An unanticipated benefit of the treatment of preterm infants with CuZn superoxide dismutase

An unanticipated benefit of the treatment of preterm infants with CuZn superoxide dismutase – Commentaries

Alan H. Jobe

ABBREVIATIONS. BPD, bronchopulmonary dysplasia; CuZnSOD, CuZn superoxide dismutase.

The clinical diagnosis of bronchopulmonary dysplasia (BPD) is a final common pathway for the lung injuries that occur in the most immature infants. BPD originally was blamed on the fibrosis and severe airway disease caused by supplemental oxygen and ventilation. (1) However, an arrest in alveolar and vascular development with less fibrosis and airway injury is more prominent in the histopathology of infants who have recently died of BPD. (2) More recently, BPD has also been associated with antenatal infection and postnatal sepsis which should cause an oxidant stress on the lung. Davis et al (3) performed a randomized, controlled trial to ask if recombinant human CuZn superoxide dismutase (CuZnSOD) would decrease the incidence of BPD in ventilated and surfactant-treated preterm infants. The trial was stopped early after the enrollment of 302 patients because there was no difference in the primary outcome of BPD at 28 days of age. In fact, the incidence of BPD was 34% in the superoxide dismutase-treated group and 26% in the controls. There were no differences in any of the acute secondary outcomes or in complications, and the incidence of BPD using the definition of oxygen use at 36 weeks was not different. The trial enrolled the correct patients to test the hypothesis, and overall the populations were well-matched. A clinical diagnosis of BPD is not a precise primary outcome because of variable oxygen use between centers and the range of severity of this poorly defined disease. (4)

The striking results were large decreases in several indicators of lung disease over the first year of life. Infants <27 weeks gestation randomized to CuZnSOD required fewer medications for asthma, had fewer emergency department visits, and fewer hospitalizations. These benefits were evaluated as secondary outcomes and complete follow-up information was available for only 72% of the infants. Assuming that these differences in outcomes are real, the question is why a treatment to decrease oxidant exposure in the acute phase of respiratory disease in preterm infants should improve long-term outcomes but not BPD. We know very little about how the preterm lung "heals" the acute injury and what causes interrupted alveolar and vascular development. (2) As pure speculation, the CuZnSOD could beneficially influence the mediators that interrupt the normal sequence of lung development and permit more rapid healing. A second possibility is that a decrease in oxidant stress might change the immune responsiveness of the lung. Recently, exposures to inflammatory mediators or antigens early in life have been linked to changes in subsequent immune responses and the incidence of asthma and other allergic diseases. (5) If the CuZnSOD-mediated decrease in oxidant stress changed immune responsiveness, then infants exposed to CuZnSOD might require fewer medications for "asthma" in the first year of life. This trial is an example of an intervention that resulted in no change in primary outcome but an apparent benefit on a delayed outcome. This delayed effect of CuZnSOD needs to be prospectively evaluated and to demonstrate benefits beyond 1 year of age to be of clear clinical value. In a disease process as complex and as poorly understood as BPD, perhaps an unexpected outcome should be expected.

ALAN H. JOBE, MD, PHD

Division of Pulmonary Biology

Cincinnati Children’s Hospital Medical Center

Cincinnati, OH 45229-3039

REFERENCES

(1.) O’Brodovich HM, Mellins RB. Bronchopulmonary dysplasia: unresolved neonatal acute lung injury. Am Rev Respir Dis. 1985;132:694-709

(2.) Jobe A, Bancalari E. NICHD/NHLBI/ORD workshop summary–bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163: 1723-1729

(3.) Davis JM, Parad RB, Michele T, Allred E, Price A, Rosenfeld W for the North American Recombinant Human CuZnSOD Study Group. Pulmonary outcome at 1-year corrected age in premature infants treated at birth with recombinant human CuZn superoxide dismutase. Pediatrics. 2003;111:469-476

(4.) Ellsbury DL, Acarregui MJ, McGuinness GA, Klein JM. Variability in the use of supplemental oxygen for bronchopulmonary dysplasia. J Pediatr. 2002;140:247-249

(5.) Braun-Fahrlander C, Riedler J, Herz U, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med. 2002;347:869-877

Received for publication Jan 6, 2003; accepted Jan 6, 2003. Address correspondence to Alan H. Jobe, MD, PhD, Division of Pulmonary Biology, Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail: alan.jobe@cchmc.org

COPYRIGHT 2003 American Academy of Pediatrics

COPYRIGHT 2003 Gale Group