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Keratinocyte growth factor in acute respiratory distress syndrome
Comment
Acute respiratory distress syndrome (ARDS) was first described fifty years ago.1 Despite intense basic and clinical research, no pharmacological therapy exists yet against this devastating syndrome and thus mortality remains unacceptably high.2 In The Lancet Respiratory Medicine, Daniel F McAuley and colleagues3 report on the effects of intravenously-administered palifermin, a truncated human recombinant variant of keratinocyte growth factor (KGF) in patients with ARDS.3 In the prospective, randomised, double-blind, allocation concealed, placebo-controlled phase 2 KARE trial, which recruited 60 patients with ARDS at two intensive care units, oxygenation index at day 7 was assessed as the primary outcome. The study established that KGF did not improve any of the physiological or clinical outcomes assessed.3 Although the trial was not powered to assess duration of ventilation, length of intensivecare unit stay, or mortality, the data suggest that these secondary outcomes could have been worsened by administration of KGF. Thus, the authors conclude that KGF cannot be recommended for the treatment of patients with ARDS. Despite these results, KGF had appeared to be a logical candidate in the treatment of ARDS for several reasons. Various rodent studies have established a key role for the growth factor in repair mechanisms on experimental acute lung injury secondary to—for example—hyperoxia, bleomycin or radiation exposure, acid instillation, or Pseudomonas aeruginosa pneumonia;4 and of note, expression of KGF might be suppressed in early ARDS.5 Furthermore, it has been reported that KGF upregulates alveolar epithelial sodium ion (Na+) transport processes and thus alveolar oedema clearance, which is of relevance, as effective removal of pulmonary oedema is necessary for survival of patients with ARDS.6 Moreover, in a recent randomised, double-blind, placebocontrolled, allocation-concealed clinical trial enrolling 36 healthy volunteers who received intravenous palifermin (60 μg/kg per day), a similar regimen to the trial by McAuley and colleagues, or placebo for 3 days before inhalation of lipopolysaccharide (LPS) to model acute lung injury, pre-treatment with KGF increased concentrations of anti-inflammatory cytokines and
markers of alveolar epithelial type II cell proliferation in bronchoalveolar lavage fluid samples that were collected 6 h after LPS inhalation.7 These data suggest that although applied systemically, palifermin might affect the alveolar epithelium with no severe adverse effects. Finally, palifermin is already routinely used at the concentration, frequency, and duration applied in the trial by McAuley and colleagues in patients with haematological malignancies and oral mucositis secondary to intensive chemotherapy and radiotherapy, for which administration of KGF reduces the duration and severity of oral mucosal injury.8 The authors elected to use oxygenation index as a primary outcome, which assesses both gas exchange and respiratory mechanics and has been previously shown to be a reliable predictor of therapy success in ARDS,9 and the authors report no benefit (or harm) on KGF therapy (mean 62·3 [SD 57·8] in the KGF group, 43·1 [33·5] in the placebo group; mean difference 19·2, 95% CI –5·6 to 44·0, p=0·13), whereas mortality, duration of ventilation, and length of stay were higher in patients treated with KGF than in the placebo group. However, drawing conclusions about the deleterious effects of KGF on the clinical outcomes is difficult since, as mentioned above, the trial was not powered to assess these readouts and because the mortality in the placebo group was certainly lower than expected for this patient cohort. Thus, although it is uncertain whether KGF caused harm in this trial, it is important that we ask ourselves why it failed to improve ARDS. There are several potential explanations for why KGF did not improve clinical outcomes in patients with ARDS in this trial. It remains unclear whether the dose and route of KGF administration used in the trial affected the injured alveolar epithelium. Although in the above-mentioned human LPS inhalation study KGF pre-treatment showed several potentially beneficial effects on alveolar epithelial cells, in that trial, the alveolar epithelium was intact at the time of drug administration.7 Indeed, it is to be expected that the under-ventilated and non-ventilated areas, which require repair, will be perfused at substantially lower levels than the regions that are less injured or uninjured;
www.thelancet.com/respiratory Published online May 16, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30172-8
Photostock-Israel/SPL
Keratinocyte growth factor in acute respiratory distress syndrome
Lancet Respir Med 2017 Published Online May 16, 2017 http://dx.doi.org/10.1016/ S2213-2600(17)30172-8 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(17)30171-6
1
Comment
therefore, it might be that local concentrations of KGF at the site of injury were too low, whereas systemic concentrations were high in comparison, which explains some of the adverse effects observed during the trial by McAuley and colleagues. In most pre-clinical studies assessing the properties of KGF in acute lung injury, the growth factor was applied directly to the lungs by inhalation or instillation. Although an inhalational drug therapy for patients with ARDS might be useful when targeting macrophages, it is uncertain whether non-ventilated areas can be effectively reached, though recruitment manoeuvres before inhalation might enhance drug distribution.10 Thus, targeting the atelectatic areas of the damaged lung is a difficult task and is perhaps one of the reasons why various promising pharmacological treatments administered in clinical studies have not improved outcomes in ARDS. Perhaps cell-based therapies using human mesenchymal stem cells will overcome this challenge,11 and it is possible that the positive effects will be further enhanced when intratracheally-applied stem cells are used as delivery vehicles for KGF or other drug-loaded nanoparticles. Taken together, systemic administration of KGF cannot be recommended to treat ARDS. Further studies are required to assess whether KGF has potential as an effective therapy with better distribution of the drug at the site of injury.
