Respiratory syncytial virus infection in childhood

Respiratory syncytial virus is the most frequent cause of respiratory tract infections in infants and is responsible for annual winter epidemics of acute bronchiolitis. Over the last decades medical therapy has remained unchanged and controversial, despite intensive research. Inhaled bronchodilators are often not effective and should be discontinued if no beneficial response can be documented. Steroids and ribavirin are not indicated in previously healthy infants with acute RSV bronchiolitis. There is some evidence, however, that certain risk groups may benefit from their use. With good supportive care the mortality from RSV infection is now low. Postinfectious alterations in lung function are usually transient and reversible. High-risk infants can be protected from severe RSV infections by monthly infusions of RSV immune globulins. This treatment modality has, however, not gained wide acceptance because of the benign nature of the disease and the high costs and side effects of regular immune globulin infusions. An international consensus statement on the treatment of RSV bronchiolitis may help to reduce the wide differences in clinical practice.     

Interpretive algorithms for the symptom-limited exercise test: assessing dyspnea in Persian Gulf war veterans

The mechanisms by which respiratory syncytial virus (RSV) infection induces bronchiolitis and airway disease are unclear. The presence of large numbers of polymorphonuclear leukocytes (PMN) in the airways of infants with RSV infection suggests a potential role of PMN in airway injury associated with RSV infection. To investigate the potential role of neutrophils in RSV bronchiolitis, human alveolar type II cells (A549 cells) were infected with different doses of RSV for 6-48 h. A 51Cr-releasing assay was used to measure PMN-induced damage and image analysis was used to determine PMN adhesion and detachment of epithelial cells. The results showed that RSV infection of epithelial cells enhanced PMN adherence in a dose- and time-dependent pattern, RSV infection alone could damage and detach epithelial cells to a limited extent and PMN significantly augmented RSV infection-induced damage and detachment of epithelial cells. These data suggest that respiratory syncytial virus infection of respiratory epithelial cells enhances neutrophil adhesion to the epithelium and that activated neutrophils augment the damage and detachment of epithelium infected with the virus. Polymorphonuclear leukocytes may contribute to the pathogenesis of respiratory syncytial virus airway disease by inducing epithelial damage and cell loss.     

Efficacy of bronchodilators in the treatment of bronchiolitis

Bronchiolitis is a common respiratory infection affecting young children. Much controversy revolves around the efficacy of bronchodilators in the treatment of bronchiolitis. This study was conducted to address this issue. AIM: To determine the efficacy of bronchodilators in the treatment of bronchiolitis. METHOD: All children less than 2 years old with bronchiolitis were randomly assigned to receive nebulisations of Salbutamol, Ipratropium bromide or normal saline. A fourth group given only humidified oxygen without nebulisation were used as a control. RESULTS: Data were obtained for 120 patients. Fifty-one (42%) had respiratory syncytial virus (RSV) isolated from their nasopharyngeal aspirates. The demographic characteristics of the 4 groups were similar. There was no significant difference between the groups in terms of severity score, number of nebulisations required in the nebulised groups and the outcome as measured by the length of hospitalisation. CONCLUSION: The use of bronchodilators did not alter the course of the disease and is therefore not effective in the treatment of bronchiolitis.     

Chromosomal response of insect and mammalian cells to streptonigrin: a comparative study

