Cardiovascular risks with Tixagevimab and Cilgavimab (Evusheld)

The FDA has a specific warning about Evusheld - it should be include in the informed consent, esp. since the prophylaxis use is off-label:


Concerns related to adverse effects:

Cardiovascular events: A higher rate of serious cardiovascular adverse events, including myocardial infarction, was observed among recipients of tixagevimab and cilgavimab, compared to placebo. All patients who experienced cardiac events had cardiac risk factors and/or a history of cardiovascular disease, and there was no clear temporal pattern. Consider potential risk and benefit in patients with a history of cardiovascular disease and advise patients to seek immediate medical attention if they experience signs/symptoms of a cardiovascular event (FDA 2021).

In the post-hoc analysis of PROVENT, the incidence of serious cardiac adverse events (eg, myocardial infarction, cardiac failure, arrhythmia) was higher in the antibody group than in the placebo group (0.6% vs 0.2%). One person who received the antibodies died of a myocardial infarction. There was no clear temporal relationship between antibody administration and cardiac adverse events.

The trial incidence of serious cardiac events was 0.6% with Evusheld according to JAMA (

As a comparioson, the AMI risk with IVIG is limited to case reports, here is an example and a review:

Again, from the FDA (

“Cardiovascular Events: A higher proportion of subjects who received EVUSHELD versus placebo reported myocardial infarction and cardiac failure serious adverse events. All of the subjects with events had cardiac risk factors and/or a prior history of cardiovascular disease, and there was no clear temporal pattern. A causal relationship between EVUSHELD and these events has not been established.

Consider the risks and benefits prior to initiating EVUSHELD in individuals at high risk for cardiovascular events, and advise individuals to seek immediate medical attention if they experience any signs or symptoms suggestive of a cardiovascular event. (5.3)”

Of note, among the PROVENT trail participants less than 1% had an immunodeficiency disorder, therefore, strictly speaking, the effect of Tixagevimab and Cilgavimab (Evusheld) in patients with immunodeficiency disorders was not studies in this trial.


The idea of “local allergic rhinitis” now returns as “local food allergy” in IBS patients


Adverse Food Reactions (click to enlarge the image).

Up to 20% of people develop gastrointestinal (GI) symptoms following a meal. Millions of people have chronic symptoms labeled as functional gastrointestinal pain or irritable bowel syndrome (IBS), with no clearly identifiable cause. 

The gut–brain axis theory is an attempt to explain IBS symptoms. Overly sensitive nerves in the GI tract react to normal functions, such as stretching and motility, that now feel painful. During periods of stress (e.g., anxiety or GI infection), symptoms may flare up. 

Mast cells and mediators (neurotropic substances) may be involved in visceral hypersensitivity. 

A new hypothesis is that GI mast cells stimulated by food-induced local IgE may be the cause of IBS symptoms. It is possible that a GI bacterial infection can break tolerance to a food antigen. The immune response toward that antigen can lead to increased GI permeability and pain when exposure to the antigen happens again. 

In a study of 12 patients with IBS there was no evidence of systemic IgE against common foods. However, when the same common allergens were injected into the rectal mucosa, every patient with IBS had a localized reaction to at least one of the antigens. 

 This test is not applicable to real-life patients yet. No one will be injecting antigens into the rectal mucosa in an allergy clinic near you anytime soon. Examination of mast cells in GI biopsy specimens is not routinely performed. 

Prolonged and high doses of a histamine H1 receptor antagonist (antihistamines) may reduce visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. 

This recent NEJM commentary (see references below) attempts to expand the term “food allergy” beyond only systemic IgE-mediated reactions. Adverse food reaction is the more appropriate term in my opinion. Adverse food reactions can be IgE-mediated, cell mediated, mixed, not mediated by the immune system, etc. This gastrointestinal tissue–IgE-specific allergic response, if mast cell mediated, is more accurately described as a mixed IgE-/cell-mediated reaction. Eosinophilic esophagitis (EoE) may be in the same category. 

The ovalbumin-specific IgE antibodies identified by Aguilera-Lizarraga et al. were detectable only in colonic tissue. This is very similar to the previously described “local allergic rhinitis”: local application of the allergen induces local sIgE and mediators. 

