Omalizumab can serve as a bridge to immunotherapy in severe asthma

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

A 14-year-old African American male is referred to the allergy clinic with a severe persistent asthma that is poorly controlled on maximum dose inhaled corticosteroids and a long acting beta-agonist. The patient required oral steroids on 4 separate occasions in the past 2 years.

Past medical history (PMH)

Severe persistent asthma, allergic rhinitis.

Medications

Advair 500/50 one inhalation BID, Singulair 10 mg po daily, albuterol prn, Rhinocort daily, loratidine 10 mg po daily.

Physical examination

VSS.
Skin: no rashes, keratosis, excoriations, or lichenifications.
HEENT: pale boggy turbinates (B).
Chest: slightly decreased air entry (B).
CVS: Clear S1S2.
Abdomen: Soft, NT, ND, +BS.
Extremities: no c/c/e.

What diagnostic tests would you suggest?

His FEV1 values ranged widely from as low as 55% to as high as 89% predicted with the higher FEV1 measurements representing recent oral steroid administration. The average FEV1 excluding those values due to oral steroid administration was 68% predicted. The average ACT score was 21.6

What happened?

Our patient was started on omalizumab and his condition stabilized. Allergen immunotherapy was added 5 months later. The patient was initially built up on immunotherapy followed by monthly maintenance doses. The total overlap period of immunotherapy and omalizumab was 19 months.

The average FEV1 during the 19 month overlap phase was 86% predicted and average ACT score was 23.8. During this time the patient had no ER visits, oral steroid doses or adverse reactions to immunotherapy.

What happened next?

Omalizumab was discontinued after 2 years. The patient has been maintained on immunotherapy alone since that time and has maintained this benefit with an average FEV1 of 103%. His average ACT score has been 23.5, with no oral steroid use. Because of overall improvement, his ICS were tapered from high to medium dose. Currently, the patient’s regimen consists of a medium dose inhaled steroid with a long acting beta- agonist, montelukast, and monthly maintenance immunotherapy.

Final diagnosis

Use of Omalizumab as a bridge to immunotherapy in severe asthma.

Summary

Asthma is the most common chronic respiratory disease, affecting up to 10% of adults and 30% of children (JACI, 2011).

Both allergen immunotherapy (IT) and omalizumab (anti-IgE antibody) are used to treat persistent perennial allergic asthma. Allergen immunotherapy can lead to long lasting improvement with a typical regimen lasting a set time period of 3-5 years. More severe asthmatic patients are at greater risk for serious and potentially life threatening reactions with allergen immunotherapy. Omalizumab treats perennial allergic asthma, acts synergistically with allergen immunotherapy and reduces anaphylactic reactions associated with immunotherapy. Allergic asthma improvements associated with omalizumab are generally present only while on therapy, and thus therapy may continue indefinitely. Our use of omalizumab is as a bridge to immunotherapy making immunotherapy more effective and safer in high risk severe asthmatics.



Severe asthma - differential diagnosis and management (click to enlarge the image).

References

Oral corticosteroids were withdrawn in 74% of severe asthma patients treated with omalizumab- Current Medical Research and Opinion, 2010.

Response to omalizumab after 16 weeks is a predictor of continuing persistent response to omalizumab in asthmatics. Allergy 2011.

Published: 03/19/2010
Updated: 01/19/2011

Alpha-1 antitrypsin (AAT) deficiency and panniculitis

Author: M. Sandhu, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

A 22 year old female presented with a 3 week history of painful eruptions on the inner aspect of both thighs. Lesions were constant, worsening in nature over the past 3 weeks. Initially the diagnosis of cellulitis was entertained and the patient was placed on a 2 week course of oral antibiotics. Despite treatment with antibiotics the lesions did not improve.

Past medical history (PMH)

As above.

Medications

None

Family medical history

There was no family history of hepatic or pulmonary disease.

Physical examination

VSS.
Skin: Lesions on inner aspect of both thighs, erythematous, indurated, nodular, warm and tender to palpation.
HEENT: normal. Eyes had no conjunctival injection or swelling, ears had no fluid or inflammation behind the TMs, nose had no mucosal edema or discharge.
Chest: CTA (B).
CVS: Clear S1S2.
Abdomen: Soft, NT, ND, +BS.
Extremities: no c/c/e.

What diagnostic tests would you suggest?