Respiratory syncytial virus (RSV) infections are characterized by upper or lower respiratory tract symptoms including bronchiolitis and pneumonia. Apnoea may be the first sign of disease in children with RSV infection. The aims of this study were the identification of independent risk factors for RSV associated apnoea and the prediction of the risk for mechanical ventilation in children with RSV associated apnoea. Medical records of children younger than 12 months of age admitted with RSV infection between 1992 and 1995 to the Sophia Children's Hospital, were reviewed. Demographic parameters, clinical features and laboratory parameters (SaO2, pCO2 and pH) were obtained upon admission and during hospitalization. Children with and without apnoea were compared using univariate and multivariate logistic and linear regression analysis. One hundred and eighty-five patients with RSV infection were admitted of whom 38 (21%) presented with apnoea. Patients with apnoea were significantly younger, had a significantly lower temperature, higher pCO2 and lower pH and had on chest radiographs also more signs of atelectasis. The number of patients admitted to the ICU because of mechanical ventilation and oxygen administration was significantly higher in children with RSV associated apnoea. Apnoea at admission was a strong predictor for recurrent apnoea. The relative risk for mechanical ventilation increased with the number of episodes of apnoea: 2.4 (95% CI 0.8-6.6) in children with one episode of apnoea (at admission) versus 6.5 (95% CI 3.3-12.9) in children with recurrent episodes of apnoea. CONCLUSIONS: Age below 2 months is the strongest independent risk factor for RSV associated apnoea. Apnoea at admission increases the risk for recurrent apnoea. The risk for mechanical ventilation significantly increases in children who suffer from recurrent apnoea.     

Diabetes mellitus and lipid metabolism (author''s transl)

Fifteen infants with pneumonia caused by respiratory syncytial virus (RSV) and 19 infants with bronchiolitis caused by RSV were studied for the influence of homologous, circulating neutralizing antibody on the severity of their illness. All infants were under nine months of age. Although maternal neutralizing antibody did not prevent infection with RSV and illness, the severity of pneumonia caused by RSV was inversely related to the level of neutralizing antibody. The severity of bronchiolitis caused by RSV was unrelated to maternal antibody levels. Chest roentgenograms showed pneumonia to be slightly more severe than bronchiolitis. Neither the severity of illness nor the presence of maternal neutralizing antibody was related to the development of complement-fixing antibody.     

Passive protection of gnotobiotic calves using monoclonal antibodies directed at different epitopes on the fusion protein of bovine respiratory syncytial virus

Two neutralizing, fusion-inhibiting bovine monoclonal antibodies (MAbs; B4 and B13) directed at different epitopes on the fusion protein of respiratory syncytial virus (RSV) protected the lungs of gnotobiotic calves from RSV infection. The MAbs were administered intratracheally 24 h before the calves were challenged with bovine RSV. A third, nonneutralizing, non-fusion-inhibiting but complement-fixing MAb, B1, provided no significant protection against infection, and the disease was not exacerbated. Pneumonic consolidation and mean virus titer in lung 7 days after challenge were significantly lower in calves given the fusion-inhibiting MAbs than in either control calves or those given MAb B1. The proliferative bronchiolitis with syncytial formation and widespread distribution of RSV antigen in the lower respiratory tract of the B1-treated and control calves were indistinguishable and typical of experimental bovine RSV infection. Syncytia were markedly absent, and little or no viral antigen was detected in either the B4- or B13-treated calves.     

13C-urea breath test in Helicobacter pylori diagnosis and eradication. Correlation to histology, origin of ''false'' results, and influence of food intake

Obliterative or constrictive bronchiolitis is characterized by narrowing of the small airways, due to submucosal and peribronchiolar fibrosis, with chronic obstruction. The vast majority of cases of bronchiolitis obliterans are associated with other diseases and only few cases are idiopathic. We report on the main computed tomography (CT) methods used study obliterative bronchiolitis, the CT findings and the differential diagnosis with other diseases. The dynamic study of alveolar ventilation with CT uses inspiratory and expiratory CT or high-resolution CT (HRCT), spiral dynamic CT or HRCT with advanced image display, ultrafast CT. In abnormal cases HRCT shows direct and indirect signs of small airways disease. The most common (> 80%) sign of obliterative bronchiolitis is the so-called mosaic oligohemia, with low attenuating lobules, caused by air trapping and best seen on expiratory CT, associated with blood flow redistribution to more normal lobules; this finding simulates the ground-glass pattern from infiltrative lung disease. Differential diagnosis is more difficult in the presence of true ground-glass patterns associated with diffuse bronchiolar obstruction and also with mosaic oligohemia due to pulmonary vascular disease and pulmonary emphysema. HRCT can distinguish these diseases and dynamic CT is more sensitive than functional tests in detecting regional abnormalities and air trapping. The combination of HRCT, rapid volumetric scanning and advanced image display is a powerful tool study the normal and abnormal features of bronchiolar function and alveolar ventilation.     

