Selected Papers

Global warming increases water evaporation rates from planetary ecosystems. Here, we show that evaporation rates encountered during human breathing in dehydrating atmospheres promote airway inflammation and potentially exacerbate lung diseases. 

Edwards, D.A., Edwards, A., Li, D. et al. Global warming risks dehydrating and inflaming human airways. Commun Earth Environ 6, 193 (2025). https://doi.org/10.1038/s43247-025-02161-z
 

Led by the team of Professor Kian Fan Chung at Imperial College London, the ERJOR paper summarizes the results from an exploratory human clinical trial in refractory chronic cough patients to assess the treatment potential of targeted hydration of the larynx by alkaline hypertonic divalent salts — as a function of pH. We had reached a conclusion that alkalinity might be the difference between hydration as hygienic intervention and hydration as treatment.  The results of this study are the first indication that this may be true. The treatment efficacy of 33-35% relative to placebo 2 days post treatment with a pH 9 aerosol is the first evidence that a purely endogenous aerosol might treat refractory chronic cough as effectively as the drugs most advanced in clinical testing.

Abubakar-Waziri H, Edwards DA, Bhatta DB, et al. Inhaled alkaline hypertonic divalent salts reduce refractory chronic cough frequency. 

ERJ Open Res 2024; 10: 00241-2024 [DOI: 10.1183/23120541.00241-2024]

Led by Professor Ana Flavia Zuim at New York University, the JAM article summarizes the results of an exploratory, randomized, double blinded, placebo-controlled study of exploring the laryngeal hydration potential of the 4 endogenous salts at identical concentrations by measuring the quality of one’s voice. Phonation threshold pressure is the most reliable measure of phonation quality currently used today — and the results of this study show that magnesium chloride lasts longer and is more effective at hydration than any other salt. The study also shows why calcium or magnesium chloride avoid the cough provocation common with sodium chloride and mannitol — and led to the composition of the therapeutic aerosol that is now advancing in clinical testing. 

Zuim, A-F, Edwards, A, Ausiello DA, Bhatta, D Edwards DA Hypertonic aerosols hydrate airways longer and reduce acidification risk with non-permeating cation and permeating anion salts. 2024.  Journal Aerosols Medicine Pulmonary Drug Delivery. DOI10.1089/jamp.2023.0039

This review, written with my colleague Fan Chung at Imperial College London, provides an overview of our discovery of mucus transpiration and the modality of treatment of chronic cough inherent in targeted hydration of the larynx. The review captures understanding at the moment of publication — in a field of inquiry that is rapidly expanding.

Edwards DA, Chung KF. Mucus Transpiration as the Basis for Chronic Cough and Cough Hypersensitivity. Lung. 2023 Dec 22. doi: 10.1007/s00408-023-00664-0. Epub ahead of print. PMID: 38135857.

We find that the breathing of dry air leads to evaporative stresses on mucus in the upper airways, and notably in the larynx and trachea, which press mucus onto underlying cilia, promoting inflammation, and cough reflex. This is a first paper that points out how mucus in the upper airways appears to be an example of a transpiring hydrogel, like the hydrogel on the surface of a leaf, which pulls by osmosis water from the roots toward the sky. The weight of the water head in a tree is an illustration of the inflammatory force that can act in the upper airways, leading to dysfunction that includes loss of cilia clearance and amplified respiratory droplet generation. The article also indicates how such dehydration stresses can be reduced by targeted hydration using hypertonic salts.

This is the first article to point to the commonality of dry airways to multiple normal/infected human conditions as a likely cause of elevated respiratory droplet generation — and that drying out of the larynx may also be responsible for diminished oxygen saturation in invected and normal human subjects. The article communicates the results of a multisite human clinical trial involving 464 human subjects in Germany, the US, and India. It is found that in dehydration-associated states of advanced age (n=357), elevated BMI-age (n=148), strenuous exercise (n=20) and SARS-CoV-2 infection (n=87) far more respiratory droplets are produced in the airways (up to 4 orders of magnitude) than in relatively hydrated (the young, the low BMI, the non-infected).  In a random control study of COVID-19 positive subjects (n=40), thrice-a-day delivery of calcium-rich hypertonic salts (FEND) targeting the upper airways suppressed respiratory droplet generation by 51% +/- 11%.  No changes were observed in the nasal saline control group. Oxygen saturation rose significantly over the course of the airway hygiene treatment in the active group and did not change in the nasal saline control group. Self-reported symptom scores fell in the active group from Day 2 with 86% of all subjects discharged without symptoms. In the control, 0% of the group ended their stay in the hospital without symptoms. Additionally, in the exercise-induced dehydration study, exhaled aerosol increased around 15 fold following one hour of exercise (between 0.5 to 1.0% whole body weight loss). Drying out of the upper airways may be a significant cause of the high rates of respiratory infection illness among high-endurance athletes.

