Diagnosis of chronic cough in children

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 NSU

Pathophysiology of cough:

- large particles reach the upper respiratory structures - removed by coughing unless lodged as foreign body
- small particles reach the bronchioles - removed by mucociliary activity
- smallest particles reach the alveoli - removed by alveolar macrophages by phagocytosis

Cough expels particles from the airway at "the speed of sound."

Acute cough

Defined as cough of less than 4-week in duration. The most common cause is acute upper respiratory infection (URTI). The cough is usually non-productive or minimally productive of sputum (phlegm).

Frequent viral infection (normal frequency is up to 8-10 per year) with acute cough can mimic chronic cough. Acute cough due to repeated viral infections is associated with normal chest X-ray. This type of cough is unresponsive to asthma therapy with ICS or LTRA.

Chronic cough

Defined as cough of greater than 4-week in duration. Evaluation is indicated.

Chronic cough is very common and it is the 5th most frequent cause of patient visits. The most common cause of chronic cough in children is cough-variant asthma.

Cough suppressants (cough syrup) are prescribed on a "massive scale" in children but there is little evidence for efficacy beyond the placebo effect and the natural resolution of the cough.

The current guidelines (see the references at the end of the article) divide chronic cough into specific and nonspecific categories.

Placebo effect can have a considerable impact, Treatment should be based on the etiology of the cough. Adult studies may not be applicable to children, for example, GERD is a common cause in adults but relatively rarer in children, foreign body aspiration should be considered in children.

Chronic productive purulent cough always requires intervention.



Differential diagnosis of cough, a simple mnemonic is GREAT BAD CAT TOM. Click here to enlarge the image: (GERD (reflux), Laryngopharyngeal Reflux (LPR), Rhinitis (both allergic and non-allergic) with post-nasal drip (upper airway cough syndrome, UACS), Embolism, e.g. PE in adults, Asthma, TB (tuberculosis), Bronchitis, pneumonia, pertussis, protracted/persistent bacterial bronchitis (PBB), Aspiration, e.g foreign body in children, Drugs, e.g. ACE inhibitor, CF in children, Cardiogenic, e.g. mitral stenosis in adults, Achalasia in adults, Thyroid enlargement, e.g. goiter, "Thoughts" (psychogenic), Other causes, Malignancy, e.g. lung cancer in adults).

Diagnosis of chronic cough

History - ask about duration (months vs. years), seasonal trends (e.g. allergic asthma triggered by ragweed), times of day when present (night cough could be GERD), associated symptoms, triggers (e.g. exercise in EIB), inhaled foreign body or choking at any age (50% of aspirated foreign bodies have no history), successful and unsuccessful therapies, recent weight loss (ominous sign - cancer or severe infection), recurrent infections (could indicate immune deficiency (PIDD) or ciliary dyskinesia).

Physical examination - assess growth and development for nutritional status and/or obesity, upper respiratory tract for signs of allergic rhinitis (pale boggy trubinates, allergic shiners, Dennie's line), chronic sinus disease, postnasal drip, nasal polyps (CF, PIDD), ear-cough reflex (foreign body in the ear triggers cough in 5% of children).

Specific chronic cough - clinical clues for diagnosis

- auscultatory findings (asthma, CF)
- cardiac abnormalities
- chest pain or dyspnea
- elevated respiratory rate
- chest wall deformity
- digital clubbing
- productive purulent cough (CF, foreign body)
- difficulty with exercise (EIB)
- failure to thrive (CF)
- recurrent bacterial pneumonia (CF, PIDD)
- feeding difficulty - aspiration from the "top" (swallowing problem) or "below" (GERD)
- hemoptysis - never "normal"
- hypoxemia
- immune deficiency
- congenital anomaly
- neurodevelopmental condition - aspiration risk

Nonspecific cough

Evaluation of nonspecific cough:

- chest X-ray - CF, pneumonia. "If you suspect meningitis, do an LP. If you suspect CF, do a sweat test." The current newborn screening identifies 95% of children with CF - this means that 5% of children with CF are not identified at birth and present with symptoms later in life.
- spirometry - asthma

If CXR and spirometry are normal, observe for 1 to 2 weeks.

