Review of Epidemiology and Clinical Risk Factors for Severe
Respiratory Syncytial Virus (SRV) Infection
Robert C. Welliver, MD
Professor of Pediatrics, Department of Pediatrics, State University of New York
at Buffalo, School of Medicine and Biomedical Sciences, and Co-Director,
Division of Infectious Diseases, Children’s Hospital of Buffalo, New York
Direct correspondence and reprint requests to:
Robert C. Welliver, MD
Children’s Hospital of Buffalo
219 Bryant Street
Buffalo, New York, 14222
Key words: premature birth, chronic lung disease, congential heart disease,
immune deficiency, bronchiolitis
ASD Atrial septal defect
BPD Bronchopulmonary dysplasia
CHD Congenital heart disease
CLD Chronic lung disease
GA Gestational age
HIV Human immunodeficiency virus
ICU Intensive care unit
RSV Respiratory syncytial virus
VSD Ventricular septal defect
Respiratory syncytial virus infection is the most frequent reason for
hospitalization of infants in developed countries. Premature birth without or,
especially, with chronic lung disease of prematurity, congenital heart disease and
T-cell immunodeficiency are conditions that predispose to more severe forms of
RSV infection. Incomplete development of the airway, damage to the airway and
airway hyperreactivity underlie the increased morbidity of RSV infection in
prematurely born infants. Pulmonary hypertension and cyanosis are associated
with worse outcomes in infants with congenital heart disease, and prolonged
viral replication accounts for more severe illness in immunocompromised
Respiratory syncytial virus (RSV) infection continues to be one of the most
important health problems in infancy. Most infants experience RSV infection
during their first RSV season.1, 2 Approximately 20% of all infants develop RSV-
associated wheezing in the first year of life, and 2 to 3 % require hospitalization
for this illness.1, 3. It has been estimated that more than 120,000 infants in the
United States will be hospitalized annually with RSV infection, with more than
200 deaths as a result of this illness.4, 5 In countries with less well-developed
programs for medical care, the corresponding figures are undoubtedly higher.
RSV infection in infants begins with several days of nonspecific symptoms of
upper respiratory illness including fever, rhinorrhea, and nasal congestion.
Evidence of lower respiratory involvement appears abruptly, including
tachypnea and an increased work of breathing, hyperinflation of the chest,
retractions of the chest wall on inspiration, and fine crackles and/or harsh
wheezing on auscultation. 6 Pathologic examination of the lungs reveals
predominantly mononuclear cell infiltration of the airway wall, the perivascular
area and, to a variable extent, the alveolar interstitium. Other prominent features
include sloughing of the respiratory epithelium, edema of the airway wall, and
especially mucus plugging of the airway (Fig 1).The events leading to this
unusual pathologic appearance have not been completely identified.7
Fortunately, most cases of RSV infection are comparatively mild and
respond to supportive therapy alone. However, several groups of infants are at
increased risk of developing severe forms of illness leading to hospitalization, the
need for intensive care and mechanically assisted ventilation, or death.8, 9 This
review will identify several predisposing conditions for increased severity of
RSV-related illness, and discuss features of each condition that lead to increased
UNDERLYING ILLNESSES LEADING TO INCREASED SEVERITY OF
In a study conducted over nearly two decades, Boyce and colleagues
determined the rate of hospitalization for RSV infection in a large population of
infants on Medicaid.3 In otherwise healthy infants <6 months of age, 4.4
hospitalizations for RSV infection occurred per 100 child-years of observation
(Table I). For infants in the second half of infancy, this rate fell to 1.5 per 100
child-years and declined thereafter. For infants born prematurely but without
chronic lung disease (CLD), the rates of hospitalization were 8.0-9.4 per 100
child-years depending on gestational age at birth, indicating prematurity alone
was associated with increased severity of illness of RSV infection.
Although it has been presumed that infants born at extremely early
gestational age would be at the greatest risk for developing severe forms of RSV
infection, in the Boyce study the rate of RSV-related hospitalization per 100 child-
years increased only minimally with marked reductions in gestational age at
birth.3 Rates in the first 6 months of life were 8.0 in infants born at 33-35 weeks of
gestation and increased only to 9.4 in infants born at < 28 weeks of gestation
(Table I). Therefore all infants born at < 35 weeks gestation are at an increased,
but approximately equal, risk for hospitalization at the time of RSV infection. In
a study of 1,516 Canadian infants hospitalized with RSV infection, 10% had been
born between 33 and 36, 3% between 29 and 32 weeks, and 1% at < 29 weeks of
gestation.8 Therefore, most premature infants hospitalized with RSV infection
will have been born between 33 and 36 weeks of gestation
Chronic Lung Disease (CLD) of Prematurity
While prematurity itself (without CLD) adversely affects the outcome of RSV
infection, the accompanying presence of CLD of prematurity (formerly referred
to as bronchopulmonary dysplasia or BPD) has a much greater negative effect.
