Pathogenesis of Severe Acute Respiratory Infections in the Developing World: Respiratory Syncytial Virus and Parainfluenza Viruses Kenneth McIntosh

From The Children's Hospital, Harvard Medical School, Boston, Massachusetts

This paper concerns the possible roles of respiratory syncytial virus (RSV) and parainfluenza viruses (PIVs) in acute respiratory infections (ARIs) , particularly severe or fatal ARIs, in the developing world. It should be said at the outset that it is not clear at this time what role these viruses do, in fact, play in the problem of ARI, although there is reason to believe, from the known roles of these viruses in ARls in the developed world, that they have considerable importance.

Epidemiologic Background In the developed world, RSV and PIVs are the most frequently isolated infectious microorganisms in infants and children with acute lower respiratory infections (LRIs) [1]. RSV is found in 40 %-80 % of infants hospitalized with bronchiolitis and in 20%-25 % of infants hospitalized with pneumonia [2]. PIVs are found in 10%-15% of infants with bronchiolitis or pneumonia and in 40 % of infants with croup [3]. Parainfluenza virus type 1 (PIVl) is the most frequent cause of viral croup, with parainfluenza virus type 3 (PIV3) and parainfluenza virus type 2 (PIV2) the second and third most frequent causes [4]. PIV3 is also a common cause of pneumonia and bronchiolitis; PIVI and PIV2 are found much less frequently.

Reprints and correspondence: Dr. Kenneth Mcintosh, Division of Infectious Diseases, The Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115. Reviews of Infectious Diseases 1991;13(Suppl 6):S492-500

© 1991 by The University of Chicago. All rights reserved. 0162-0886/91/1303-0067$02.00

The peak age at which bronchiolitis and pneumonia due to RSV occur is 2-3 months [5]. Although the peak age at which these diseases due to PIV3 occur is 2-4 months, PIVassociated croup (most of it caused by Plvljpeaks at 9-24 months [4]. RSV has a characteristic seasonality, being seen almost exclusively in the winter or early spring months. PIVl is also seasonal, with outbreaks occurring every other year in the autumn. PIV2 has the same seasonality as PIVI but is somewhat less restricted. The seasonality of PIV3 is also more variable, and the virus can be endemic, with infections found throughout the year. Recently, PIV3 has tended to produce yearly outbreaks in the late winter and spring. Further epidemiologic studies from the developed world have shown that the natural immunity induced by RSV is shortlived. Reinfections in subsequent winter epidemics are frequent and sometimes very significant [6, 7]. This short period of immunity has also been seen in PIV3 infections, although the degree of protection from year to year is perhaps somewhat greater [8]. PIVl and PIV2 induce responses that are somewhat more protective, although this protection wanesover time, as does protection against all respiratory viruses.

Pathogenesis of Viral Bronchiolitis and Pneumonia in the Normal Child The pathogenesis of LRI due to RSV is illustrated schematically in figure 1. Inoculation of RSV and PIVs presumably occurs through the nasal mucosal surface [9]. RSV can also be successfully introduced through the conjunctival mucosa. It would not be surprising if PIVscould also be transmitted via this route, but there is no experimental information on the subject. In the child who has not previously

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Respiratory syncytial virus (RSV) and parainfluenza viruses (PIVs) are the most frequently isolated pathogens in infants and children with acute lower respiratory infection (LRI) in the developed world. Less information is available about their importance in LRI in the developing world, but they are probably important there also. The pathogenesis of viral bronchiolitis and pneumonia involves inoculation and early replication in the upper respiratory tract, followed by aspiration into the lower respiratory tract when both the mucosal and systemic immune systems are involved in a specific response. Both disease and recovery reflect processes of viral replication (with attendant cellular destruction) and of immune response (with attendant direct cellular destruction and release of pathogenic, along with beneficial, mediators). Factors predisposing to bacterial superinfection are poorly understood except in animal models. Conditions leading to heightened susceptibility to severe disease in the developed world are particularly common in the developing world. Increasing information on RSV and PlY infections in the developing world will likely point to their importance. Strategies for prevention of severe illnesses due to these viruses will followfrom concepts elucidated through animal models and studies of infants in the developed world.

