Evidence for a causal relationship between respiratory syncytial virus infection and asthma

Respiratory syncytial virus (RSV) infects all children early in life, is the most common cause of infant lower respiratory tract infections, and causes disease exacerbations in children with asthma. Episodes of lower respiratory tract infection in early life are associated with asthma development. Whether RSV infection early in life directly causes asthma or simply identifies infants who are genetically predisposed to develop subsequent wheezing is debatable. Recent studies suggest that these two explanations are not mutually exclusive, and are likely both important in asthma development. An open-label study of RSV immunoprophylaxis administered to preterm infants reduced recurrent wheezing by 50%. Clinical trials of infant RSV prevention, delay or severity reduction on the outcome of childhood asthma would confirm the causal relationship between RSV infection and asthma, and offer a primary prevention strategy.     

Interleukin-11: stimulation in vivo and in vitro by respiratory viruses and induction of airways hyperresponsiveness.

To address the role of IL-11 in viral airways dysfunction, we determined whether infectious agents that exacerbate asthma stimulate stromal cell IL-11 production, determined whether IL-11 could be detected at sites of viral infection and evaluated the effects of IL-11 on airway physiology. Respiratory syncytial virus (RSV), parainfluenza virus type 3 (PIV3), and rhinovirus (RV) 14 were potent stimulators while cytomegalovirus and adenovirus only weakly stimulated and herpes simplex virus type 2 and bacteria did not stimulate IL-11 elaboration. IL-11 was not detected or barely detected in nasal aspirates from children without, but was detected in aspirates from children with viral upper respiratory tract infections. The levels of IL-11 were highest in patients with clinically detectable wheezing. IL-11 also caused nonspecific airways hyperresponsiveness in BALB/c mice. These studies demonstrate that three major causes of viral-induced asthma, RSV, RV, and PIV, in contrast to other viruses and bacteria, share the ability to induce stromal cell IL-11 production. They also demonstrate that IL-11 can be detected in vivo during viral respiratory infections, that the presence of IL-11 correlates with clinical bronchospasm and that IL-11 is a potent inducer of airways hyperresponsiveness. IL-11 may be an important mediator in viral airways disorders.     

Evidence for a causal relationship between respiratory syncytial virus infection and asthma

Respiratory syncytial virus (RSV) infects all children early in life, is the most common cause of infant lower respiratory tract infections, and causes disease exacerbations in children with asthma. Episodes of lower respiratory tract infection in early life are associated with asthma development. Whether RSV infection early in life directly causes asthma or simply identifies infants who are genetically predisposed to develop subsequent wheezing is debatable. Recent studies suggest that these two explanations are not mutually exclusive, and are likely both important in asthma development. An open-label study of RSV immunoprophylaxis administered to preterm infants reduced recurrent wheezing by 50%. Clinical trials of infant RSV prevention, delay or severity reduction on the outcome of childhood asthma would confirm the causal relationship between RSV infection and asthma, and offer a primary prevention strategy.     

Novel therapies for an old virus: treatment of RSV infections in the 21st Century

Respiratory syncytial virus (RSV) is a pathogen whose existence has been known for decades, causing mild-to-severe upper and lower respiratory tract infections that bear the risk of subsequent asthma and can even lead to a fatal outcome. RSV infects all groups of patients and is a major cause of hospitalization in children and in the elderly. This review briefly summarizes the current status of RSV drug development and clinical trials for drugs available for the treatment of RSV infections.     

Palivizumab: where to from here?

Respiratory syncytial virus (RSV) is a common cause of respiratory tract infections. In severely immunosuppressed patients RSV can cause significant morbidity and mortality. The only FDA-approved drug for RSV is aerosolized ribavirin. Given the high morbidity and mortality in high-risk populations and inconsistent results with aerosolized ribavirin, new strategies for prevention and treatment of RSV are being sought. Palivizumab is an RSV-specific monoclonal antibody. A randomized, double-blind, placebo-controlled multicenter study showed significant reduction in hospitalization rates among children at high risk of RSV infection who had been given prophylactic palivizumab; these findings led to palivizumab's approval by the FDA in June 1998. Palivizumab also has a role in prevention of severe respiratory tract infections in high-risk infants. In immunocompromised patients, palivizumab has an excellent safety profile and may be beneficial in the prevention and treatment of RSV infections; however, clinical trials are needed to determine its effectiveness. In this article, we review the role of palivizumab in prevention and treatment of RSV infections in immunocompetent and immunocompromised patients.     

