Because of the lack of consensus on the description, assessment and treatment of recurrent
wheezing in young children, these cases are quite difficult for clinicians to manage.
Many unnecessary investigations are conducted, and inadequate treatment is provided.
We investigated the demographics, the requested investigations, and the results for
pre-school children with recurrent hospitalizations resulting from wheezing. A comparison
of the patients with 2 and the patients with 3 or more hospitalizations resulting
from wheezing revealed that the patients with 3 or more hospitalizations had a statistically
significantly higher rate of BPD and anemia relative to the other group. The regression
analysis revealed that a GER history and presence of anemia were significant risk
factors in patients with 3 or more hospitalizations resulting from wheezing.
Several studies have reported that boys have an increased risk of early persistent
wheezing and allergic sensitization 9], 10]. In our study, 64 % of the patients with recurrent wheezing attacks were boys.
Breastfeeding protects against respiratory infections during the early period of life.
However, the relationship between breastfeeding and wheezing has not been elucidated
11]. Whereas there are clinical studies suggesting that breastfeeding is protective against
wheezing, other studies have not detected an association. We failed to detect an association
between breastfeeding and recurrent wheezing, although 34 % of the patients were breastfed
for less than 6 months, which is most likely because of the small sample size.
Passive smoking has a strong correlation with respiratory complaints 12]. In this study, we detected a rate of passive smoking as high as 66 %; however, we
failed to show passive smoking as a risk factor in patients with 3 or more hospitalizations
resulting from wheezing. In the British Cohort Study, a strong correlation was demonstrated
between maternal smoking and the presence of wheezing during early childhood; however,
such a correlation could not be shown for the subsequent period 13]. The Tucson CRS study suggested that maternal prenatal smoking affects in utero lung
function and increases the risk of wheezing during the first 3 years of life 14]. A recent mother and child cohort study in Norway reported that smoking by the grandmother
while pregnant with the mother increases the risk of asthma in the grandchild, independent
of the maternal smoking status 15]. In this study, we did not investigate the history of smoking during pregnancy.
A review of the cases with 3 or more hospitalizations for wheezing revealed that the
presence of anemia increased the risk of hospitalization 17.02 fold. The studies investigating
the association between anemia and lower respiratory infections are limited. Iron
deficiency anemia affects the immune response and alters the metabolism of pathogens.
A low tissue hemoglobin level impairs tissue oxygenation and represents a risk for
lower respiratory infections in children 16]. The literature data suggest that the presence of anemia increases the risk of acute
lower respiratory infection 3 to 6 fold 16], 17]. In a randomized, controlled study in Sri Lanka, iron supplementation reduced morbidity
in children with and without an upper respiratory tract infection 18]. There are studies suggesting that maternal anemia during pregnancy is a risk factor
for recurrent wheezing 19]. Maternal anemia was not investigated in our study.
Reviewing the patients with recurrent hospitalizations resulting from wheezing, we
observed that the presence of GER increased the risk of 3 or more hospitalizations
6.29 fold. In our study, 14 patients had been on GER treatment, and 5 of the 14 had
abnormal pH monitoring results. The presence and treatment of GER has a significant
role in recurrent wheezing. A systematic review of the clinical studies conducted
between 1966 and 2008 revealed a mean GER prevalence of 20 % (ranging from 19.3 to
80 %) in children with asthma 20]. A study investigating the association between the recurrence of respiratory symptoms
and GER detected GER in 35 % of the patients, which included 40 % of the enrolled
cases of reactive airway disease. In the same study, the respiratory complaints had
started below the age of one in 86 % of the patients with GER. A marked reduction
in wheezing was observed 3–6 months after anti-reflux treatment 21]. Empiric GER treatment would be an appropriate approach in patients with recurrent
hospitalizations resulting from wheezing and in cases of no response or an inadequate
response to ICS treatment.
Patra et al. found that 42 % of the patients below the age of 1 with wheezing had
positive GER investigations. They report that GER is a significant cause of recurrent
wheezing in patients below 2 years of age and recommend GER investigations in patients
with severe attacks having an onset below the age of 1 year 22]. A trial by Sheikh et al. detected silent chronic aspiration secondary to difficulty
of swallowing without GER in 13 infants with chronic respiratory symptoms 23].
Consensus was not achieved on the description, assessment and treatment of wheezing
in pre-school children; however, a trial of ICS and montelukast treatment in patients
with recurrent wheezing, with discontinuation of treatment in non-responders, was
recommended 24].
In an observational study by Saglani et al., invasive tests, including computed chest
tomography, blood tests, a nasal cilia biopsy, flexible bronchoscopy with bronchoalveolar
lavage, and pH monitoring, were performed in 47 patients, between 3 months and 5 years
of age, who experienced recurrent wheezing despite ICS treatment. One-third of the
patients had abnormal investigation results, and these patients were diagnosed with
an airway abnormality, GER, eosinophilic airway inflammation, and bacterial infection
25]. In our study, 80 % of the patients had not received previous ICS treatment or were
not using the therapy regularly.
Regardless of the age at onset, atopic findings, triggering factors or the frequency
of wheezing, the most common cause of recurrent wheezing is asthma 26]. A study in Finland suggested that, based on a 6-month follow-up, more than one-third
of children below 2 years of age, hospitalized for wheezing, were diagnosed with asthma,
and the risk was high, particularly in those with recurrent wheezing and allergic
findings 27].
Salbutamol syrup remains in use for the treatment of wheezing. Whereas the Global
Initiative for Asthma (GINA) and National Asthma Education and Prevention Program
(NAEPP) consensus reports do not include salbutamol syrup in the treatment protocol
for asthma for patients below 5 years of age, the syrup is frequently used in the
treatment of wheezing 28]–31]. Whereas salbutamol syrup should not be used because of the absence of efficacy for
the treatment of wheezing and the presence of side effects, this treatment remains
in use because of economic reasons and the societal prejudice against inhaled treatments
32]. Physicians have a great role in the implantation of treatment protocols through
efforts to inform society and establishing consensus reports.
Considering that the study was conducted in winter and that one-half of the pulmonary
radiography investigations were reported as increased ventilation and infiltration/atelectasis,
the most likely cause of wheezing was infection. We were unable to perform a respiratory
viral panel. There were 14 patients with GER findings (31.8 %), and 5 patients (11.4
%) had esophageal pH monitoring results consistent with reflux. The sensitivity, specificity
and clinical utility of pH monitoring for extra esophageal indications are not well
established.
The high serum IgE level, eosinophilia, inhalant/food panel detected in 53 %, 14 %,
and 10 % of the patients, respectively, suggest the presence of changes secondary
to infection rather than an atopic background. An increased serum IgE level might
be associated with an acute viral infection in atopic and non-atopic children 33]. IgE production is secondary to an inflammatory process occurring in the asthmatic
airway rather than to a specific allergen 34]. The presence of eosinophilia might be explained by parasitosis as well as atopy.
Of the other tests requested, the immunoglobulin panel, PPD, sweat test and ECHO investigation
yielded normal results in a larger portion of patients. The low frequency of the diagnoses
of immunodeficiency, cystic fibrosis and cardiac abnormality that should be considered
in the differential diagnosis of recurrent wheezing might be attributed to the small
number of patients. If the number of the patients were larger, we could hypothesize
that the probability of diagnosing the above conditions would increase.
The strength of our study is that it is the first to assess the risk factors for 2
or more recurrent hospitalizations resulting from wheezing. An important limitation
of this retrospective study results from missing data, incomplete data, unknown confounders,
and the small sample size.