For infants in the first 6 months of life with underlying CLD, the rate of RSV-
related hospitalization is 56.2 per 100 child–years.3 This suggests that more than
half of infants with CLD of prematurity who develop RSV infection in the first 6
months of life will require hospitalization.. The rate continues to be 21.4
hospitalizations per 100 child-years during the second half of infancy, and
remains at 7.3 hospitalizations per 100 child-years in the second year of life. CLD
of prematurity therefore represents a substantial risk factor for severe RSV
disease through the age of 2 years. In the Canadian study, 6% of all infants
hospitalized with RSV infection had underlying CLD.8 The presence of other
underlying CLD (ie, cystic fibrosis) may also be associated with increased risk of
severe RSV illness and is present in 4% of all infants hospitalized with RSV
Congenital Heart Disease (CHD)
Infants with CHD also are at increased risk for severe illness at the time of
RSV infection.3, 10, 11 In the Boyce study of RSV hospitalizations, the rate of
hospitalization for RSV infection per 100 child-years in infants with CHD was
12.1 for infants in the first 6 months of life, and 6.3 for infants from 6-12 months
of age. 3 In another Canadian study, 260 of 1,584 (16.4%) infants hospitalized with
RSV infection had underlying CHD.11
Infants with compromised immunity also have difficulty containing RSV
infection.11-14 Various reports identify a variety of conditions associated with
immunodeficiency in infants and children, including cancer and organ
11, 12 severe combined immunodeficiency,13
immunodeficiency virus (HIV) infection.14 in which RSV infection may be
unusually severe. Children on long-term corticosteroid therapy but no other
immunocompromising condition appear to have outcomes similar to otherwise
healthy children with RSV infection.12
In addition to an increased rate of hospitalization, these four underlying
conditions are also associated with an increased need for mechanically assisted
ventilation and death at the time of RSV infection.11 Once hospitalized,
approximately one-third of infants in these high-risk categories were admitted to
the intensive care unit (ICU) (Fig 2). This fraction is essentially the same as that
for previously healthy infants hospitalized for hypoxia alone (32.8%). However,
the need for ventilatory assistance progressively increased in infants with
premature birth alone prematurity plus CLD, and CHD compared to those
hospitalized for hypoxia alone; deaths were observed essentially only in the CLD
and CHD groups. In summary, infants with these underlying illnesses have an
increased need for hospitalization, and increased risk for respiratory failure and
RATIONALE FOR INCREASED SEVERITY OF ILLNESS
Several factors undoubtedly explain why prematurity predisposes to an
increased severity of RSV-related illness. Two of the most important mechanisms
are probably an inadequate defense against infection and incomplete
development of the airway.
At birth, a full-term infant has normal adult levels of antibody in the
immunoglobulin G (IgG) isotype because placental transport of maternal IgG is
efficient late in gestation and provides the infant with the same titers as in the
serum of the mother.15 Consequently, full-term infants have reasonably high
titers of neutralizing antibody against RSV, since these antibodies are in the IgG1
and IgG3 subclasses of immunoglobulin. Several lines of evidence support the
idea that IgG provides partial immunity to RSV infection. In one study, the titer
of maternally acquired RSV antibody in cord blood specimens of infants
correlated with each infant's age at the time of initial RSV infection, suggesting
higher titers were protective against infection.16 Next, a study of adult volunteers
challenged intranasally with live RSV showed the quantity of serum antibody
correlated with the degree of resistance to infection, while the titer of antibody in
secretions did not correlate with immunity.17 Finally, the passive administration
of neutralizing antibody to RSV to high-risk infants before RSV infection
produced a reduction of approximately 50% in the rate of hospitalization
following subsequent RSV infection.18 These results support the idea that
neutralizing antibody in serum is partially protective against RSV infection.
Maternal antibody transfer across the placenta begins fairly late in gestation,
primarily near the end of the third trimester.15 Therefore, premature infants,
especially extremely premature infants, will have very low levels of
neutralizing antibody against RSV, and not unexpectedly would be more
susceptible to severe forms of illness.