2
István Vadász Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen 35392, Germany [email protected] I declare no competing interests. 1
Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2: 319–23. 2 Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016; 315: 788–800. 3 McAuley DF, Cross LJ, Hamid U, et al. Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir Med 2017; published online May 16. http://dx.doi. org/10.1016/S2213-2600(17)30171-6. 4 Ware LB, Matthay MA. Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol 2002; 282: L924–40. 5 Chandel NS, Budinger GR, Mutlu GM, et al. Keratinocyte growth factor expression is suppressed in early acute lung injury/acute respiratory distress syndrome by smad and c-Abl pathways. Crit Care Med 2009; 37: 1678–84. 6 Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012; 122: 2731–40. 7 Shyamsundar M, McAuley DF, Ingram RJ, et al. Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury. Am J Respir Crit Care Med 2014; 189: 1520–29. 8 Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004; 351: 2590–98. 9 Go L, Budinger GR, Kwasny MJ, et al. Failure to improve the oxygenation index is a useful predictor of therapy failure in acute respiratory distress syndrome clinical trials. Crit Care Med 2016; 44: e40–44. 10 Herold S, Hoegner K, Vadasz I, et al. Inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome. Am J Respir Crit Care Med 2014; 189: 609–11. 11 Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med 2015; 3: 24–32.
www.thelancet.com/respiratory Published online May 16, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30172-8
Acute respiratory distress syndrome (ARDS) was first described fifty years ago.1 Despite intense basic and clinical research, no pharmacological therapy exists yet against this devastating syndrome and thus mortality remains unacceptably high.2 In The Lancet Respiratory Medicine, Daniel F McAuley and colleagues3 report on the effects of intravenously-administered palifermin, a truncated human recombinant variant of keratinocyte growth factor (KGF) in patients with ARDS.3 In the prospective, randomised, double-blind, allocation concealed, placebo-controlled phase 2 KARE trial, which recruited 60 patients with ARDS at two intensive care units, oxygenation index at day 7 was assessed as the primary outcome. The study established that KGF did not improve any of the physiological or clinical outcomes assessed.3 Although the trial was not powered to assess duration of ventilation, length of intensivecare unit stay, or mortality, the data suggest that these secondary outcomes could have been worsened by administration of KGF. Thus, the authors conclude that KGF cannot be recommended for the treatment of patients with ARDS. Despite these results, KGF had appeared to be a logical candidate in the treatment of ARDS for several reasons. Various rodent studies have established a key role for the growth factor in repair mechanisms on experimental acute lung injury secondary to—for example—hyperoxia, bleomycin or radiation exposure, acid instillation, or Pseudomonas aeruginosa pneumonia;4 and of note, expression of KGF might be suppressed in early ARDS.5 Furthermore, it has been reported that KGF upregulates alveolar epithelial sodium ion (Na+) transport processes and thus alveolar oedema clearance, which is of relevance, as effective removal of pulmonary oedema is necessary for survival of patients with ARDS.6 Moreover, in a recent randomised, double-blind, placebocontrolled, allocation-concealed clinical trial enrolling 36 healthy volunteers who received intravenous palifermin (60 μg/kg per day), a similar regimen to the trial by McAuley and colleagues, or placebo for 3 days before inhalation of lipopolysaccharide (LPS) to model acute lung injury, pre-treatment with KGF increased concentrations of anti-inflammatory cytokines and
markers of alveolar epithelial type II cell proliferation in bronchoalveolar lavage fluid samples that were collected 6 h after LPS inhalation.7 These data suggest that although applied systemically, palifermin might affect the alveolar epithelium with no severe adverse effects. Finally, palifermin is already routinely used at the concentration, frequency, and duration applied in the trial by McAuley and colleagues in patients with haematological malignancies and oral mucositis secondary to intensive chemotherapy and radiotherapy, for which administration of KGF reduces the duration and severity of oral mucosal injury.8 The authors elected to use oxygenation index as a primary outcome, which assesses both gas exchange and respiratory mechanics and has been previously shown to be a reliable predictor of therapy success in ARDS,9 and the authors report no benefit (or harm) on KGF therapy (mean 62·3 [SD 57·8] in the KGF group, 43·1 [33·5] in the placebo group; mean difference 19·2, 95% CI –5·6 to 