Several studies have demonstrated the relationship between bronchial asthma and respiratory infections in children.1"5 Infection alone may be the etiologic event precipitating the attack in an asthmatic child; when this is the case, the condition is described as primary infectious asthma. Most asthma in infants is of this type.
In secondary infectious asthma, the child has developed the asthmatic attacks before the infection; the causative factor is some allergic event, and the infection is a subsequent complication. So, as the child gets older and allergic asthma develops, the infections that once triggered primary infectious asthma now appear as secondary infectious asthma.
In this article, I shall review the microbiology and epidemiology of respiratory infections in asthmatic children and summarize current thinking about the relation between infection and asthma.
Primary infectious asthma usually begins before the age of six and rarely after the age of eight.6 The child wheezes each time he develops a respiratory infection, and he wheezes only with infection. There is no evidence of extrinsic etiologic factors, such as ingestant or inhalant allergy. Skin tests and provocative tests are usually negative (Table 1). The only effective environmental control measure is to isolate the child from others with infection.*
In infants (under age two years}, asthma is often related to food allergy; over age five years, inhalant allergy is the primary enologie factor. Infection in such children is secondary to ingestant or inhalant allergy. Twenty-nine of the 32 asthmatic children studied by McIntosh et al.4 were allergic; respiratory infections were secondary. Minor et al.7 studied infections as précipitants of asthmatic attacks in children between ages three and five with primary infectious asthma and older children with secondary infectious asthma in whom extrinsic allergens were present but noncontributory to the problem. Whether infections are primary or secondary, these studies4,7"9 have shown that such infections are etiologically related to wheezing. These studies establish that viruses and mycoplasma, rather than bacteria, are the principal infectious agents during acute asthmatic attacks.
COMPARISON OF PRIMARY AND SECONDARY INFECTIOUS ASTHMA
Before discussing the relationship between viruses and infectious asthma and between bronchiolitis and asthma, it might be helpful to review briefly a classification of viruses, the pathology of respiratory viruses, and the epidemiology of viral infections in a pediatrie population. The current virus classification is based on the kind of nucleic acid in the core of the organism, DNA or RNA (Table 2). Viruses contain either acid, not both. Viruses that spread by cellular fusion are RNA viruses - e.g., picorna vi ruses. Their spread is limited by both a humoral and a cell-mediated immune mechanism, either of which is capable of protecting the host in the absence of the other. Other viruses spread extracellula rly. Their spread is controlled by a humoral mechanism involving secretory IgA. The latter group includes both DNA and RNA viruses - e.g., myxoviruses, poxviruses, and herpesviruses.
Respiratory viruses include rhinovirus, myxovirus, coronavirus, rubella, adenovirus, and herpesvirus (Table 2). There are one or two predominant viruses in each respiratory syndrome, and the predominant organisms vary with age. It is also a truism that all respiratory viruses can cause all respiratory syndromes. The common cold is most often associated with rhinovirus, frequently with coronavirus, and occasionally with enterovirus, influenza, and parainfluenza. Croup is usually associated with parainfluenza 1 virus. Respiratory syncytial virus (RSV) is the most common organism in viral pneumonia in children under five, while Mycoplasma pneumoniae predominates between the ages of five and 15. The vast majority of infants with bronchiolitis have RSV isolated from their trachéal secretions. Under age three years, RSV is the main cause of infectious asthma.4 Between ages three and 12 years, rhinovirus predominates.7 Older children and adults often have a more complex kind of asthma in which infection is associated with extrinsic allergies, emotional problems, or other diseases, particularly chronic bronchitis. A predominant organism is less conspicuous in this older age group and correlates with geography and season as well as with age.
CLASSIFICATIONOF VIRUSES IN CHI WREN
Respiratory viruses multiply within epithelial cells of the upper respiratory tract. They spread by fusion of infected cells with their uninfected neighbors. They can destroy the host cell and liberate more virus or can grow in the cell without destroying it. They may remain in the nasopharynx or may spread down the bronchial tree to the alveoli. All viruses grow in respiratory epithelium, but damage varies with the particular organism. Influenza virus is the most damaging to ciliated epithelium, parainfluenza viruses and RSV come next, and rhinovirus and coronavirus are the least destructive.