RID 1991;13 (Suppl 6)

ARI Due to RSV and Parainfluenza Viruses


Inoculum _


Rhinorrhea _

Figure 1. Schematic diagram of events following first-time infection of an infant with RSV and the resulting involvement of the lower respiratory tract. The events apply to a child at the most susceptible age, rv6 weeks, who has a low level of placentally transmitted serum antibody before infection. Note that upper respiratory tract symptoms begin before immunity is detectable but that lower tract symptoms coincide with the appearance of immunity and often last through the disappearance of virus from the respiratory tract.

Cough Wheeze Hospitalization

IgA In secretions





14 16



Days after inoculation experienced infection with one of these viruses, inoculation is followed by an asymptomatic incubation period of 4-5 days for RSV and 2-4 days for PIVs. At the end of that time, the infected child develops symptoms of an upper respiratory infection (URI). This phase of the illness begins with rhinorrhea and progresses over several days to nasal obstruction, low-grade fever, and cough. The infection usually resolves slowly from this point on, the only common complication of such a URI being otitis secondary to obstruction of the eustachean tube. In moreseverely-affected infants, however, the disease spreads to the lower respiratory tract. Presumably, such spread of virus occurs through aspiration of infected secretions. During the peak of rhinorrhea in RSV infection, which usually occurs just before onset oflower tract symptoms, secretions are profuse and contain large amounts of virus (10 5-1Q6 infectious units/mL of secretion) [10, 11]. Thus, aspiration of even small volumes of secretions into the bronchi or bronchioles would risk lower tract infection. Since bronchiolitis and pneumonia due to RSV or PIVs are virtually always bilateral and diffuse, either aspiration must also be diffuse or the viruses must spread widely and quickly to involve all lobes and all lobules as soon as aspiration occurs. Presumably this spread from the upper to the lower tract occurs during the period of profuse rhinorrhea, but this point has never been examined, and spread may occur earlier. During progression of this viral activity, the immune system also is responding. The earliest known evidence of specific immunologic response is the appearance of a coating of 19A and IgM on virus-infected cells shed from the respiratory epithelium [12]. In children with RSV bronchiolitis and pneu-

monia, these antibodies are almost always present during the first or second day of hospitalization, which is roughly 3-5 days after onset of symptoms and thus 6-9 days after virus inoculation. No data are available on early immunologic response with regard to PlY infections. Within the next 1-4 days, antibody to either RSV or PIV is found free in the respiratory secretions as well [13, 14]. This antibody is uniformly of the 19A isotype and usually IgO and transiently IgM as well. Antibodies also appear in the serum at about the same time, although in many children this is against the background of maternal IgO, and the increase in IgO is thus difficult to measure. The secretory and serum antibody responses appear to be progressively weaker in progressively younger children 1,OOO-fold lower than that for the well-nourished controls, titers of pulmonary virus were higher, the infection was prolonged (9 days rather than 5 days), and lung infection was established with a lower viral inoculum. The pathologic features of pneumonia in the normally nourished animals were those of dense mononuclear interstitial inflammation. The histology of the disease in malnourished mice was character-

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ARI Due to RSV and Parainfluenza Viruses

monia occurred, with the production of high titers of virus in the lung. Since PIVspresumably require exogenous extracellular proteolytic enzymes to cleave their fusion proteins from an inactive to an active form, it appears possible that a similar interaction might take place by which some resident pathologic bacterium increases the efficiency of viral replication by supplying the missing enzyme. However, no proof for this mechanism is presently available.

RSV and PIV Infections in Children in the Developing World

Possible reasons for more severe ARI due to purely viral infection are as follows (table 1): Crowding may, by increasing the viral inoculum, lead to more severe disease [1, 80]. Air pollution might injure the airway and lead to earlier or more frequent spread of infection to the lower respiratory tract. There is some evidence that this is a factor in parts of the developed world [81, 82]. The frequent occurrence of LRI might predispose to more severe illnesses because recovery between episodes is incomplete. Malnutrition or deficiencies in particular nutrients such as vitamin A might exacerbate the problem of recovery between successive infections, making infections, either viral or bacterial, increasingly severe. Parasite burden is another factor that might contribute to inadequate recovery between infections. Malnutrition might lead to either immunodeficiency or immunologic dysregulation. Either condition could lead to either prolonged or severe pure viral infections. Data from the murine models of viral respiratory infection emphasize that a proper balance of immune responses is necessary for a smooth recovery. Malnutrition and/or frequent or prolonged infections with other organisms (parasites being important candidates) might, by increasing the catabolism of proteins, deplete important immunoglobulins and - particularly with respiratory virus infections, which frequently reoccur even under the best of circumstances -lead to increased susceptibility to reinfection. Since little is known about the role of respiratory viruses in predisposing to bacterial pneumonia, this area becomes even more speculative. If early superinfection of viral disease is an important mechanism of bacterial invasion in the respiratory tract, such an event may be more likely in the child in whom carriage of pathogenic bacteria in the upper respiratory tract is more frequent [83] or, possibly, more intense. In addition, the long-term damage to the airway and to the physiology of breathing following viral infection, which has been well described [44-46], would presumably increase susceptibility to later bacterial infection. Finally, since early antibiotic treatment of bacterial superinfection would likely lessen its impact, either limited access to health care or circulation of an.tibiotic-resistant organisms would render such superinfections more severe.