Proteolytic cleavage of MHC class I by complement C1-esterases--an overlooked mechanism?

This paper reviews recent changes in morbidity and mortality of respiratory syncytial virus (RSV) infection in infants with congenital heart disease. Mortality since the late 1970s has declined substantially, from approximately 37% to 3%. Although the frequency of admission to intensive care units has declined from approximately 60% to 30%, the frequency for mechanical ventilatory support has not changed significantly. Because mortality dropped prior to the widespread use of ribavirin, it is difficult to ascribe the improvement to this therapy. In infants with congenital heart disease (CHD), nosocomial infection remains a significant problem, accounting for approximately 33% of the RSV cases. Some authors report significant reductions in hospital-acquired RSV by use of gloves and gowns for contacts with infectious cases. Efforts at primary prevention have encountered problems with development of an RSV vaccine. Preliminary data from studies of passive immunization using immune globulins with high RSV antibody titers suggest that this therapy may reduce the severity of RSV infection in infants with serious heart disease.     

Respiratory syncytial virus-infected pulmonary epithelial cells induce eosinophil degranulation by a CD18-mediated mechanism

Respiratory syncytial virus (RSV)-induced bronchiolitis in infants is characterized by wheezing, respiratory distress, and the histologic findings of necrosis and sloughing of airway epithelium. High concentrations of eosinophil cationic protein (ECP), a cytotoxic protein contained in the granules of eosinophils, have been found in the airways of RSV-infected infants. The mechanisms of eosinophil degranulation in vivo remain largely unknown. Since RSV-infected respiratory epithelial cells are a rich source of cytokines with eosinophil-activating properties, our studies were designed to mimic in vitro the interaction between RSV, pulmonary epithelial cells (A549), and eosinophils in the airway mucosa. We report in this work that, in the absence of epithelial cells, neither RSV, in the form of purified virions, nor UV-irradiated culture supernatant of RSV-infected epithelial cells (RSV-CM) induced eosinophil degranulation. On the other hand, eosinophils released significant amount of ECP when cultured with RSV-infected A549 cells. Uninfected A549 cells, which failed to induce eosinophil degranulation, were equally effective in triggering ECP release if they were cultured with eosinophils in the presence of RSV-CM. Although RSV-CM induced the up-regulation of the beta2 integrin CD11b on eosinophils and the expression of ICAM-1 on A549 cells, release of ECP was inhibited significantly by anti-CD18 mAb, but not by anti-ICAM-1 mAb. These results suggest a novel mechanism by which respiratory viruses may trigger the detrimental release of eosinophil granule proteins in the airway mucosa.     

Respiratory syncytial virus (RSV) disease and prospects for its control

Respiratory syncytial virus (RSV) is a major virus pathogen of infants and young children, an important cause of disease in adults and is responsible for a significant amount of excess morbidity and mortality in the elderly. It also can be devastating in immunosuppressed populations. Vaccines are being developed, but none are currently licensed. Moreover, even if one or more are approved, they may not be suitable for some populations vulnerable to RSV (e.g. very young infants and the immunosuppressed). Ribavirin and immunoglobulin preparations with high titers of RSV-specific neutralizing antibodies are currently approved for use to treat and prevent RSV infection. However, neither of these is cost-effective or simple to administer. New agents are needed to reduce the impact of RSV. This review is concerned with the means currently available for controlling RSV, the search for new agents effective against this virus, and future prospects for preventing and treating RSV infections.     

