Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study

Flavia Galdi, Claudio Pedone, Christopher A McGee, Margaret George, Annette B Rice, Shah S Hussain, Kadambari Vijaykumar, Evan R Boitet, Guillermo J Tearney, John A McGrath, Audrey R Brown, Steven M Rowe, Raffaele A Incalzi, Stavros Garantziotis, Flavia Galdi, Claudio Pedone, Christopher A McGee, Margaret George, Annette B Rice, Shah S Hussain, Kadambari Vijaykumar, Evan R Boitet, Guillermo J Tearney, John A McGrath, Audrey R Brown, Steven M Rowe, Raffaele A Incalzi, Stavros Garantziotis

Abstract

Background: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) carry significant morbidity and mortality. AECOPD treatment remains limited. High molecular weight hyaluronan (HMW-HA) is a glycosaminoglycan sugar, which is a physiological constituent of the lung extracellular matrix and has notable anti-inflammatory and hydrating properties.

Research question: We hypothesized that inhaled HMW-HA will improve outcomes in AECOPD.

Methods: We conducted a single center, randomized, placebo-controlled, double-blind study to investigate the effect of inhaled HMW-HA in patients with severe AECOPD necessitating non-invasive positive-pressure ventilation (NIPPV). Primary endpoint was time until liberation from NIPPV.

Results: Out of 44 screened patients, 41 were included in the study (21 for placebo and 20 for HMW-HA). Patients treated with HMW-HA had significantly shorter duration of NIPPV. HMW-HA treated patients also had lower measured peak airway pressures on the ventilator and lower systemic inflammation markers after liberation from NIPPV. In vitro testing showed that HMW-HA significantly improved mucociliary transport in air-liquid interface cultures of primary bronchial cells from COPD patients and healthy primary cells exposed to cigarette smoke extract.

Interpretation: Inhaled HMW-HA shortens the duration of respiratory failure and need for non-invasive ventilation in patients with AECOPD. Beneficial effects of HMW-HA on mucociliary clearance and inflammation may account for some of the effects (NCT02674880, www.clinicaltrials.gov ).

Conflict of interest statement

The authors declare no conflict of interest for this article.

Figures

Fig. 1
Fig. 1
Study schema. Of 150 patients admitted with AECOPD during the study period, 51 were eligible to participate and 41 consented to be included in the study
Fig. 2
Fig. 2
HMW-HA treatment reduces duration of NIPPV in AECOPD. a Kaplan–Meier curve of cumulative hours on NIPPV in intention-to-treat analysis. HMW-HA treated patients have significantly shorter time to liberation from NIPPV N = 20 for HMW-HA patients, N = 21 for placebo patients, intention-to-treat analysis. Patients who suffered an adverse event and were withdrawn from the study (N = 1 from each group), or withdrew consent (N = 2 for placebo, N = 1 for HMW-HA), were censored as “not liberated from NIPPV” for this analysis. One patient in the placebo group failed NIPPV, was orotracheally intubated and was censored as “not liberated from NIPPV” at 125 h (point of intubation). b Duration of NIPPV measured in hospital days. HMW-HA treated patients were liberated from NIPPV on average 1 day earlier compared to placebo-treated patients. N = 18 for both groups (2 patients in placebo group and one in HMW-HA group withdrew consent, and one patient each suffered an adverse event and was withdrawn from the study by the study physician). c Total length of stay. HMW-HA treated patients were discharged from the hospital on average 2 days earlier. N = 18 for both groups (explanation as in b)
Fig. 3
Fig. 3
Improved lung function and serum markers of inflammation in HMW-HA treated patients. a HMW-HA-treated patients have lower peak pressures, as recorded by the NIV apparatus, throughout NIVVP. b paO2/FiO2 ratio improves significantly in HMW-HA patients. c paCO2 improves significantly in both groups. N = 17 per group. d Joint analysis of 4 serum inflammatory markers shows a significant improvement in HMW-HA treated patients, but not in placebo patients. e Among the 2 inflammatory markers (CRP and IL-6) that decreased with treatment in both groups in a, more robust improvement can be seen in HMW-HA patients compared to placebo-treated patients. N = 13 per group
Fig. 4
Fig. 4
Mucociliary transport is augmented by HMW-HA. a–h Terminally-differentiated primary HBE monolayers derived from patients with COPD were treated with HMW-HA (0.3%) or an equal volume of vehicle control, then assessed at baseline and after 24 h by µOCT. Representative cross-sectional µOCT images at 24 h after vehicle (a) or HA (c) treatment. EP = epithelial monolayer; ASL depth denoted with yellow bar; F = transwell filter; white scale bar = 20 µm. Streak diagram showing time-dependent reprocessing for vehicle (b) or HA (d) are also shown. The angle of the streaks, as denoted by the red arrow, correspond to MCT rates. Quantitation of airway surface liquid (ASL) depth (e), periciliary layer (PCL) depth (f), ciliary beat frequency (CBF, g), and mucociliary transport (MCT) rate (h). N = 8 monolayers/condition derived from 2 different donors. i MCT from similar study conducted from HBE cells derived from a lung-healthy donor treated with CSE (1%, apically) and vehicle control or HMW-HA (0.3% apically) for 24 h. N = 12 monolayers/condition derived from 3 different donors. ns not significant

