key: cord-023721-e0zp2gux authors: Meissner, H. Cody title: Bronchiolitis date: 2013-02-10 journal: Principles and Practice of Pediatric Infectious Diseases DOI: 10.1016/b978-1-4377-2702-9.00033-7 sha: doc_id: 23721 cord_uid: e0zp2gux nan All references are available online at www.expertconsult.com Bronchiolitis, a disease primarily of the first 2 years of life charac terized by signs and symptoms of obstructive airway disease, is caused most commonly by viruses. 1 Approximately 2% to 3% of infants in the first 12 months of life are hospitalized with bron chiolitis, accounting for approximately 125,000 hospitalizations and 200 to 500 deaths annually in the United States. 2 Data from the Centers for Disease Control and Prevention (CDC) indicate that the number of yearly hospital admissions attributable to bronchiolitis increased more than twofold between 1980 and 1996. 3 Increasing survival rates for premature infants as well as infants with compromised cardiac, pulmonary, and immune status increase the number of children at risk for severe bronchiolitis. Many viruses can cause bronchiolitis, although respiratory syn cytial virus (RSV), human metapneumovirus, and parainfluenza virus type 3 are the most common etiologic agents. [1] [2] [3] [4] [5] [6] [7] Other viruses are implicated less frequently (Table 331) . [8] [9] [10] During the winter months, RSV is identified as the etiologic agent by cell culture or antigen detection assays in up to 80% of children hos pitalized with bronchiolitis or pneumonia. Epidemics of bronchi olitis in early spring and fall often are caused by parainfluenza virus type 3. [11] [12] [13] [14] The yearly cycles of these respiratory viruses are depicted in Figure 331 . Other viral causes of bronchiolitis include rhinoviruses and coronaviruses. Bordetella pertussis, Mycoplasma pneumoniae, measles, influenza, and adenovirus have been associated with a severe form of bron chiolitis, bronchiolitis obliterans. [15] [16] [17] [18] This uncommon obstructive pulmonary disease is characterized histologically by the progres sion of acute airway inflammation to necrosis of the cells lining the lumen with severe obliterative fibrosis in the final stages. The pathogenesis of bronchiolitis obliterans probably differs from that of simple viral bronchiolitis. Bronchiolitis may be defined as an episode of obstructive lower airway disease precipitated by a viral infection in infants younger than 24 months of age. The peak incidence of severe disease occurs between 2 and 6 months of age. 1, 19, 20 Rates of hospitalization are higher in boys and among infants living in industrialized urban settings rather than in rural settings. 21 Hospitalization rates are about 5 times higher among infants and children in highrisk groups than among nonhighrisk infants. Highrisk groups include premature infants (<35 weeks' gestation), infants born with hemodynamically significant congenital heart disease, as well as infants with chronic lung disease of prematurity (previously called bronchopulmonary dysplasia). [22] [23] [24] [25] [26] [27] Although mortality has been reduced in recent years, morbidity among highrisk patients can be high, with average hospital length of stay and intensity of care several times that of previously healthy infants. 2, 28 Occurrence of the respiratory virus season is predictable, even though the severity of the season, the date of onset, the peak of activity, and the end of the season cannot be predicted with preci sion. There can be variation in timing of community outbreaks of disease due to RSV from year to year in the same community and among neighboring communities, even in the same season. In the U.S., communities in the south tend to experience the earliest Limited numbers of cases of bronchiolitis occur during summer and early fall, and they are likely to be caused by viruses other than RSV, such as rhinovirus and parainfluenza viruses. These cases are generally milder than RSVrelated cases. In tropical coun tries, the annual epidemic of RSV coincides with the rainy season or "winter," although sporadic cases can occur throughout the year. 10 RSV can be divided into A and B strains, each with numerous subtypes or genotypes. Type A strains may be associated more commonly with epidemics, severe disease, and a higher hospitali zation rate than type B strains, although not all studies are consist ent with regard to differences in severity. [30] [31] [32] [33] Both strains may circulate during the same season, and infants may be reinfected within the same year. A progressive increase in hospitalization rates for bronchiolitis in the U.S. has occurred since the late 1980s. 3, 22 This increase may be related to a greater ability to identify hypoxic infants through the use of pulse oximetry. Alternatively, the increase in hospitaliza tion may reflect increased use of daycare centers or changes in criteria for admission. 