Host or virus?: Respective roles in acute and chronic morbidity associated with RSV infection

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Host or virus?: Respective roles in acute and chronic morbidity associated with RSV infection.
Dr Mark L Everard Dept of Respiratory Medicine Sheffield Children’s Hospital Western Bank Sheffield S10 2TH UK Tel 44 114 271 7400 Fax 44 114 273 0522 email [email protected]
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Background
The respiratory syncytial virus is an extremely successful respiratory virus causing
annual epidemics affecting the whole population[1-9]. Epidemics are observed
throughout the world with a winter peak in temperate climes though in more tropical
environments the epidemics more often coincide with the wet seasons. In terms of
morbidity and mortality the effect of the virus is most evident in the very young and in
the elderly though it is only in recent years that its full impact in the elderly and those
with co-morbidities such as chronic obstructive airways disease [COPD][6,7] has been
recognized. In large part this because it is more difficult to identify the virus in this
population.
In children, the most visible manifestation of the annual epidemics are the large numbers
of young, typically predominantly under six months of age, admitted to hospital with
‘acute bronchiolitis’. In general more than 60% of infants with acute bronchiolitis are
infected by the virus but many other viruses including rhino virus, influenza and human
metpneumovirus can cause the same clinical picture. Sixty years ago a mortality rates of
20% was reported amongst infants admitted to hospital with bronchiolitis [8]. However
the introduction of supplemental oxygen to treat such children led to a dramatic decline
in mortality. With improvements in intensive care deaths are now generally, but not
exclusively, associated with significant risk factors such as prematurity, cardiac disease
with pulmonary hypertension and immunodeficiency. Indeed management based on
good supportive care has essentially remained unaltered since Reynolds and Cook
observed in 1963 that ‘oxygen is vitally important and there is little evidence that any
other intervention is helpful’[9]. Hypoxic infants with acute bronchiolitis become
distressed and agitated; death was in most probably due to a combination of exhaustion
and dehydration rather than progressive hypoxia.
Is there a specific immunopathology associated with RSV bronchiolitis?
The suggestion that there may be a specific immunopathology associated with RSV
bronchiolitis was first made in the late 1960’s. This was based on the observation that
large numbers of very young infants were being admitted to hospital with severe lower
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respiratory tract disease due to RSV at an age when, in theory, they would have high
levels of passively acquired protective antibodies. The suggestion was reinforced by the
results of a formalin inactivated vaccine study during which those vaccinated had higher
levels of morbidity and an excess of deaths. Suggests for possible specific
immunopathologies have included an immune complex mediated disease, a RSV specific
IgE response, excessive cytotoxic T-cell activity and an aberrant Th2 response to the
virus. At present there is little to suggest that any of these represent a dominant and
specific immunopathology underlying RSV bronchiolitis. In retrospect the effects of the
vaccine were probably due to an aberrant response to the vaccine.
For more than four decades it has been recognised that many infants admitted to hospital
with bronchiolitis had increased respiratory morbidity in subsequent years[10]. The
debate as to the nature of these symptoms continues to rage with a minority still believing
that RSV bronchiolitis in particular is a major initiating event in the development of
asthma.
In order to try and disentangle the morass of often conflicting results and opinions it is
important to try and step back and consider the complex interaction of disease phenotype
and viral pathogen.
Importance of disease phenotype
It is important when considering published studies to understand the phenotype of illness
experienced by included subjects[11]. The term acute bronchiolitis for example is used
in the UK, Australia and some European countries to describe an illness associated with
an apparent respiratory tract infection characterized by airways obstruction, increased
work of breathing and widespread crepitations bilaterally with or without wheeze – true
wheeze is rarely prominent. In the USA and parts of Europe the term is used to describe
a first episode of wheeze associated with a respiratory viral infection - a phenotype
referred to as wheezy bronchitis or viral associated wheeze in the UK. This discrepancy
is a key factor if one is to understand the apparently contradictory studies published over
the years.
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Figure 1 illustrates the type of LRTI that may be caused by RSV. The RSV can be
substituted by any of the other respiratory viruses. For example with parainfluenza the
croup component would increase in size while the others would reduce. For rhino virus,
acute bronchiolitis would be significantly smaller while the wheezy bronchitis and
asthmatic circles would be a little larger.
The lack of precision in using the term wheeze both by parents and by clinicians add
further uncertainty into attempting to untangle the impact of viruses and host factors in
very young children[12,13]
Does RSV cause asthma?
It is apparent that although certain respiratory viruses are typically associated with a
particular phenotype with RSV being particularly associated with acute bronchiolitis,
parainfluenza with croup and rhino virus with viral induced wheeze, all of the distinct
phenotypes of lower respiratory tract infection can be caused by any of the respiratory
viruses. Similarly, subjects with the same phenotypes of disease suffer similar levels of
morbidity subsequently. Indeed a wheezing episode due to rhino virus in the first year of
two of life is more predictive of later asthma than a similar illness caused by RSV[15-18].
