FROM AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

Children with poor lung function will be more likely to develop asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS), suggesting that prevention of this disease should be attempted in early life, a study shows.

While other research has found that patients with poor lung function in early life have poor lung function as adults, this was the first study to investigate the relationship between childhood lung function and ACOS in adult life, according to Dinh S. Bui of the University of Melbourne, and his colleagues.

The study, published in the American Journal of Respiratory and Critical Care Medicine, used multinomial regression models to investigate associations between childhood lung parameters at age 7 years and asthma, COPD, and ACOS at age 45 years (Am J Respir Crit Care Med. 2017 Feb 1. doi: 10.1164/rccm.201606-1272OC ).

“We found that ACOS participants showed evidence of persistently lower FEV1 [forced expiratory volume in 1 second] and FEV1/FVC [forced vital capacity] from childhood. This suggests that poorer childhood lung function tracked to early adult life, leading to impaired maximally attained lung function,” the researchers said.

“The study highlights that low childhood lung function is a risk factor for COPD (and ACOS) independent of smoking,” they noted.

The 1,355 study participants who had postbronchodilator (post-BD) lung function available were categorized into the following four mutually exclusive groups at age 45 years based on their asthma and COPD status: having neither asthma nor COPD (unaffected) (n = 959); having asthma alone (n = 269); having COPD alone (n = 59); having ACOS (n = 68).

Once adjusted for the sampling weights, the prevalence of current asthma alone was 13.5%, COPD alone was 4.1%, and ACOS was 2.9%. The researchers defined COPD at age 45 years as post-BD FEV1/FVC less than the Global Lung Initiative lower limit of normal. Because the associations between childhood lung function and both ACOS and COPD alone were nonlinear, the patients were grouped into quartiles based on their characteristics, such as their percent predicted FEV1 and percent predicted FEV1/FVC at 7 years, the investigators said.

Patients in the lowest quartile for FEV1 percent predicted at 7 years were 2.93 times more likely to have ACOS, compared with patients in the other quartiles for FEV1 percent predicted. Patients in the lowest quartile for FEV1/FVC percent predicted at 7 years were 16.3 times more likely to have ACOS and 5.76 times more likely to have COPD alone, compared with patients in the higher quartiles.

The researchers found large variation in childhood lung function among patients in the lowest quartiles for FEV1 and FEV1/FVC. To account for this, they conducted a sensitivity analysis, which excluded those with less than 80% predicted FEV1 and FEV1/FVC (n = 76 and 13, respectively).The associations between lung function measures and diseases in adulthood for patients in the lowest quartiles differed slightly following this adjustment. The sensitivity analysis showed that patients in the lowest quartile for FEV1 had an odds ratio of 2.4 for ACOS and that those patients in the lowest quartile for FEV1/FVC had an odds ratio of 5.2 for COPD alone and 15.1 for ACOS.

A sensitivity analysis that excluded patients with remitted asthma from the unaffected group showed childhood FEV1 was more strongly associated with ACOS for patients in the lowest quartile, compared with patients in the highest quartile (OR: 7.0, 95% CI: 2.7-18.3). This same analysis found that patients from the lowest quartile and second quartile for childhood FEV1/FVC were 6.8 and 3.9 times more likely to have COPD, respectively, compared with patients in the other quartiles. This sensitivity analysis also found that patients in the first quartile for FEV1/FVC were 19.1 times more likely to have ACOS, and patients in the second quartile for FEV1/FVC were 5.3 times more likely to have ACOS.

The researchers analyzed data from the Tasmanian Longitudinal Health Study, which began in 1968 when Tasmanian children born in 1961 and attending school in Tasmania were studied with respiratory health surveys and prebronchodilator (pre-BD) spirometry measurements. The most recent survey started in 2002. Survey respondents who had participated in past follow-up studies and/or reported symptoms of asthma or cough were invited to participate in a more detailed laboratory study from 2006 to 2008. That study included completing a questionnaire, pre-BD and post-BD spirometry, and skin prick testing. The predicted and percent predicted values for spirometry were derived from the Global Lung Initiative reference equations.

The final multinomial model was adjusted for various factors including childhood asthma, maternal smoking, and paternal smoking during childhood.