A biopsy was subsequently performed, which showed panniculitis. The patient was evaluated for possible causes of panniculitis including alpha-1 antitrypsin deficiency. Alpha-1 antitrypsin level was found to be less than 25mg/dl. Phenotyping analysis demonstrated a ZZ pattern. Pulmonary function testing was normal as was the CT scan of the chest. Liver function tests were also found to be normal except for a slightly elevated alkaline phosphatase.

What treatment would you suggest?

The patient was started on intravenous augmentation therapy with pooled plasma-derived alpha 1-antiprotease (Prolastin) at a dose of 60mg/kg weekly. The panniculitis had nearly completely resolved after the second dose.

Final diagnosis

Panniculitis in alpha-1 antitrypsin (AAT) deficiency.

Summary

Panniculitis is an uncommon manifestation of alpha-1 antitrypsin deficiency, with fewer than 50 cases reported in the English-language scientific literature. It is characterized by inflammation of the panniculus, which is the fibro-fatty tissue layer that lies below the superficial layers of the skin. The architecture resembles a honeycombing pattern, with globules of fat separated by walls (septae). Panniculitis is categorized as either being septal or lobular depending on whether if affects the septae or the fat globlules respectively. In AAT panniculitis, the mechanism resembles that of emphysema, namely the unopposed breakdown of tissue by the absence of alpha-1 antitrypsin, allowing proteases within the body to affect structures underlying the skin. Panniculitis typically presents with red nodular spots on the skin which may break down and ulcerate, causing an oily discharge. The lesions may progress to deep ulceration with necrosis. Common sites include the thighs and buttocks and areas subject to trauma. The presumed mechanism in our patient was from repeated trauma/friction during sexual intercourse.

Panniculitis can arise from many underlying causes. Potential causes include AAT deficiency, connective tissue disease such as Systemic Lupus Erythematosus and Scleroderma, lymphoproliferative disorders, pancreatic disease, gout, chronic kidney disease and adverse reactions to medications.

Various therapies have been evaluated to treat panniculitis, including corticosteroids, antibiotics (doxycycline and dapsone), full plasma exchange, and augmentation therapy with intravenous pooled human plasma alpha-1 antitrypsin. Of these various treatments, augmentation therapy has been the most dramatically successful. Several reports describe resolution of panniculitis after as few as three doses of intravenous augmentation therapy. The dose of augmentation therapy for panniculitis is the same as that for established emphysema, 60 mg/kg once weekly.

In summary, panniculitis can be a potentially disabling complication of AAT deficiency. Fortunately, it is an uncommon manifestation that is amenable to various treatment options, namely augmentation therapy. Since AAT deficiency is an under recognized syndrome, we should be aware of all its potential presentations, to aid in early diagnosis and subsequent treatment.

Importantly, panniculitis in Alpha-1 can accompany various phenotypes (or genetic types of Alpha-1 Antitrypsin Deficiency), some with severe deficiency of serum levels of alpha-1 antitrypsin (e.g., ZZ and SNull) and others with only mild deficiency (e.g., MZ and MS). In one series by Humbert and colleagues, of the 26 patients with panniculitis and Alpha-1 Antitrypsin Deficiency described, 62% were ZZ, 15% were MZ, 8% were MS, and 4% were SNull; in the remaining 8%, the phenotype was not stated. The reported experience suggests that panniculitis occurs equally among men and women and that the mean age of onset is approximately 40 years old.

Related reading

Therapy with alpha-1 antitrypsin cannot be recommended, in view of the lack of evidence of clinical benefit and the high cost of treatment. The Cochrane Collaboration, 2010.

Published: 03/19/2010
Updated: 06/19/2010

Allergic reaction after consumption of "meat-free chicken” (Quorn mycoprotein) by a patient with mold allergy

Authors: M. Sandhu, M.D., Allergist/Immunologist; R. Hopp, D.O., Allergist/Immunologist
Reviewer: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

A 14-year old African American male had a suspected allergic reaction while eating “meat-free chicken” and a vegetable stir fry. The allergic reaction manifested within 2-minutes as throat irritation followed by generalized pruritis, difficulty breathing, lip, tongue, eye and laryngeal edema.

The reaction required an emergency room visit and overnight hospitalization. While in the hospital, he received 2 doses of subcutaneous epinephrine, intravenous corticosteoids (methylprednisolone, Solu-Medrol), H1- blocker (diphenhydramine, Benadryl) and H-2 blocker (famotidine, Pepcid). After 24 hours of observation, he was discharged.

The patient presented to the allergy clinic two months after the allergic reaction. He and his mother were uncertain of the contents of the stir fry. He did recall sampling the “meat-free chicken”.