References

    1. World Health Organization Website. Chronic Respiratory Diseases: Burden of COPD. Accessed 15 May 2020.
    1. . Health, United States, 2016: With Chartbook on Long-term Trends in Health. Hyattsville (MD); 2017.
    1. Centers for Disease Control and Prevention. COPD Costs. . Accessed 15 May 2020.
    1. Seemungal TA, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608–1613. doi: 10.1164/ajrccm.161.5.9908022.
    1. Lim S, Lam DC, Muttalif AR, et al. Impact of chronic obstructive pulmonary disease (COPD) in the Asia-Pacific region: the EPIC Asia population-based survey. Asia Pac Fam Med. 2015;14(1):4. doi: 10.1186/s12930-015-0020-9.
    1. Andersson F, Borg S, Jansson SA, et al. The costs of exacerbations in chronic obstructive pulmonary disease (COPD) Respir Med. 2002;96(9):700–708. doi: 10.1053/rmed.2002.1334.
    1. Hutchinson A, Brand C, Irving L, Roberts C, Thompson P, Campbell D. Acute care costs of patients admitted for management of chronic obstructive pulmonary disease exacerbations: contribution of disease severity, infection and chronic heart failure. Intern Med J. 2010;40(5):364–371. doi: 10.1111/j.1445-5994.2010.02195.x.
    1. Khakban A, Sin DD, FitzGerald JM, et al. Ten-Year Trends in Direct Costs of COPD: A Population-Based Study. Chest. 2015;148(3):640–646. doi: 10.1378/chest.15-0721.
    1. Mulpuru S, McKay J, Ronksley PE, Thavorn K, Kobewka DM, Forster AJ. Factors contributing to high-cost hospital care for patients with COPD. Int J Chronic Obstructive Pulmonary Dis. 2017;12:989–995. doi: 10.2147/COPD.S126607.
    1. Ogston AG, Stanier JE. The dimensions of the particle of hyaluronic acid complex in synovial fluid. Biochem J. 1951;49(5):585–590. doi: 10.1042/bj0490585.
    1. Pignataro L, Marchisio P, Ibba T, Torretta S. Topically administered hyaluronic acid in the upper airway: a narrative review. Int J ImmunopatholPharmacol. 2018;32:2058738418766739.
    1. Garantziotis S, Li Z, Potts EN, et al. Hyaluronan mediates ozone-induced airway hyperresponsiveness in mice. J Biol Chem. 2009;284(17):11309–11317. doi: 10.1074/jbc.M802400200.
    1. Lazrak A, Creighton J, Yu Z, et al. Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury. Am J Physiol. 2015;308(9):L891–903.
    1. Johnson CG, Stober VP, Cyphert-Daly JM, et al. High molecular weight hyaluronan ameliorates allergic inflammation and airway hyperresponsiveness in the mouse. Am J Physiol. 2018;315(5):L787–L798.
    1. Petrigni G, Allegra L. Aerosolised hyaluronic acid prevents exercise-induced bronchoconstriction, suggesting novel hypotheses on the correction of matrix defects in asthma. PulmPharmacolTher. 2006;19(3):166–171.
    1. Zhou T, Yu Z, Jian MY, et al. Instillation of hyaluronan reverses acid instillation injury to the mammalian blood gas barrier. Am J Physiol. 2018;314(5):L808–L821.
    1. Jiang D, Liang J, Fan J, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11(11):1173–1179. doi: 10.1038/nm1315.
    1. Liang J, Zhang Y, Xie T, et al. Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice. Nat Med. 2016;22(11):1285–1293. doi: 10.1038/nm.4192.
    1. Wedzicha JAC, Miravitlles M, Hurst JR, et al. Management of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. EurRespir J. 2017;49:3.
    1. Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662–671. doi: 10.1164/rccm.201104-0597OC.
    1. Wedzicha JA, Seemungal TA, MacCallum PK, et al. Acute exacerbations of chronic obstructive pulmonary disease are accompanied by elevations of plasma fibrinogen and serum IL-6 levels. ThrombHaemost. 2000;84(2):210–215.
    1. Sneh A, Pawan T, Randeep G, et al. Acute phase proteins as predictors of survival in patients with acute exacerbation of chronic obstructive pulmonary disease requiring mechanical ventilation. Copd. 2020;17(1):22–28. doi: 10.1080/15412555.2019.1698019.
