Good News: FDA-Approved Generic of Albuterol Inhaler Available for $23 as of April 2020

On April 8, 2020, the U.S. Food and Drug Administration approved the first generic of Proventil HFA (albuterol sulfate) Metered Dose Inhaler, 90 mcg/Inhalation, for the treatment or prevention of bronchospasm in patients 4 years of age and older who have reversible obstructive airway disease/asthma, as well as the prevention of exercise-induced bronchospasm (EIB).

According to the National Heart, Lung, and Blood Institute, bronchospasms occur when the muscles surrounding the airways swell and tighten, causing them to squeeze the airways and make them smaller. Exercise and other physical activity can bring on symptoms in most people who have asthma and may occur either during or right after being active. Asthma causes recurring periods of wheezing (a whistling sound when breathing), chest tightness, shortness of breath and coughing. The coughing often worsens at night or early in the morning. Asthma affects people of all ages, but it most often starts during childhood. In the United States, more than 26 million people are known to have asthma, about 7 million of these people are children.
The most common side effects associated with Albuterol Sulfate Metered Dose Inhaler, 90 mcg/Inhalation, are upper respiratory tract infection, rhinitis, nausea, vomiting, rapid heart rate (tachycardia), tremor and nervousness.

The lowest GoodRx price for the most common version of albuterol is around $23.13, 57% off the average retail price of $54.09: https://www.goodrx.com/albuterol



Asthma Treatment Options (click to enlarge the image).

References:

https://www.fda.gov/news-events/press-announcements/fda-approves-first-generic-commonly-used-albuterol-inhaler-treat-and-prevent-bronchospasm

Should I stop intranasal and inhaled steroid medications during the COVID-19 pandemic? No, continue the medications

From ACAAI Statement on Intranasal and Inhaled Corticosteroids and the COVID-19 Pandemic:

As spring allergy season sets in, allergy and asthma sufferers may be concerned that continuing their normal use of inhaled and intranasal corticosteroids may not be advisable during the pandemic. However, it is more important than ever for these patients to keep their symptoms well controlled.

The ACAAI has provided the following statement:

With the COVID-19 pandemic coinciding with the Spring allergy season, you may be concerned about using your intranasal corticosteroids for nasal allergies and your inhaled corticosteroids for your asthma. 

There is no data that continuing these allergy and asthma medications will have any effect on increasing your risk of getting the COVID-19 infection or if you get the infection, lead to a worse outcome.

It is important to control your allergy and asthma symptoms as they may lead to misdiagnosis of COVID-19 as there are some overlap of symptoms.

References:

https://college.acaai.org/acaai-statement-covid-19-and-asthma-allergy-and-immune-deficiency-patients-3-12-20

Montelukast/Singulair now has a "black box" warning by the FDA due to neuropsychiatric events

The U.S. Food and Drug Administration is requiring a boxed warning – the agency’s most prominent warning – for montelukast (sold under the brand name Singulair and in generic form) to strengthen an existing warning about the risk of neuropsychiatric events associated with the drug, which is used to treat asthma and allergic rhinitis (hay fever).

The boxed warning advises health care providers to avoid prescribing montelukast for patients with mild symptoms, particularly those with allergic rhinitis.

Neuropsychiatric events included agitation, depression, sleeping problems, and suicidal thoughts and actions.

The incidence of neuropsychiatric events associated with montelukast is unknown as of 2020, but some reports were serious. Many patients and health care professionals are not fully aware of these risks as per Sally Seymour, M.D., director of the Division of Pulmonary, Allergy and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.

The drug was first approved in 1998. The FDA determined the risks of montelukast may outweigh the benefits in some patients, particularly when the symptoms of the disease are mild and can be adequately treated with alternative therapies. For allergic rhinitis in particular, the FDA has determined that montelukast should be reserved for patients who have not responded adequately to other therapies — or who cannot tolerate these therapies.
 
Importantly, there are many other safe and effective medications to treat allergies with extensive history of use and safety, such that many products are available over the counter without a prescription. Immunotherapy ("allergy shots") is a safe treatment used for more than 120 years, widely available, prescribed and managed by board-certified allergists in the U.S.

