Читать книгу Cases in Medical Microbiology and Infectious Diseases - Melissa B. Miller - Страница 73

1. The differential diagnosis for this patient’s bronchiolitis included respiratory viruses such as the parainfluenza viruses, adenovirus, influenza A and B viruses, coronavirus, rhinovirus, metapneumovirus, and respiratory syncytial virus (RSV). Mycoplasma pneumoniae or Bordetella pertussis also could have caused her illness. RSV causes ~70% of bronchiolitis cases in children <2 years of age, with more severe cases typically occurring in children <6 months of age and premature infants. In the day care setting, any of these agents could spread easily. However, the fact that another child had recently been hospitalized supports RSV or influenza as the most likely causes, as these viruses generally cause more severe disease. All of the potential viral causes circulate in the winter months, with RSV infections typically occurring between December and February. Increased RSV incidence often overlaps with both influenza and metapneumovirus, so those viruses cannot be excluded based on the time of the year the patient presented. To definitively diagnose this patient with RSV, a laboratory test must be performed, but this patient’s clinical presentation and epidemiologic setting points to RSV as the most likely etiology.

2. RSV is the most important viral etiology of childhood respiratory illness in the industrialized world in terms of morbidity and mortality, particularly in children <1 year old. The World Health Organization estimates that ~160,000 deaths occur worldwide annually due to RSV. Approximately two-thirds of infants have an RSV infection during the first year of life, with nearly all children infected by the end of the second year. Clinical manifestations of RSV infection range from mild upper respiratory tract illness to severe lower respiratory tract illness, including bronchiolitis, croup, and pneumonia. Lower airway disease occurs in 15 to 50% of young children, with approximately 1 to 3% requiring hospitalization. This represents about 125,000 hospitalizations annually in the United States due to RSV. Premature infants, infants with chronic lung disease, and infants with significant congenital heart disease have hospitalization rates four to five times higher than healthy infants. Although deaths from RSV are uncommon outside of developing countries, premature infants and those with preexisting pulmonary or cardiovascular disease are at greatest risk. Incomplete protective immunity following RSV infection leads to reinfections throughout life. Reinfections in older children and adults generally result in minimal respiratory tract symptoms. However, immunocompromised individuals, patients with chronic cardiopulmonary disease, and the elderly who reside in long-term care facilities are at greater risk for developing severe lower respiratory tract disease. RSV is second only to influenza as a cause of death due to viral respiratory infections in elderly individuals.

RSV is spread by large droplets and on fomites. In hospitals and day care centers, it can be spread to the susceptible child on the hands of caregivers who do not use good hand-washing practices. Epidemics of RSV occur each winter in temperate climates. In the United States, peak disease incidence is seen from mid-December to early February. Although there is only one serotype of RSV, it has two antigenically distinct subgroups, designated A and B. RSV-A and RSV-B cocirculate during epidemics, although one type tends to predominate. Both epidemiologic and in vitro data have suggested that RSV-A causes more severe disease. However, the antigenic heterogeneity that occurs within the subgroups makes this hypothesis difficult to confirm.

3. First, RSV must bind and enter the target cells, which are the apical ciliated epithelial cells of the airway lumen. The virus attaches to the cell membrane using electrostatic interactions and the viral G protein. Then the viral F protein, along with a cellular receptor, mediates fusion to the cell membrane and thereby viral entry. The fusion protein also causes neighboring cells to coalesce, resulting in multinucleated cells, or syncytia (where the virus gets its name). The end result of the infection is damage to the airway epithelium and loss of ciliated epithelial cells. Histopathologic evidence shows sloughed epithelial cells, fibrin, mucus, and inflammatory cells in the large airways. In vivo evidence of apoptosis and syncytia formation has also been noted. Only recently, with the use of the well-differentiated primary airway epithelial cell culture model, has RSV pathogenesis started to be understood. In this model, much of the RSV-infected epithelium remains intact; this has also been observed in vivo. These observations suggest that airway damage is not a direct effect of RSV but rather is caused by the immune response to RSV. RSV infection induces an innate immune response leading to the production of cytokines and chemokines by the epithelium, which recruits white blood cells and results in epithelial injury. The resulting necrosis and edema can lead to collapse and blockage of the small-diameter bronchioles, with air trapping distally causing the wheezing and stridulous cough that are often seen in infants with RSV infection.