3 Household crowding is an important risk factor for severe viral lower respiratory tract illness due to RSV as well as other respiratory viruses. 34, 35 Generally it is recognized that as the number of household members increases, the risk of expo sure to infectious respiratory secretions also increases. Childcare attendance has been correlated with an increased risk of bronchi olitis in some studies. Unlike other respiratory virus infections, exposure to passive household tobacco smoke has not been asso ciated with an increased risk of RSV hospitalization on a consist ent basis. In contrast to the welldocumented beneficial effect of breastfeeding against some viral illnesses, existing data are con flicting regarding the specific protective effect of breastfeeding against RSV infection. [35] [36] [37] [38] [39] Parental history of bronchiolitis or Week no. onset of RSV activity and the midwest tends to experience the latest onset. 29 The duration of the season for the west and the northeast is typically between that in the south and the midwest. Nevertheless, these variations occur within the overall pattern of RSV outbreaks, usually beginning in November or December, peaking in January or February, and ending by the end of March or April. All references are available online at www.expertconsult.com asthma is associated with a higher risk for the development of lower respiratory illness in offspring. 40, 41 Young chronologic age at the beginning of the RSV season is a consistent risk factor for RSV hospitalization. Several reasons may account for this increase in risk. Most severe RSV disease occurs in the first 6 months of life so that birth shortly before or early after the onset of the RSV season will result in a longer period of exposure to RSV earlier in life. Second, maternal antibody concen trations to RSV show seasonal variation and infants born early in the RSV season are more likely to be born to mothers with low serum antibody concentrations to the F (fusion) protein of RSV. 42,43 Low concentrations of RSV antibody correlate with susceptibility to severe RSV disease in infants. Acute bronchiolitis generally implies disease of infectious etiology, usually due to viruses with specific tropism for bronchiolar epi thelium. Because most healthy infants recover from bronchiolitis without incident, information regarding the pathologic changes caused by infection is inferred from animal studies and from biopsy or autopsy materials in severe cases. Viral infection causes profound alterations in the epithelial cell and mucosal surfaces of the human respiratory tract. The characteristic histopathology in bronchiolitis is a lymphocytic infiltration of the bronchiolar walls and edema of the surrounding tissue. Disease progression is asso ciated with proliferation and necrosis of the bronchiolar epithe lium. The sloughed necrotic epithelium and the increased mucus production lead to obstruction of the lumen of the infant's small airways. Air movement is restricted during inspiration and expira tion but is more restricted during expiration when the lumen is further compromised by positive expiratory pressure, resulting in expiratory wheezing. The obstruction results in air trapping and the characteristic appearance of hyperinflation on chest radio graphs. As this air is absorbed, the radiographic pattern evolves to show atelectasis. [44] [45] [46] [47] [48] [49] The presence of high serum concentrations of immunoglobulin IgG antibodies to RSV (whether transplacentally acquired or administered intramuscularly) ameliorates RSV illness. 50-54 Severe obstructive illness may be related to stimulation of virusspecific IgEmediated hypersensitivity responses or altered cellmediated immune responses. 55-60 Bronchiolitis represents the late stage of a respiratory disease that progresses over several days. Upper respiratory tract symptoms consisting of nasal discharge and mild cough begin about 3 to 5 days after onset of infection. Approximately 30% to 40% of RSV infected infants have progression of disease to involve the lower respiratory tract. Spread to the lower airway occurs either by aspi ration of RSVinfected epithelial cells or by celltocell spread of the virus. Lowerairway involvement is marked by a sudden increase in the work of breathing, cough, tachypnea, wheezing, crackles, use of accessory muscles, and nasal flaring. 