Premature birth may also predispose to severe RSV disease because the
airway is not fully developed. One might consider that the lung becomes
completely formed early in gestation and then grows symmetrically. Indeed, all
major branching of the airways has been accomplished by 17 weeks gestation
and no further branching of the main airways will occur as the lung grows to
adult size. During this period of development, cartilage appears around the
airway, smooth muscle encircles the airway and lung vasculature, and columnar,
epithelial cells, serous cells, goblet cells and ciliated cells are observed. However,
the terminal bronchioles, which are the most peripheral airway structures, only
later differentiate into respiratory bronchioles and alveolar ducts. Therefore,
although the airway is nearly completely formed, there is no structure for gas
exchange, and the organism is nonviable.19
Between 17 and 27 weeks gestation, terminal bronchioles increase in
number, approaching the 25,000 present in the adult lung. A simple alveolus
forms at the end of each terminal bronchiole, capillaries begin to approach the
potential air spaces, e alveolar epithelial cells become thinner to permit gas
exchange, and surfactant begins to be evident. Thus, although the lung is more
completely formed, oxygenation is limited by the extremely small size of the
airway and mechanical barriers to gas exchange.19.
From 28 weeks of gestation to term, there is thinning of the interstitium
between capillaries and alveoli, and invagination of septa into alveoli to increase
the surface area. In the last few weeks of gestation, the formation of true alveoli
accelerates. During the last trimester, the diameter of the terminal bronchioles
doubles, the diameter of alveoli increases by 5-fold, and the surface area of the
lung increases by more than 10-fold (Table II). An increase in alveolar numbers
and, of course, lung growth continues after birth.
This interval between 27 and 40 weeks is a potentially critical period,
because damage to the centers of airway differentiation and growth could
severely restrict eventual lung development. One aspect that bears consideration
is that RSV bronchiolitis could damage terminal airway growth areas, resulting
in reduced small airway diameter in childhood and adult life. However, there is
currently almost no evidence to support this concept.
Nevertheless, these observations on lung development illustrate clearly
how premature infants have airways of small diameter that might be obstructed
easily by the inflammatory changes occurring during bronchiolitis. In addition,
the low numbers of alveoli and anatomic barriers to gas exchange would also
increase the lethality of bronchiolitis and any other lung infection.
Chronic Lung Disease (CLD) of Prematurity
The airways of premature infants are not only small, but are also
viscoelastic structures that are more capable of distending and collapsing
compared to a rigid tube. Numerous factors may contribute to stretching of the
airway, including positive pressure within the airway, increased airflow,
acidosis, hypercapnia, and atelectasis. The increased volume within the stretched
airway is non-ventilated, resulting in increased ”dead space” and carbon dioxide
Mechanical ventilation of the airway brings on further adverse changes.
The cartilage and smooth muscle surrounding and supporting the airway may
become thinned, leading to airway collapse. The endotracheal tube may abrade
the respiratory epithelium, resulting in hemorrhage, granulation, and fibrosis of
the airway wall. Further, epithelial cells exposed to stress may release mediators
such as interleukin (IL) 6, IL 8, IL 1-beta and tumor necrosis factor 1-alpha,
leading to further inflammation. Although the airway is normally sterile, the
presence of the endotracheal tube permits bacterial colonization and infection of
the airway wall.20.
Several reports describe improvements in airflow in infants with CLD
following the administration of bronchodilating agents.21-23 These findings
indicate the airways of infants with CLD are also hyperactive to environmental
stimuli. This increased reactivity is present in infants born as early as 26 weeks of
gestation,22 and can be demonstrated as early as the first day of life.23 RSV
bronchiolitis occurring in the context of such a deformed, inflamed and
hyperreactive airway would be expected to result in a greater degree of
obstructive airway disease.
Congenital Heart Disease (CHD)
When RSV infection occurs in infants with CHD, there are increases in
duration of hospitalization, need for intensive care, and occurrence of respiratory
failure, and death compared to infected infants without CHD.10 Although no
particular structural lesion is associated with greater morbidity from RSV
infection, deaths are more frequent in infants with cyanotic cardiac lesions and
pulmonary hypertension.10, 11 In a large Canadian study published in 1992, once
infants with CHD were hospitalized with RSV infection, one-third required
admission to the ICU, almost 20% required assisted ventilation, and 3.4% died.11
Deaths occurred in 9.4% of infants with pulmonary hypertension, but in only 2%
of those without this complication. Improved medical care can be expected to
decrease death rates from RSV in infants with CHD. In a recent study of a
monoclonal antibody to RSV (administered to prevent severe RSV infection in
infants with CHD), the death rate in the untreated control group was 0.8%.24
In infants with pulmonary hypertension, relatively unoxygenated blood in
the pulmonary artery is shunted away from the lung into the systemic
circulation. Thus, hypoxia is already present in infants with cyanotic heart
defects and/or pulmonary hypertension before RSV infection occurs.
Consequently, these infants are then more likely to succumb to the increased
hypoxia that occurs during RSV lower respiratory tract infection.