Morphologic features and function of the airways in early asbestosis in the sheep model

Previous studies of asbestos exposure in humans and small animals have suggested that air flow limitation associated with small airway disease may be an early manifestation of asbestosis, but the subject is still controversial. In this report, we present the airway morphologic aspects and function of our sheep model of the disease. Three groups of 6 sheep were exposed to repeated intratracheal injections of either saline (control group), 2 mg of UICC Canadian chrysotile asbestos in saline (low exposure group), or 128 mg of the same fibers (high exposure group). At the end of the twelfth month of exposure, an alveolitis had developed in the high exposure group only. Detailed pulmonary function tests were followed within 48 by lung biopsies according to methods described, to which were added air-helium flow-volume curves. Lung biopsies in control and low exposure groups did not demonstrate significant morphologic changes, whereas all biopsies in the high exposure group showed alveolitis characterized by an alveolar and interstitial accumulation of macrophages and mononuclear cells without interstitial fibrosis. On all biopsies, over half of the airways were altered by a similar peribronchiolar process, which at times compressed the peripheral airways. Functionally there was no significant difference between low exposure and control groups. However, compared with the control group, the high exposure group had significantly lower vital capacity (2.0 +/- 0.1 versus 2.9 + 0.1 L, p less than 0.01), lower static lung compliance (91 + 13 versus 132 + 9 ml/cmH2O, p less than 0.05), higher isoflow volume (2.15 + 0.08 versus 1.4 + 0.1 L, p less than 0.01), and higher upstream resistance below the isoflow volume (3.3 + 0.2 versus 1.3 + 0.3 cmH2O L/s, p less than 0.02). These data demonstrate that in the early asbestos-induced peribronchiolar alveolitis of the sheep, which restricts lung volumes, there is a concomitant small airway disease that significantly limits air flow.     

Gender differences in N-alkyl protoporphyrin IX production in rats after the administration of porphyrinogenic xenobiotics

OBJECTIVE: To study the effect of an educational intervention on the management of hospitalized infants with bronchiolitis. DESIGN: Sequential, prospective cohort study. SETTING: A 235-bed children's hospital with nearly all private rooms. PATIENTS: Consecutively admitted, previously healthy children younger than 24 months with symptoms of bronchiolitis. The first cohort was enrolled between January 1 and January 21, 1996; the second cohort between January 29 and February 18, 1996, following a 1-week intervention period; the third (follow-up) cohort between December 1996 and February 1997. INTERVENTION: Educational program and practice guidelines aimed at appropriate utilization of diagnostic tests, decreased antibiotic and bronchodilator use, increased compliance with isolation, decreased length of stay, and maintenance of quality care. MAIN OUTCOME MEASURES: Utilization of respiratory syncytial virus (RSV) enzyme immunoassay, initiation and duration of parenteral antibiotic therapy, number of nebulized bronchodilator treatments, isolation orders, length of stay, and readmission rate. RESULTS: A total of 90 patients were studied preintervention, 63 postintervention, and 90 during the follow-up period. The groups were comparable in demographic and clinical features. No patient had a documented serious bacterial infection; however, almost half in each group received parenteral antibiotics, despite recommendations against this. Immediately postintervention, children with positive RSV test results received antibiotics on fewer days than other children (median 0.6 vs 2.4 days; P=.004), suggesting that physicians stopped treatment with antibiotics once a viral diagnosis was confirmed. This effect did not persist into the follow-up period. Viral testing was reduced and isolation orders increased. Use of bronchodilators was reduced from 91% preintervention to 80% during the follow-up period (P=.046), and the median number of treatments was reduced from 15.0 to 10.0 (P=.005). There was no change in length of stay, which was 2 to 3 days, or in readmission rate, which was 1% to 4%. CONCLUSION: Educational efforts centered around practice guidelines can improve some aspects of the treatment of patients hospitalized with bronchiolitis.     

A bovine model of vaccine enhanced respiratory syncytial virus pathophysiology

A critical issue has been the observation that vaccination of children with a formalin-inactivated respiratory syncytial virus (RSV) vaccine is associated with disease enhancement. We have taken advantage of bovine RSV and our experience with this disease in calves to develop a natural model that parallels human disease. Using formalin-inactivated bovine RSV vaccine calves were either sham-vaccinated/infected, vaccinated/infected, or vaccinated/sham-infected and their clinical signs, pulmonary function, and histological lung lesions quantitatively scored. Interestingly there was significantly greater disease in vaccinated/infected calves and histological lesions in calves were similar to those of affected children. Finally, we note that vaccination did not induce neutralizing antibodies, but IgG antibodies were detected by ELISA. Our model of RSV enhanced disease is important because it provides quantifiable evidence of disease severity that can be applied to evaluate the mechanisms of immunopathology and the safety of candidate RSV vaccines.     