61,62 The respi ratory rate often exceeds 60 to 70 breaths/minute in young infants, and expiration is prolonged. Intercostal and subcostal retractions with wheezing are evident. Initially, wheezing occurs during the expiratory phase only and is only audible through a stethoscope. As wheezing progresses, it can be heard without a stethoscope. The chest becomes hyperexpanded and hyperresonant, respirations more labored, and retractions more severe. Hypoxemia out of proportion to clinical distress is typical of RSV infection. Mild hypoxemia occurs even in otherwise wellappearing infants, the socalled happy wheezers. Respiratory failure can be due to hypox emia (an early and sometimes sudden occurrence) or progressive hypercapnia due to fatigue. The small airways of young infants can become so narrowed that wheezing is inaudible. In this setting disease severity is recognized by the absence of audible air exchange, flaring of the alae nasae, expiratory grunting, severe subcostal, supraclavicular, and intercostal retractions, and hypox emia. Progressive illness often is accompanied by a rapid fall in oxygen saturation after minimal manipulation. A child with these findings usually requires intubation and ventilatory support. Apnea can be an early manifestation of RSV infection, at times resulting in respiratory failure. 63 RSVrelated apnea is mediated by the central nervous system, occurring in young, often prematurely born infants. 64 Because the severity of bronchiolitis often waxes and wanes prior to consistent improvement, assessment of respira tory status can vary markedly over a short period. The ability of the young infant to breast or bottlefeed without distress over time often provides a practical guide to disease severity and man agement. An infant who has substantial difficulty feeding as a result of respiratory distress has moderate or severe illness and usually requires hospitalization. Otherwise healthy infants younger than 2 months of age, infants born prematurely (less than 35 weeks' gestation), and infants with chronic lung disease of prematurity (previously called broncho pulmonary dysplasia) or infants born with congenital heart disease have the highest morbidity and mortality rates due to bronchiolitis. 65, 66 Infants born with congenital heart disease at greatest risk of hospitalization due to bronchiolitis include those with moderate to severe pulmonary hypertension and infants with cyanotic heart disease. RSVinfected infants and children with the following hemodynamically insignificant heart disease are gener ally not considered to be at increased risk of hospitalization: secundum atrial septal defect, small ventricular septal defect, pulmonic stenosis, uncomplicated aortic stenosis, mild coarcta tion of the aorta, and patent ductus arteriosus, as well as infants with lesions adequately corrected by surgery (unless they continue to require medication for management of congestive heart failure). 67, 68 Severe respiratory distress with bronchiolitis can be the presenting manifestation of previously unrecognized con genital heart disease. Once hospitalized, the RSVinfected infant may have a highly variable course of illness. [69] [70] [71] [72] [73] Among otherwise healthy infants, intensive care unit admission because of respiratory deterioration is uncommon. 74 A decision to admit to the intensive care unit is based on the possible need for intubation because of progressive hypercapnia, increasing hypoxemia despite supplemental oxygen, or apnea. The typical course for a previously healthy infant older than 6 months is one of improvement over 2 to 5 days, as evi denced by decreases in respiratory rate, retractions, duration of expiration, and oxygen requirement. The median duration of symptoms in 95 infants with firsttime bronchiolitis who came to medical attention at an emergency department in Wisconsin was 15 days and onequarter of the infants remained symptomatic after 3 weeks. 75 Pulmonary function abnormalities and evidence of mild desaturation (oxygen saturations in the range of 93% to 95%) can persist for several weeks. 76 The differential diagnosis of bronchiolitis includes airway hypersensitivity to environmental irritants, anatomic abnormality of the airway, cardiac disease with pulmonary edema, cystic fibrosis, foreignbody aspiration, and gastroesophageal reflux. The diagnosis of bronchiolitis is based on clinical criteria with supporting radiographic findings. Typical chest radiographic find ings are hyperinflation, with flattening of the diaphragms and hyperlucency of the lungs, and patchy atelectasis, especially involving the right upper lobe (Figures 332 and 333) . 