Past medical history (PMH)

Negative.

Medications

None.

Physical examination

Stable vital signs (VSS).
Skin: no rashes, keratosis, excoriations, or lichenifications.
HEENT: normal. Eyes had no conjunctival injection or swelling, ears had no fluid or inflammation behind the TMs, nose had no mucosal edema or discharge.
Chest: clear to auscultation bilaterally (CTA (B)).
CVS: Clear S1S2.
Abdomen: Soft, non-tender, non-distended with normal bowel sounds (NT, ND, +BS).
Extremities: no cyanosis, clubbing or edema (c/c/e).

What diagnostic tests would you suggest?

Immediate type hypersensitivity skin tests to commercial food allergens (Hollstier Stier 1:20) demonstrated a negative reaction to soy and +1 positive reactions to corn and eggs.

What happened?

The patient's mother was asked to bring the product he ate during the follow-up appointment in one week.

The patient returned the following week with the product. It was a meatless, soy-free mycoprotein with egg binder. A skin test to the mycoprotein (100 mg in 2 ml normal saline) produced a 30 x 20 mm wheal and 100 x 100 mm flare (positive reaction).

Skin testing to molds was positive, including Fusarium vasinfectum, Alternaria tenuis, and to a lesser extent Aspergillus fumigatus. The Fusarium reaction was particularly "aggressive" with a 10 x 12mm wheal and 40 x 40mm flare with pseudopod formation.

Final diagnosis

Type I Hypersensitivity Reaction to Ingestion of Mycoprotein in a Patient With Mold Allergy.

Mycoprotein is a food made by continuous fermentation of the fungus, Fusarium venenatum (fungal family, fusarium genus). The fungus is grown in a large fermentation tower to which oxygen, nitrogen, glucose, minerals and vitamins are added. After harvesting, the fungus is heat treated to reduce its RNA content to the WHO recommended levels before being filtered and drained. The resulting sheet of fungal mycelia is mixed with egg albumin which acts as a binder. The mycoprotein is then textured to resemble meat.

Summary

Mycoprotein is marketed as Quorn. Quorn may be purchased as chunks, mince, sausages, burgers, fillets and is found in a wide array of frozen ready meals such as pies, curries and casseroles. In the United kingdom it enjoys around 60% of the meat-replacement food market, with annual sales of around £95 million. Mycoprotein was introduced in the USA in 2002. Approximately 1/140 000 consumers report adverse reactions after eating Quorn. Few case reports have been published describing the type I hypersensitivity reaction of ingested mycoprotein. Crossreactivity studies have shown that mycoprotein shares common allergenic determinants with molds such as Aspergillus fumigatus, Cladosporium herbarum, Alternaria alternate. The most likely allergenic determinant is the 60S ribosomal protein P2, which was identified as allergen Fus c 1 from Fusarium culmorum.

Related reading

Anaphylaxis to ingested molds in a mold-allergic patient. AAAAI, 2011.

Type I Hypersensitivity Reaction to Ingestion of Mycoprotein (Quorn) in a Patient With Mold Allergy. Manbir Singh Sandhu M.D., Russell J. Hopp D.O., FAAAAI, FAAP. Pediatric Asthma, Allergy & Immunology. March 2009, 22(1): 5-6. doi:10.1089/pai.2008.0518.

'Quorn' Meat Substitute Raises Allergy Concern. WSJ, 2011.

Infectious Fungus Common In Household Drains (Fusarium) - NPR, 2011. "Meatless chicken" (Quorn) is made of Fusarium.

Published: 03/19/2010
Updated: 11/30/2011

Comments from Twitter

@sarahjchapman: well isnt it mold anyway? its black slime made in vats, skimmed and bleached anyway, often has egg white added. Isn't it a mold so has links to mold allergy? i suppose its a new type of food to go into the food supply. I have heard that there are no pictures on net of it 'growing' as its so disgusting. we avoid mainly due to egg allergy as well. Obviously egg allergy more common, but can grasp idea of a up and coming new allergen in form of quorn.

@AllergyNet: Valuable case. New to me. Just checked, Quorn launched in Australia last year.

@DrVes: WSJ interviewed me last week about allergy to Quorn (different from corn) - see the report here: goo.gl/XcIJO - It was published by 2 of my colleagues, UpToDate now quotes it in the section about quorn allergy - very few reports so far. Apparently the Quorn label does not mention anything about mold allergy... http://goo.gl/SKwUc

@sarahjchapman: it wouldn't , apart from allergy wouldnt mention the 'mold' aspect in case it put off consumers. I wonder how many people have had cross reactive reaction to quorn and not connected reaction to it?