Infants with deficits of cell-mediated immunity also have more severe
outcomes at the time of RSV infection.9, 12-14 However, the type of illness seen in
these infants is different from that in immunologically intact patients, and is
characterized by prominent inspiratory crackles on auscultation with wheezing
as a less important part of the clinical picture. In immunocompromised
individuals, there is a profuse and persistent replication of the virus in the lung,
and histological examination reveals extensive alveolar exudates consistent with
pneumonia (Fig 3). This is in contrast to the picture seen in bronchiolitis where
there is predominantly peribronchiolar infiltration with relative sparing of the
alveoli. Deaths from RSV infection are more common in these
These findings indicate cytotoxic T-lymphocytes are responsible for
termination of viral shedding during RSV infection, and their absence would
delay recovery from infection. The role of cytotoxic lymphocytes in prevention of
infection is unknown, but some evidence suggests at least a partial role for CD8
lymphocytes in immunity to infection.25
Data presented indicate that infants in the four patient groups discussed
(ie, premature, CLD, CHD, immune deficiency) are at high risk for severe,
prolonged, and occasionally fatal illness due to RSV infection. These infants are
the ones most likely to benefit from measures to prevent RSV infection, including
active and passive immunization. Most clinicians familiar with RSV infection
suspect that other high-risk groups exist, including children with tracheostomies,
cystic fibrosis, neurologic devastation, muscular weakness, and other conditions.
At present, the next step beyond passive prophylaxis is uncertain. An effective
RSV vaccine is many years away, and potent antiviral agents have not as yet
been developed. It is possible that combined anti-inflammatory and antiviral
therapy will be the most useful approach. Until effective strategies are
developed, extensive efforts are needed to educate caretakers on how to prevent
RSV infection in these high-risk infants. These include avoidance of day care and
crowded living conditions, and effective handwashing before handling susceptible infants.
Breast feeding, timing pregnancies so that children are born during spring and summer
months, and a reduction in exposure of the infant to cigarette smoke (both during and
after pregnancy) may also reduce the severity of RSV infection when it occurs, although
this requires further confirmation. It can also be argued that health care dollars might
alternatively be expended on measures to prolong pregnancies beyond 35 weeks gestation,
but whether this can be accomplished in the United States remains uncertain.
Comments from the audience:
Douglas F. Willison, MD, Associate Professor of Pediatrics and Director Pediatric
Intensive Care Unit, University of Virginia Health System, Charlottesville, VA:
You mentioned the Medicaid data on the hospitalization rate in the infant with CLD less
the 6 months old. Is that pre-palivizumab, and are there any data that looked at what
Dr. Welliver: All the data were pre-palivizumab, and I'm unaware of any subsequent
report in that population that looks at before and after. Presently, however, I think
everyone's experience in that regard is positive. What we see in the ICU are all full-term
infants, rather than preemies and infants with CLD of prematurity or BPD. Although
that analysis hasn't been done, I think it would be positive.
Charles A. Scott, MD, President, New Jersey, American Academy of Pediatrics,
Medford, NJ: In clinical practice we see a lot of patients with heart murmurs, and some
will actually have congenital heart disease; most CHD cases, of course, are of minor
concern. How far do we go with recommendations and administering palivizumab
prophylaxis on perhaps small ventricular septal defects (VSDs) or insignificant PDAs?
Many defects resolve spontaneously within the next few months and likely will pose no
clinical problem. Will these also benefit from palivizumab?
Dr. Welliver: That's an important question. Studies of palivizumab included only those
infants with hemodynamically significant heart lesions. Infants with small VSDs or atrial
septal defects, minor mitral regurgitation, or other cardiac findings that don't require
therapeutic intervention probably are going to handle RSV infection better than infants
with less stable cardiac lesions.
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Figure 1. Pathologic appearance of the lung in bronchiolitis. There is extensive
inflammatory cell infiltration of the bronchiolar wall, with mucus plugging of the
airway (black arrow). Some interstitial infiltration is also present (white arrow),
although the alveolar spaces are relatively spared. The photograph was
reproduced from reference 6.
Figure 2. Rates of admission to intensive care units, need for mechanically
assisted ventilation and mortality among infants with various underlying
conditions hospitalized with respiratory syncytial virus infection. CHD =
congenital heart disease, CLD = chronic lung disease of prematurity, premature
= birth at < 37 weeks gestation, hypoxia = reduced oxygen saturation alone, in
the absence of any underlying condition. Data are from reference 11.
Figure 3. Pathologic appearance of the lung in a child with severe combined
immunodeficiency and respiratory syncytial virus infection. In comparison with
Fig 1, there is much greater interstitial thickening and the alveoli are filled with
necrotic cells and exudates. The photograph was reproduced from reference 13.