This review explores the likely pathophysiologic mechanisms involved in this 19-year-old with severe AAT deficiency presenting with severe COPD. The interaction of adverse genetic, host and environmental factors led to the phenotype of severe airflow obstruction with airspace enlargement. Severe chronic airflow obstruction developed consequent to an interaction of AAT deficiency, neutrophil-mediated inflammation, and oxidative stress-related lung injury sustained during lifesaving treatment for CDH. Features of the presentation point to AAT deficiency as playing a contributing role in the development of the spirometric criteria for severe COPD. First, the patient has bilateral emphysema; second, the severest emphysema is predominantly basal (as is more common in AAT deficiency);7
third, the degree of airflow obstruction as noted on pulmonary function tests is much more severe than is generally reported in the literature where airflow obstruction tends to be milder,8
and fourth, the surgeon’s report suggests that the right lung was hypoplastic and that emphysema of the right lower lobe developed during subsequent lung growth.
AAT, a member of the serine protease inhibitor family, is the major inhibitor of neutrophil elastase. Severe AAT deficiency is found in approximately 1% of cases of COPD and predisposes to the development of premature emphysema in those susceptible.7
Development of emphysema almost always occurs in middle age so the presence of emphysema in this case is unique. Smoking is by far the most common environmental factor accelerating FEV1
decline in those with the severe deficiency, usually requiring 20–30 years of smoke exposure to cause clinical disease. Cigarette smoke reduces the anti-elastase inhibitory activity of AAT through methionine oxidation and also supports a pro-elastolytic environment through the recruitment of alveolar neutrophils. But in this case it was the severe oxidative stress and neutrophil-mediated inflammation during a period of formative lung development that accelerated the development of emphysema.
BPD, a form of neonatal chronic lung disease, and emphysema share common pathophysiologic features.6
BPD as a cause of severe airflow obstruction usually develops during lung injury in premature infants yet many of the clinical features of this young man, who was born at term, are consistent with BPD; namely, prolonged oxygen therapy, chronic wheezing, bronchial hyper-responsiveness, dyspnea, and computed tomography scan and lung volumes that show air-trapping.6
The definition of BPD is the requirement for oxygen 28 days after birth and would be graded in this patient as severe.6
Development of emphysema has also been described as a consequence of BPD6
and in this case is strongly suggested by the focal airspace enlargement and reduced lung attenuation on computed tomography scan.
In this case, SJMS represents an extreme example of focal emphysema in a patient with severe AAT deficiency and diffuse obstructive lung disease. SJMS is usually considered to be the result of post-inflammatory obliterative bronchiolitis, with the characteristic radiographic appearance, as in this case, of localized increase in radiographic lucency, bronchiectasis, and decreased vascularity.1
As suggested by the operative findings in our case and in prior work,14
SJMS developed over 19 years from the abnormal development of an immature right lung. It is plausible that genetic, host, and environmental factors have led to airspace enlargement from a paucity of alveolar development with alveolar destruction, favored by protease–anti-protease imbalance during and after oxidative and neutrophil-mediated lung injury.
In the early 1980s ECMO was introduced as salvage therapy for neonates with CDH. Late sequelae include hyperinflation, airway obstruction, and lower oxygen saturation with exercise.5
ECMO activates neutrophils, resulting in free circulating elastase concentrations.16
Our patient was exposed to high-pressure ventilation resulting in barotrauma, very high oxygen concentrations which caused additional oxidative stress, inflammation, and acute lung injury with sepsis during the perinatal period. Lung injury occurs with associated local production and systemic release of inflammatory mediators such as interleukin-8, interleukin-6, and tumor necrosis factor. These have been measured in high alveolar concentrations in infants who develop BPD.17
Elastin modeling is critical in the development of normal alveolar septation during lung growth19
but also accelerated elastin degradation is part of the protease–anti-protease model for emphysema as typified by severe AAT deficiency. The likely consequence of the injury sustained in this case was disruption of normal elastin modeling with destruction of mature elastin and inhibition of normal alveolar development. The latter is a feature more commonly associated with the development of BPD.6
Indeed desmosine, an elastin breakdown product, is increased in those developing BPD.19
Furthermore AAT is susceptible under high oxidative conditions to methionine oxidation that leads to reduced anti-elastase activity and conversion to a pro-inflammatory molecule.21
Abnormal elastin turnover enhanced by the extreme lack of anti-protease protection from elastolysis during a critical early period of lung development resulted in impaired alveolar development and the propensity to hyperinflation and structural emphysema.
An association of asthma with AAT deficiency has been suggested. Severe AAT deficiency is likely to increase susceptibility to asthma,22
a diagnosis supported in this patient by the bronchodilator response, the presence of bronchial hyper-responsiveness, symptom control with standard asthma medications during childhood, and wheezing during respiratory infections. Furthermore, the presence of a bronchodilator response on spirometry accelerates FEV1
decline in those with AAT deficiency.22
In this young patient the complex causes of airflow obstruction were not recognized because diagnostic bias evoked asthma as an explanation for the symptoms of wheezing.22
This case illustrates that genetic and host factors and environmental interactions have led to chronic obstructive lung disease in a 19-year-old. The development of chronic lung disease was caused by lung injury under high oxidative and inflammatory conditions in the setting of CDH. In the absence of normal AAT levels and activity, pro-elastolytic lung inflammation in the neonatal period of lung growth enhanced the development of SJMS and precocious obstructive lung disease.