Conclusion and Areas for Further Research Much is known about the epidemiology and pathophysiology of infections by RSV and PIVs in the developed world and in the normal host, and the subject has been reviewed briefly here. Despite this knowledge and a growing body of

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Most of what can be said about the consequences of RSV and PIV infection in children in the developing world is speculative since the actual body of knowledge is still fairly small. Nevertheless, it is worth reviewing what is known, then making a few guesses about what is not known, and finally outlining research questions whose answers might fill in some of the large gaps in our understanding. The epidemiology of RSV infections in the developing world is not dissimilar to that in the developed world. It appears that epidemics do occur, although their timing is perhaps a little less predictable in some areas that lack clearly differentiated cold and warm seasons. These epidemics correspond in time both to cooler seasons and to rainy seasons. In some areas these are the times of year when religious festivals bring large numbers of people into the same place at the same time [75-79]. Little is known at the present about the seasonal epidemiology of PIV infections in tropical climates. In most series of ARI in populations in tropical countries, the reported number of children with croup is notably small [75] in comparison with the numbers reported in similar series from the developed world. No formal analysis of this disparity has been made. The disparity may be due to any of several factors: clinical definitions of croup may be different, and a true difference in incidence may exist that is dependent on some physiologic or environmental difference between the developed and the developing world. The most likely reason for the difference would seem to be an environmental difference; in the developed world croup tends to be most common in dry climates, and the tropical climates of most developing countries are very humid. Aside from these rather sketchy epidemiologic observations, little else of substance can be gathered from the known epidemiology or pathogenesis of RSV and PIV infections in the developing world. A number of speculations are possible: (1)some of the increased ARI-associated mortality may be due to purely viral infection, which is more severe under conditions in the developing world; and (2) some of the increased incidence of severe bacterial pneumonia in children of the developing world may be due to aspects of simultaneous or preceding viral ARI that are in some waydifferent from those associated with viral ARI in the developed world and more likely to predispose to either early or late bacterial superinfection.




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data from animal models, little has been published about the role of these viruses in severe ARI among children living in developing countries and even less information is available concerning possible differences in the pathogenesis of disease under those conditions. There is reason to believe, from the data that exist, that viral respiratory infections,including pneumonia and bronchiolitis, are frequent throughout the world. It is likely that these infections are occasionally severe, both on their own and as illnesses that predispose to bacterial superinfection. Conditions such as crowding, malnutrition, vitamin and micronutrient deficiencies, environmental pollution, and limited access to medical care all exist in parts of the developing world and are likely to exacerbate the problem. Despite these statements, however, few hard data on any of these issues have been obtained directly or have direct application to the developing world. The areas for further research are multiple, and many can be identified from the outline in table 1 because most of the information on which the table is based is, at best,fragmentary. The pertinent portions of the immunologic condition of infants and children under conditions of malnutrition and high-frequency infections need to be further delineated with particular attention to immune dysregulation. Likewise, we need much more information about the severity of repetitive respiratory infections under these conditions. The role of micronutrients and vitamins should be the subject of further inquiry, and the conditions that predispose children to bacterial superinfection need to be better defined. Finally, at the same time we continue to ask questions about disease mechanisms, we need to search for modes of risk reduction, prevention, and cure. These problems are complex, and solutions should be sought with urgency.

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ARI Due to RSVand Parainfluenza Viruses

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RID 1991;13 (Suppl 6)

Pathogenesis of severe acute respiratory infections in the developing world: respiratory syncytial virus and parainfluenza viruses.

Respiratory syncytial virus (RSV) and parainfluenza viruses (PIVs) are the most frequently isolated pathogens in infants and children with acute lower...
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