Before discussing the epidemiology of virus and mycoplasma infections in asthmatic children, it may be helpful to review the epidemiology of virus infections in a nonasthmatic pediatrie population. In a large study reported by Glezen et al.,10 a pathogen (virus or M. pneumoniae) was identified in approximately 28 per cent of the children with infections of the lower respiratory tract. Of the viral agents identified, 75 per cent belonged to one of four types - respiratory syncytial virus, parainfluenza virus types 1 and 3, and M. pneumoniae. Almost all the RSV isolates came from children under the age of six, and about a fourth of them came from infants under the age of one. Parainfluenza 1 virus came primarily from children ranging in age from one through five, although 15 per cent of the children with this virus were less than one and another 15 per cent were older than five. Parainfluenza type 3 had an age distribution similar to that of RSV. M. pnewnoniae infections were most common in school-age children.
In Glezen's study, almost 80 per cent of the children who were found to have influenza virus A2 (Hong Kong) were under the age of two. Some workers contend that males are more susceptible to both bacterial infections and enteroviruses than females. Glezen found little difference in attack rates in boys and girls insofar as M. pneutnoniae or parainfluenza 3 virus were concerned; there was, however, a higher incidence in boys of lowerrespiratory-tract infections due to RSV and parainfluenza 1 virus.
There is a similarity between Glezen's findings in a nonasthmatic pediatrie population and studies made of asthmatic populations. Working with 136 asthmatics ranging in age from six months to 16 years, Berkovich et al.11 demonstrated serologically that RSV, parainfluenza and influenza viruses, and M. pneumoniae were the predominant organisms associated with acute asthmatic attacks. In another study, of 32 children under the age of six who were chronically hospitalized in Denver, Mclntosh et al.4 reported that viral infections were associated with 42 per cent of all asthmatic attacks. RSV was responsible for the largest number of wheezing attacks, followed by parainfluenza virus and coronavirus. Influenza virus was fairly prevalent but caused no wheezing.
In a study of older children (with an age range of three to 12) in Madison, Wis., Minor et al.7 found that almost half of infections were caused by rhinovirus, and two-thirds of these were associated with wheezing. Of the 55 infections studied, six were due to influenza A virus and all were associated with wheezing - a finding quite different from that of the Denver group. Minor's finding that rhinovirus was the most common virus isolated from asthmatic children was confirmed by Horn and Gregg,12 who also reported that wheezing accompanied infections in children with parainfluenza virus, RSV, and Coxsackie virus. Minor et al., in a later study,13 were unable to identify any particular rhinovirus serotype as being associated with asthma; 14 of the 21 types identified had been associated with wheezing. This suggests that many serotypes may precipitate attacks of wheezing.
These studies make it clear that viruses are the precipitating agents in most infectious asthmatic attacks. (Pathogenic bacteria were occasionally found and were usually not associated with wheezing. More will be said about this below.)
The difference in patient selection appears to explain the difference in findings between Mclntosh's study of chronically hospitalized children in Denver and Minor's study in Madison, Wis. The Denver study covered only younger children, while the Madison study excluded infants and toddlers. It is evident from these studies, as well as Glezen's, that, as Mclntosh puts it, "the viruses which cause the most severe infections in any given group cause the most asthma."14 In young children these are RSV and parainfluenza; in older children, they are rhinoviruses and influenza A.
Bronchiolitis is often an early form of infectious asthma.* Because it appears to be part of a spectrum between infantile virus infactions and asthma, bronchiolitis is of particular importance to the clinician who wishes to understand infectious asthma in children. Bronchiolitis is usually caused by RSV and occurs epidemically in the winter and endemically throughout the rest of the year. The epidemic form usually does not recur. Between 30 and 50 per cent of children with bronchiolitis develop bronchial asthma.15 Characteristically, respiratory obstructions of bronchiolitis do not respond either to epinephrine16 or to corti coster oids.17 Bronchiolar obstruction is caused by peribronchiolar edema, epithelial proliferation due to RSV (which is strongly attracted to epithelial cells), and mucus hypersecretion.