This article is the first to show that hydration of the upper airways, as occurs when we breathe humid air, diminishes respiratory droplet generation in our upper airways. This suppression lasts for about an hour on return to a dry room. Wearing a cotton face mask accomplishes the same thing — humidifying our upper airways with our own moist air.  Delivering sodium chloride salt droplets sized to land in the upper airways mimics the suppression effects of the humid room and the face mask. Replacing sodium chloride by calcium chloride prolongs the cleansing effect for 4-5 hours.  Upper airway hydration appears to equivalently occur by water and salt exposure, as water and salt balance to hydrate the upper airways. Previous peer-reviewed research, cited in the article, shows that sustained breathing of humid air reduces risks of COVID-19. Our article is the first to show from public county-level data in the US a preliminary correlation between 25-30% suppression of COVID-19 incidence and death rates and residency in (Pacific and Gulf) coastal US counties where wind blows off the sea. Among the roles of upper airway hydration in reducing risks of lower-respiratory-tract disease may be the suppression of respiratory droplet generation — which lowers traffic of inhaled contaminants to the lower respiratory tract.

A most recent 2021 PNAS article begins to explore the connection between respiratory droplets and COVID-19 self-infection and transmission via human and non-human primate exhaled aerosol data. The article reports a “super spreading” distribution of exhaled aerosol in the human population — 20% of the subjects exhaled 80% of the aerosol of the group. Consistent with earlier research, the finding suggests that super spreading of airborne infectious disease may be an inherency in the nature of respiratory droplet heterogeneity, ie that in any group of individuals some people exhale many more droplets than others. The article reports a strong correlation between high respiratory droplet generation and old age and high BMI — and with nonhuman primates a correlation between exhaled aerosol and degree of pathogen (SARS-CoV-2 and TB) proliferation in the airways.

The 2020 Quarterly Reviews Biophysics Discovery article shares much of the research of the period 2008–2012 as well as the new insight that for the purposes of airway hygiene (cleansing of the airways of respiratory droplets) it is unnecessary to deliver salt aerosol to the entire lungs. It is more efficient to deliver salts through the nose to the upper airways only. The observation that the upper airways are the principal site of respiratory droplet generation is a key finding of this paper.  Delivering salts via the nose to the upper airways for airway cleansing leads to faster delivery (seconds not minutes) and non-drug effects.  Link to article

By manufacturing a single-particle system in two particulate forms (i.e., micrometer size and nanometer size), we have designed a bacterial vaccine form that exhibits improved efficacy of immunization. Microstructural properties are adapted to alter dispersive and aerosol properties independently. Dried “nanomicroparticle” vaccines possess two axes of nanoscale dimensions and a third axis of micrometer dimension; the last one permits effective micrometer-like physical dispersion, and the former provides alignment of the principal nanodimension particle axes with the direction of airflow. Particles formed with this combination of nano- and micrometer-scale dimensions possess a greater ability to aerosolize than particles of standard spherical isotropic shape and of similar geometric diameter. Here, we demonstrate effective application of this biomaterial by using the live attenuated tuberculosis vaccine bacille Calmette–Guérin (BCG). Prepared as a spray-dried nanomicroparticle aerosol, BCG vaccine exhibited high-efficiency delivery and peripheral lung targeting capacity from a low-cost and technically simple delivery system. Aerosol delivery of the BCG nanomicroparticle to normal guinea pigs subsequently challenged with virulent Mycobacterium tuberculosis significantly reduced bacterial burden and lung pathology both relative to untreated animals and to control animals immunized with the standard parenteral BCG. Link to article

With the increasing incidence of tuberculosis and drug resistant disease in developing countries due to HIV/AIDS, there is a need for vaccines that are more effective than the present bacillus Calmette-Guérin (BCG) vaccine. We demonstrate that BCG vaccine can be dried without traditional freezing and maintained with remarkable refrigerated and room-temperature stability for months through spray drying. Studies with a model Mycobacterium (Mycobacterium smegmatis) revealed that by removing salts and cryoprotectant (e.g., glycerol) from bacterial suspensions, the significant osmotic pressures that are normally produced on bacterial membranes through droplet drying can be reduced sufficiently to minimize loss of viability on drying by up to 2 orders of magnitude. By placing the bacteria in a matrix of leucine, high-yield, free-flowing, "vial-fillable" powders of bacteria (including M. smegmatis and M. bovis BCG) can be produced. These powders show relatively minor losses of activity after maintenance at 4 degrees C and 25 degrees C up to and beyond 4 months. Comparisons with lyophilized material prepared both with the same formulation and with a commercial formulation reveal that the spray-dried BCG has better overall viability on drying. Link to article

The 2004 PNAS article reports the first observation of salt reduction of respiratory droplet generation. The article also reveals the contrary effect of surfactants on respiratory droplet generation — an effect that eventually underlies variations in respiratory droplet generation (reported in more recent articles) with changes in viral load and airway lining fluid volume given the presence of lung surfactant in the upper airways — Link to article

A new type of inhalation aerosol, characterized by particles of small mass density and large size, permitted the highly efficient delivery of inhaled therapeutics into the systemic circulation. Particles with mass densities less than 0.4 gram per cubic centimeter and mean diameters exceeding 5 micrometers were inspired deep into the lungs and escaped the lungs' natural clearance mechanisms until the inhaled particles delivered their therapeutic payload. Inhalation of large porous insulin particles resulted in elevated systemic levels of insulin and suppressed systemic glucose levels for 96 hours, whereas small nonporous insulin particles had this effect for only 4 hours. High systemic bioavailability of testosterone was also achieved by inhalation delivery of porous particles with a mean diameter (20 micrometers) approximately 10 times that of conventional inhaled therapeutic particles.