Treatment of nonspecific cough

Consider prescribing:

- an antibiotic (macrolide) for "wet" productive cough. A 2-week course of amoxycillin clavulanate achieves cough resolution in children with chronic wet cough, supporting the diagnosis of protracted/persistent bacterial bronchitis (PBB, http://goo.gl/4Vmtd).

- a trial of inhaled steroid (ICS) for dry cough

Specific chronic cough

Diagnostic evaluation includes:

- in­fants and toddlers - chest X-ray and sweat chloride test

- in­fants and toddlers - evaluate for aspiration - due to either gastroesophageal reflux (GERD) ("bottom") or swallowing disorder ("top")

- in­fants and toddlers - immunodeficiency studies - quantitative immunoglobulins (IgGAME), nitroblue tetrazolium test (NBT) or even better DHR, complete blood count with differential

- reversible airway obstruction - spirometry if older than 5 years, followed by aerosolized bronchodila­tor, check for reversible obstruction 15 minutes later. If positive (more than 12% reversibility), treat for asthma.

- older children - chest X-ray, sweat chloride, pulmonary function tests (PFTs), and immunodeficiency studies

- computed tomography (CT) for bronchiectasis, interstitial lung disease (ILD), and congenital lesions. Use a pediatric CT protocol to minimize radiation

- flexible bronchoscopy for microbiological culture and airway assessment

- rigid bronchoscopy (performed by otolaryngologist (ENT) for aspirated foreign body (right mainstem bronchus is the typical place)

Chronic cough causes in children when using a step-by-step approach:

- 25% asthma. Asthma is the most common chronic respiratory disease, affecting up to 10% of adults and 30% of children (JACI, 2011).
- 23% prolonged bronchitis, protracted/persistent bacterial bronchitis (PBB) (responds to antibiotics)
- 20% upper airway cough syndrome or UACS (post-nasal drip)
- 5% GERD
- 2% bronchiectasis

Chronic cough causes in children when using "order all test from the beginning" approach. Work-up included chest X-ray, bronchoscopy, pulmonary function tests (PFTs) with bronchial challenge, sweat chloride, pH probe for GERD, and immunoglobulin levels (IgGAME):

- 28% GERD
- 22% allergic rhinitis or post-nasal drip (upper airway cough syndrome, UACS)
- 13% asthma
- 5% infection
- 3% aspiration
- 20% multiple etiologies - this is due to all tests done concurrently

Age-based diagnosis of chronic cough:

- infancy - aspiration, asthma, cystic fibrosis, recurrent re­spiratory tract infections, passive smoke exposure, congenital heart disease

- early childhood - aspiration, asthma, foreign body aspiration, cystic fibrosis, bronchiectasis, chronic sinusitis

- late childhood and adolescence - asthma, bronchiectasis, cystic fibrosis, infection, foreign body aspiration, active or passive cigarette smoke, psychogenic cough, sinusitis, post-nasal drip

Aspirated (retained foreign body

This can occur at any age. There is a positive initial history only in 30% of cases - the yield can be increased to 50% by focused questioning.

Ask about high risk habits - eating nuts, chewing on pencil eraser, etc.

Imaging: inspiratory-expiratory or bilateral decubitus plain films, CT may be necessary

The ultimate diagnosis and treatment is with rigid bronchoscopy by ENT.

Psychogenic cough (habit cough)

Typically diagnosed in pre-teens and teenagers. It disappears during sleep. Diagnostic evaluation is non-revealing. There is no response to medications (ICS or antibiotics).

Cough-variant asthma

Chronic, persistent cough - without wheezing - may be the only manifestation of asthma. More than 60% bronchial obstruction is needed to produce wheezing - asthma can occur without wheezing - spirometry is required for diagnosis.

Cough-variant asthma presents as dry cough at night. It worsens with exercise (EIA) and nonspecific triggers (cold air).

Cough-variant asthma responds to asthma therapy with ICS.

