From the Journals

Inhaled hyaluronan may bring sigh of relief to COPD patients



Aerosolized high-molecular-weight hyaluronan (HMW-HA) may improve acute exacerbations of chronic obstructive pulmonary disease (COPD), findings of a new study suggest.

Dr. Flavia Galdi, of Campus Bio-Medico University Hospital, Rome

Dr. Flavia Galdi

HMW-HA was associated with a significantly shorter duration of noninvasive positive-pressure ventilation (NIPPV), lower systemic inflammatory markers, and lower measured peak airway pressure, compared with placebo, reported lead author Flavia Galdi, MD, of Campus Bio-Medico University Hospital, Rome, and colleagues.

“HMW-HA is a naturally occurring sugar that is abundant in the extracellular matrix, including in the lung,” the investigators wrote in Respiratory Research. “[It] has been used routinely, together with hypertonic saline, in cystic fibrosis patients [for several years] with no reported side effects; rather, it improves tolerability and decreases the need for bronchodilators in these patients.”

According to Robert A. Sandhaus, MD, PhD, FCCP, of National Jewish Health, Denver, the role of hyaluronan in lung disease was first recognized decades ago.

Dr. Robert A. Sandhaus, of National Jewish Health, Denver,

Dr. Robert A. Sandhaus

“Data stretching back into the 1970s has identified decreases in hyaluronan content in emphysematous lung tissue, protection of lung connective tissue from proteolysis by hyaluronan, and potential therapeutic roles for hyaluronan in a variety of disease, especially of the lungs,” he said in an interview.

For patients with COPD, treatment with HMW-HA may provide benefit by counteracting an imbalance in diseased lung tissue, wrote Dr. Galdi and colleagues.

“Emerging evidence suggests that imbalance between declining HMW-HA levels, and increasing smaller fragments of hyaluronan may contribute to chronic airway disease pathogenesis,” they wrote. “This has led to the hypothesis that exogenous supplementation of HMW-HA may restore hyaluronan homeostasis in favor of undegraded molecules, inhibit inflammation and loss of lung function, and ameliorate COPD progression.”

To test this hypothesis, the investigators screened 44 patients with a history of acute exacerbations of COPD necessitating NIPPV, ultimately excluding 3 patients because of heart failure. Following 1:1 randomization, 20 patients received HMW-HA while 21 received placebo, each twice daily, in conjunction with NIPPV and standard medical therapy. Treatment continued until NIPPV failure or liberation from NIPPV. Most patients received NIPPV in the hospital; however, home/chronic NIPPV was given to four patients in the placebo group and three patients in the HMW-HA group.

The primary outcome was duration of NIPPV. Secondary outcomes included markers of systemic inflammation associated with acute exacerbations of COPD and respiratory physiology parameters. Adverse events were also reported.

Results showed that patients treated with HMW-HA were liberated sooner from NIPPV than were those who received placebo (mean, 5.2 vs 6.4 days; P < .037). Similarly, patients in the HMW-HA group had significantly shorter hospital stay, on average, than those in the placebo group (mean, 7.2 vs 10.2 days; P = .039). Median values followed a similar pattern.

“These data suggest that HMW-HA shortened the duration of acute respiratory failure, need for NIPPV and, consequently, hospital length of stay in these patients,” the investigators wrote.

Secondary outcomes further supported these therapeutic benefits. Compared with placebo, HMW-HA was associated with significantly lower peak pressure and greater improvements in both pCO2/FiO2 ratio and inflammatory markers. No adverse events were reported.

Further analyses involving human bronchial epithelial cell cultures offered some mechanistic insight. Using micro-optical coherence tomography imaging, the investigators found that HMW-HA treatment was associated with “a prominent effect on mucociliary transport” in cell cultures derived from COPD patients and in healthy nonsmoker cell cultures exposed to cigarette smoke extract.

“Our study shows for the first time the therapeutic potential of an extracellular matrix molecule in acute exacerbation of human lung disease,” the investigators concluded, noting a “clinically meaningful salutary effect” on duration of NIPPV.

Dr. Galdi and colleagues went on to predict that benefits in a real-world patient population could be even more meaningful.

“Since the serum samples were collected at the end of NIPPV, HMW-HA–treated patients were on average sampled a day earlier than placebo-treated patients (because they were liberated from NIPPV a day earlier on average),” the investigators wrote. “Thus, HMW-HA treatment effects may have been underestimated in our study.”

According to Dr. Sandhaus, “The current report, while a relatively small single-center study, is well controlled and the results suggest that inhaled hyaluronan decreased time on noninvasive ventilation, decreased hospital stay duration, and decreased some mediators of inflammation.”

He also suggested that HMW-HA may have a role in the prophylactic setting.

“The limitations of this pilot study are appropriately explored by the authors but do not dampen the exciting possibility that this therapeutic approach may hold promise not only in severe exacerbations of COPD but potentially for the prevention of such exacerbations,” Dr. Sandhaus said.

Dr. Jerome O. Cantor, of St. John’s University, Queens, New York,

Dr. Jeromen O. Cantor

Jerome O. Cantor, MD, FCCP, of St. John’s University, New York, who previously conducted a pilot study for using lower molecular weight hyaluronan in COPD and published a review on the subject, said that more studies are necessary.

“Further clinical trials are needed to better determine the role of hyaluronan as an adjunct to existing therapies for COPD exacerbations,” he said.

The study was supported by the National Institutes of Health. The investigators and Dr. Sandhaus declared no conflicts of interest. Dr. Cantor disclosed a relationship with MatRx Therapeutics.

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