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Many people are suggesting...

..."novel" therapies for COVID-19 ARDS.
What has been tried in the past and how did it go?


This piece is Part II of a series, courtesy of Dr. Dan Okin.

Part I may be found here.
The FLARE Four:
 
  1. The therapy for ARDS, including ARDS associated with COVID-19, is centered on lung-protective ventilation, conservative fluid management and treatment of the underlying process.
  2. ARDS is thought to result from a complex interaction between the inciting insult and the host response.
  3. Numerous studies are currently evaluating novel therapies targeting the pathologic cascade of ARDS and the host response to SARS-CoV-2.
  4. It is important to consider future studies in the historical context of failed investigational therapies for ARDS.
In tonight's FLARE, continuing from yesterday’s, we will review the literature on investigational therapies for ARDS prior to COVID-19.
Briefly, from Part I: the biologic underpinnings of ARDS
The pathogenesis of ARDS is complex and involves a poorly understood set of interactions between insult, host immune response, clotting cascades, and pulmonary mechanics. We will not give an in-depth review of each phase of pathophysiology here, but rather will briefly discuss the pathophysiology relevant to the four major categories of previously investigated therapies in ARDS: (1) immune effector functions, (2) reactive oxygen species generation, (3) alterations in the coagulation cascade, and (4) alterations in at the level of the alveolus. A common theme that runs through the ARDS literature is the uncertainty surrounding which biological processes are adaptive and which are pathologic. The observation that essentially all targeted therapies in ARDS have failed indicates that our knowledge of the underlying pathophysiology is incomplete and necessitates further research.
Therapies targeting immune effector function
What’s the scientific rationale? 
Critical illness is associated with a robust inflammatory response. This response may be adaptive - acting to eliminate a pathogen (Kotas and Medzhitov, 2015) - or maladaptive, negatively impacting the affected organ. The significant elevation of inflammatory markers (Calfee et al., 2018) often seen in ARDS has led to the hypothesis that, at least in some cases, maladaptive responses predominate and might therefore be therapeutically targeted. Strategies to do so have included inhibiting neutrophil elastase, attempted modulation of inflammatory response with statins (Greenwood et al., 2006), immune stimulation and frank immunosuppression with steroids or more targeted therapies.
Neutrophil elastase
Recruitment of neutrophils results in elevated production and secretion of the proteolytic enzyme ”neutrophil elastase” (NE), leading to direct tissue damage and amplification of the local inflammatory response. To test the hypothesis that excessive secretion of NE is maladaptive in ARDS, the STRIVE trial evaluated the efficacy of the NE inhibitor sivelestat (Zeiher et al., 2004). STRIVE enrolled 429 patients but was stopped due to a trend towards increased mortality in the experimental arm. While the mechanistic basis for this effect remains unclear, it suggests that inhibition of NE may result in impairment of adaptive immunity and impaired resolution of lung injury (Wynn et al., 2013).
Statins
HMG-CoA reductase inhibitors, potent negative regulators of cholesterol synthesis, have immunomodulatory effects independent of their effect on circulating LDL. Statins reduce intracellular cholesterol and trigger the reorganization of the plasma membrane, altering numerous intracellular signaling cascades (Hancock, 2003). Among these is prenylation, a post-translational modification that directs proteins to intracellular membranes. Important prenylated proteins include about 100 small GTPases which function to regulate organization of the cytoskeleton, intracellular membrane trafficking, cell proliferation, and gene expression. On this basis, statins are thought to regulate multiple important functions of the immune system: leukocyte motility, diapedesis, leukocyte activation and proliferation, antigen uptake and presentation, and phagocytosis (Greenwood et al., 2006).

Prior FLARE pieces (March 22, March 24) have reviewed the clinical data regarding statin treatment in ARDS. As discussed previously, HARP-2, a randomized trial of simvastatin 80 mg for treatment of unselected ARDS patients, showed no benefit to therapy. A latent class analysis of the HARP-2 trial suggested improved outcomes in association with simvastatin use in the hyperinflammatory subtype of ARDS, defined by elevated biomarkers such as IL-6. Another randomized trial of statins in ARDS (SAILS) evaluated the effect of rosuvastatin in sepsis-associated ARDS (National Heart, Lung, and Blood Institute ARDS Clinical Trials Network et al., 2014). The study was stopped due to futility. Subsequent latent class analysis failed to identify a benefit in the hyperinflammatory subtype (Sinha et al., 2018).
Steroids and immunomodulators
Multiple trials have evaluated the efficacy of steroids in treatment of ARDS. Please see the FLARE from March 24 where we discuss this in greater detail.