Cough-variant asthma is diagnosed with pulmo­nary function testing (PFTs) with response to bronchodilator.

The most common cause of chronic cough in children is cough-variant asthma.

Cough suppressants in children - there are no randomized controlled trials to support efficacy. The suppression could be hazardous, especially with productive cough.

Treat viral-related cough with increased fluid intake and humidity (aerosolized saline, etc.).

The cough suppressant dosing guidelines for adults are imprecise in children. An alternative is throat lozenges ("Halls", etc.).

References

Chronic cough in children – Sally L. Davidson Ward. Audio-Digest Pediatrics, Volume 56, Issue 10, May 21, 2010.
Guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Chang AB, Glomb WB. Chest. 2006 Jan;129(1 Suppl):260S-283S.
Guidelines for evaluating chronic cough in pediatrics: ACCP evidence-based clinical practice guidelines. Agency for Healthcare Research and Quality.

Related reading

How should one investigate a chronic cough? Cleveland Clinic Journal of Medicine, 2011.
Tips to Remember: Cough in Children. Allergy Tips brochures by AAAAI.
Allergies are bad, sure -- but do you know what happens when your kid inhales a nut. ChicagoTribune.com, 2011.
Green or yellow phlegm likely to be bacterial - confirming beliefs by doctors & patients http://goo.gl/zff8X and http://goo.gl/cwKGs
Diagnostic algorithm for the approach to children with chronic cough. ER, 2011.
Diagnostic Checklist (mobile version) - UToronto and standard web version
Childhood cough - 2012 BMJ review.
Child with chronic cough - WAO interactive case http://goo.gl/yK48I
AInotes - Chronic Cough (Pediatric) http://bit.ly/Ue0g83
Differential diagnosis of chronic cough in children. Allergy and Asthma Proceedings, Volume 35, Number 2, March/April 2014 , pp. 95-103(9) http://buff.ly/1mpq9oy

Figures





Clinical approach from the concept of cough hypersensitivity - figure: http://buff.ly/1Jej9Cq

Video

Chronic Cough - COLA video lecture http://bit.ly/URcUQa:



Published: 11/12/2010
Updated: 11/26/2013

Subcutaneous Immunotherapy (SCIT)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist

Allergen immunotherapy was introduced by Leonard Noon 100 years ago and is the only disease-modifying treatment for allergic individuals (Allergy, 2012).

What is allergen-specific immunotherapy?

The practice of administering to allergic patients gradually increasing doses of an allergen to achieve and maintain hyposensitization toward the allergen. CPT Code 95165 is from the Medicare physician fee schedule for allergy immunotherapy.

Benefits of immunotherapy

- Effective for venom anaphylaxis, allergic rhinconjunctivitis and asthma cause by
inhalant allergen
- Provides long-term benefits - there was still a significant clinical benefit six years
after discontinuation of grass pollen immunotherapy in childhood (Allergy 2002 57:4 306).
- Modifies the natural course of the disease (allergic rhinitis)
- Prevents new sensitizations
- Reduces progression of allergic rhinitis to asthma in children with allergic rhinitis, if started early

Mechanisms of allergen-specific immunotherapy


Mechanisms of allergen-specific immunotherapy (click to enlarge the image). CD27 expression on allergen-specific T cells may be a new surrogate for successful allergen-specific immunotherapy (JACI, 2012).

Cellular mechanisms

- Expands allergen-specific Th1 immunity
- suppresses Th2 response
- Induces regulatory T cells (Tregs) - Tr1 produce IL-10 and Th3 produce TGF-β
- Increases mRNA for Th1 cytokines (IFN-gamma, IL-2, IL-12)
- Reduces mRNA for Th2 cytokines (IL-4)

Successful immunotherapy is often associated with a shift from TH2 to TH1 CD4+ lymphocyte immune response to allergen.

Humoral mechanisms

- Reduction in allergen-specific IgE
- Increase in allergen specific IgG antibodies lead to neutralization of allergen, blockage of IgE-facilitated allergen presentation to T cells, and blockage of IgE-dependent activation of mast cells and basophils

However, increases in allergen-specific IgG blocking antibody titer are not predictive of the duration and degree of efficacy of immunotherapy.

