Infant Lung Disease Predicted by Pattern of Gene Expression

Equipped with data from umbilical cord gene chips, researchers may be able to predict which preterm infants are at greater risk for developing bronchopulmonary dysplasia (BPD), a disease that scars and inflames underdeveloped lungs in premature infants.

Courtesy Isaac Kohane

Crossing the line. Since the gray dots are as likely to fall above the horizontal line as below it, their pattern indicates that no individual gene was expressed at a substantially different level in infants who went on to develop bronchopulmonary dysplasia (BPD) compared with those who did not. Yet the genes in the chromatin-remodeling pathway— represented by red squares—are significantly more likely to fall below the line, indicating that as a group they are turned on less often in infants who develop BPD.

The study, which appeared online Oct. 4 in Genome Biology, found that infants whose chromatin-remodeling pathway is aberrantly expressed have a greater tendency to develop the disease. BPD occurs in 20 to 40 percent of infants born below 1,000 grams and before the 28th week of gestation. The study defined cases as infants who needed supplemental oxygen at 36 weeks from the mother’s last menstrual period.

Infants who developed BPD were born earlier, weighed less, required more days of supplemental oxygen and ventilation, and had higher rates of sepsis and retinopathy of prematurity. There was no difference in the sex ratio of infants affected. Other factors associated with the disease—the second leading cause of death at this gestational age—include surfactant deficiency and maternal infections like chorioamnionitis.

Although researchers have identified factors that accompany BPD, they are unsure why only some infants develop the disease, said the study’s senior author, Isaac Kohane, the Lawrence J. Henderson associate professor of pediatrics and health sciences and technology at HMS and Children’s Hospital Boston. He is also a faculty member in the Harvard–MIT Division of Health Sciences and Technology.

Kohane, lead author Jennifer Cohen, a neonatology fellow at Children’s, and their colleagues collected the umbilical cords of 54 premature infants—20 of whom developed BPD. After analyzing RNA expression profiles for each of the umbilical cords, the researchers found that the genes themselves showed little difference between the BPD and control infants, but that three specific pathways, including those for oxidative phosphorylation, mitochondrial energy metabolism, and DNA repair, were differentially expressed. In particular, infants with a predisposition for BPD showed a lower level of expression in genes of the chromatin-remodeling pathway, which may leave portions of the genome exposed for continual or increased transcription.

A similar dysregulation of the chromatin-remodeling pathway exists in adults with chronic obstructive lung disease. Histone deacetylase–inhibiting (HDI) drugs, Kohane said, are currently in test trials for patients with this disorder. It is thought that the aberrant chromatin-remodeling pathway in these adults enables increased expression of inflammatory genes. HDI drugs prevent the transcription of these genes by causing DNA to wrap more tightly around histones.

“If these results are reproduced in subsequent studies, it would allow us to predict at birth who is at a greater risk,” said Kohane. “Maybe we could prevent BPD before it develops.”

Larger sample sizes are necessary to produce prognostic markers from umbilical cord profiles, Kohane cautioned. Still, he speculated that infants with BPD may have the same genetic vulnerability as adults who face oxidative stressors like pollution and smoking before developing lung disease. “The same disease may be manifested at different times in life because of different oxidative exposures,” he said.

—Laura Geggel

Antigens from Skin Cause Immune Cell to Inflame Airways

The ramifications of eczema can be more than skin deep. The majority of children who develop the condition, also called atopic dermatitis, succumb to asthma as they get older. HMS researchers have new clues as to why that is. Writing in the Oct. 2 Proceedings of the National Academy of Sciences, Raif Geha, the James L. Gamble professor of pediatrics at Children’s Hospital Boston, and colleagues report that a specialized type of T helper cell, the Th17 cell, not only sensitizes the immune system to antigens introduced through the skin but also helps drive inflammation of the lungs and air passages if they are subsequently exposed to the same antigen.
“This helps explain why the asthma in people with eczema may be different from that in people without the skin condition,” said Geha. The findings may also help researchers develop new strategies to treat asthma.

Identified only in 2005 and named after the interleukin-17 (IL-17) that they produce, Th17 cells are potent stimulators of neutrophils, releasing cytokines that attract the white blood cells. Even though neutrophils and IL-17 are often elevated in the lungs of asthma patients, the role of Th17 cells in airway inflammation has been controversial. What Geha and colleagues have found is that, as is often the case with immune cells, their responses are heavily biased by presentation.

