In this study we presented respiratory and allergic problems in the geographically based cohort of ELBW children at the mean age of 6.7 years.
In our opinion, the study has significant value because: 1/ the study group included almost all newborns from the whole Malopolska region born in a period of 2 years that reached the age of 6–7 years. The data in our multi-center study comes from all the tertiary referral centers from the Malopolska region. It is a complete group of patients with a high percentage of observation (91%). 2/ The assessment of the past and current health status of the child was based on a validated, standardized ISAAC questionnaire and all responses were verified by a physician. Moreover, all children were examined by an investigator for the presence of symptoms characteristic of eczema, rhinoconjunctivitis, wheezing, and other clinical signs of allergic disorders. 3/ The current study limited the study group to ELBW children, most of the previous studies included VLBW infants. 4/ Lung function was evaluated by spirometry according to the recommendations of ATS/ERS published in 2005 . 5/ In addition, FeNO measurements which are a marker of eosinophilic airway inflammation were done as well.
One of the major limitations of the study was the fact that the spirometry results suitable for evaluation were completed by only a quarter of the ELBW participants (22/81) and half of the control group (20/40). Considering the fact that VLBW infants are at a greater risk of neurodevelopmental delay, cerebral palsy, hearing impairment and cognitive and emotional problems later in life , cooperation in this group of children is a challenge and the achievement of reproducible spirometric efforts is extremely difficult. Not to mention the fact that this task can be sometimes difficult among term born children as well.
One of the major results of this study was the observation that among ELBW subjects, the children with wheezing episodes in the last year more often had the need for hospitalization in the first 2 years of life compared to other (non-wheeze in the last year) ELBW children. Surprisingly we found no difference in birth weight, gestational age, length of mechanical ventilation, oxygen therapy in the first 28 days of life or at 36 weeks PMA between ELBW children with and without wheeze in last year. There was no significant difference in family history of atopy, pets at home between ELBW children with and without wheeze in last year. Furthermore those children were not exposed more often to passive smoking. Interestingly enough, positive SPT were not more frequent and serum tIgE levels were not greater in the ELBW population with wheeze in last year. Thus there was no evidence of atopy contributing to persistent respiratory problems in those children. The baseline FEV1 values were similar, but %FEV1 values were greater in the ELBW children with wheeze in last year and in half of them there was a significant bronchodilator response.
Our results suggest that symptoms of asthma observed in the ELBW population correlated more strongly with respiratory morbidity in infancy rather than perinatal problems or atopic factors. We have shown that the need for re-hospitalization in the first 2 years of life, was a more important risk factor of respiratory problems at the age of 7 than perinatal factors or the diagnosis of bronchopulmonary dysplasia. Furman et al. who followed 98 out of 124 VLBW infants with BPD up to the age of 2 years also showed that the severity of BPD correlated with the duration of neonatal hospital stay and total hospital stay during the first 2 years of life. A similar finding was also mentioned in another study by Ballow et al.  which followed 43 VLBW preterm infants until 10 months chronological age and found that they had a considerably higher incidence of infections (especially lower respiratory tract infections) than term infants, what’s more none of them turned out to be bacterial infections. Among lower respiratory tract infections RSV has been shown to be the most common cause in high risk infants such as prematurely born infants  in addition it has been shown preterm infants are more likely to have a more severe clinical course of the disease than term infants (more prolonged hospital stays, requiring oxygen for longer periods of time, more frequent usage of nasal continuous positive airway pressure, CPAP, or mechanical ventilation) .
In light of these facts it is highly probable that the increased hospitalisation rate in ELBW infants is not only due to the immaturity of the lungs, not fully recovered from the morbidity of the perinatal period but also due to the damage to the lungs that is incurred with each subsequent infection and also through the use of respiratory support (volutrauma, barotrauma, oxygen toxicity) causing a state of chronic inflammation and lung injury.
Our study confirmed previous observations that ELBW children had more frequent respiratory problems at the age of 6–7 years compared to children born at term. In ELBW children, wheeze in the last year or ever in the past and an established diagnosis of asthma were observed more frequently in these subjects than in their peers. The need for hospitalization due to respiratory disease at any time was significantly higher in the ELBW population. This tendency was also present in the last year, however it did not have full statistic significance. However the results of the pulmonary function tests were significantly poorer in ELBW subjects than in controls. This explains why the use of medications – first and foremost- inhaled steroids were more common in the ELBW group. The need for hospital admissions also suggested that the severity of respiratory disease was greater in ELBW children. Fortunately there has been a decrease in the need for hospitalization in the last year.
Similar observations have been noted in others studies. McLeod et al. studied a group of very low birth weight (VLBW) children who were evaluated at the age of 8–9 years and reported that they used inhaled drugs and were admitted to hospital more often than their classroom peers . Siltanen et al. reported an increased prevalence of wheezing in preterm infants (43%) at the age of 10 years compared to term-born subjects (17%) . A reduction in the number of hospital admissions after the second year of life, including children with BPD, was reported in another study .