Subcutaneous immunotherapy (SCIT)

Subcutaneous immunotherapy (SCIT) was first introduced by Leonard Noon in 1911. There is a small but real risk of IgE-mediated reactions, including anaphylaxis and death. Systemic reactions occur in 0.05-0.6% of doses administered.

Terms

Other terms that have been used for allergen immunotherapy are hyposensitization, allergen-specific desensitization, and the common terms allergy shots or injections.

Major allergen refers to any antigen that binds to human IgE sera in more than 50% of patients in a clinically sensitive group.

Vaccine, or allergen vaccine, is the recommended term for the therapeutic preparations used in allergen immunotherapy.

Extracts, or allergen extracts, are solutions of proteins and glycoproteins extracted from source materials such as pollen, mold cultures, and pelt.

Desensitization is a process by which effector cells are rendered less reactive or nonreactive to IgE-mediated immune responses by the rapid administration of incremental doses of an allergenic substance.

Rush immunotherapy: incremental doses of allergen are administered at intervals varying between 15 to 30 minutes and 24 hours, until the optimal effective dose is achieved.

Modified rush immunotherapy: subcutaneous allergen injections are administered at 24-hour intervals.

Cluster immunotherapy is the administration of two or more injections per visit to achieve a maintenance dose. It is a type of rush immunotherapy characterized by the giving of several allergen injections in a single day of treatment.

There are Different Build-Up Regimens

1. Conventional / routine (once-twice/week)
2. Daily
3. Cluster (two or more injections per visit)
4. Rush / modified rush / Ultra-rush

Build Up Phase

– Conventional SCIT involves receiving injections with increasing amounts of the allergen. Injections ranges from 1 to 3 times a week.The duration of generally ranges from 3 to 6 months at a frequency of 2 times and 1 time per week, respectively.

– Cluster immunotherapy is an accelerated build-up schedule that entails administering several injections at increasing doses (generally 2-3 per visit) sequentially in a single day of treatment on nonconsecutive days. The maintenance dose is generally achieved within 4 to 8 weeks.

– Rush immunotherapy is an accelerated immunotherapy build-up schedule that entails administering incremental doses of allergen at intervals varying between 15 and 60 minutes over 1 to 3 days until the target therapeutic dose is achieved.

Cluster SCIT

SCIT 1 or 2 times per week with a schedule that contains fewer total injections than are used with conventional immunotherapy.

2 or more injections are given per visit on nonconsecutive days. The injections are typically given at 30-minute intervals. The patient can reach a maintenance dose in 4 weeks.

The cluster schedule is associated with the same or a slightly increased frequency of systemic reactions compared with immunotherapy administered with more conventional schedules.

The occurrence of both local and systemic reactions to cluster immunotherapy can be reduced with administration of an antihistamine 2 hours before dosing.

Rush SCIT

The most accelerated schedule that has been described for inhalant allergens involves
administering 7 injections over the course of 4 hours.

Ultra-rush immunotherapy schedules have been described for stinging insect hypersensitivity to achieve a maintenance dose in as little as 3.5 to 4 hours.

Maintenance Phase for all forms of SCIT (conventional, cluster and rush)

The maintenance phase begins when the effective therapeutic dose is reached. Once the maintenance dose is reached, the intervals between the allergy injections are increased.

The dose generally is the same with each injection, although modifications can be made based on several variables (ie, new vials or a persistent large local reaction causing discomfort).

The intervals between maintenance immunotherapy injections generally ranges from 4 to 8 weeks for venom and every 2 to 4 weeks for inhalant allergens but can be advanced as tolerated if clinical efficacy is maintained.

Definitions for Maintenance Phase SCIT

- Maintenance concentrate - preparation that contains individual or mixtures of manufacturer’s allergen extracts intended for allergen immunotherapy treatment. A maintenance concentrate can be composed of a concentrated dose of a single allergen or a combination of concentrated allergens to prepare an individual patient’s customized allergen immunotherapy extract mixture.