74, 76 Atel ectasis is due to airway narrowing or mucous plugging and is associated with volume loss; it may be confused with lobar con solidation or aspiration pneumonia, both of which are generally volumeexpanding lesions. Bacterial pneumonia infrequently occurs as a complication of bronchiolitis but should be suspected in the infant with fever persisting for more than 2 to 3 days and lack of response to supportive management. Establishing a specific etiologic diagnosis is helpful in predict ing the clinical course, in cohorting in the hospital, and may become increasingly useful as more antiviral agents effective against respiratory viruses become available. Although viral culture of respiratory secretions has been the "gold standard" for reverse transcription-polymerase chain reaction-enzyme hybridi zation assay (Hexaplex) is available to test a single nasopharyngeal sample for RSV, influenza A and B viruses, parainfluenza virus, and adenoviruses. 84 Antigen detection tests are useful in diagnosing certain viral infections, but, as with all tests, the positive predictive value decreases as disease incidence goes down. Specificity of antigen detection assays are lowest during the off season and at the onset and end of the respiratory virus season. Most infants with bronchiolitis can be managed at home with supportive care, but hypoxia or inability to feed adequately neces sitate hospitalization. Once hospitalized, most infants respond to administration of supplemental oxygen and replacement of fluid deficits. 1 The value of mist inhalation by vaporizer or tent is not proven; its use can provoke reflex bronchoconstriction. The spe cific treatment strategies used differ widely across children's medical centers. 71 Fewer than 10% of previously healthy infants hospitalized for bronchiolitis require intubation and mechanical ventilation because of respiratory failure or apnea; the percentage is higher for prematurely born infants and infants with chronic lung disease or congenital heart malformations. The therapeutic role of bronchodilator agents in bronchiolitis is controversial. 1,85 Bronchodilator therapy is not recommended for routine management of first time wheezing associated with RSV bronchiolitis. Occasionally, a single administration of an aero solized bronchodilator elicits a response, but this improvement is not seen in most infants with bronchiolitis and is not generally reproducible with subsequent doses. [86] [87] [88] [89] [90] [91] [92] Modest improvement in clinical scores and in tests of pulmonary function have been reported with use of inhaled racemic epinephrine [91] [92] [93] and βadrenergic agents, principally salbutamol and albuterol. [92] [93] [94] However, clinical improvement following repeated doses of epine phrine is not sustained and favorable response to βadrenergic agents, as measured by clinical score and oxygenation, is inconsistent. 95-100 Flores and Horwitz 101 performed a metaanalysis of eight studies with similar designs. Overall, their analysis sup ported a beneficial effect in certain infants, but identifying those infants could not be consistently accomplished at the time of initial presentation. On balance, an initial trial of bronchodilator therapy for the hospitalized infant with bronchiolitis is reasona ble, although brief episodes of hypoxia can be precipitated by adrenergic agents. Bronchodilator therapy should only be contin ued if consistent improvement in respiratory distress or oxygen saturation is observed. Racemic epinephrine should not be con tinued beyond one or two doses. Although corticosteroids reduce the inflammatory changes observed with bronchiolitis, they may increase viral replication and prolong shedding. Most studies examining the role of corti costeroids alone in the treatment of bronchiolitis have not demonstrated a consistent clinical benefit. [102] [103] [104] [105] [106] [107] [108] [109] [110] Although one metaanalysis of previously published reports of corticosteroid use in bronchiolitis concluded that there may be slight improvements in duration of symptoms, length of hospital stay, and clinical scores, these benefits appear to be limited. 111 The routine use of corticosteroids in bronchiolitis is not recommended. However, a national collaborative, blinded, placebocontrolled trial con ducted in Canada demonstrated that the combination of neb ulized epinephrine and oral dexamethasone treatment for children with bronchiolits evaluated in emergency departments reduced the subsequent rate of hospitalization by 9% compared with placebo or either treatment alone (P=0.07) and was less costly. 112, 113 diagnosis of RSV infection, it often is too slow a method to be clinically useful. Enzyme immunoassays and direct fluorescent antibody (DFA) techniques for the identification of RSV, influenza virus, parainfluenza viruses, and adenoviruses permit rapid and accurate diagnoses. [77] [78] [79] [80] [81] Nasal wash is the preferred method of specimen collection. The DFA test permits evaluation of adequacy of the specimen's number of epithelial cells for antigen detection. A respiratory screening of nasal secretions using pooled mono clonal antibodies to the common agents of bronchiolitis, followed by specific identification for a positive reaction, is a cost and timesaving procedure compared with standard tissue culture iso lation. Amplification of virus using the shell vial method, fol lowed by use of specific monoclonal agents, and amplification of viral genome by the polymerase chain reaction offer the promise of improved sensitivity for rapid detection but are not as widely available nor as rapid as enzyme immunoassay and fluorescent antibody techniques. 