Symptoms, causes and treatment challenges

During an allergic reaction, a person releases mediators from their mast cells, basophils and inflammatory cells^[ix]. These mediators cause the allergic inflammatory reactions associated with anaphylaxis, such as swollen lips and itchy eyes.

An allergic reaction happens when a person’s immune system perceives an allergen as a threat. When an allergen comes into contact with the body, through a person’s eyes, skin, nose, respiratory or gastrointestinal tracts, an allergic reaction can occur. Allergens can be injected, swallowed or inhaled^[x].

Symptoms can start within minutes and involve multiple organs

Allergic reactions range in severity, from mild to severe. One of the most common allergic reactions is hayfever, which is in response to pollen exposure and usually seasonal. Other examples include bee stings, medicines, and certain foods. Usually, symptoms start very quickly, although they can take place several hours after exposure.

Mild symptoms include a runny nose, cough, localised redness or swelling. Local treatment protocols for mild allergic reactions differ, with avoidance being the most common recommendation^[xi]. Sometimes the body has a mild reaction to an allergen the first time it encounters it, which sensitizes the body to that allergen and triggers a more severe reaction on a subsequent exposure.

Symptoms of anaphylaxis typically involve multiple organs, and can include:

• Itchy skin with redness, and hives (rashes);
• Swelling of the lips, tongue and/ or throat, affecting swallowing or speaking;
• Breathing difficulties, with shortness of breath and wheezing;
• Heart rate (pulse) changes;
• Abdominal (tummy) pain with sickness and/ or vomiting;
• Dizziness and/ or fainting.

Intramuscular epinephrine is the first-line treatment

The World Allergy Organization guidelines (2020) and World Health Organization^[xii] recommend intramuscular epinephrine (adrenaline) for the first-line treatment of anaphylaxis^[xiii], although it can also be given intravenously, which increases the speed and intensity of the response^[xiv]. Outside hospital settings, which is where many reactions happen, people with a severe allergy, or those at risk of repeated episodes are usually prescribed epinephrine/adrenaline auto-injectors. These have been available in the US since 1987^[xv] and there are currently several different types available.

Epinephrine is a prescription only medication that needs to be administered very quickly during anaphylaxis to treat a patient and prevent loss of life. In day-to-day life, this relies on people keeping their auto-injector with them and being confident to use it in an emergency. However auto-injectors, and the epinephrine itself, come with many challenges.

Epinephrine is costly and degrades rapidly during storage

Robert Rönn explains: “epinephrine is inherently unstable. There are several different epinephrine injectable solutions on the market in the US, but in this form, they deteriorate rapidly on exposure to air, heat or light.”

Epinephrine appears as a white to nearly-white crystalline powder or granules^[xvi], and changes from a clear, colourless solution to pink (caused by oxidation) and brown (forming melanin)^[xvii]. When this happens, the solution is unfit for administration and must be destroyed. Manufacturing is complex and expensive. It takes place under nitrogen and the solution needs to be protected from light. An antioxidant is added, and sometimes also a chelating agent.

Inside hospitals, withdrawing from multiple-dose vials introduces air, making the remaining epinephrine susceptible to oxidation. Oxidation poses further challenges with alternative administration routes, such as orally, where it oxidises as it passes through the gastrointestinal tract and into the ^{liver[xviii],} so absorption through this method is slight.

Epinephrine injection must be stored in light-resistant containers at room temperatures (approximately 25C)^[xix], and it cannot be frozen. It also has a short shelf-life of under 2 years, although the remaining shelf-life once it has reached the patients is closer to 1 year. This gives rise to significant cost and logistical concerns, particularly in remote areas. Careful handling and storage are required to ensure the epinephrine solution is fit for administration and can be relied upon to work effectively in an emergency.

20-30 percent of young adults experience needle fear

Needle fear (also known as trypanophobia) is a well-documented concern for people across the age spectrum who rely on self-injecting medication due to their health needs. Recent findings indicate that 20-50 percent of adolescents and 20-30 percent of young adults experience needle fear^[xx]. People with needle fear can feel anxious, giving rise to panic attacks, nausea, palpitations, feeling faint and sweats. Many of these symptoms mimic those of anaphylaxis, which can make diagnosis difficult, particularly where the individual wants to avoid the needle altogether with potentially life-threatening consequences.

Safety issues with auto-injectors are also well-documented, associated with usability defects of the devices themselves but also user errors[xxi]. Ease of use is paramount to ensure people feel comfortable and confident using them in an emergency. A common negative outcome of auto-injectors is an unintentional needle-stick injury caused by an error in how the device is held^[xxii]. Additional use errors include failing to remove the device’s safety cap before attempting to use it, choosing an incorrect injection site, and not injecting for the right amount of time. Infection control is also a challenge, particularly in community settings where there may not be appropriate clinical sharps bins for disposal.

Looking ahead to an innovative solution

Overcoming the instability of epinephrine would create ground-breaking treatment opportunities, with improved handling and storage and access to non-invasive administration routes.