with 2.5 mg nebulized rhDNase twice daily. Following administration of nebulized recombinant human deoxyribonuclease, clinical and radiological parameters improved quickly. Mechanical ventilation could be avoided in two infants while in three infants on artificial ventilation, clinical recovery started following the first dose of the drug. A therapeutic trial of recombinant human deoxyribonuclease may be an option in the treatment for atelectasis in severe or complicated respiratory syncytial virus bronchiolitis in infancy.

Macrophage inflammatory protein-1alpha (not T helper type 2 cytokines) is associated with severe forms of respiratory syncytial virus bronchiolitis.

It has been suggested that the pathogenesis of respiratory syncytial virus (RSV) infection is related to the development of T helper (Th) type 2 cytokine responses. The presence of Th1 and Th2 cytokines and the chemokines macrophage inflammatory protein (MIP)-1alpha and monocyte chemotactic protein (MCP)-1 were assessed by ELISA in nasopharyngeal secretions of infants with RSV infection. Infants with mild bronchiolitis had increased Th1 cytokines and reduced Th2 cytokines, compared with infants with upper respiratory tract illness alone. Severe bronchiolitis was characterized by a more balanced Th1-Th2 response that did not differ from that of infants with upper respiratory tract illness alone. In contrast, MIP-1alpha was markedly increased in infants with severe bronchiolitis. MIP-1alpha and MCP-1 levels also were inversely related to oxygen saturation (P<.005). Thus, the severity of RSV bronchiolitis appears to be related more to chemokine release than to Th2 cytokine production.

Monocyte interleukin-12 production is inversely related to duration of respiratory failure in respiratory syncytial virus bronchiolitis.

The correlation of clinical and immunological parameters with the duration of respiratory failure was investigated to identify factors determining the clinical outcome of respiratory syncytial virus (RSV) bronchiolitis necessitating mechanical ventilation. At initiation of mechanical ventilation in 30 patients with RSV, production of interleukin (IL)-12 and IL-10 was measured in 48-h peripheral blood cell cultures that were stimulated with lipopolysaccharide and interferon-gamma. The ventilation index (VI)-an indicator of respiratory dysfunction that includes partial pressure of arterial CO2, peak airway pressure, and respiratory rate-correlated with the duration of mechanical ventilation (r=.47; P=.013). Age was not associated with the duration of mechanical ventilation. A highly significant inverse correlation was found between the duration of mechanical ventilation and the production of IL-12 at admission (r=-.62; P<.001). This correlation was independent of VI. No correlation was found between IL-10 production and the duration of mechanical ventilation. It is hypothesized that low monocyte IL-12 response during initial RSV infection adversely affects clinical outcome of patients with severe RSV bronchiolitis.

Peripheral blood cytokine responses and disease severity in respiratory syncytial virus bronchiolitis

The role of cellular immunity in disease severity in respiratory syncytial virus (RSV) bronchiolitis is largely unknown. This study investigated the association between disease severity and systemic cytokine responses in hospitalized ventilated and nonventilated RSV bronchiolitis patients. In whole blood cultures stimulated with phytohaemagglutinin (PHA), lymphoproliferative responses and interferon (IFN)-gamma and interleukin (IL)-4 production during acute illness were measured. In addition, plasma cytokines were measured. Measurements were repeated in the convalescent phase, 3-4 weeks after admission. Fifty patients were included. The median age in ventilaled patients was significantly lower than in nonventilated patients (1 versus 4 months, p<0.05). In comparison with nonventilated patients, the ventilated patients had significantly lower lymphoproliferative responses and a lower production of IFN-gamma and IL-4. In fact, IFN-gamma and IL-4 production in ventilated patients was almost completely undetectable. Plasma IL-8 levels in ventilated patients were significantly higher than in nonventilated patients. In the convalescent phase, lymphoproliferative and cytokine responses as well as plasma IL-8 levels were normal in both patient groups. Since RSV bronchiolitis is associated with the subsequent development of asthma, the possible skewing of the T-helper (Th1/Th2) cytokine balance was investigated. This was found neither in the acute nor in the convalescent phase. In conclusion, the data indicate that depressed lymphocyte function and elevated plasma interleukin-8 levels are markers of severe disease. It is suggested that age and maturation related immune mechanisms could explain the occurrence of severe respiratory syncytial virus bronchiolitis requiring mechanical ventilation in young infants.

Respiratory syncytial virus infection: immune response, immunopathogenesis, and treatment.

Respiratory syncytial virus (RSV) is the single most important cause of lower respiratory tract infection during infancy and early childhood. Once RSV infection is established, the host immune response includes the production of virus-neutralizing antibodies and T-cell-specific immunity. The humoral immune response normally results in the development of anti-RSV neutralizing-antibody titers, but these are often suboptimal during an infant's initial infection. Even when the production of RSV neutralizing antibody following RSV infection is robust, humoral immunity wanes over time. Reinfection during subsequent seasons is common. The cellular immune response to RSV infection is also important for the clearance of virus. This immune response, vital for host defense against RSV, is also implicated in the immunopathogenesis of severe lower respiratory tract RSV bronchiolitis. Many details of the immunology and immunopathologic mechanisms of RSV disease known at present have been learned from rodent models of RSV disease and are discussed in some detail. In addition, the roles of immunoglobulin E, histamine, and eosinophils in the immunopathogenesis of RSV disease are considered. Although the treatment of RSV bronchiolitis is primarily supportive, the role of ribavirin is briefly discussed. Novel approaches to the development of new antiviral drugs with promising anti-RSV activity in vitro are also described.

Use of extracorporeal membrane oxygenation in the treatment of respiratory syncytial virus bronchiolitis: The national experience, 1983 to 1988

In an effort to obtain data to provide the basis for the design of controlled clinical trials, we contacted all U.S. participants in the National ECMO Registry to assemble the national experience on the use of extracorporeal membrane oxygenation in respiratory syncytial virus bronchiolitis during the past 5 years. Twelve infants were treated at nine centers between 1983 and 1988. Eight had been born prematurely, and five had bronchopulmonary dysplasia. The mean age at onset of infection with respiratory syncytial virus was 108 +/- 102 days. The mean length of ventilator management before extracorporeal membrane oxygenation was 7.8 +/- 7.1 days. All infants had persistent hypoxemia with a mean arterial oxygen pressure of 39.2 +/- 11.7 torr (5.3 +/- 1.6 kPa) despite high ventilator pressures (mean airway pressure 19.7 +/- 6.4 cm H2O) and 100% inspired oxygen; six had air leak syndrome. Seven infants survived (58%). The mean duration of extracorporeal membrane oxygenation for survivors was 233 +/- 139 hours. Preexisting chronic lung disease did not predict a poor outcome: four of the five infants with bronchopulmonary dysplasia survived. Six of the survivors have subsequently achieved expected developmental milestones and one has slight motor delay. We conclude that, for infants with severe respiratory syncytial virus bronchiolitis whose condition deteriorates despite maximal ventilator management, extracorporeal membrane oxygenation may provide lifesaving support. The duration of successful treatment with this therapy may be longer than that for conventional neonatal indications, but excellent neurologic outcome may be expected in survivors.

HLA class I antigens in severe RSV bronchiolitis.

Cytotoxic T-lymphocytes (CTL) recognize virus-infected cells in association with HLA class I antigens. There is strong evidence of the importance of CTL in respiratory syncytial virus (RSV) infections. We looked for but were unable to demonstrate an association between particular HLA class I antigens and severe RSV bronchiolitis in infants.