- Maintenance dose (effective therapeutic dose) - the dose that provides therapeutic efficacy without significant adverse local or systemic reactions. The effective therapeutic dose may not be the initially calculated projected effective dose.

- Maintenance goal (projected effective dose) - the allergen dose projected to provide therapeutic efficacy. The maintenance goal is based on published studies, but a projected effective dose has not been established for allergens. Not all patients will tolerate the projected effective dose, and some patients experience therapeutic efficacy at lower doses.

The average duration of immunotherapy is 3-5 years.

Evidence for Efficacy for SCIT (in declining order of efficacy)

- Grass pollens
- Ragweed pollen
- Birch pollen
- Mountain cedar pollen
- Parietaria species pollen
- Cat and dog dander
- Dust mites

Effective Doses of Extracts

Ragweed
4-24 mcg Amb a 1

D. pt
3.25-12 mcg Der p 1

D far
10 mcg Der f 1

Timothy
15-20 mcg Phl p 5

Cat
11-17 mcg Fel d 1

Dog
5 mcg Can f 1

Birch
3.28-12 mcg Bet v 1

Alternaria
1.6 mcg Alt a 1

Standardized extracts are preferred.

- BAU (Bioequivalent Allergy Unit) is based on ID(50) EAL method.

- AU (Allergy Units) was used before BAU and is based upon the major allergen content. Dust mites have AU=BAU.

- Major allergen: Amb a 1, (One FDA unit of Amb a 1 equals 1 mg of Amb a 1, and 350 units of Amb a 1/mL is equivalent to 100,000 BAU/mL). Can f 1 allergen now is also standardized.

Extract concentrations

- WT/Vol - If the extract is 1:10, use 1 ml, if the extract is 1:20, use 2 ml
- Each vial is usually 5 ml or 10 ml
- Dust mite – Use 1 ml of each type & 2ml (max) (5000 AU/ml). If dust mite concentration is 10,000 AU/ml, then use 0.5ml of each type.
- Cat - can use up to 3 ml - up to 30,000 U (10,000 U/ml)
- Bermuda - Use 0.4ml - 4000 U (10,000 U/ml)
- Northern Grasses - Use 0.4 ml - 40,000 U (100,000 U/ml)
- Ragweed - Use 0.5 or 0.6 ml (200 Ag EU/ml)

Venom extract dose

- Vespid venom 100 mcg/ml
- Mixed vespid venom 300 mcg/ml

Commercial honey bee venom vaccine is prepared from venom obtained by electrical stimulation. Commercial vespid venom protein vaccines are prepared by extraction of dissected venom sacs.

Starting Dose in Conventional SCIT

Common starting dilutions from the maintenance concentrate are 1:10,000 (vol/vol) or 1:1000
(vol/vol). Even more diluted concentrations frequently are used for patients who are highly
sensitive, as indicated by history or skin test reaction.

Conventional SCIT Build-up Phase

The frequency of allergen immunotherapy administration during the build-up phase is usually 1 to 2 injections per week.

With this schedule, a typical patient can expect to reach a maintenance dose in 4 to 6 months. The interval between injections is empiric but might be as short as 1 day without any increase in the occurrence of systemic reactions.

Example SCIT schedule:

Vial #4, 1:1000, Schedule A
0.05 ml
0.15 ml
0.25 ml
0.5 ml

Vial #3, 1:100, Schedule B
0.05 ml
0.1 ml
0.2 ml
0.3 ml
0.4 ml
0.5 ml

Vial #2, 1:10, Schedule C
0.05 ml
0.07 ml
0.1 ml
0.2 ml
0.3 ml
0.4 ml
0.5 ml

Vial #1, 1:1, Schedule D
0.05 ml
0.07 ml
0.1 ml
0.15 ml
0.2 ml
0.25 ml
0.3 ml
0.4 ml
0.5 ml