To address the role of Th17 cells in airway inflammation, research fellow in pediatrics Rui He, who is first author on the paper, and colleagues used a mouse model of atopic dermatitis developed by Geha. “This model recapitulates a lot of what happens in human eczema,” said Geha. In these mice, epicutaneous sensitization—induced by simply peeling Scotch tape from the skin—mimics the dermatitis found in human eczema. He and colleagues found that Th17 cells are present at sensitization sites exposed to a foreign antigen—in this case ovalbumin—and that the antigen also induces IL-17 production. Significantly, the response was not limited to the skin. Th17 cells also turned up in the lymph nodes that drain the skin, and serum IL-17 levels rose more than 10-fold, indicating a systemic response. In contrast, mice injected with ovalbumin had normal serum IL-17.

But it was in the airways where the most relevant changes occurred. When the sensitized mice were allowed to inhale ovalbumin, IL-17 mRNA and protein levels increased around fivefold in the lungs. No such increases were seen in mice that were sensitized by intraperitoneal injection. Furthermore, the inhalation challenge caused a sevenfold increase in neutrophil-attracting chemokines and an influx of neutrophils into the lungs. These white cells contributed to airway hyperreactivity (asthma) because blocking their influx with anti–IL-17 blocked airway hyperreactivity.

How does skin exposure sensitize the lungs to antigens? The researchers found that skin dendritic cells respond to antigens by traveling to the lymph nodes and activating IL-17–producing T cells. They also found that activation of these dendritic cells depends on cytokines released in mouse skin in response to injury. This is consistent with the pathophysiology of atopic dermatitis. “In eczema, antigens are typically introduced through a skin that would normally be impermeable but has been injured due to scratching elicited by a genetically inherited dry skin,” said Geha.

The findings suggest that blocking IL-17, or the cytokines that respond to skin injury, might be useful approaches to controlling eczema-related asthma.

—Tom Fagan

HMOs Give Better Care to Patients in Commercial Health Plans Than to Those in Medicaid

Once viewed as a solution to the nation’s health care problems, HMOs have lost much of their luster. Commercially insured patients who flooded into health maintenance organizations in the early 1990s left in droves by the end of the decade. Medicaid patients, however, do not always have the option of choosing their health plan, and the proportion of Medicaid beneficiaries enrolling in HMOs continues to increase.

A new study by researchers at HMS and HSPH shows that under managed care, Medicaid patients fare worse than patients who are commercially insured on 10 of 11 quality measures. “There was a lot of hope that managed care would eliminate disparities between the Medicaid population and the commercial population,” said Bruce Landon, HMS associate professor of health care policy and first author on the paper, which appears in the Oct. 10 Journal of the American Medical Association. “HMOs may have moved care in that direction, but there is still a gap in the care that Medicaid and commercial patients receive.”

Using data from 383 health plans, the researchers looked at four groups of beneficiaries: Medicaid enrollees in HMOs that serve only the Medicaid population; Medicaid enrollees in HMOs that serve the Medicaid and commercial populations; commercial-plan enrollees in HMOs that serve the Medicaid and commercial populations; and commercial-plan enrollees in HMOs that serve only the commercial population.

The researchers evaluated care in three main areas—prevention and screening, chronic disease management, and care for pregnant women—and discovered striking differences. Female Medicaid beneficiaries, for example, receive 25 percent less postpartum care than their commercial counterparts, and Medicaid patients with diabetes were 15 percent more likely to have unacceptable blood sugar levels than their commercial counterparts.

HMOs serving only the Medicaid population and HMOs serving both the Medicaid and commercial populations appear to provide about the same quality of care to Medicaid patients. But the care falls short of that provided to commercial patients in HMOs. Even within the same health plan, commercial enrollees received higher quality of care than Medicaid enrollees on almost all of the measures examined.
“Across the 10 measures, we saw quality-of-care differences ranging from 5 to 25 percent, a difference that has substantial clinical implications for patients with chronic conditions such as diabetes,” said senior author Arnold Epstein, the John H. Foster professor of health policy and management at HSPH and chair of that department. “Medicaid patients received better care than commercial patients in only one area—chlamydia screening.”

The study did not include Medicaid patients who are not enrolled in managed care, so it is possible that HMOs serve the Medicaid population better than traditional Medicaid. But HMOs do not eliminate the quality of care gap between Medicaid patients and the commercial population.

“Part of the gap might be explained by the patients themselves, for it’s possible that the Medicaid population is less able to adhere to doctors’ recommendations than the commercial population,” said Landon, who is also an HMS associate professor of medicine at Beth Israel Deaconess Medical Center. “But I suspect Medicaid patients may also fare worse because they visit doctors and hospitals of lower quality.”

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