Constrictive (obliterative) bronchiolitis: diagnosis, etiology, and a critical review of the literature

Constrictive bronchiolitis (CB) (or obliterative bronchiolitis) designates inflammation and fibrosis occurring predominantly in the walls and contiguous tissues of membranous and respiratory bronchioles, with resultant narrowing of their lumens. It differs from bronchiolitis obliterans-organizing pneumonia in its histopathology and clinical course. Most cases of CB occur in the setting of organ transplants, particularly lung and heart-lung transplants, but also in bone marrow transplants. Other bona fide cases are rare: infection, particularly viral infection, appears to be a well-documented precursor to CB in children, but not in immunocompetent adults. Constrictive bronchiolitis also has been reported in the course of rheumatoid arthritis, in certain other autoimmune diseases such as pemphigus vulgaris, after inhalation of toxic gases such as nitrogen oxide, after ingestion of certain drugs or medicinal agents such as Sauropus androgynous, and as a cryptogenic illness. Recent reports suggest that CB, as defined by clinical criteria (that is, bronchiolitis obliterans syndrome), is very common in lung allograft recipients who survive more than 5 years and, although it is associated with significant mortality, it also can be clinically stable. Furthermore, with the current practice of close monitoring of these patients, it appears that CB may now be diagnosed at an earlier stage, at which resolution, or at least stabilization of progression, is possible. A histopathologic diagnosis of CB in lung transplant and other patients may be difficult to make due to the patchy distribution of lesions, the technical difficulty in obtaining tissue in late lesions with extensive fibrosis, and the failure to recognize lesions. With regard to the last of these, in early stages of disease, CB may be subtle and easily missed in routine hematoxylin-eosin-stained specimens, while in advanced stages the disease may be equally difficult to diagnose if the patchy scarring in the lung is interpreted as nonspecific. The relative loss of bronchioles and the relationship of the scars to contiguous arteries should signal the need for elastic stains to look for the residual elastica of the bronchioles amidst the foci of fibrosis. Increasingly, clinical grounds, including pulmonary functions studies and high-resolution computed tomography findings, are proving to be relatively sensitive methods of detecting CB. Finally, the progressive airway destruction in chronic transplantation rejection appears to be a T-cell-mediated process. The "active" form of constrictive bronchiolitis, with attendant lymphocytic inflammation of the airways, likely precedes the "inactive" or scarred form of constrictive bronchiolitis.     

Ultraviolet-B irradiation of leukapheresis. Products: dose-response relationship with the mixed lymphocyte reaction

Our aim was to study the influence of infection with the respiratory syncytial virus (RSV) in non-hospitalized infants on sensitization to aeroallergens and the early manifestation of atopy. Six hundred and nine infants from the prospective German Multicenter Cohort Study on Atopy were included, 38% of whom had an elevated atopic risk. RSV IgG and IgM antibodies were tested by ELISA with gradient purified RSV antigen. Specific IgE against mites, cat dandruff, birch and grass pollens and relevant nutritional antigens were tested with CAP-RAST-FEIA (Pharmacia, Sweden). Of the cord sera 99% were positive for RSV-IgG, 44.7% at one year and 64.2% (n = 265) at two years of age. The positivity rate after 12 months varied with the season of birth, the number of siblings and the degree of exposure to tobacco smoke; and correlated closely with attacks of wheezing during infancy. Twenty (2.8%) children were found to be sensitized against at least one aeroallergen at one year, and 28 (10.5%) at two years. By the first birthday, mite sensitization (n = 3) could only be seen in the RSV-infected children; grass pollen sensitization (n = 9) was associated with RSV seropositivity (logistic regression model including the confounders mentioned above: with RSV IgG < p = 0.048 > and IgM < p = 0.0006 >), as was birch sensitization (n = 5) with RSV IgM (p = 0.009). No such differences could be detected at two years. No correlation of RSV seropositivity to any allergic manifestation could be found. We conclude, that it is only in the first year of life, that RSV infection plays a significant role in promoting sensitization against aeroallergens, which do not at this time produce allergic symptoms.     