44·0, p=0·13), whereas mortality, duration of ventilation, and length of stay were higher in patients treated with KGF than in the placebo group. However, drawing conclusions about the deleterious effects of KGF on the clinical outcomes is difficult since, as mentioned above, the trial was not powered to assess these readouts and because the mortality in the placebo group was certainly lower than expected for this patient cohort. Thus, although it is uncertain whether KGF caused harm in this trial, it is important that we ask ourselves why it failed to improve ARDS. There are several potential explanations for why KGF did not improve clinical outcomes in patients with ARDS in this trial. It remains unclear whether the dose and route of KGF administration used in the trial affected the injured alveolar epithelium. Although in the above-mentioned human LPS inhalation study KGF pre-treatment showed several potentially beneficial effects on alveolar epithelial cells, in that trial, the alveolar epithelium was intact at the time of drug administration.7 Indeed, it is to be expected that the under-ventilated and non-ventilated areas, which require repair, will be perfused at substantially lower levels than the regions that are less injured or uninjured;
www.thelancet.com/respiratory Published online May 16, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30172-8
Photostock-Israel/SPL
Keratinocyte growth factor in acute respiratory distress syndrome
Lancet Respir Med 2017 Published Online May 16, 2017 http://dx.doi.org/10.1016/ S2213-2600(17)30172-8 See Online/Articles http://dx.doi.org/10.1016/ S2213-2600(17)30171-6
1
Comment
therefore, it might be that local concentrations of KGF at the site of injury were too low, whereas systemic concentrations were high in comparison, which explains some of the adverse effects observed during the trial by McAuley and colleagues. In most pre-clinical studies assessing the properties of KGF in acute lung injury, the growth factor was applied directly to the lungs by inhalation or instillation. Although an inhalational drug therapy for patients with ARDS might be useful when targeting macrophages, it is uncertain whether non-ventilated areas can be effectively reached, though recruitment manoeuvres before inhalation might enhance drug distribution.10 Thus, targeting the atelectatic areas of the damaged lung is a difficult task and is perhaps one of the reasons why various promising pharmacological treatments administered in clinical studies have not improved outcomes in ARDS. Perhaps cell-based therapies using human mesenchymal stem cells will overcome this challenge,11 and it is possible that the positive effects will be further enhanced when intratracheally-applied stem cells are used as delivery vehicles for KGF or other drug-loaded nanoparticles. Taken together, systemic administration of KGF cannot be recommended to treat ARDS. Further studies are required to assess whether KGF has potential as an effective therapy with better distribution of the drug at the site of injury.
2
István Vadász Department of Internal Medicine, Justus Liebig University, Universities of Giessen and Marburg Lung Center, Member of the German Center for Lung Research, Giessen 35392, Germany [email protected] I declare no competing interests. 1
Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet 1967; 2: 319–23. 2 Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016; 315: 788–800. 3 McAuley DF, Cross LJ, Hamid U, et al. Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir Med 2017; published online May 16. http://dx.doi. org/10.1016/S2213-2600(17)30171-6. 4 Ware LB, Matthay MA. Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair. Am J Physiol Lung Cell Mol Physiol 2002; 282: L924–40. 5 Chandel NS, Budinger GR, Mutlu GM, et al. Keratinocyte growth factor expression is suppressed in early acute lung injury/acute respiratory distress syndrome by smad and c-Abl pathways. Crit Care Med 2009; 37: 1678–84. 6 Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012; 122: 2731–40. 7 Shyamsundar M, McAuley DF, Ingram RJ, et al. Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury. Am J Respir Crit Care Med 2014; 189: 1520–29. 8 Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 2004; 351: 2590–98. 9 Go L, Budinger GR, Kwasny MJ, et al. Failure to improve the oxygenation index is a useful predictor of therapy failure in acute respiratory distress syndrome clinical trials. Crit Care Med 2016; 44: e40–44. 10 Herold S, Hoegner K, Vadasz I, et al. Inhaled granulocyte/macrophage colony-stimulating factor as treatment of pneumonia-associated acute respiratory distress syndrome. Am J Respir Crit Care Med 2014; 189: 609–11. 11 Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med 2015; 3: 24–32.
www.thelancet.com/respiratory Published online May 16, 2017 http://dx.doi.org/10.1016/S2213-2600(17)30172-8