Martinez et al. reported that children who started wheezing early in life and continued to wheeze at the age of six years were more likely to have a family history of asthma and elevated serum tIgE. However, the gestational age of the subjects was not revealed in that study . In our population the ELBW children did not present with: allergic rhinitis, rhinoconjunctivitis or eczema more frequently than their term born peers. Bűhrer et al. also showed a decreased prevalence of atopic eczema in VLBW infants compared to term and near-term infants in the first year of life suggesting that early antigen exposure in VLBW infants could lead to tolerance and a decreased risk of sensitization .
Risk factors of allergy development such as: family history of atopy, exposure to tobacco smoke, contact with animals (pets at home, indoor allergens), place of residence, presence of siblings at home were similar in both groups. The only differentiating factor was duration of breast feeding, which in ELBW children frequently lasted less than one month, meanwhile breast feeding lasting more than 4 months has been proven to reduce the risk of asthma at the age of 6 years .
Asthma was diagnosed more often in the ELBW group (32%) than in the control group (7.5%). In other reports, asthma was also diagnosed more frequently in ELBW children (24.7%) than in controls (13.9%) at the age of 8–9 years  and 28% vs 14% at the age of 10 years, respectively . Large-scale analysis conducted by Brooks et al. confirmed a strong independent association between low birth weight and asthma, diagnosed by a physician at the age of 3 years . It is important to note, that the prevalence of asthma in our controls corresponded with the results of the ISAAC survey of 6–7 year old children in a proper geographic region .
Siltanen et al. reported that atopy was more frequent in term than in the ELBW infants, and reduced pulmonary function in that group was not related to atopy [9, 10, 22]. Mieskonen et al. showed that atopy was less common in VLBW children with BPD than without BPD, furthermore atopic children had higher birth weights, a shorter need for ventilator and oxygen therapy than non-atopic children born prematurely . In our study the serum tIgE was higher and its level more frequently above the upper limits for age in the control group. The SPT were also more frequently positive in the control group, but the difference was not statistically significant. Thus, we can conclude that symptoms of asthma in our cohort of ELBW children were not associated with atopy.
In our study FEV1 below 80% of predicted value was observed in the nearly half of ELBW children and not in the control subjects. Similar observations were made in children with symptoms suggestive of asthma and bronchopulmonary dysplasia .
Doyle et al. reported that all respiratory function variables reflecting airflow were diminished in the ELBW group compared to term-born controls at the age of 8–9 years (reduction in FEV1 below 75% was observed in 19.7% ELBW children vs 2.4% in control subjects) . Mieskonen et al. reported that BPD and non-BPD VLBW children had significantly lower FVC, FEV1, FEF50 than controls, but the BPD VLBW children had significantly lower values than non-BPD VLBW at 8 years of age . Mai et al. evaluated VLBW compared to term children at the age of 12 years, a history of asthma was more frequently noted in VLBW children and the only significant risk factor was prolonged oxygen therapy. Spirometric values were similar among VLBW and term children . The improvement in spirometry results (FEV1) obtained in VLBW subjects between 6 and 12 years of age indicated that there was an acceleration of the lung development, although they did not catch up with their peers in weight and height [8, 28].
Eosinophilic airway inflammation was assessed by measurement of FeNO. Atopy and atopic asthma leads to the increase in FeNO levels [30, 32]. Diminished levels of FeNO were observed in children with virus-associated acute wheezy bronchitis . The level of FeNO correlated with BAL fluid or sputum eosinophil percentage, but not with other inflammatory cells, and is considered to be a marker of eosinophilic inflammation [34, 35]. A relationship between FeNO and blood eosinophils was also confirmed . In our study, the FeNO levels were not higher in the ELBW population (particularly not greater than 20 ppb), which can indicate the absence of an eosinophilic inflammatory process in their respiratory tract. However, we could not exclude the effect of inhaled steroids on FeNO levels in some patients. Glucocorticosteroids decrease FeNO in asthmatic, but not healthy subjects . Baraldi et al. showed that FeNO was significantly lower in VLBW children with BPD than in VLBW without BPD (however, all results were below 11 ppb) . Mieskonen et al. found no significant differences in FeNO levels between BPD and non-BPD non-atopic subjects . Both authors revealed no difference in FeNO between VLBW children and healthy controls. The atopic VLBW children had significantly higher FeNO levels (mean 14.8 ppb) than non-atopic prematurely born subjects (mean 6.3 ppb), although it was not significantly higher than healthy term controls (mean 6.4 ppb) . These authors found that flow limitation was not associated with increased NO production and lack of reversibility of airflow limitation and low FeNO values suggested different than asthma mechanism of lower forced expiratory flows. We had similar observations.