RSV604, a novel inhibitor of respiratory syncytial virus replication

Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.     

Treating acute bronchiolitis associated with RSV

Treatment for infants with bronchiolitis caused by respiratory syncytial virus (RSV) includes supplemental oxygen, nasal suctioning, fluids to prevent dehydration, and other supportive therapies. High-risk children who should be hospitalized include those younger than three months and those with a preterm birth, cardiopulmonary disease, immunodeficiency, respiratory distress, or inadequate oxygenation. Inhaled beta2-agonist bronchodilators, the anticholinergic agent ipratropium bromide, and nebulized epinephrine have not been shown to be effective for treating RSV bronchiolitis. However, the Agency for Healthcare Research and Quality states that nebulized epinephrine and nebulized ipratropium bromide are possibly effective. The appropriate use of corticosteroids remains controversial. They may provide some benefit but meta-analyses of clinical trial results are inconsistent. Prophylaxis with RSV intravenous immune globulin or palivizumab, a human monoclonal antibody, can reduce hospitalization rates in high-risk patients, although difficulties with administering the medications and high costs may preclude their widespread use. The use of common infection-control measures can reduce nosocomial transmission of RSV infections.     

Role of atypical bacterial infection of the lung in predisposition/protection of asthma

Asthma is a common inflammatory disease of the airways that results in airway narrowing and wheezing. Allergic asthma is characterised by a T-helper cell-type (Th) 2 response, immunoglobulin (Ig) E production, and eosinophilic influx into the airways. Recently, many clinical studies have implicated Mycoplasma pneumoniae and Chlamydia pneumoniae in the development and exacerbation of both chronic and acute asthma. It is widely accepted that M. pneumoniae and C. pneumoniae infections require Th1 immunity for clearance; therefore, according to the hygiene hypothesis, these infections should be protective against asthma. Here, we review the clinical evidence for the association and mechanisms of predisposition to and protection against asthma by these infections. We will examine the following question: Is it the absence of infection or the age of the individual on infection that confers susceptibility or resistance to asthma and does this vary between normal and predisposed individuals? We put forward a hypothesis of the effects of these infections on the development and prevention of asthma and how novel preventative and treatment strategies involving these microbes may be targeted against asthma.     

RSV infection in infants and young children. What's new in diagnosis, treatment, and prevention?

RSV is the most important respiratory pathogen in infants and young children. About 1% of primary RSV infections result in hospitalization. The virus is spread by large droplets of secretions or contact with contaminated secretions. Infants infected with RSV may demonstrate poor feeding, rhinorrhea, apnea, lethargy, wheezing, and respiratory distress. Diagnosis may be made by clinical signs and symptoms (especially those observed during epidemics), by chest radiographs showing hyperinflation, or by rapid antigen detection with immunofluorescence of nasopharyngeal aspirates. Risk factors for severe disease accompanied by complications include chronic heart disease, chronic lung disease, immunodeficiency, HIV, and prematurity. Immunity is incomplete and of short duration, and reinfection is common. Treatment remains supportive and consists of oxygen administration, hydration, and diligent monitoring. Use of corticosteroids, bronchodilators, antibiotics, and ribavirin is controversial and is dependent largely on physician preference. Use of ribavirin should be reserved for patients who have severe underlying conditions associated with increased mortality rates. Intravenous RSV Ig has been replaced by palivizumab, which is generally recommended for infants at high risk for severe RSV, including those with a history of prematurity and those with chronic lung disease.     

Levofloxacin inhibits rhinovirus infection in primary cultures of human tracheal epithelial cells