Because of certain characteristics, bronchiolitis is sometimes thought of as an immunologie disorder. Anti-RSV IgG antibodies are transmitted placentally to the infant.18 The high incidence of bronchiolitis, primarily due to RSV, in the first three months of life may result from the presence of these antibodies and suggests type 3 (Arthus) hypersensitivity. There are reports of children vaccinated with RSV killed virus vaccine who developed severe bronchiolitis after exposure to natural RSV infection, suggesting a type 4 (delayedtype) hypersensitivity.19 Because bronchiolitis and asthma appear to be part of the same clinical spectrum, type 1 (immediate) hypersensitivity might result from the presence of IgE antibodies.4
An important finding was reported by Buckley and Dees20 after a review of patients with selective IgA deficiency: the children had high levels of milk predpitins and hemagglutinins. About half of these children were atopic, and some had asthma. Ammann and Hong21 reported that children with selective IgA deficiency have an unusually high incidence of autoimmune disease. And patients with low IgA levels have been found to have unusually high levels of IgE.22
These studies suggest that secretory IgA provides a barrier to the absorption and digestion of antigens. Patients with absent IgA may absorb proteins abnormally, precluding adequate digestion and thus permitting these proteins to act antigenically. According to this theory, the child with a certain genetic composition would make IgE antibodies against these antigens. The hypothesis is certainly attractive in explaining milk allergy and the high incidence of autoimmune disease in such patients.
Selective IgA deficiency is common enough in asthmatics to warrant at least one routine IgA determination during the course of their care. Absent secretory IgA in respiratory mucosa may explain the relatively easy entry of viruses in asthmatic children as compared with nonasthmatics.8
The difficulties of conducting viral and bacterial cultures in patients with asthma and other respiratory diseases should be mentioned. In fact, the study of pathogens in the respiratory tract is fraught with so many problems that some have questioned the usefulness of sputum cultures altogether.23 Pathogens are fragile, susceptible to drying and temperature changes, and almost always contaminated with organisms from the mouth. Results vary markedly with the frequency in which cultures are obtained. Culture media must be selected carefully if reliable results are to be expected. So, before concluding that no pathogens are present, the physician must know details of the culture - when it was obtained, where, how, and how often.
When adequate precautions are taken, bacteria cultures can be obtained from a large percentage of patients. For example, Dorff et al.24 were able to isolate pathogenic bacteria from a single sample in more than 70 per cent of the patients hospitalized with pneumonia in a municipal hospital. They achieved these results only after very definite precautions were taken. They made sure that no patients were given antibiotics before the culture was taken; they had inoculating media at the bedside; and plates were transported to the laboratory and planted immediately after the culture was taken.
This study and others raise questions about why so few bacterial pathogens were isolated in the asthmatic children studied in Denver,4 Madison,7 and England.12 If the low incidence was not due either to poor culture-taking techniques or to the unreported administration of antibiotics before the culture was taken, the possibility remains that these asthmatic children had developed a significant defense mechanism against bacteria.
Viruses are much more difficult to grow than bacteria, but their cultures are not complicated by previous therapy. There are other problems, however. Some viruses can cause subclinical infections; their presence as a pathogen must be confirmed by at least a fourfold rise in antibodies in convalescent serum. Like bacteria, viruses may require serial culturing. Many are fragile and live only briefly outside the host. For example, an RSV culture of bedside nasal washes inoculated immediately produces three times the yield obtained from standard nasopharyngeal swabs, which are not inoculated for two to four hours.25
In summary, asthma in infancy is usually caused by viral infections. As the child gets older, primary infectious asthma tends to become secondary as allergic asthma develops. Wheezing is often triggered in these allergic children by viral infections. Recent studies have not been able to corroborate earlier reports of bacterial infection and allergy and indicate viral, rather than bacterial, infections associated with childhood asthma. Because of problems inherent in obtaining bacteria cultures, the subject of bacterial infection and allergy in asthma cannot yet be considered closed.
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22 Stokes, C. R., Taylor, B., and Turner, M. W. Associatbn of house dust and grass pollen alterg^s with specific IgA antibody deficiency. Lancef 2 (1974), 485.
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COMPARISON OF PRIMARY AND SECONDARY INFECTIOUS ASTHMA
CLASSIFICATIONOF VIRUSES IN CHI WREN