The importance of EPPD and PD is that infants who have these respiratory patterns are at very high risk of CLD. Early descriptions of CLD noted its association with severe early lung disease that would be categorized as EPPD in our study. More recently, an additional pattern of early disease preceding CLD has been reported. Among infants who developed CLD, Charafeddine et al2
observed 2 groups of infants who did not have antecedent EPPD. Infants in these groups were either well throughout the first week of life or had recovered from their acute lung disease by the end of the first postnatal week, but then developed an oxygen requirement during the second postnatal week. The authors were the first to describe this experience as “atypical CLD.”2
These infants experienced what we call PD.
Streubel et al6
identified a group of infants who had an Fio2
of <0.25 for 3 days after recovery from respiratory distress syndrome (RDS) and a subsequent increase in Fio2
to at least 40%; these infants were classified as having atypical CLD. All infants in this atypical CLD group developed bronchopulmonary dysplasia (BPD). Compared with infants with no BPD, infants with atypical CLD were smaller, less mature, and had a higher rate of sepsis and pneumothorax. In a similar study, Panickar et al3
reported that ~40% of all who developed BPD had an antecedent history of PD. We confirmed this relationship, finding that >50% of children with EPPD or PD developed CLD compared with <20% of children in the low Fio2
The terms in current use in the literature are confusing. We feel that our terms (PD and EPPD) describe a clinical pattern of respiratory disease, defined by Fio2
, which may or may not develop into CLD. Previous authors identified patients as having CLD (usually at 36 weeks' adjusted gestation), and then looked retrospectively to identify the pattern of lung disease (eg, “atypical RDS”2
). We do not believe that infants with PD or EPPD necessarily have RDS. The advantage of using our terms is threefold: first, we, and other investigators, will be able to relate events that occur after the pattern of lung disease to these patterns (eg, CLD and, in future studies, neurodevelopmental outcomes); second, a clinician is now able to distinguish these patterns by the 14th postnatal day and place infants into appropriate risk categories of morbidities associated with prematurity (namely, CLD); and third, therapeutic modalities designed to reduce the incidence of morbidities associated with prematurity (eg, CLD) can use these patterns as markers of risk.
In our cohort of ELGANs, PD occurred in 38% of infants, a prevalence similar to that of EPPD (43%). Only 19% of ELGANs were in the consistently low Fio2 group, having little or no evidence of lung dysfunction throughout the first 2 postnatal weeks. We found that infants with PD had a risk factor profile that was intermediate between that of infants with consistently low Fio2 and infants with EPPD. This risk factor profile included birth weight, gestational age, and a variety of treatments and complications that are associated with low gestational age, such as higher SNAP-II values, treatment with mechanical ventilation, patent ductus arteriosus, treatment with hydrocortisone, and confirmed bacteremia.
To our knowledge, the entity of PD is unique to ELGANs. The peculiar predisposition of ELGANs to PD could be explained on the basis of processes that are developmentally regulated resulting in vulnerability by virtue of birth at extreme prematurity (eg, adrenal glucocorticoid synthesis and antioxidant production).17–19
This possibility is supported by our observation of the association between PD and early gestational age.
ELGANs may also be vulnerable because of a unique environmental exposure that is distinct to this population. One possibility is an intrauterine exposure. The most common feature that distinguishes the intrauterine environment of ELGANs from more mature neonates is the far greater likelihood of intrauterine infection.20
Although not a consistent finding, intrauterine infection has been associated with the development of CLD, either as a risk factor by itself21
or when antenatal infection is associated with the need for prolonged mechanical ventilation.22
Neither EPPD nor PD had an increased frequency of histologic expressions of inflammation in the placenta as chorioamnionitis and funisitis. Therefore, we explored the possibility that placental infection with a specific organism might be associated with risk for PD. In previous work, postnatal recovery of Ureaplasma urealyticum
from tracheal samples has been associated with the development of CLD.23
Although not statistically significant, among our study subjects Mycoplasma
species, including Ureaplasma
, was detected more frequently among the placentas of infants who developed EPPD.
Besides gestational age and birth weight, the most consistent risk factor for PD was treatment with mechanical ventilation (conventional or high-frequency ventilation) on postnatal day 7. It is not clear whether this association reflects a causal link between ventilation mode and PD or whether ventilation mode identifies infants with more severe lung disease. Treatment with oxygen during the first week of life in the low Fio2 and PD groups was similar, as was the frequency of the diagnosis of apnea at any time during the study period.
Two neonatal events, confirmed bacteremia and persistent PDA, have been associated with adverse outcomes, including CLD.24
However, prophylactic treatment of the PDA has not been demonstrated to reduce the risk of CLD.25
We examined both of these antecedents in relation to patterns of early lung disease. Bacteremia was a risk factor for EPPD but not for PD. This finding suggests that the etiology of persistent, severe lung disease may be different from the etiology of PD. The relationship between EPPD and both intrauterine exposure to specific organisms and postnatal infection implicates an infectious/inflammatory exposure in the pathogenesis.21
The diagnosis of PDA at any time during the first 2 weeks of life may be a risk factor for both EPPD and PD as this association approached statistical significance for both entities. A cause-and-effect relationship between shunting through a PDA and lung disease has biological plausibility.15,16
It is possible that our finding an association between PDA and both EPPD and PD is explained on the basis of an acquisition bias, in that infants with more severe lung disease were more likely to be clinically suspected of having a PDA and to be subjected to diagnostic testing (ie, echocardiography). Alternatively, PDA may be causally related to PD. Our data about indomethacin and/or ligation for PDA do not allow us to assess if these therapies reduced the risks of EPPD or PD. Determining the contribution of the PDA is important, because it may be a modifiable risk factor.