In addition to the therapies discussed above, multiple trials have investigated immunomodulatory strategies in related critical illnesses such as septic shock. These have included IL-1 receptor antagonists (no benefit (Fisher et al., 1994)), inhibitors of inducible nitric oxide synthase (increased mortality (López et al., 2004)), interferon gamma and GM-CSF (no benefit (Vincent et al., 2002)) and anti-TNFalpha (no benefit (Abraham et al., 1995)).
Therapies targeting alveolar fluid clearance and surfactant replacement
What is the scientific rationale?
Activation of the previously discussed molecular pathways culminate in alveolar instability and in derangements of pulmonary mechanics. Characteristic changes include microthrombi, surfactant dysfunction, reduced alveolar fluid clearance and decreased lung compliance. 
Alveolar fluid clearance
An imbalance between edema formation and reabsorption leads to accumulation of extravascular lung water. Resorption is an active process that relies upon ATP-mediated electrolyte transport. Studies of explanted human lungs demonstrated that the ß-agonist terbutaline was capable of increasing alveolar fluid clearance 2-3 fold over baseline (Sakuma et al., 1994, 1996), forming the basis for the BALTI trial evaluating intravenous salbutamol in patients with ARDS (Perkins et al., 2006). The trial found that salbutamol improved plateau pressures but not mortality. A follow up trial, BALTI-2, was stopped early as patients receiving IV salbutamol had increased mortality, predominantly due to side effects related to excess adrenergic tone (Gao Smith et al., 2012).
Surfactant replacement
Dysfunction of pulmonary surfactant is a major driver of the reduced compliance seen in ARDS. Surfactant replacement is a highly effective therapy for neonatal respiratory distress syndrome (RDS).
Eight RCTs have examined replacement of surfactant in ARDS with varying types of surfactant preparations. While most demonstrated an improvement in oxygenation there were no changes in mortality (Dushianthan et al., 2012). This is in stark contrast to the dramatic decrease in RDS mortality with surfactant therapy. The explanation for these divergent results is likely complex. One possibility is that the ongoing disruption of surfactant function in ARDS is less amenable to surfactant replacement than is RDS, due to ongoing inflammation and surfactant inactivation. Another possibility may simply be inefficient delivery of the replacement surfactant to the affected regions of the adult lung. An intriguing report from 2015 suggests some of the failure to replicate promising early results in subsequent large trials may stem from the complex physics of surfactant migration from the site of installation in the trachea to the site of action in the alveoli (Filoche et al., 2015).
To sum it all up
Clinical trials have historically enrolled broad populations of ARDS patients. Thus, past trials are likely to contain patients who have a variety of responses to any given treatment. This is due both to heterogeneity inherent to the biology of an individual patient's response to illness and due to the related variation in disease severity (Iwashyna et al., 2015). The data summarized above do not imply that none of these therapies can benefit an individual patient, or a subset of patients, but, rather, that signals for benefit may be diluted or unrecognizable in a clinical trial. Older trials may also be confounded by failure to adhere to lung protective ventilation and other mainstays of modern critical care.

It is by no means assured that the problem of heterogeneity does not apply to COVID-19 merely because the disease is caused by a single pathogen. There will still be variations in disease severity and in patient immune response. In particular, we still have no reliable way of determining, in an individual patient, which features of the immune response are an appropriate response to ongoing viral activity, and which are maladaptive. We anticipate progress in research that classifies patients on the basis of molecular, biologic, and clinical phenotypes (Prescott et al., 2016). In the meantime, given the decades of experience in ARDS trials, we strongly encourage caution in the adoption of any unproven therapy in broad populations of ARDS patients.
FLARE is a collaborative effort within the Pulmonary and Critical Care Division and the Department of Medicine at Massachusetts General Hospital. Its mission is to appraise the rapidly evolving literature on SARS-CoV-2 with a focus on critical care issues.