It is too soon to jump to the conclusion that IBS is a food-induced “allergic” disorder. It may still be food induced as many patients will verify. However, the application of the term “food allergy” to IBS in this case may not be helpful, especially for the same patients that need nothing more than a relief of the GI symptoms that may severely affect their quality of life. A follow-up with a gastroenterologist is recommended for patients with IBS. 


Modifiable risk factors for the development of allergy (#ACAAI19 Twitter summary)

Dr. Ellis @DrAnneEllis: Next up we have Dr. Syed Ashad - Risk factors for developing allergic disease - Lessons from the Isle of Wight.

The Isle of Wight cohort has 1536 parents and 495 children.

Modifiable risk factors for the development of atopy:
Air Pollution
Breast feeding

Carina Venter PhD RD @VenterCarina Love this data from the Isle of Wight. - obesity trajectories and asthma risk

Michael R. Rupp, MD @Docallergy: Obesity is a huge problem with some association with asthma. Time of influence is in the first few years of life. Maternal smoking and obesity seem to have the most increased risk for wheeze. Multigenerational smoking can increase DNA methylation and pass through generations to children increasing risk for wheeze even if child doesn’t smoke.

PARS is the best way to predict asthma

Dr. Ellis @DrAnneEllis: Childhood obesity in the Isle of Wight study - if child is obese at the age of 4, highly likely to have persistent obesity.

Risk factors for childhood obesity - maternal obesity, maternal smoking - leads to a significant risk of asthma by age 18.

If both the mother and the grandmother were smokers, even more dramatic effect on the risk of asthma in the child.

Smoking by the grandmother induced epigenetic changes present in the index child.

Traffic related air pollution (TRAP) in the Isle of Wight study shown to lead to a number of epigenetic alterations affecting a number of tissues.

Microbiome analysis from children in the Isle of Wight cohort showed Enterobacteriaceae strongly associated at the family level with eczema, bacteroidetes predominated in 4 of 6 samples from infants without eczema.

Acetaminophen use in adolescence associated with an increased risk of wheezing/asthma in the IoW study. Breastfeeding for at least 4 months led to improved lung function at age 10 and 18yo.

Preschool wheeze is common. Only 1/3rd of these early wheezers will go on to develop asthma, however.

Family history of asthma, chest infections, positive allergy skin test and absence of nasal symptoms are major risk factors for wheezy infants to go onto develop asthma.

Cannabis allergy (#ACAAI19 Twitter summary)

Atoosa Kourosh @AllergyHealth: 30% of patients with true cannabis allergy will test negative to Can S 3 so it’s good to send component testing from and

Nicole Ramsey @IDnibbler Xolair effective for cannabis allergy in a police officer who was unable to avoid exposure at work. Children with asthma can be allergic to MJ smoked by their parents. This has been proven by basophil activation test in a recent report. Short term mj smoking acts like a bronchodilator (such as albuterol) but long term effects are more obstructive or COPD-like. No sig change in PFTs or CXR however vs cigarette use.

E-cigarette use causes significant pulmonary toxicity. Marijuana smoking is actually worse for you than nicotine cigarettes. Vaping and e-cigarette use is increasing nicotine addiction NOT decreasing it, as was originally intended.

Since recreational use was legalized in CO, mj use remained the same and alcohol and cigarette use has decreased.

LTP syndrome can be seen associated with MJ exposure. Kiwi banana avocado are also implicated in OAS.

Atoosa Kourosh @AllergyHealth: We are seeing more allergic reactions to marijuana products. Several Allergens identified in Cannabis thus far but reaction to Can S 3 may be predictive of systemic reaction and plant food syndrome to peach, peanut, apple. Important to distinguish between symptoms of cannabis ingestion and allergic reaction.

Nicole Ramsey @IDnibbler: Important point for allergists skin testing marijuana in states where it is recreationally legal. It is still federally illegal so could cause issues with your institution.

Primary Immunodeficiency Disease (PIDD) (#ACAAI19 Twitter summary)

Dr Alexei Gonzalez @alexeigonzmd: ESID data: between 5-66% of patients with CVID will develop Lund disease; 1/4 will have ILD.

