Recent Advances in Patient Treatment and Care (Track)



Developing a new paradigm in respiratory hygiene to control transmission of infectious respiratory diseases and to optimize respiratory secretions management

Jose Gustavo Zayas
Mucophysiology Laboratory 173 Heritage medical Research Centre University of Alberta Edmonton, Alberta Canada T6G 2S2

Abstract:

The emergence of epidemic-prone infectious respiratory diseases (IRD) such as Influenza A H1N1 virus, the re-emergence of dangerous IRD, i.e. Tuberculosis, and the possible deliberate release of biological materials are issues of great concern worldwide. When the layer of mucus lining the airways interacts with the high-speed airflow of coughing, droplets of different sizes are formed and expelled into the environment as aerosol. As a result, infectious respiratory pathogens are transmitted via direct, indirect, and/or airborne routes, to non-infected subjects whenever an infected patient coughs.

CHALLENGE: to develop new approaches and design novel methods and technologies to control the transmission of IRD, and optimize respiratory secretions management.

APPROACH: Selectively increase elasticity relative to viscosity of the mucus macromolecule of the airways to modulate its physical and biochemical characteristics to achieve a dual goal: reduce cough aerosol formation while optimizing mucus management (Mucomodulation). We found in our literature review no reports in regards to this truly innovative, non-intuitive approach, which will reduce the number and/or increase the size of infectious droplets contained in the cough aerosol.

The concept of mucomodulation, first conceived and patented by King and Zayas at the University of Alberta, Canada is as follows: an intervention that modulates the physical characteristics of airway fluids viscoelasticity, cohesivity and surface tension by increasing crosslinking binding sites in the mucin glycoprotein gel network to reduce the aerosolizability of respiratory secretions (surrogate of transmissibility), while enhancing mucus clearance function.

The mucomodulation approach introduces a reversal in current thinking about respiratory disease management, and has the potential to break the chain of transmission of an influenza or Tuberculosis infection since more cohesive mucus will be more resistant to break-up during high-speed airflow interaction; hence fewer particles will be released as aerosol.

King and Zayas found that increasing cross linking and cohesiveness in mucus simulant (MS) appears to predict reduced fine aerosol formation, but enhanced bulk mucus flow. Mathematical models studying mucus instabilities and droplet formations during cough related perturbations, found that the modulus of elasticity needs to be adjusted in different ways depending on whether we intend to suppress droplet formation or to increase the size of the droplet without compromising airway mucus clearance. They have also acquired pre-clinical evidence of acceptable mucociliary clearance in an exvivo epithelial model (frog palate), and enhanced tracheal mucus clearability in an in-vivo mammalian model (dogs).

Furthermore, they have developed the basis of a human cough aerosol model. This model demonstrates great potential in becoming a fundamental tool for assessing droplet-spread IRD such as the Influenza A H1N1 virus and Tuberculosis, as well as in assessing the effectiveness of preventative and protective procedures against those diseases. For example, assessed N95/99 respirators and cough etiquettes commonly promoted, appear to be insufficient in their protection against Influenza A H1N1 virus, and merit a critical review (ATS 2010, New Orleans, USA).

Additionally, they have developed the groundwork of a novel non-invasive method of rapid screening, monitoring and follow-up in real time of individuals with acute IRD, such as Influenza A H1N1 virus (ERS2010, Barcelona, Spain).

APPLICATIONS: The mucomodulation approach improved tracheal mucociliary clearance in our mammalian model far better than other approaches. Our modulators could be considered as an enhanced new generation of compounds capable of improving airway hygiene and respiratory host defense.

Mucomodulator therapy is designed to enhance the clearance of mucus from the respiratory tract as well as to optimize aspects of lung defense that depend on the mucous layer. Due to its counteraction to mucus retention, mucomodulation therapy is a major consideration in the treatment of acute airway injuries like smoke inhalation and other chronic lung diseases in which mucus hypersecretion and impaired airway clearance require adequate secretion management.