82,83 A multitest system for quantitative in infancy increases the likelihood of childhood asthma. Numer ous studies have defined a higher risk of recurrent wheezing throughout childhood after bronchiolitis in infancy, and abnor malities of smallairway function have been identified in school aged children with a history of bronchiolitis in infancy. However, each of these findings may simply be a reflection of hereditary tendencies that are expressed both at the time of bronchiolitis and upon allergen exposure in later childhood. [130] [131] [132] [133] [134] Moreover, by adolescence, the rate of recurrent wheezing in subjects who had bronchiolitis in infancy appears to fall to the rate observed in subjects without a history of bronchiolitis. 134 Thus, it is uncertain whether bronchiolitis is causally associated with longterm respi ratory morbidity. Strategies that reduce contact of vulnerable infants with individu als with respiratory tract infections, minimizing passive exposure to cigarette smoke, and limiting nosocomial transmission of caus ative agents offer immediate opportunities to reduce bronchiolitis morbidity. Monthly administration of monoclonal antiF anti body (palivizumab) throughout the RSV season reduces the inci dence of hospitalization due to RSV infection in infants with bronchopulmonary dysplasia, congenital heart disease, and pre maturity by about 50% (see Chapter 225, Respiratory Syncytial Virus). The high cost and modest effect of palivizumab limit its use for passive immunoprophylaxis to the most medically fragile infants. No vaccine to prevent infection with RSV or parainfluenza viruses, the most common causes of bronchiolitis, is licensed or near licensure. Trivalent influenza vaccine is recommended for all infants older than 6 months of age during the influenza season. Because this is not approved for use in infants younger than 6 months, routine influenza vaccination is important for family members and caregivers of these young patients. Potential RSV vaccine candidates currently being evaluated include inactivated preparations of the purified fusion protein of RSV, DNA vaccines coding for the major immunogenic proteins of the virus, and rep licating mutants of the virus that replicate in the upper respiratory tract but are inactivated at the higher temperatures of the lung. 135 Ribavirin is a nucleoside analogue with in vitro activity against RSV, adenovirus, influenza A and B viruses, and parainfluenza viruses. Early trials indicated that ribavirin therapy was associated with modest improvement in clinical scores, oxygenation, and duration of mechanical ventilation for infants with severe bron chiolitis due to RSV infection. These studies were challenged on the basis that control groups received water aerosols, which may produce bronchospasm in individuals with hyperreactive airways. Clinical trials with ribavirin have not demonstrated a consistent decrease in need for mechanical ventilation, decrease in length of stay in the intensive care unit, or reduction in days of hospitaliza tion. Conflicting results from efficacy trials, concern about poten tial toxic effects among exposed healthcare professionals, aerosol route of administration, and high cost have all resulted in limited use of ribavirin. [114] [115] [116] Guidelines for the use of ribavirin in RSV disease are presented in Chapter 225, Respiratory Syncytial Virus. Potential options for the treatment of bronchiolitis, if caused by influenza A or B viruses, are discussed in Chapter 229, Influ enza Viruses. [117] [118] [119] [120] [121] Immune Globulins and Other Therapies Antibody preparations containing high titers of neutralizing anti body against RSV as well as a preparation of monoclonal antibod ies directed against one of the two major RSV surface glycoproteins (fusion glycoprotein) reduce the risk of hospitalization due to RSV infection. 50,51 Used therapeutically, they result in more rapid clear ing of virus from the respiratory tract but do not alter the course of illness and should not be used for the treatment of RSV infection. [122] [123] [124] [125] [126] Although vitamin A levels have been demon strated to be low in infants with RSV bronchiolitis, a therapeutic benefit of vitamin A therapy has not been demonstrated. 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