GLILD has three pathologic patterns: granulomas, lymphocytic interstitial pneumonitis, and follicular bronchiolitis. GLILD future treatment: RTX x 4 cycles followed by 18 months of AZA or MMF. GLILD: steroids are 50% ineffective - consider dual immunosuppressive therapy.

Sasha Alvarado, DO @sashaaalvarado: Elena Perez, MD: 29% of patients with CVID have autoimmune manifestations.

Lisa Forbes, MD: Whole exome sequencing is preferred, but commercial labs offer accessible PID panels, and there are many experts who are happy to collaborate with private practitioners on variants of unknown significance.

Case Simulation for the Education on Anaphylaxis Management (#ACAAI19 Twitter summary)

Dr. Ellis @DrAnneEllis: Gearing up to moderate/facilitate my new favourite workshop "Hands On - The use of Case Simulation for the Education of Allergic Emergencies - Spotlight on Anaphylaxis".

Simulation for Anaphylaxis Management is a tremendous tool. Studies has shown simulation to be more effective than classroom training and increases closed loop communication, teamwork skills, confidence in managing life-threatening events.

Direct observations of simulated emergencies allows detection of critical errors with risk of real harm to a real patient.

Technicians with high fidelity simulators can be the "voice of the patient". Cyanosis, wheezing, rashes can emerge on the mannequin.

In one study - only half of trainees in an internal medicine program going through a simulation scenario of anaphylaxis recognized the diagnosis, only half of those gave epinephrine.

In another study, epinephrine dosing errors were noted in 46 - 94% of participants.

Food challenges in infants (#ACAAI19 Twitter summary)

Dr. Ellis @DrAnneEllis Dr. Justin Greiwe - Best practices for oral food challenges on infants - which patients and when?

Food allergy is a family disease, not an individual problem.

Huge social and psychological consequences to a food allergy diagnosis - some children will be home schooled, not allowed to go to sleep overs or birthday parties, avoid airplanes/sporting events. So we have to get this diagnosis right! Oral food challenges are the Gold standard for diagnosing food allergy - they are underutilized in clinical practice, unfortunately.

Why perform an oral food challenge?
Make the diagnosis
Monitor for resolution
Assess the status of tolerance to cross-reactive foods
Relieve parental or patient anxiety
Determine if patient is a candidate for oral immunotherapy

The Ultimate Goal is to accurately identify patients who will benefit from oral food challenge - it does require ingestion of a meal-sized portion of tested food prepared in usual state.

Kevin Parks MD @kparksmd Dr Greiwe: a test does not define allergy. We've heard this so many times yet clinical decision-making hasn't caught up... history + exam + tests = data needed to assess food allergy.

Carina Venter PhD RD @VenterCarina No need to avoid food allergens during pregnancy or lactation for prevention.

Dr. Ellis @DrAnneEllis Testing via skin prick test or in vitro tests have advantages and pitfalls
IgE to Ara H2 is a strong predictor of peanut allergy. High IgE levels of Gal d1 and Bos d8 associated with more persist allergy to egg and milk, respectively. Skin prick testing to food has a high negative predictive value but overall positive predictive challenge of only ~50%.

Many factors can affect the accuracy of a specific IgE - clear history of previous reaction - if IgE 0.36 to 2 kU/L, 44% of patients passed a challenge despite that history.

Younger age important -lower levels of allergen specific IgE have increased clinical relevance in young children - having concomitant environmental allergy can artificially drive up the food specific IgE level.

A survey of US allergist showed that 92% of practitioner felt there was a need to perform OFC in their practice, but a minority actually did them.

ACGME requirements now dictate that Allergy Fellows in Training need to participate in a minimum of 5 oral food challenges.

Late phase and biphasic anaphylactic reactions very rare following oral food challenge - my editorial opinion is because of the rapid administration of epinephrine at the first sign of concerns anaphylaxis symptoms during an OFC.

RDN @PeanutFarmers @PeanutRD And Dr. Greenhawt mentioned yesterday that quality of life improves regardless of whether individual passes or does not pass the oral food challenge.

Kevin Parks MD @kparksmd Broad panel in vitro food-specific IgE tests are NEVER a good idea!