Alternative SCIT schedule

Vial #5, 1:10,000
0.05, 0.1, 0.2, 0.35, 0.5 ml

Vial #4, 1:1000
0.05, 0.1, 0.2, 0.35, 0.5 ml

Vial #3, 1:100
0.05, 0.1, 0.2, 0.35, 0.5 ml

Vial #2, 1:10
0.05, 0.1, 0.2, 0.35, 0.5 ml

Vial #1, 1:1
0.05, 0.1, 0.2, 0.35, 0.5 (this is maintenance dose)

Dosing adjustments in SCIT

Late or missed doses:
- 7 days or less - no change
- 8-13 days - repeat previous dose
- 14-21 days - decrease dose by 25%
- 21-28 days - decrease dose by 50%
- If the patient missed the injections for more than 6 weeks, go back to the previous vial

New vial - reduce dose by 50%. No need to reduce in venom SCIT.

Systemic reactions - decrease to the last tolerated dose or even lower.

Preservatives of extracts

The glycerinated allergen extract formulation is based on 50% glycerin.

Extracts prepared in saline or buffer solutions with less than 50% glycerin are referred to as aqueous.

Most standardized allergenic extracts are available only as glycerinated products. For most of the standardized products the expiration date is three years from the date of manufacture. The only standardized aqueous product, short ragweed extract, has an expiration dating of 12 months from the date of manufacture.

Non-standardized extracts

- w/v: the weight of allergen source material extracted with a given volume of fluid (weight by
volume)

– 1:100 indicates that 1 g of dry allergen was added to 100 ml of a buffer for extraction

- PNU: protein nitrogen unit, an estimate of the protein nitrogen content of an extract, where 0.01 g of protein nitrogen equals 1 PNU

Extracts with a particular wt/vol or PNU potency can have widely varying biologic activities.

Outdoor molds: Alternaria, Cladosporium, Drechslera (Helminthosporium).

Indoor molds: Penicillium and Aspergillus - they also have the highest extract protease concentration, in the 200s mcg range. Cockroach extract has a protease concentration of 168 mcg. Alternaria is 29 mcg and house dust mite is less than 5 mcg.

Indications for SCIT

- Allergic Rhinitis
- Allergic Asthma
- Venom Allergy

SCIT is Not Indicated

- Atopic Dermatitis
- Food Allergy

Relative Contraindications for SCIT

- Chronic Urticaria/ Angioedema
- Unstable Asthma
- Concurrent use of Beta-blockers (including topicals, e.g. eye drops) or ACE Inhibitors
- Severe Coronary Artery Disease
- Malignancy
- Unable to Communicate Clearly (children younger than 5 years old)
– Significant immunodeficiency
– Severe psychological disorders
– Poor compliance with medications
– Severe obstructive lung disease (limited reserve)
– Conditions that contraindicate epinephrine use

Venom Immunotherapy (VIT)

VIT with 300-mcg doses of mixed vespid venom provides 98% efficacy. Honeybee VIT is 75% to 85% effective.

VIT is generally not necessary in children 16 years of age and younger who have experienced cutaneous systemic reactions without other systemic manifestations.

Adults who have experienced only cutaneous manifestations to an insect sting are generally considered candidates for VIT, although the need for immunotherapy in this group of patients is controversial.

Because the natural history of fire ant hypersensitivity in children who have only cutaneous manifestations has not been well elucidated and there is increased risk of fire ant stings in children who live in areas where fire ants are prevalent, immunotherapy might be considered.

Pregnancy and SCIT

Allergen immunotherapy is usually not initiated during pregnancy because of risks associated with systemic reactions and their treatment (ie, spontaneous abortion, premature labor, or fetal hypoxia).

The initiation of immunotherapy might be considered during pregnancy for a high-risk medical condition, such as anaphylaxis caused by Hymenoptera hypersensitivity.

When a patient receiving immunotherapy reports that she is pregnant, the dose of immunotherapy is usually not increased, and the patient is maintained on the dose that she is receiving at that time.

Allergists should provide an EpiPen prescriptions to all patients on SCIT.

References

Allergen-specific immunotherapy for respiratory allergies: From meta-analysis to registration and beyond. JACI, 2010.