    1. Gallego M, Pomares X, Capilla S, et al. C-reactive protein in outpatients with acute exacerbation of COPD: its relationship with microbial etiology and severity. Int J Chronic Obstructive Pulmonary Dis. 2016;11:2633–2640. doi: 10.2147/COPD.S117129.
    1. Jonsdottir B, Jaworowski A, San Miguel C, Melander O. IL-8 predicts early mortality in patients with acute hypercapnic respiratory failure treated with noninvasive positive pressure ventilation. BMC Pulmonary Med. 2017;17(1):35. doi: 10.1186/s12890-017-0377-7.
    1. Tao J KK, Gibbs P, SAS Institute Inc. SAS Paper 1919–2015. Advanced Techniques for Fitting Mixed Models Using SAS/STAT Software. 2020; . Accessed 11 April 2020.
    1. Osadnik CR, McDonald CF, Jones AP, Holland AE. Airway clearance techniques for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;3:CD008328.
    1. Karmouty-Quintana H, Weng T, Garcia-Morales LJ, et al. Adenosine A2B receptor and hyaluronan modulate pulmonary hypertension associated with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2013;49(6):1038–1047. doi: 10.1165/rcmb.2013-0089OC.
    1. You Y, Richer EJ, Huang T, Brody SL. Growth and differentiation of mouse tracheal epithelial cells: selection of a proliferative population. Am J Physiol. 2002;283(6):L1315–1321.
    1. Lin VY, Kaza N, Birket SE, et al. Excess mucus viscosity and airway dehydration impact COPD airway clearance. EurRespir J. 2020;55:1.
    1. Raju SV, Lin VY, Liu L, et al. The cystic fibrosis transmembrane conductance regulator potentiator ivacaftor augments mucociliary clearance abrogating cystic fibrosis transmembrane conductance regulator inhibition by cigarette smoke. Am J Respir Cell Mol Biol. 2017;56(1):99–108. doi: 10.1165/rcmb.2016-0226OC.
    1. Birket SE, Chu KK, Liu L, et al. A functional anatomic defect of the cystic fibrosis airway. Am J Respir Crit Care Med. 2014;190(4):421–432. doi: 10.1164/rccm.201404-0670OC.
    1. Birket SE, Chu KK, Houser GH, et al. Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy. Lung Cell Mol Physiol. 2016;310(10):L928–L939. doi: 10.1152/ajplung.00395.2015.
    1. Liu L, Chu KK, Houser GH, et al. Method for quantitative study of airway functional microanatomy using micro-optical coherence tomography. PLoS ONE. 2013;8(1):e54473. doi: 10.1371/journal.pone.0054473.
    1. Pedone C, Chiurco D, Scarlata S, Incalzi RA. Efficacy of multiparametrictelemonitoring on respiratory outcomes in elderly people with COPD: a randomized controlled trial. BMC Health Serv Res. 2013;13:82. doi: 10.1186/1472-6963-13-82.
    1. Brown H, Dodic S, Goh SS, et al. Factors associated with hospital mortality in critically ill patients with exacerbation of COPD. Int J Chronic Obstructive Pulmonary Dis. 2018;13:2361–2366. doi: 10.2147/COPD.S168983.
    1. Dalal AA, Christensen L, Liu F, Riedel AA. Direct costs of chronic obstructive pulmonary disease among managed care patients. Int J Chronic Obstructive Pulmonary Dis. 2010;5:341–349. doi: 10.2147/COPD.S13771.
    1. Jiang D, Liang J, Noble PW. Hyaluronan in tissue injury and repair. Annu Rev Cell Dev Biol. 2007;23:435–461. doi: 10.1146/annurev.cellbio.23.090506.123337.
    1. Forteza R, Lieb T, Aoki T, Savani RC, Conner GE, Salathe M. Hyaluronan serves a novel role in airway mucosal host defense. FASEB J. 2001;15(12):2179–2186. doi: 10.1096/fj.01-0036com.
    1. Garantziotis S, Li Z, Potts EN, et al. TLR4 is necessary for hyaluronan-mediated airway hyperresponsiveness after ozone inhalation. Am J Respir Crit Care Med. 2010;181(7):666–675. doi: 10.1164/rccm.200903-0381OC.
    1. Liang J, Jiang D, Jung Y, et al. Role of hyaluronan and hyaluronan-binding proteins in human asthma. J Allergy ClinImmunol. 2011;128(2):403–411. doi: 10.1016/j.jaci.2011.04.006.