In survey of allergists the 3 top reasons OFC's are not performed were lack of time, lack of staff, and lack of office space - not safety.

Dr. Ellis @DrAnneEllis Issues unique to infant challenges:
Appropriate portion sizes for age
Appropriate vehicles/food forms
Mixing vehicles infant has previously tolerate
Allow ample time to feed!!

Subtle clues for infant reactions - ear picking, tongue rubbing, putting hand in mouth more than usual, neck scratching, change in general demeanor (quiet/withdrawn, clingy, fussy).

Stopping Criteria for OFC have been published. Don't be a cowboy, known when to quit.

Critical to do an oral challenge before enrolling someone on oral immunotherapy. Don't go through the burden of OIT if the disease isn't there.

Katherine Anagnostou @PedAllergyDoc As food OIT develops there will be a high need and demand for oral food challenges.

Dr. Ellis @DrAnneEllis Exacerbations of skin disease related to food do exist, but nowhere near as commonly as patients/public believe.

Use the failed oral food challenge as a teaching point both during and after the reaction - our responsibility as allergists to reduce anxiety and fear - instill healthy respect for food without crippling parent and children. Instill Confidence not Fear in our food allergy patients - Empowerment not Despair. Ensure that food allergy does not define the patient.

Kevin Parks MD @kparksmd Primary teaching points for families with food allergy: confidence rather than fear, empowerment rather than despair. Lowering the psychosocial cost of food allergy should be a primary goal. Passing a food challenge should be followed by including the food in the child's diet. Recent data suggests they don't. Follow up is key.

Dr. Ellis @DrAnneEllis Dr. Benjamin Prince now discussing Practical Aspects of Infant (and toddler) oral food challenges.

Oral food challenges are a necessary procedure for any allergist who is going to be diagnosing food allergy.

Sometimes getting the patient to eat can be the most difficult and frustrating part of the challenge.

The good news about infant OFCS- most reactions are mild and cutaneous, only a few cases have required epinephrine in the RCTs.

Before you begin - counsel the family on how to prepare and what to expect - review what medications to stop and more importantly which ones not to stop (Asthma meds!). Send a written reminder prior to the day of challenge; reschedule if the child appears to be getting sick. Obtain written informed consent on the day of the oral food challenge.

Pre-draw up the medications that may be needed to treat a reaction; obtain baseline weight, vital signs and detailed physical exam.

A 5 yr retrospective chart review of children seen for peanut allergy who had 2 different skin prick tests at two different times - 2mm difference on average after 5 to 8 months (got bigger).

Important to consider both protein content and total volume of food. Protein content should mirror a normal meal sized portion.

Initial dose is usually base on overall risk of reaction - lower risk 5-10% of total dose, higher risk -0.1-1% of total dose.

Most clinic oral food challenges involve 4 to 6 doses; consider more gradual initial doses in patients planning on undergoing OIT later.

How much time between doses? typically 10 to 30 min - shorter time for lower SPT/sIgE, longer time with higher SPT/sIgE, history of wheeze/asthma or past severe reaction.

For the non-verbal patient it is critical to perform a good baseline physical exam and vitals.

Tips for feeding infants and toddlers - Vehicles are EXTREMELY important - applesauce, pudding, yogurt, ice cream, juices, baby food often successful. Encourage the family to bring favorite foods that can be combined with the challenge food. Encourage the family to try foods with similar textures at home prior to the challenge (e.g. the muffin for a baked egg or milk challenge without the egg or milk).

Minimize skin contact with food as much as possible.

Provide several food options at one time - a Bamba stick, a serving of peanut butter and a Reese's pieces to choose from, for example. Nut butters are the best way to do tree nut challenge as that's the source with the highest amount of protein compared to nutella for e.g. or almond milk for e.g.

Kevin Parks MD @kparksmd Feeling less like a loser allergist after this talk. Lots of kids who pass food challenge/have negative SPT/sIgE tests, green light to reintroduce the food at home, they come back a year later having NOT eaten the food! Good to hear the FA experts fight the same battle.

Dr. Ellis @DrAnneEllis Its why it's now 'part of the deal'. If the patient doesn't promise to eat the food after the challenge, I won't offer it. My 2 yr wait list for the oral challenges can't allow for this to happen.