@IgECPD4: It's not quite the same thing but I had a patient with anaphylaxis to quinoa--a "new" gluten free grain from South America.

@scanman: I wonder how long it will be before this meat substitute 'vegetarian' fungus based Quorn is available in India

Urticaria after sexual activity and dermatographism

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

A 25-year-old Caucasian male is at the allergy clinic for evaluation of chronic urticaria for the last one and a half years, precipitated by sexual activity, hot showers, exercise, pressure and touch. The urticarial lesions appear on his trunk, arms, and face. He reports no angioedema, shortness of breath (SOB), wheezing, abdominal pain or any other systemic symptoms. There is no history of loss of consciousness or reaction to cold weather.

His primary physician mentioned that the patient has had wheals/rash on his abdomen after having sex with his wife. The rash occurs almost every time after sex and lasts several minutes. It begins on his back and wraps around to his abdomen but has occasionally been present on his neck. It shows up during of slightly after sex and resolves within one hour afterward. He states that hsi wife has attempted to stop use of various lotions, body creams etc. and rarely wears perfume. His physician suspected that the rash might be due to contact dermatitis to some cosmetic product used by the patient's wife. CBCD, ESR and ANA were all within normal limits. He was referred for skin testing.

The patient shows a picture of the rash from his cell phone:


Urticarial lesions on the trunk. Image source: Wikipedia, public domain.

Past Medical History (PMH)

Negative, apart from urticaria for one and a half years.

Medications

None.

Physical examination

Normal.

What is the most likely diagnosis?

Chronic urticaria? What type?
Dermatographism?
Contact dermatitis?

What diagnostic test would you suggest?

Pressure test for dermatographic urticaria with a tongue depressor.

What happened?

The test for dermatographism was strongly positive on both forearms:

Dermatographic urticaria is sometimes called "skin writing". Image source: Wikipedia, public domain.

What treatment would you suggest?

The patient has chronic urticaria and dermatographism. The most likely explanation of his symptoms is dermatographism, although physical urticaria, and specifically cholinergic urticaria cannot be completely ruled out. Vibratory urticaria is typically observed at the friction site rather than in widespread distribution and is therefore unlikely in his case.

Contact dermatitis or a reaction to any cosmetic products is unlikely with his clinical history. Skin prick testing or patch testing is not indicated.

The patient was prescribed a H1- and H2- blocker, loratidine 10 mg po daily and ranitidine 150 mg po daily. He is to follow up with the allergy clinic in 3 months.

Summary

There is a mnemonic for fifferential diagnosis of chronic urticaria: VIP

Vasculitis, confirmed by biopsy
Idiopathic, 75% of patients
Physical, benign

Physical urticaria

Physical urticaria is defined as hives provoked by physical stimulus such as:

CDC S (mnemonic)

Cold urticaria due to cooling the skin
Dermographism due to stroking the skin
Cholinergic urticaria due to exercise, emotion, or heat
Solar urticaria due to sun exposure

Physical urticaria can be confirmed by challenge testing, and is best treated symptomatically by avoidance of provocative stimuli and antihistamines.

Testing procedures for diagnosis of physical urticarias depend on the cause (stimulus):

- Dermographism: Stroking with narrow object, e.g. a tongue depressor

- Cold urticaria: ice cube test

- Heat urticaria: test tube water at 44°C (111°F)

- Pressure urticaria: Sandbag test or a bag with heavy books (Middleton's Allergy textbook, 2 volumes)

- Vibratory urticaria: vibration with laboratory vortex for four minutes

- Cholinergic urticaria: exercise for 15-20 minutes or leg immersion in 44°C (111°F) bath

- Aquagenic urticaria: challenge with tap water at various temperatures

References

Urticaria: A Short Review. V. Dimov. Clinical Notes in Allergy and Immunology.
Chronic Idiopathic Urticaria. Current Opinion in Allergy and Clinical Immunology, Medscape, 2003.

Related reading

Anti-FceR1 Autoantibodies in Chronic Urticaria

Flickr user: "I have a weird allergy called "Dermatography" where the skin welts up from contact"

"Young mother must wrap up all year round because she is allergic to the cold"http://goo.gl/w25WB - Cold urticaria in Daily Mail.

Self-referential illustration of dermatographic urticaria. Wikipedia, Creative Commons Attribution-Share Alike 3.0 Unported license.

Published: 03/10/2010
Updated: 03/10/2011