AN 8-MONTH-OLD GI RL W I TH SHORTNESS
OF BREATH AND W HEEZI NG
Maarten Blanken, Louis Bont
Wilhelmina Children’s Hospital, Utrecht, Division Pediatric Infectious
R EASON FOR CONSULTI NG
An 8-month-old girl was admitted to the emergency department of a
secondary hospital for recurrent episodes of shortness of breath. She had
been referred to the hospital by the general practitioner after 3 days of
gradually worsening symptoms of difficult breathing, cough and expiratory
wheeze. No medication had been given.
CLI NI CAL EX AMI NATI ON
Physical examination on admission showed a well-developed, well-
nourished infant. There were no congenital abnormalities. The patient had
a normal weight and length.
Blood pressure: 90/65 mmHg
Heart rate: 140/min regular
Respiratory rate: 65/minute with nasal flaring and intercostal
Pulse oximetry: 95% on room temperature
She was alert, but dyspneic. The nose contained copious clear mucus. Ear
and oropharynx examination showed no inflammation. Lung auscultation
revealed a prolonged expiratory phase with end-expiratory wheeze. There
were normal heart sounds and no heart murmurs. Further physical
examination showed no abnormalities.
On admission she received humidified oxygen by mask and intravenous
MEDI CAL HI STOR Y
She was born at full term by normal vaginal delivery after an uncomplicated
gestation. At the age of 7 weeks she experienced a similar period of difficulty
breathing. She was then diagnosed with acute bronchiolitis. A nasal aspirate
was positive for respiratory syncytial virus (RSV) as determined by
immunofluorescence. Chest radiograph showed hyperexpansion and
interstitial markings consistent with bronchiolitis. Bronchoscopy showed
normal airway anatomy. She was transferred to the pediatric intensive care
unit for 4 days because of continuous hypoxemia (pulse oximeter readings
< 90% ) during the first hours in the hospital. She was mechanically
ventilated. Treatment with nebulized salbutamol and ipratropium bromide, did
not have a significant effect. After day 2 she improved and after 10 days she
was discharged from the hospital. During the following months she
experienced 3 relapses of moderate wheeze without the need for hospital
admission. There was no family history of heart or lung disease, cystic
fibrosis, congenital malformations or other disorders. None of her family
members had asthmatic or allergic symptoms.
DI AGNOSTI C APPROACH
This case report represents a common symptom associated with viral
respiratory infections of childhood with RSV as the dominant etiologic agent.
But are there underlying risk factors for the recurrent episodes described
here? Is there a logical explanation for this course of events?
I NVESTI GATI ONS PERFORMED
Plain chest radiograph (Fig.1) showed normal osseous and soft tissue
structures. No evidence of congenital
abnormalities of the pulmonary or
cardiac systems was present. The
diaphragms had a normal
representation on both sides. There
was a distinct interstitial haziness
visible over all lung fields.
Laboratory test results are shown in
Table 1. Besides a slightly elevated
leukocyte-count, her lab values are
within normal range.
LABORATORY FI NDI NGS
Capillary Blood gas Analysis
A specimen of the nasal secretions was positive for RSV as determined by
DIFFERENTIAL DIAGNOSIS HYPOTHESES
Along with her cough as a sign of general airway irritation, shortness of
breath was her major complaint with a clearly audible expiratory wheeze.
Wheezing is a symptom of bronchial obstruction caused by malformations,
compression, infections or accompanies other pathological processes as a
secondary symptom, e.g. aspiration or immunodeficiency. The girl in this case
had experienced previous episodes with the same complaints, but not as
severe. After exclusion of congenital and other pathological processes, the
positive test result of the nasal secretions provides a clear diagnosis of RSV
reinfection. But what makes this virus so pathogenic every time it reappears
in the winter season?
S Y NTHESI S AND CONCLUSI ON
Bronchiolitis is a common illness affecting young children. It is primarily a
disease with respiratory distress, crepitation and expiratory wheeze
associated with respiratory viral infections, including RSV, rhinovirus and
wheezing infants/quarter (%)
Quarter following RSV LRTI
1-5 wheezing days/quarter
> 5 wheezing days/quarter
parainfluenza viruses. RSV is one of the most important respiratory
pathogens in infancy causing the majority of lower respiratory tract infections
during the winter season. Almost all young children experience RSV infection
at least once in the first two years of life, and > 65% become infected during
their first year, with the peak incidence for lower respiratory disease occurring
between 2 and 7 months of age (1, 2). Hospitalization rates for RSV illness
are 5-20 cases per 1000 infants < 1 year of age (3, 4, 5). Mechanical
ventilation is required in 7-21% of hospitalized infants with RSV bronchiolitis,
with lower gestational age, requirement of neonatal oxygen supplementation
and bronchopulmonary dysplasia as significant risk factors (6, 7, 8). Mortality
in RSV-infected infants with lower respiratory tract symptoms is < 1% (9).