Dr. Ellis @DrAnneEllis now Dr. Jay Lieberman - Prevention and Management of Infant Anaphylaxis. Foods are clearly the most common trigger for infant anaphylaxis. Food triggers in infants may vary by country/region - Peanut most common in Tennessee, whereas as Milk most common in Massachusetts.

If we are to prevent food induced anaphylaxis we must do our best to prevent food allergy - the Addendum guidelines for early introduction of peanut based on results from the LEAP trial are well known. There will be reactions in the low risk population. Not a lot - but they will happen. LEAP doesn't prevent ALL peanut allergy, just significantly reduces the risk.

Kevin Parks MD @kparksmd Lieberman: infant food challenges are annoying, "they suck", but we have to own them. It's our deal.

KristinSokolMD @kristinkrasnow If we are not doing oral food challenges, even in our infant patients, we are doing a disservice to our patients. - Dr. Leiberman.

Dr. Ellis @DrAnneEllis There is universal agreement that epinephrine is the first line therapy for anaphylaxis in infants. Dose is 0.01mg/kg (as will any other age group). One of the challenges of using an epinephrine autoinjector in an infant, however, is that they may be at risk for an intraosseous injection based on the needle length from ultrasound study.

Very important to hold the child still when administering an epinephrine auto injector - grasp the thigh firmly to avoid lacerations , pinch up the skin to ensure intramuscular injection. Remember dosing of epinephrine is weight based not age based!

Kevin Parks MD @kparksmd currently available 0.15mg epi AI's (US market) may hit bone in nearly 1/2 of infants based on skin-to-bone distance. We don't know the physiologic effects of intraosseous injection of epi vs IM or SC.

Dr. Ellis @DrAnneEllis Consider rephrasing a "failed" oral challenge as a "B+" - look what you WERE able to eat, not focusing on that the entire amount of food was not eaten.

Before you order any test for food allergy - ask your self (and the parents!) what you are going to do with the information. False positive tests are common. Greenhawt now doesn't allow parents to make their own muffins for baked challenges to ensure no cross-contamination with other food allergens.

No other specialty owns food allergy, drug allergy or anaphylaxis. We owe it to our patients to do the best for their allergic needs!

Asthma (#ACAAI19 Twitter summary)

Dr. Ellis @DrAnneEllis Professor Stephen Holgate - Asthma - Inflammation is the Symptom not the Cause.

Epithelial injury and airway remodeling are a common feature of even mild asthma.

Beyond allergen exposure, there are many other environmental factors contributing to airway inflammation in asthma - air pollution (especially diesel exhaust) tops the list. Air pollution now accepted as a causal factor in asthma development, symptoms and mortality. Ambient black carbon particles reach the fetal side of the human placenta.

Holgate: the asthmatic epithelium behaves like a non-healing wound.

Gene signatures from the airways of "wheezers" vs non atopic control show predominant presence of Type 2 inflammation pathways as well as repair molecules.

Targeting alarmins such as TSLP, IL25 and 33 may be the future as you are striking at the "top of the chain" rather than all the downstream effects.

Kevin Parks MD @kparksmd Stephen Holgate MD on asthma: the airway epithelium is damaged by irritants, infections, and allergens - suggesting that epithelial targets may be a more optimistic therapeutic paradigm in asthma. Holgate making a good case for epithelium as a cause.

Dr. Ellis @DrAnneEllis Starting off the day with my favorite speaker ever. Dr. Paul O'Byrne - Dean of
@MacHealthSci and asthma expert and scholar and gentleman!

Drs Hurd and Lenfant founded GINA - 25 years ago- A strategy document, not a guideline - meant to be used anywhere in the world.

GINA describes the control-based asthma management cycle - Diagnosis first - must confirm it is actually asthma one is trying to treat.

GINA describes asthma management from Step 1 to 5 - Step 1 and 2 are the biggest group of patients who can/should be managed by primary care.

The biggest problem with Asthma management? Despite the safety of inhaled corticosteroids, adherence to therapy is abysmal - 40% of patients in one study never filled more than one refill of the ICS/LABA there were given.