Respiratory virus infections, including infections with rhinoviruses (RVs), are related to exacerbations of chronic obstructive pulmonary disease (COPD). A new quinolone antibiotic, levofloxacin (LVFX), has been used to treat bacterial infections that cause COPD exacerbations as well as bacterial infections that are secondary to viral infection in COPD patients. However, the inhibitory effects of LVFX on RV infection and RV infection-induced airway inflammation have not been studied. We examined the effects of LVFX on type 14 rhinovirus (RV14) (a major human RV) infection of human tracheal epithelial cells pretreated with LVFX. LVFX pretreatment reduced the RV14 titer, the level of cytokines in the supernatant, the amount of RV14 RNA in the cells after RV14 infection, and the cells' susceptibility to RV14 infection. LVFX pretreatment decreased the mRNA level of intercellular adhesion molecule 1 (ICAM-1), a receptor for RV14, in the cells and the concentration of the soluble form of ICAM-1 in the supernatant before RV14 infection. LVFX pretreatment also decreased the number and the fluorescence intensity of the acidic endosomes from which RV14 RNA enters the cytoplasm. LVFX pretreatment inhibited the activation of nuclear factor κB proteins, including p50 and p65, in nuclear extracts. LVFX pretreatment did not reduce the titers of RV2 (a minor human RV) but reduced the titers of RV15 (a major human RV). These results suggest that LVFX inhibits major-group rhinovirus infections in part by reducing ICAM-1 expression levels and the number of acidic endosomes. LVFX may also modulate airway inflammation in rhinoviral infections.     

Respiratory syncytial virus disease: update on treatment and prevention

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in infants and young children, accounting for more than 100,000 hospitalizations per year in the USA. The majority of hospitalizations occur in infants less than 1 year of age. Worldwide, RSV is associated with an annual mortality rate of 160,000-600,000 deaths. Premature infants, and infants with congenital heart disease, neuromuscular disease, structural airway abnormalities and immunodeficiencies are at increased risk for severe RSV disease. Despite the magnitude of RSV disease, treatment remains primarily supportive. Trials of bronchodilators, corticosteroids and montelukast have not demonstrated conclusive clinical benefit. The antiviral drug ribavirin has demonstrated only marginal clinical benefit and is not routinely indicated in treatment of RSV disease. Palivizumab is beneficial in prophylaxis for infants at high-risk for severe RSV infection although optimal indications based on cost-effectiveness considerations have not been defined. Future directions in treatment and prevention of RSV infections likely include the second-generation monoclonal antibody motavizumab, more potent antiviral compounds and more unique anti-inflammatory agents. Vaccination against RSV is in development but not eminent.     

Nosocomial respiratory syncytial virus infections in children's wards

During community outbreak, nosocomial infections caused by both groups (A and B) of respiratory syncytial virus (RSV) occur as the most common nosocomial infections at pediatric wards. RSV cross-infection is considered to have taken place when a child acquires an infection after being in the ward longer than 7 days, and its frequency at the ward could be calculated in several ways. That frequency ranges worldwide between 30% and 70% in neonatal units, and between 20% and 40% at pediatric wards. The infections are manifested as lower respiratory tract infections (LRTI) in 20-60% and 30-40% of cases, respectively.These infections could be early diagnosed by an RSV rapid detection method. In RSV-positive children who develop LRTI and belong to the category with a high risk of developing severe RSV disease, a specific therapy is recommended.The frequency of RSV nosocomial infections at children's wards could be considerably reduced (to only a few per cent) by providing education to hospital personnel in the etiology and transmission of respiratory viruses and by compliance with pediatric droplet precautions (cohort nursing, and gown and glove wearing/handwashing in any contact with infected children).     

小儿呼吸道合胞病毒免疫反应的研究进展

呼吸道合胞病毒(RSV)是引起下呼吸道感染的主要病毒因素,有较高的发生率和一定的死亡率,且RSV感染可能会对肺部发育产生不良影响,导致感染后易出现喘息、哮喘和气道高反应性.目前治疗上以支持性治疗为主,尚无安全有效的特异抗病毒治疗方法.宿主免疫反应失调可能在该疾病严重程度分布中起着重要作用.本文就近年小儿RSV免疫反应研...     

Intravenous immunoglobulin treatment of respiratory syncytial virus infections in infants and young children.

Respiratory syncytial virus (RSV)-infected cotton rats (Sigmadon hispidus) and owl monkeys (Aotus trivirgatus) showed significant reductions in RSV shedding from their respiratory tracts following parenteral therapy with human intravenous immunoglobulin (IVIG) containing high titers of RSV-neutralizing antibody. Because this therapy was well tolerated and appeared safe, a double-blind, placebo-controlled IVIG immunotherapy pilot study was performed on 35 hospitalized, RSV-infected infants and children. The treatment was well tolerated and resulted in significant reductions in nasal RSV shedding and in improvements in transcutaneous oximetry readings. However, the mean duration of hospitalization was not reduced by IVIG treatment. Followup to date has revealed no harmful effects resulting from immunotherapy of RSV infections. These studies appear to refute the hypothesis that passively acquired antibody may exacerbate RSV bronchiolitis or pneumonia in infants. Studies with larger numbers of seriously ill children will be required to determine if immunoglobulin G immunotherapy of RSV infections in infants is of clinical value.     