    1. Garantziotis S, Brezina M, Castelnuovo P, Drago L. The role of hyaluronan in the pathobiology and treatment of respiratory disease. Am J Physiol. 2016;310(9):L785–L795.
    1. Lauer ME, Dweik RA, Garantziotis S, Aronica MA. The Rise and Fall of Hyaluronan in Respiratory Diseases. Int J Cell Biol. 2015;2015:712507. doi: 10.1155/2015/712507.
    1. Papakonstantinou E, Roth M, Klagas I, Karakiulakis G, Tamm M, Stolz D. COPD exacerbations are associated with pro-inflammatory degradation of hyaluronic acid. Chest. 2015;8:9.
    1. Cantor J, Armand G, Turino G. Lung hyaluronan levels are decreased in alpha-1 antiprotease deficiency COPD. Respir Med. 2015;109(5):656–659. doi: 10.1016/j.rmed.2015.03.006.
    1. Dentener MA, Vernooy JH, Hendriks S, Wouters EF. Enhanced levels of hyaluronan in lungs of patients with COPD: relationship with lung function and local inflammation. Thorax. 2005;60(2):114–119. doi: 10.1136/thx.2003.020842.
    1. Papakonstantinou E, Bonovolias I, Roth M, et al. Serum levels of hyaluronic acid are associated with COPD severity and predict survival. EurRespir J. 2019;53:3.
    1. Matuska B, Comhair S, Farver C, et al. Pathological Hyaluronan Matrices in Cystic Fibrosis Airways and Secretions. Am J Respir Cell Mol Biol. 2016;55(4):576–585. doi: 10.1165/rcmb.2015-0358OC.
    1. Turino GM, Ma S, Lin YY, Cantor JO. The Therapeutic Potential of Hyaluronan in COPD. Chest. 2018;153(4):792–798. doi: 10.1016/j.chest.2017.12.016.
    1. Cantor JO, Cerreta JM, Armand G, Turino GM. Aerosolized hyaluronic acid decreases alveolar injury induced by human neutrophil elastase. ProcSocExp Biol Med. 1998;217(4):471–475. doi: 10.3181/00379727-217-44260.
    1. Cantor JO, Cerreta JM, Ochoa M, Ma S, Liu M, Turino GM. Therapeutic effects of hyaluronan on smoke-induced elastic fiber injury: does delayed treatment affect efficacy? Lung. 2011;189(1):51–56. doi: 10.1007/s00408-010-9271-2.
    1. Furnari ML, Termini L, Traverso G, et al. Nebulized hypertonic saline containing hyaluronic acid improves tolerability in patients with cystic fibrosis and lung disease compared with nebulized hypertonic saline alone: a prospective, randomized, double-blind, controlled study. TherAdvRespir Dis. 2012;8:987.
    1. Ros M, Casciaro R, Lucca F, et al. Hyaluronic acid improves the tolerability of hypertonic saline in the chronic treatment of cystic fibrosis patients: a multicenter, randomized, controlled clinical trial. J Aerosol Med Pulmonary Drug Delivery. 2014;27(2):133–137. doi: 10.1089/jamp.2012.1034.
    1. Hansen IM, Ebbesen MF, Kaspersen L, et al. Hyaluronic acid molecular weight-dependent modulation of mucin nanostructure for potential mucosal therapeutic applications. Mol Pharm. 2017;14(7):2359–2367. doi: 10.1021/acs.molpharmaceut.7b00236.
    1. Fernandez-Petty CM, Hughes GW, Bowers HL, et al. A glycopolymer improves vascoelasticity and mucociliary transport of abnormal cystic fibrosis mucus. JCI Insight. 2019;4:8. doi: 10.1172/jci.insight.125954.
    1. Muto J, Yamasaki K, Taylor KR, Gallo RL. Engagement of CD44 by hyaluronan suppresses TLR4signaling and the septic response to LPS. MolImmunol. 2009;47(2–3):449–456.
    1. Gebe JA, Yadava K, Ruppert SM, et al. Modified High Molecular Weight Hyaluronan Promotes Allergen-Specific Immune Tolerance. Am J Respir Cell Mol Biol. 2016;23:78.
    1. Dentener MA, Louis R, Cloots RH, Henket M, Wouters EF. Differences in local versus systemic TNFalpha production in COPD: inhibitory effect of hyaluronan on LPS induced blood cell TNFalpha release. Thorax. 2006;61(6):478–484. doi: 10.1136/thx.2005.053330.
    1. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist. 1969;9(3):179–186. doi: 10.1093/geront/9.3_Part_1.179.
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med. 1985;13(10):818–829. doi: 10.1097/00003246-198510000-00009.

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