Reinfection with RSV occurs frequently and usually has a mild character with
symptoms of uncomplicated upper respiratory tract infection (10). However,
in our case RSV reinfection had caused the severe wheezing episode. Post-
bronchiolitis wheeze occurs in about 42–71% of cases of RSV bronchiolitis.
Post-bronchiolitis wheeze is characterized by recurrent episodes of wheeze
during pre-school years (Fig.2).
studies do not find an
association between post-
bronchiolitis wheeze and
the development of
allergic asthma, although
this issue is subject to
debate in literature.
Figure 2 Number of days with respiratory wheeze per quarter following RSV LRTI.
Parents recorded daily respiratory symptoms which were analysed per quarter.
Infrequent wheeze (1-5 days/quarter) and frequent wheeze (> 5 days/quarter) are
distinguished. Data from Thorax. 2004Jun; 59(6):512-6
It is generally assumed that wheezing episodes following RSV LRTI are
associated with viral upper respiratory tract infections and not allergen
exposure, in contrast to children who suffer allergic asthma (11).
The pathogenesis of post bronchiolitis wheeze is not fully understood. Is it the
virus-induced pathogenic effect on the airway epithelium which leaves these
children with vulnerable lungs and wheezing episodes (serial hypothesis)? Or are
these children born with small or vulnerable airways making them susceptible
for both viral infections and wheezing episodes (parallel hypothesis)? This
serial versus parallel hypothesis (Fig.3) is an important challenge in the
attempts to understand the pathogenesis of post-bronchiolitis wheeze. Pre-
existent morbidity has been shown to be a factor. The risk of having a
wheezing illness is almost 4 times higher in children with pre-existent lung
function abnormalities. The children whose initial values for lung volume at
the end of tidal expiration were in the lowest third, even had an 10-16 fold
increased risk (12). There is also evidence that several genetic phenotypes
are of influence to disease severity and post-bronchiolitis symptoms. It was
shown that disease severity is associated with a common single nucleotide
polymorphism close to the IL-8 gene and an increased IL-8 production upon
stimulation (13). Another such polymorphism has recently been found which
clearly depicts early post-bronchiolitis wheezing and wheezing later in
childhood as distinct pathophysiological entities. We found a significant
overrepresentation of an IL-13 polymorphism in children with late wheezing,
but this polymorphism was not associated with severe RSV LRTI (unpublished
data). As such, these results support the concept that mechanisms underlying
the development of severe RSV LRTI are to be studied separately from the
pathophysiology of wheezing illness.
In addition to pre-existent factors, the immune response seems to be the
major contributor to disease severity as is demonstrated in several studies.
Especially in early infancy the immune system doesn’t seem able to elicit an
appropriate Th1 immune response against the invading virus. Kristjansson
found a local Th2 response and signs of eosinophils activation due to an
elevated production of the Th2-type cytokine IL-4 (14).
Figure 3 Pathogenesis of post-bronchiolitis wheeze: serial vs. parallel hypothesis.
The treatment possibilities for RSV infection are very limited. An attempt to
prevent RSV infection using formalin-inactivated RSV became a disastrous
event, but researchers continue their search for a safe and effective vaccine.
High-risk children can be given prophylaxis, by monthly administration of a
monoclonal antibody against the RSV F-protein (passive immunization).
Especially high-risk children who are younger than 6 months of age at the
start of the RSV season should receive this therapy. Because of high costs,
this type of prophylaxis can not be used for all infants.
Several therapies, including ribavirin, bronchodilatators, racemic epinephrine
and corticosteroids are not recommended as standard therapies because of
lack of benefit found in RCTs. In two different longitudinal studies intermittent
inhaled corticosteroid therapy had no effect on the short- or long term benefit
and had no disease modifying effect after the therapy was discontinued.
There was also no significant difference between corticosteroid and control
groups in the development of persistent wheezing (15,16). Recently,
Lehtinen and colleagues found that systemic steroids during the first episode
of wheezing prevented post-bronchiolitis wheeze, but only when the initial
bronchiolitic episode was caused by rhinovirus, and not by RSV (17). Use of
montelukast, a leukotriene receptor antagonist, during RSV infection is
(premature, CHD, BPD, < 5 wk)
Serial hypothesis Parallel hypothesis
another therapy which has been suggested to post-bronchiolitis wheeze.
However, this study needs to be confirmed before it can be accepted as
standard treatment. Taken together, there is no effective treatment for RSV
bronchiolitis or an intervention that effectively prevents post-bronchiolitic
(1) Parrott, R. H., H. W. Kim, J. O. Arrobio, D. S. Hodes, B. R. Murphy, C. D. Brandt, E.
Camargo, and R. M. Chanock. 1973. Epidemiology of respiratory syncytial virus infection
in Washington, D.C. II. Infection and disease with respect to age, immunologic status,
race and sex. Am. J. Epidemiol. 98:289.