These observations alone would suggest that it is not the virus per se that is linked with
later asthma but the hosts pre-existing asthmatic phenotype.
There are a number of large studies that clearly indicate that RSV bronchiolitis is not
associated with an excess of atopic asthma[19-25]. In contrast there are a limited number
supporting such a link [26,27] and in general these ‘positive’ studies have included
wheeze as a key diagnostic feature. The importance of the illness phenotype has been
highlighted in a recent study[28] which prospectively followed up infants admitted to
hospital with RSV induced acute bronchiolitis [creps] or a viral associated wheeze
phenotype [wheeze without crepitations]. The former groups when reviewed at 3 years
of age, when compared with controls, had relatively low levels of excess morbidity,
generally associated with intercurrent viral illnesses, no increase in inhaled steroid use
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and a slightly lower level of personal atopy compared with controls. The RSV wheeze
group had greater levels or morbidity, inhaled steroid use and personal atopy. If RSV per
se induces atopic asthma this study would suggest it is only in those greater than six
months of age which seems very unlikely. A more convincing explanation is that those
who wheeze with the virus include infants in whom the first exacerbation of asthma
happened to be with a RSV infection and that the viral wheeze group consists of atopic
asthmatics and those with wheezy bronchitis – the tendency to wheeze with viruses - that
is distinct from atopic asthma in early childhood. Two further small study using similar
categories of RSV LRTIs would support this suggestion[29,30]. The association of
‘post bronciolitis’ symptoms with subsequent viral infections was also noted in a recent
prospect study following infants with RSV bronciolitis[31].
What is distinct about RSV?
The inflammatory process in the airways of infants with RSV bronchiolitis is
characterized by an intense influx of neutrophils driven in large part by IL-8 produced by
infected epithelial cells[32,33]. The survival of neutrophils attracted to the site of
inflammation is also prolonged by anti-apoptotic factors[34]. This again is probably not
unique to RSV with neutrophilic influx being a feature of rhino viral infections. In adults
experimentally infected with rhino virus, symptoms only developed in those with an
influx of neutrophils[35]. Neutrophils produce a variety of products including human
neutrophil elastase and myeloperoxidases which drive mucus secretion and induce
coughing and sneezing which are important routes of dissemination to other potential
hosts. It is not known whether the neutrophils are involved in helping to limit viral
replication.
The probability is that the pattern of inflammation in acute bronchiolitis and wheezy
bronchitis are essentially the same and that the differences in clinical phenotype are due
to the rapid changes in airways size and physiology that occur during the first year of life.
While phenotypically those with and exacerbation of asthma and wheezy bronchitis can
look very similar there are likely to be important differences in the pathophysiology with
the later for example having more in the way of bronchoconstriction.
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One of the key characteristics features of RSV are its ability to cause annual epidemics of
disease and its almost complete disappearance between epidemics. While there are
subgroups of the virus[36] it does not appear that the virus success is dependent upon
either the existence of multiple subtypes or due to significant antigenic shift. Rather it
appears that the virus is able to prevent the production of long term effective immune
responses leaving a large proportion of the population vulnerable to infection and perhaps
more importantly for the paediatrician, leaving large numbers of infants vulnerable due to
the lack of passively acquired neutralizing antibodies. Recent studies have shown that
the virus is able to effectively infect dendritic cells[37,38] and it is possible that this is a
key step in limiting the effectiveness of the induction of memory B cells. Recent studies
have also shown that the virus is able to inhibit apoptosis of dendritic cells and remain
dormant within them for many months[38]. Replication of the dormant virus can be
stimulated by nitric oxide and iNOS inhibitors. Reactivation of productive infection has
also been observed spontaneously during the subsequent epidemic season. These results
would suggest that the reservoir for the virus is human dendritic cells within the lungs
and indeed virus has been isolated from resected adult lung in the middle of summer.
Summary
The respiratory syncytial virus infects most infants during their first year of life. In many
this involves the lower airway with lower airways involvement being most likely in those
born with low protective antibody titres either because of low maternal levels or being
born prematurely. The phenotype of the illness is determined in large part by the host
factors including airways size and physiology which alter with age and co-existing
conditions such as early asthma. It is unclear whether the post- bronchiolitic symptoms
are due to pre-existing airways changes, differences in the exuberance of the innate
response or changes induced by the intense neutrophilic inflammation such as mucus
gland and goblet cell hyperplasia. In those with asthma these features are overwhelmed
by the chronic inflammation associated with this condition.
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