In addition to the boxed warning, the FDA is also requiring a new Medication Guide to be given to patients with each montelukast prescription.

References:

https://www.fda.gov/news-events/press-announcements/fda-requires-stronger-warning-about-risk-neuropsychiatric-events-associated-asthma-and-allergy

Is there an allergy to magnesium sulfate IV?

There is no IgE-mediated allergy to magnesium sulfate IV. However, magnesium sulfate-induced nonallergic anaphylaxis has been reported in the literature (only 2-3 cases).

Case presentation

A 50-year-old female reported intolerance to magnesium sulfate, on multiple occasions, as per her recollection, she had immediate symptoms with magnesium sulfate IV, with throat discomfort, symptoms resolved after the infusion was stopped and Benadryl was given. No symptoms with oral or NG magnesium replacement were reported. Magnesium replacement was needed during hospitalization because blood magnesium level was 0.9. History of sulfonamide antibiotic allergy was also reported.

Sulfonamide antibiotics do not cross react with sulfates, or even with non-antibiotic sulfonamides or pharmaceuticals with sulfur.

There is no reported IgE-mediated allergy to magnesium sulfate in the medical literature. There is no available skin or blood test for magnesium sulfate. These tests detect IgE-mediated allergy.

There are 2-3 case reports in the medical literature (referenced below) of suspected non-IgE-mediated anaphylaxis to magnesium sulfate. The reactions occurred within 60 min and 30 min, respectively (reference 1).
 
Based on the literature review (see above), if blood Mg level can be maintained at 1.0 or above, no IV replacement is recommended. Replacement PO or via NGT can be sufficient.

If Mg level is below 1.0 and there is no alternative, magnesium sulfate can be administered via a modified graded dose drug challenge with the medication in ICU with 1:1 observation following the protocol below:

The patient agreed to proceed and signed a the consent form. A sample text is below: Procedure: drug allergy test and challenge. I have informed the patient of all risks, benefits and alternatives to treatment including but not limited to the following: reactions may consist of any or all the following symptoms: itchy eyes, nose, or throat; nasal congestion; runny nose; tightness in the throat or chest; coughing; increased wheezing; lightheadedness; faintness; nausea and vomiting; hives; generalized itching; and shock, the last under extreme conditions. The anaphylactic shock reaction can lead to death. The opportunity has been provided for the patient to ask questions. Patient understands the risks and agrees to proceed.

Instructions are below. The allergist on call was available for questions.

To be available at bedside: EpiPen 0.3 mg (2 pens), Cetirizine 10 mg  (2 doses), Solu-Medrol 125 mg IV (2 doses).
 
Magnesium sulfate challenge
Time BP P RR

Magnesium sulfate Dose          
1 10% of dose          
2 90% of dose     

Procedure
1. Obtain vital signs (BP, Pulse and Respiration) before the start of the test and at the end of each dosing interval.
2. Administer the doses sequentially
3. Wait 30 minutes between doses 1 and 2.
4. Document the time of each dose.
5. Notify the doctor if the patient develops any symptoms and document above.
6. Observe patient for 120 minutes (2 hours after the last dose).
7. If there are severe symptoms or anaphylaxis, administer EpiPen 0.3 mg x 1. The dose can be repeated x 1.

The patient's magnesium level was corrected successfully with Mg oxide via NGT and PO and IV Mg was not needed.

References:

1. https://www.annallergy.org/article/S1081-1206(10)60724-7/abstract
2. https://www.aaaai.org/ask-the-expert/sulfate
3. https://www.ncbi.nlm.nih.gov/pubmed/2801834

Transition from Fellow to Practice - Dr Siegel's COLA lecture



From COLA Video Lectures: Dr. Charles Siegel shares his experience with starting an allergy practice and provides helpful advice for fellows who are transitioning from fellowship to practice. Held on December 9, 2019.

Can dietary fructose intolerance cause urticaria?