Acute bronchiolitis due to Mycoplasma pneumoniae and successfully treated with steroids

A high fever, coughing, stridor, and dyspnea developed in a 52-year-old woman on October 19, 1995. She went to a local clinic and was treated with oral penicillin and intravenous cefpirome. The symptoms worsened, and she was admitted to our hospital on October 26. Coarse crackles and wheezing were heard in both lung fields. The white blood cell count was 9000/mm3 and arterial blood gas analysis revealed a PaO2 of 49.8 Torr on room air. A chest roentgenogram obtained on admission showed a few small bibasilar nodular infiltrates, and a chest CT scan showed thickened bronchial walls along with small nodules having a centrilobular distribution. Of the cells in bronchoalveolar lavage fluid, 88% were neutrophils, but tests for bacteria and mycobacteria were negative. The cold-agglutinin titer was 1:512. The Mycoplasma pneumoniae antibody titer (IIIA) was 1:640 and viral serology tests were negative. Acute bronchiolitis due to M. pneumoniae was diagnosed and treatment with intravenous minocycline was started. The symptoms (coughing, fever, and stridor) resolved and the small nodules on chest CT scan disappeared, but hypoxemia remained. At the same time, an obstructive ventilatory defect (FEV1% 62.8%) and abnormal ventilation/perfusion lung scans were noted. Development into bronchiolitis obliterans was suspected, so administration of methyl prednisolone (1 g/day for 3 days) and prednisolone was started. The response to steroids was good. Pulmonary function improved and the arterial PaO2 at the time of discharge was 86 Torr (room air). Use of steroid therapy in the early phase of bronchiolitis obliterans seemed to be effective.     

Analysis of the uncoupling protein-1 (UCP1) gene in obese and lean subjects: identification of four amino acid variants

We report the case of a patient with fatal obstructive lung disease after an HLA-haploidentical sibling cord blood transplant (CBT), with severe acute GVHD. A 2-year-old girl developed expiratory air trapping gradually with acute and chronic GVHD after CBT for the treatment of ALL. Anti-CMV and immunosuppressive therapy were ineffective, and the patient died of progressive respiratory acidosis. Necropsy of the lung revealed severe bronchiolitis obliterans with cytomegalic inclusion cells in the granulation tissues of the bronchiolitis. Thus, immunologic and GVHD problems can occur even in CBT.     

The critical first six months in cystic fibrosis: a syndrome of severe bronchiolitis

The syndrome of infantile bronchiolitis in cystic fibrosis (CF) carries a high mortality. Fifteen cases of CF encountered over the past 19 years with severe bronchiolitis with onset during the first 6 months of life are described. Treatment include steroids in high doses. All patients recovered. Further progress resembled the usual natural course of CF and showed no evidence of persisting lung damage. The mechanism of this syndrome is not clear and is probably dependent on many factors involved in early lung disease in CF. The frequency of severe bronchiolitis in cystic fibrosis may not be high, but it continues to be seen in clinical practice today.     

Bronchiolitis obliterans with organizing pneumonia and cold agglutinin disease associated with phenytoin hypersensitivity syndrome

Phenytoin hypersensitivity syndrome (PHS) is a rare delayed hypersensitivity reaction which occurs following exposure to phenytoin sodium. Pulmonary involvement is uncommonly described. Herein is reported the first case of histopathologic bronchiolitis obliterans organizing pneumonia (BOOP) found on open-lung biopsy in a patient with severe PHS. New onset, clinically significant, cold agglutinin disease was also documented. Hemodynamic parameters mimicking sepsis were present in the absence of significant clinical infection. Rapid, dramatic improvement followed high-dose steroid therapy.