4. There are several diagnostic approaches that offer a rapid result, each with varying sensitivities. Rapid enzyme immunoassays (EIAs), or rapid antigen tests, offer results in ~15 minutes. However, these tests can have sensitivities as low as 59% and have been shown to be a source of significant false-positive results, particularly at the beginning and end of RSV season, due to the decreased prevalence and positive predictive value. The advantage of the EIA method, and the reason it is widely used, is that it is easy to perform. A disadvantage of this technique is that specimen quality cannot be assessed. Another rapid method is the direct fluorescent-antibody assay (DFA), which offers results in 1 to 2 hours. Unlike the rapid EIA, DFA requires well-trained laboratory personnel to correctly perform and interpret the fluorescent results. The sensitivity and specificity of DFA can be directly correlated with laboratory expertise, but in general its performance is at least as good as culture. Specimen quality can be judged by the DFA technique, as the patient’s nasopharyngeal cells can be quantified. Culture can be performed relatively rapidly using the rapid centrifugation, or shell vial, culture technique. The patient’s specimen is gently centrifuged onto a permissive cell layer to promote virus-cell contact and decrease the time needed to detect infected cells if the virus is present in the patient’s specimen. To visualize viral infection, the laboratory uses an antibody pool consisting of antibodies specific for RSV, parainfluenza viruses, influenza A and B viruses, and adenovirus to fluorescently stain the shell vial monolayer after 24 to 48 hours of incubation. Depending on the antibody pool used, either the color of fluorescence can indicate which virus is present or antibodies specific for individual viruses can be used to detect the specific agent causing the infection. This method is typically used only if other rapid methods, such as EIA and DFA, are negative. Shell vial cultures are very specific, with 70 to 80% sensitivity, but take ~2 days to obtain results.

More recently, molecular methods have become commercially available to diagnose respiratory viral infections. Most of these products detect a panel of respiratory viruses, including RSV. Some detect only influenza A, influenza B, and RSV, while others detect 12 or more viruses. The time to result for these molecular platforms varies from 70 minutes to 8 hours. Some of the tests provide random access testing, while others are more efficiently performed in daily batches. The main advantage of molecular detection of RSV is increased sensitivity, but specimen quality is not determined. The primary obstacle in routinely performing these tests in the clinical laboratory is the cost of the equipment, reagents, and personnel needed to perform molecular testing. Independent of the method used to diagnose RSV in the laboratory, a rapid result is important for management decisions, including infection control and treatment. Although rapid detection of respiratory viruses has been hypothesized to decrease unnecessary use of antibiotics and decrease length of hospital stay, there are few supporting data in the literature.

5. Since there is not a vaccine available to prevent infection nor is there a broadly effective antiviral agent to treat RSV, infants who are at risk for severe RSV disease should receive passive immunoprophylaxis with a humanized mouse monoclonal antibody preparation against RSV called palivizumab. Although expensive, palivizumab has been shown to decrease hospitalization rates by 50% and total wheezing days in the first year of life by 61%. At-risk infants receive five monthly doses of palivizumab during RSV season, typically November through March. This includes infants/children <24 months old with hemodynamically significant congenital heart disease or chronic lung disease and infants <12 months old who were born prematurely or have congenital abnormality or neuromuscular condition of the airway.

Like all respiratory viruses, RSV can cause health care-associated infections; therefore, patients with RSV infections should be put on droplet and contact precautions to prevent spread to other patients via health care personnel. If patients are not isolated and stringent infection control practices are not followed, secondary infection rates of 20 to 50% can occur. Cohorting of RSV-positive children and their health care providers, plus the use of gloves and gowns during contact with infected children and consistent hand washing before and after patient contact, has been shown to significantly lower RSV health care-associated infection rates. Though positive patients may be cohorted when private rooms are not available, many centers do not consider the sensitivity of the EIA high enough to place a child with a negative test in the same room as another child if there is a clinical suspicion of RSV. However, the negative predictive value of most of the molecular tests available would alleviate this concern. As with primary RSV infections, hospitalized patients with congenital heart disease, pulmonary disease, or an immunodeficiency are at greatest risk for life-threatening RSV infections.

6. No drugs that specifically target RSV are available for treatment. However, ribavirin (a nucleoside analog) has good in vitro activity against RSV and is FDA approved for RSV treatment. Ribavirin is generally delivered by aerosol since oral or intravenous administration may result in hepatic or bone marrow toxicity. The American Academy of Pediatrics recommends against the routine use of ribavirin in infants and children with lower respiratory tract illness because its efficacy in this population has not been proven. Randomized, controlled trials have demonstrated conflicting results. Further, ribavirin treatment is expensive. Treatment of RSV infection with ribavirin is reserved for immunosuppressed patients with severe RSV infection. Several reports have demonstrated that early administration of ribavirin significantly decreased lower respiratory tract illness, morbidity, and mortality in adult hematopoietic stem cell transplant recipients. Palivizumab cannot be used as a treatment for RSV; it only provides passive protection against infection.