(2) Glezen, W. P., L. H. Taber, A. L. Frank, and J. A. Kasel. 1986. Risk of primary infection
and reinfection with respiratory syncytial virus. Am. J. Dis. Child 140:543.
(3) Karron, R. A., R. J. Singleton, L. Bulkow, A. Parkinson, D. Kruse, I. DeSmet, C. Indorf,
K. M. Petersen, D. Leombruno, D. Hurlburt, M. Santosham, and L. H. Harrison. 1999.
Severe respiratory syncytial virus disease in Alaska native children. RSV Alaska Study
Group. J. Infect. Dis. 180:41.
(4) Shay, D. K., R. C. Holman, R. D. Newman, L. L. Liu, J. W. Stout, and L. J. Anderson.
1999. Bronchiolitis-associated hospitalizations among US children, 1980-1996. JAMA
(5) Glezen, W. P. 2004. The changing epidemiology of respiratory syncytial virus and
influenza: impetus for new control measures. Pediatr. Infect. Dis. J. 23:S202-S206.
(6) Frankel, L. R., N. J. Lewiston, D. W. Smith, and D. K. Stevenson. 1986. Clinical
observations on mechanical ventilation for respiratory failure in bronchiolitis. Pediatr.
(7) Tissing, W. J., H. A. van Steensel-Moll, and M. Offringa. 1993. Risk factors for
mechanical ventilation in respiratory syncytial virus infection. Eur. J. Pediatr. 152:125.
(8) Flamant, C., F. Hallalel, P. Nolent, J. Y. Chevalier, and S. Renolleau. 2005. Severe
respiratory syncytial virus bronchiolitis in children: from short mechanical ventilation to
extracorporeal membrane oxygenation. Eur. J. Pediatr. 164:93.
(9) Thompson, W. W., D. K. Shay, E. Weintraub, L. Brammer, N. Cox, L. J. Anderson, and K.
Fukuda. 2003. Mortality associated with influenza and respiratory syncytial virus in the
United States. JAMA 289:179.
(10) Henderson, F. W., A. M. Collier, W. A. Clyde, Jr., and F. W. Denny. 1979. Respiratory-
syncytial-virus infections, reinfections and immunity. A prospective, longitudinal study in
young children. N. Engl. J. Med. 300:530.
(11) Pullan, C. R., and E. N. Hey. 1982. Wheezing, asthma, and pulmonary dysfunction 10
years after infection with respiratory syncytial virus in infancy. Br. Med. J. (Clin. Res. Ed)
(12) Martinez, F. D., W. J. Morgan, A. L. Wright, C. J. Holberg, and L. M. Taussig. 1988.
Diminished lung function as a predisposing factor for wheezing respiratory illness in
infants. N. Engl. J. Med. 319:1112.
(13) Hull, J., A. Thomson, and D. Kwiatkowski. 2000. Association of respiratory syncytial
virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax 55:1023.
(14) Kristjansson, S., S. P. Bjarnarson, G. Wennergren, A. H. Palsdottir, T. Arnadottir, A.
Haraldsson, and I. Jonsdottir. 2005. Respiratory syncytial virus and other respiratory
viruses during the first 3 months of life promote a local TH2-like response. J. Allergy
Clin. Immunol. 116:805.
(15) Guilbert, T. W., W. J. Morgan, R. S. Zeiger, D. T. Mauger, S. J. Boehmer, S. J. Szefler, L.
B. Bacharier, R. F. Lemanske, Jr., R. C. Strunk, D. B. Allen, G. R. Bloomberg, G. Heldt,
M. Krawiec, G. Larsen, A. H. Liu, V. M. Chinchilli, C. A. Sorkness, L. M. Taussig, and F.
D. Martinez. 2006. Long-term inhaled corticosteroids in preschool children at high risk
for asthma. N. Engl. J. Med. 354:1985.
(16) Bisgaard, H., M. N. Hermansen, L. Loland, L. B. Halkjaer, and F. Buchvald. 2006.
Intermittent inhaled corticosteroids in infants with episodic wheezing. N. Engl. J. Med.
(17) Lehtinen, P., A. Ruohola, T. Vanto, T. Vuorinen, O. Ruuskanen, and T. Jartti. 2006.
Prednisolone reduces recurrent wheezing after a first wheezing episode associated with
rhinovirus infection or eczema. J. Allergy Clin. Immunol.
We have described an infant with recurrent episodes of wheeze following RSV
bronchiolitis. Pre-existent as well as virus-induced pathophysiological
mechanisms have been discussed. It remains a challenge to identify children
with persistent asthma among those who experience post-bronchiolitis
wheeze. To date, no single treatment has convincingly been shown to be
effective. The precise underlying mechanisms of post-bronchiolitis wheeze
need to be unraveled before safe and effective preventive and treatment
strategies can be developed.