Prior FLAREs can be found here, under "Fast Literature Updates".
Thank you for everything you are doing!
 - MGH FLARE
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References:
  • Abraham, E., Wunderink, R., Silverman, H., Perl, T.M., Nasraway, S., Levy, H., Bone, R., Wenzel, R.P., Balk, R., Allred, R., et al. (1995). Efficacy and Safety of Monoclonal Antibody to Human Tumor Necrosis Factor α in Patients With Sepsis Syndrome: A Randomized, Controlled, Double-blind, Multicenter Clinical Trial. JAMA 273, 934–941.
  • Calfee, C.S., Delucchi, K.L., Sinha, P., Matthay, M.A., Hackett, J., Shankar-Hari, M., McDowell, C., Laffey, J.G., O’Kane, C.M., McAuley, D.F., et al. (2018). Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med 6, 691–698.
  • Dushianthan, A., Cusack, R., Goss, V., Postle, A.D., and Grocott, M.P.W. (2012). Clinical review: Exogenous surfactant therapy for acute lung injury/acute respiratory distress syndrome--where do we go from here? Crit. Care 16, 238.
  • Filoche, M., Tai, C.-F., and Grotberg, J.B. (2015). Three-dimensional model of surfactant replacement therapy. Proc. Natl. Acad. Sci. U. S. A. 112, 9287–9292.
  • Fisher, C.J., Jr., Dhainaut, J.F., Opal, S.M., Pribble, J.P., Balk, R.A., Slotman, G.J., Iberti, T.J., Rackow, E.C., Shapiro, M.J., Greenman, R.L., et al. (1994). Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 271, 1836–1843.
  • Gao Smith, F., Perkins, G.D., Gates, S., Young, D., McAuley, D.F., Tunnicliffe, W., Khan, Z., Lamb, S.E., and BALTI-2 study investigators (2012). Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet 379, 229–235.
  • Greenwood, J., Steinman, L., and Zamvil, S.S. (2006). Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat. Rev. Immunol. 6, 358–370.
  • Hancock, J.F. (2003). Ras proteins: different signals from different locations. Nat. Rev. Mol. Cell Biol. 4, 373–384.
  • Iwashyna, T.J., Burke, J.F., Sussman, J.B., Prescott, H.C., Hayward, R.A., and Angus, D.C. (2015). Implications of Heterogeneity of Treatment Effect for Reporting and Analysis of Randomized Trials in Critical Care. Am. J. Respir. Crit. Care Med. 192, 1045–1051.
  • Kotas, M.E., and Medzhitov, R. (2015). Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827.
  • López, A., Lorente, J.A., Steingrub, J., Bakker, J., McLuckie, A., Willatts, S., Brockway, M., Anzueto, A., Holzapfel, L., Breen, D., et al. (2004). Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock*. Read Online: Critical Care Medicine | Society of Critical Care Medicine 32, 21.
  • National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, Truwit, J.D., Bernard, G.R., Steingrub, J., Matthay, M.A., Liu, K.D., Albertson, T.E., Brower, R.G., Shanholtz, C., Rock, P., et al. (2014). Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N. Engl. J. Med. 370, 2191–2200.
  • Perkins, G.D., McAuley, D.F., Thickett, D.R., and Gao, F. (2006). The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am. J. Respir. Crit. Care Med. 173, 281–287.
  • Prescott, H.C., Calfee, C.S., Thompson, B.T., Angus, D.C., and Liu, V.X. (2016). Toward Smarter Lumping and Smarter Splitting: Rethinking Strategies for Sepsis and Acute Respiratory Distress Syndrome Clinical Trial Design. Am. J. Respir. Crit. Care Med. 194, 147–155.
  • Reilly, J.P., Calfee, C.S., and Christie, J.D. (2019). Acute Respiratory Distress Syndrome Phenotypes. Semin. Respir. Crit. Care Med. 40, 19–30.
  • Sakuma, T., Okaniwa, G., Nakada, T., Nishimura, T., Fujimura, S., and Matthay, M.A. (1994). Alveolar fluid clearance in the resected human lung. Am. J. Respir. Crit. Care Med. 150, 305–310.
  • Sakuma, T., Suzuki, S., Usuda, K., Handa, M., Okaniwa, G., Nakada, T., Fujimura, S., and Matthay, M.A. (1996). Preservation of alveolar epithelial fluid transport mechanisms in rewarmed human lung after severe hypothermia. J. Appl. Physiol. 80, 1681–1686.
  • Sinha, P., Delucchi, K.L., Thompson, B.T., McAuley, D.F., Matthay, M.A., Calfee, C.S., and NHLBI ARDS Network (2018). Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study. Intensive Care Med. 44, 1859–1869.
  • Vincent, J.-L., Sun, Q., and Dubois, M.-J. (2002). Clinical trials of immunomodulatory therapies in severe sepsis and septic shock. Clin. Infect. Dis. 34, 1084–1093.
  • Wynn, T.A., Chawla, A., and Pollard, J.W. (2013). Macrophage biology in development, homeostasis and disease. Nature 496, 445–455.
  • Zeiher, B.G., Artigas, A., Vincent, J.-L., Dmitrienko, A., Jackson, K., Thompson, B.T., Bernard, G., and STRIVE Study Group (2004). Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study. Crit. Care Med. 32, 1695–1702.






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