History of active smoking was significantly more frequent in patients with ACOS (73.5%) and COPD alone (73%) than in the unaffected (57%) groups. Childhood asthma, maternal asthma and atopy were more prevalent in the ACOS and asthma alone groups. ACOS and COPD participants had a higher prevalence of maternal smoking during childhood.

Individuals with ACOS had the lowest pre-BD FEV1 (percent predicted values) over time. Those with COPD alone or ACOS had significantly lower pre-BD FEV1/FVC (percent predicted values) at all time points, when patients were assessed, compared with unaffected participants. “Participants with COPD alone had significantly higher FVC at 7 and 13 years, while ACOS participants had significantly lower FVC at 45 years,” the researchers said,

“There was no evidence of effect modification by childhood lung infections, childhood asthma, maternal asthma, maternal smoking, or paternal smoking during childhood on the associations between childhood lung and the disease groups,” they noted.

The study was limited by its “relatively small sample sizes for the ACOS and COPD alone groups” and the absence of post-BD spirometry at 7 years, they added.

The researchers concluded that “screening of lung function in school-aged children may provide an opportunity to detect children likely to have ongoing poorer lung health, such as those with lung function below the lower limit of normal,” and that “[multifaceted] intervention strategies could then be implemented to reduce the burden of COPD and ACOS in adulthood.”

Asked to comment on the study, Aparna Swaminathan, MD, a pulmonary/critical care fellow at Duke University, Durham, N.C., and an incoming Duke Clinical Research Institute fellow, said she would want to know “what is driving the effects in the study” before designing an intervention.

“I suspect that genetics may play a big role in the results, and there is increasing interest in learning how genetics are involved in COPD. A better understanding of the risk factors for lower lung function in children may also provide targets of intervention. The groups with ACOS and COPD have higher rates of maternal smoking, and while this study determined that the association between childhood low lung function and development of COPD and ACOS is independent of maternal smoking, maternal smoking still seems like a good area to target,” she said in an interview.

It would also be interesting to further study the first quartile of patients, she added. “The clinical disease for this quartile of patients covers a wide range of severities. I would be interested in dividing this group up further and learning the outcomes of their lung function and development of COPD and ACOS.”

Aggressively treating childhood asthma and poor lung function is one method that may have altered the destiny of the children with lower lung function, if it had been used, Eric Gartman, MD, FCCP, said in an interview.

Using inhaled corticosteroids and other medications for maintenance control, reducing and monitoring impairment, educating patients and patients’ guardians on triggers, avoiding triggers, and having an action plan for changing therapy based on symptoms or measured flows are ways to aggressively treat such conditions, Dr. Gartman said. He cited avoiding exposure to smoke, environmental pollutants, and living near highways, for those with low childhood function, as interventions that might prevent people with low lung function from later developing COPD.

Dr. Gartman added that differences between the availability of medication for children with asthma today and at the time of the study may mean there are differences between the children with low lung function in the study and those children who have low function today. A population of children with low lung function now may be experiencing relatively less asthma and more chronic lung disorders brought on by prematurity or cystic fibrosis, he noted. “As such, identification of poor function in today’s young children may carry with it a significantly different set of interventions and challenges,” Dr. Gartman said.

While asthma in children is better controlled now than it was at the time of the study, because the researchers did not provide any information about the asthma control of the study participants, “it [is] hard for me to say if better asthma drugs in those children would have made a difference in long-term outcomes of COPD and ACOS as an adult,” Dr. Swaminathan noted.

“The best thing we currently can do for children with low lung function is try and determine the underlying cause and treat any active diseases [such as asthma] that we can. This study reminds us of the need to keep searching for causes of low lung function that may be reversible,” she said.

The investigators recommended future research to understand the risk factors for lower lung function in children. They called for studies that address “the risk factors over adulthood that interact with lower lung function to increase the risk of rapid lung function decline.”

The study was supported by a National Health and Medical Research Council of Australia research grant, the University of Melbourne, Clifford Craig Medical Research Trust of Tasmania, the Victorian, Queensland & Tasmanian Asthma Foundations, The Royal Hobart Hospital, Helen MacPherson Smith Trust, GlaxoSmithKline, and John L Hopper. Five authors were supported by the research grant; the others reported no conflicts. Dr. Swaminathan and Dr. Gartman had no disclosures.

klennon@frontlinemedcom.com

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