We have invented a novel and non-intuitive approach to improve airway mucus clearance by adding crosslinks in a selective and controlled manner through a specialized new generation of mucomodulators. Essentially, we have found that certain mucomodulators that increase cohesive interactions between mucin macromolecules lead to a mucus that is more easily clearable, particularly by airflow-dependent mechanisms. Such an improvement in mucus quality related to clearance would benefit many, if not most, patients with chronic airway disease, like those suffering from Chronic Obstructive Pulmonary Disease, who depend in whole or in part on airflow clearance mechanisms to maintain airway hygiene. This novel approach might be of particular importance for those in the ICU or those with spinal cord lesions who require assisted ventilation, as well as in Biodefense. At the same time, increasing the cohesiveness in this manner leads to a reduction in fine aerosol formation during expectoration – a clear advantage in helping to control the spread of airborne infections.

We have four different approaches that applied alone or in combination have the potential to accomplish these goals and that we intend to test and develop.

One approach is to increase the concentration of divalent cations in the mucus. Conceptually, this is the opposite of what occurs in nature during mucin exocytosis, where intracellular mucin granules, which were held tightly through ion crosslinks, give way to much looser interactions as ion exchanges occur during fusion with the apical membrane.

A second approach is to administer a high molecular weight agent that has approximately the same molecular weight as the subunits of mucin macromolecules; in this case mucin-agent crosslinks are approximately as effective as the original mucin-mucin crosslinks.

A third approach is the use of a crosslinking agent, which causes reversible crosslink formation between galactose units, the major neutral sugar component of mucin. We have recently carried out pilot studies on the effect of added agent on the clearability and aerosolizability of mucus simulant. The results are quite striking: We were able to achieve increased “expectoration” in our cough machine model, along with acceptable mucociliary clearance in frog palate testing, enhanced mucus clearability in preliminary trials in dogs known not to have hypersecretion and yet achieve our desired target of a significant reduction in fine aerosol formation.

A fourth approach involves the use of polycationic peptides, as mucomodulators. These molecules have the capacity to interact with the negative charges along the mucous glycoprotein, producing additional crosslinks.

Potential impact on respiratory health and disease control
The pathway to achieve a positive health impact through mucomodulator therapy may not be as prolonged as otherwise might be expected. Our results so far are limited but striking.

There are a couple of critical advantages to this novel technology: several of the compounds under consideration are already approved by the US FDA and other regulatory agencies for pharmaceutical use. Two are active ingredients in dozens of approved formulations for intravenous and intraperitoneal use. Another is approved as an inert ingredient and has OTC approval for several other indications. If any of these compounds (or a combination thereof) is judged suitable for clinical trials, established safety data could be utilized to fulfill some of the regulatory requirements for pre-clinical studies. The next step would be clinical trials for inhalation use in airway mucus management and in transmission prevention of clinically and epidemiologically important respiratory pathogens like in tuberculosis, cystic fibrosis and in acute airway injury.

The prototype compound we are proposing to use via inhalation is a non-protein colloid that has been administered by intravenous injection in emergency and urgency situations mainly for early fluid replacement and as a plasma volume expander to correct hypovolemia in patients with shock due to circulating volume deficit, as well as for the prophylaxis of postoperative or post-traumatic thromboembolism, for many decades now, and adverse effects have been reported using it IV.

The prototype compound is a natural biodegradable, biocompatible product used in food, biochemical, and pharmaceutical industries for more than five decades. The compound that we plan to use first is a drug that was marketed in Canada and has been administered by intravenous injection as a plasma expander for many decades.

Preclinical studies show that Mucomodulators can achieve a dual goal of reducing aerosolization while enhancing airway mucus clearance by cilia and by cough, the two most important clearance mechanisms of the respiratory system.

In summary the mucomodulator technology is innovative in that it represents a reversal in current thinking about respiratory disease management. The resulting product will be an unprecedented tool in airway hygiene, in secretion management, as well as in prevention of droplet-spread illnesses (close person-to-person-contact and airborne transmission) – a safe, efficacious, non-vaccine preventative therapy.