Bench-to-bedside review: Rare and common viral infections in the intensive care unit – linking pathophysiology to clinical presentation

Viral infections are common causes of respiratory tract disease in the outpatient setting but much less common in the intensive care unit. However, a finite number of viral agents cause respiratory tract disease in the intensive care unit. Some viruses, such as influenza, respiratory syncytial virus (RSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV), are relatively common. Others, such as adenovirus, severe acute respiratory syndrome (SARS)-coronavirus, Hantavirus, and the viral hemorrhagic fevers (VHFs), are rare but have an immense public health impact. Recognizing these viral etiologies becomes paramount in treatment, infection control, and public health measures. Therefore, a basic understanding of the pathogenesis of viral entry, replication, and host response is important for clinical diagnosis and initiating therapeutic options. This review discusses the basic pathophysiology leading to clinical presentations in a few common and rare, but important, viruses found in the intensive care unit: influenza, RSV, SARS, VZV, adenovirus, CMV, VHF, and Hantavirus.     

Bench-to-bedside review: rare and common viral infections in the intensive care unit--linking pathophysiology to clinical presentation

Viral infections are common causes of respiratory tract disease in the outpatient setting but much less common in the intensive care unit. However, a finite number of viral agents cause respiratory tract disease in the intensive care unit. Some viruses, such as influenza, respiratory syncytial virus (RSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV), are relatively common. Others, such as adenovirus, severe acute respiratory syndrome (SARS)-coronavirus, Hantavirus, and the viral hemorrhagic fevers (VHFs), are rare but have an immense public health impact. Recognizing these viral etiologies becomes paramount in treatment, infection control, and public health measures. Therefore, a basic understanding of the pathogenesis of viral entry, replication, and host response is important for clinical diagnosis and initiating therapeutic options. This review discusses the basic pathophysiology leading to clinical presentations in a few common and rare, but important, viruses found in the intensive care unit: influenza, RSV, SARS, VZV, adenovirus, CMV, VHF, and Hantavirus.     

Bench-to-bedside review: Rare and common viral infections in the intensive care unit – linking pathophysiology to clinical presentation

Viral infections are common causes of respiratory tract disease in the outpatient setting but much less common in the intensive care unit. However, a finite number of viral agents cause respiratory tract disease in the intensive care unit. Some viruses, such as influenza, respiratory syncytial virus (RSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV), are relatively common. Others, such as adenovirus, severe acute respiratory syndrome (SARS)-coronavirus, Hantavirus, and the viral hemorrhagic fevers (VHFs), are rare but have an immense public health impact. Recognizing these viral etiologies becomes paramount in treatment, infection control, and public health measures. Therefore, a basic understanding of the pathogenesis of viral entry, replication, and host response is important for clinical diagnosis and initiating therapeutic options. This review discusses the basic pathophysiology leading to clinical presentations in a few common and rare, but important, viruses found in the intensive care unit: influenza, RSV, SARS, VZV, adenovirus, CMV, VHF, and Hantavirus.     

Type 4 phosphodiesterase inhibitors attenuate respiratory syncytial virus-induced airway hyper-responsiveness and lung eosinophilia

Viral respiratory infections are considered one of the triggers of exacerbations of asthma. In a model of virus-induced airway hyper-responsiveness (AHR), mice infected with human respiratory syncytial virus (RSV) were shown to develop AHR accompanied by lung eosinophilia. Inhibitors of cyclic nucleotide phosphodiesterase (PDE) have been shown to affect airway responsiveness and pulmonary allergic inflammation. In this study, we assessed the effects of type 4 PDE (PDE4) inhibitors on AHR following RSV infection and compared them with a PDE3 inhibitor. In mice infected by intranasal inoculation of RSV, treatment with the PDE4 inhibitor rolipram or Ro-20-1724 reduced both AHR and the eosinophil infiltration of the airways. In contrast, the PDE3 inhibitor, milrinone, did not influence airway responsiveness or eosinophilic inflammation. These results demonstrate that PDE4 inhibitors can modulate RSV-induced AHR and lung eosinophilia and indicate that they have a potential role in treating exacerbations of asthma triggered by viral infection.