Dietary intolerances to fructose, fructans and FODMAPs (Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols) are common, yet poorly recognized and managed.

Can dietary fructose intolerance cause urticaria?

No, according to a large study of 1,300 patients. See table 1, linked below: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672687/. There was no statistical difference in the reported skin symptoms.

References:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3934501/
ttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672687/
https://www.uwhealth.org/healthfacts/nutrition/376.pdf

Auto-inflammatory Syndromes - Twitter summary from #CSACI19 meeting

Dr. Ellis @DrAnneEllis: Dr. Marcus Shaker "Auto-inflammatory Syndromes".

Recurrent fever - common things are more common! Recurrent viral illness (think day care) recurrent bacterial infection (think immunodeficiency), pseudo fever explain most.

Cryopyrinopathies are rare but described association with celiac disease.

Cryopyrin Associated Periodic Syndromes (CAPS) include Familial Cold Autoinflammatory syndrome (FCAS), Muckle-Wells Syndrome and Neonatal onset multisystem inflammatory disease (NOMID).

Canakinumab (human monoclonal antibody targeted at interleukin-1 beta) led to a 98% response rate for CAPS in the pivotal @NEJM publication.

Autoinflammatory syndromes are issues with the innate immune syndrome rather than adaptive.

TRAPS presents with recurrent fevers, serositis, abdominal pain, rash, myalgias and amyloidosis. Treatment is steroids and anti-Il1.

Shaker: Sometimes discussing auto-inflammatory conditions can feel like Alphabet Soup.

Chronic Sinusitis - Twitter summary from #CSACI19 meeting

Dr. Ellis @DrAnneEllis: About to give my interactive workshop on Dilemmas in Chronic Rhinosinusitis.

Polyp recurrence after endoscopic sinus surgery is almost 90%.

Dr. Desroisers - Not everything that can be added to a sinus rinse should go into the nose! Many dangers to 'home remedies'.

Inflammation is central to the multifactorial etiology of chronic rhinosinusitis. Eosinophils are a biomarker of the underlying disease if Type 2 inflammation is causing issues.

CRS epithelium heals poorly following injury. Microbiome is disrupted post sinus surgery as well. Those who do not do well post ESS are more likely to have Staph aureus.

Mary McHenry MD @maryjmchenry: Many reasons to treat other than the patient has stuffy nose: CRS impairs sleep, QoL, sense of smell, risk for antibiotics, risk for Type 2 disease, side effects of antibiotics - the list goes on!

Dupilumab led to polyp resolution as impressive as surgery in the Phase 3 trials - Desrosiers "it's like surgery to the immune system".

Stepwise approach to management of CRS -medication, well performed surgery, post EES budesonide irrigation.

Mary McHenry MD @maryjmchenry: Biologic therapy for CRSwNP: "surgery of the immune system" as per Dr Desrosiers (ENT). A great way to describe biologic therapy for Type 2 inflammation.

Food allergy, OIT and Epicutaneous immunotherapy (EPIT) - Twitter summary from #CSACI19 meeting

Dr. Ellis @DrAnneEllis: Epicutaneous immunotherapy - a "patch" is applied with standardized, controlled allergen content with an aim to increase tolerance to a food - peanut and milk best studied thus far. PEPITES was a pivotal Phase 3 study of EPIT, showed benefit of the peanut patch over placebo patch, but it didn't meet the FDA requirement for the confidence interval to claim true statistical significance. Adverse events to patch were common - (most, local irritation at the patch site) but almost completely matched numerically in the placebo arm.



Food allergy - Only 3 ways to treat allergies (click to enlarge the image).

Dr. Mariam Hanna, MD @PedsAllergyDoc: Dr Chan reviews EPIT- PEPITES reviewed, 5 Canadian co-authors - 356 peanut allergic children (age 4-11yo), intervention 250mcg protein - primary outcome 35% vs 13% didn’t meet FDA lower bound confidence interval (clinical relevance of this?).