Short acting beta agonists (SABAs) are the most widely used asthma medication worldwide - despite the fact that SABAs have been shown to worsen asthma control, enhance EIB, promote airway inflammation and overuse is associated with increased mortality.

SYMGA trials, published in @NEJM aimed to show the efficacy and safety of using an ICS paired with a fast acting LABA - to be used on an add needed basis.

Regular use of budesonide led to more well controlled asthma weeks compared to PRN Symbicort - but adherence in the trial was 80% - not real world experience. No difference in exacerbations between PRN Symbicort and regular budesonide. More important finding IMO!

Michael R. Rupp, MD @Docallergy Study showed that at 1 year patients with moderate asthma less than 10% filled Rx as directed. ADHERENCE IS KEY!

Dr. Ellis @DrAnneEllis Benefit in Asthma exacerbation risk for PRN Symbicort was seen with an 83% reduction in steroid exposure.

Patients in SYGMA 1 used, typically, 1 dose of reliever every 2 weeks - almost no one used the maximum 8 inhalations per day. Not a single patient who used 8 inhalations of Symbicort per day went on to have a severe exacerbation compared to 9% of patients using the same amount of SABA.

The PRACTICAL study from New Zealand completely mirrored the results of the SYGMA2 Study (but was government funded rather than via @AstraZenecaCA). Exacerbations were significantly reduced by PRN Symbicort.

These trials led to GINA making one of the largest changes in their recommendations. As needed low dose ICS/formoterol now the prefered reliever medication for asthma - across all Steps - not just mild/moderate.

Implications for practice - Adherence to maintenance therapy is poor, overuse of SABAs worsen most asthma outcomes, Symbicort 80 mcg reliever therapy that contains an ICS is superior to SABAs for all asthma outcomes. Off label in USA.

Alpha-gal Food allergy (#ACAAI19 Twitter summary)

Dr. Ellis @DrAnneEllis Pork kidney allergy is driven by alpha-gal allergy. Co-authors such as exercise needed to elicit reactions.

Jason K Lee @lee_jasonk 19% of Forrest workers and hunters have alpha gal IgE, not all react clinically.

Dr. Dave Stukus @AllergyKidsDoc Fascinating story about ‘red meat’ allergy at #ACAAI19. Different than traditional food allergy:
-Delayed onset hours later
-Caused by sugar (alpha-gal) not protein
-Most people not allergic to other foods
-Sensitization caused by lone star tick bite

Kevin Parks MD @kparksmd dose response relationship between tick exposure and reactivity. more tick bites = increased likelihood of alpha-gal allergy. NOT just caused by Lone Star tick (as was originally thought based on the geography of initial cases).

Dr. Ellis @DrAnneEllis while the Lone Star tick is what we in North America associate with a cause of alpha gal allergy, many different ticks world wide have been associated. Amblyomma testudarium tick bites associated with alpha gal sensitization, for example.

Jason K Lee @lee_jasonk The antigen in alpha gal maybe an inherent tick protein and not from external. There is boosting of igE if bitten repeatedly by ticks. Waning of igE over time. May not need to avoid meat all the time with alpha gal. Possible desensitization can occur (case report level evidence).

Kevin Parks MD @kparksmd Recurrent tick bites boost alpha-gal reactivity. Avoiding ticks categorically can result in loss of sensitization, and tolerance to beef, pork, lamb.

Eosinophilic esophagitis (#ACAAI19 Twitter summary)

Kevin Parks MD @kparksmd Presidential Plenary at #ACAAI19 Matt Rank MD on EoE: how long do we continue topical glucocorticoids in responders? Very low quality of evidence, but the committee recommends continuing treatment in responders. In our Oregon experience, adherence is low in responders.
Dr Rank: very few studies compare TCS vs PPI in EoE. In the 2 trials that attempt to address this, no significant difference in outcomes between the treatement groups were observed. No comment yet about the value of PPI as a steroid-sparing strategy (but I bet he'll address it).

Gerald Lee MD @DrGerryLee @MatthewRankMD presents a forest plot of the response of EoE to PPI - very heterogeneous, leading to the conditional recommendation of PPI. Biomarkers are sorely needed to predict response to therapy, especially since biopsy is how efficacy is measured!