Final comments from Dr. Chan re immunotherapy: 1) The ship has sailed, 2) Use of OIT outside research is a reality and 3) No one size fits all. Most importantly: Oral food challenges and OIT go hand in hand.

Stuart Carr @allergydoc4kidz: EPIT: Relatively small increase in peanut threshold but perhaps sufficient to protect against cross contamination and some evidence of improved QOL.

Dr. Ellis @DrAnneEllis: Many other trials underway with the EPIT technology developed by @DBVTechnologies We look forward to seeing the results!

AR101 and PALISADE trial evaluated the Peanut OIT product from @aimmune - 600mg of peanut protein allows 60% of patients to meet the primary outcome of tolerating a large dose of peanut on oral food challenge at the conclusion of trial.

Adverse events, including anaphylaxis, were unfortunately not uncommon - 14.2% had systemic allergic reactions in the active group. But this is not actually surprising based on other studies of OIT.

Lancet study by Dr. Derek Chu from @MacHealthSci highlights the issues with anaphylaxis from peanut OIT. Avoidance of peanut leads to less anaphylaxis, but avoidance doesn't improve the underlying condition the way OIT does...risks/benefits/SHARED DECISION MAKING key:).

Summary - OIT is very controversial. Pros and Cons to EPIT, OIT and avoidance. Once again, we need to talk or our patients and ensure Shared Decision Making is in place.

Quality of life improves throughout the entire journal of oral immunotherapy.

Wait times for oral food challenges in Canada are long. Even busy centers who do lots of them still face 1 to 2 year wait lists.

Dr. A for Allergy MD @Health_Ontario_: Chan: Systemic reactions and severe reactions strikingly low in young pre school children compared to the older children in #OIT.

Chronic Urticaria - Twitter summary from #CSACI19 meeting

Dr. Mariam Hanna, MD @PedsAllergyDoc:

Dr Begin - Reviewing Omalizumab’s mechanism of action: 1) Formation of Allergen-specific blocking complexes. 2) Decrease in free allergen-specific IgE. 3) Disarming/dissociation of IgE from its receptor.

Proposed mechanism for Chronic Spontaneous Urticaria (CSU):
1) Autoimmune urticaria - anti IgE and to receptor
2) Autoallergic urticaria - IgE against self

Dr. Ellis @DrAnneEllis: Ligelizumab is a new "Hyper-Xolair" - much higher affinity for IgE antibody - showing promise for the management of chronic spontaneous urticaria (CSU).



Chronic Urticaria Treatment Options (click to enlarge the image).

Starting off the morning with Dr. Franks Siebenhaar from Charite, Germany- the role of PAF in itch of urticaria.

Chronic Urticaria is chronic - 20% of patients have hives for more than 20 years. Chronic urticaria is associated with a low QOL.

CSU in children - if symptoms are severe, it predicts it will be long lasting.

Goal of management for CSU: "Treat the disease until it is gone".

Treatment algorithm for CSU in international guidelines - 2nd generation antihistamines first and foremost - then double the dose, then quadruple the dose, then omalizumab.

Response to antihistamines indeed is dose dependent. 4 fold updosing has clearly been shown to more effective than licensed doses.

Siebenhaar: Mast cells are immunologic bombs.

Platelet Activating Factor (PAF) Increases vascular permeability - can cause a wheal and flare reaction similar to histamine. PAF induces itch just like other neuropeptides. Importantly, however, PAF does not release histamine from skin mast cells. Yet we still see a wheal and flare reaction. So it's independent. PAF levels have been shown to be elevated in chronic spontaneous urticaria (CSU).

Rupatadine is designed to inhibit both histamine and PAF. Has proven in vivo anti histamine as well as anti PAF activities. Siebenhaar: Rupatadine is also clearly efficacious in the treatment of cold induced urticaria. Histamine causes itch. PAF causes itch and burning sensation. Recent study in Japan show clear benefit of itch reduction with rupatadine regardless of the reason for their itchy skin. Siebenhaar: PAF should be considered a target for treatment of urticaria.

No clinically relevant drug interactions have been observed for any second generation antihistamines.