Related reading

Immunotherapy reduces asthma symptoms and use of asthma medication. Cochrane Review, 2010. http://bit.ly/bXXITA - http://bit.ly/bRNiXY - http://bit.ly/bED4BH
Allergen Immunotherapy: A History of the First 100 Years. Medscape, 2011.
Immunotherapy can provide lasting relief - AAAAI info sheet for patients (PDF).
Dose adjustments for patients late for allergen immunotherapy injections. AAAAI Ask The Expert, 2010. http://goo.gl/je9tE
Pollen immunotherapy induces allergen-specific IgG antibodies with inhibitory activity against IgE that are persistent. JACI, 2011.
Your allergy meds may be making you fat - Regular use of OTC antihistamines has been linked to weight gain. NBC, 2011.
SCIT ("allergy shots") is at least as potent as pharmacotherapy in controlling the symptoms of allergic rhintis as early as the first season of therapy. JACI, 2011.
100 years since Leonard Noon published historic paper on SCIT “PROPHYLACTIC INOCULATION AGAINST HAY FEVER” in the Lancet http://goo.gl/Zw3FG
Allergen immunotherapy practice in the United States: guidelines, measures, and outcomes (2011) http://goo.gl/xHYjG
Best Immunotherapy for Allergic Rhinitis and Asthma: SCIT or SLIT? SCIT is likely more effective, SLIT is safer. Medscape, 2011.
Allergen-specific immunotherapy. Allergy, Asthma & Clinical Immunology 2011, 7(Suppl 1):S5.
Allergy immunotherapy: Reduced health care costs in adults and children with allergic rhinitis. http://buff.ly/12sDYdh

Published: 06/27/2010
Updated: 02/27/2013

New approaches to immunotherapy

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 NSU

Allergen immunotherapy was introduced by Leonard Noon 100 years ago and is the only disease-modifying treatment for allergic individuals (Allergy, 2012).


Mechanisms of allergen-specific immunotherapy (click to enlarge the image).

Novel approaches to immunotherapy

- Sublingual immunotherapy (SLIT)
- Peptide-based immunotherapy
- CpG-enhanced immunotherapy
- Anti-IgE and immunotherapy
- Recombinant allergen vaccines
- Epicutaneous allergen-specific immunotherapy. Skin patches coated with allergens to treat hay fever - check the caveats too listed by WSJ and JACI, 2011.

SLIT

Interesting fact: The longest human tongue ever recorded was that of Stephen Taylor and measures 9.8 centimetres (3.86 in). The longest tongue for a female is that of Annika Irmler at 7 centimetres (2.76 in).

The World Health Organization concluded that SLIT was a viable alternative to SCIT in 1998.

Practical aspects of SLIT

- Self-administered by patients
- Soluble tablets or drops
- Sublingual-swallow: keep under the tongue for 1-2 min, then swallow. Contact time with the oral mucosa is critical to the effectiveness of SLIT - if the allergen is immediately swallowed, there are negligible clinical effects.
- Dose of allergen greater than for SCIT (3-300 times higher)
- Administration schedule and amount of allergen vary, depending on the manufacturer
- Amount of allergen given during a course of SLIT is higher than in SCIT: there is a bild-up phase (very rapid), followed by a maintenance phase

Efficacy of SLIT in allergic rhinitis

The magnitude of clinical efficacy ranged from 20-60% reduction of symptoms. House dust mite (HDM) SLIT was less effective, but results were comparable to SCIT. For HDM, duration of treatment seems to be crucial - treatments that lasted longer than 24 months had positive results.

Clinical safety of SCIT vs. SLIT

Safety of SCIT

Systemic reactions occur in 0.05-0.6% of doses administered. Rare fatalities have been reported.

Safety of SLIT

No life-threatening adverse events reported since 1986. Most common adverse effects include oral/sublingual itching, stomachache, and nausea. No increased risk in patients with oral allergy syndrome.

Sublingual immunotherapy is safe during pregnancy, it is also safe when initiated for the first time in pregnancy (study) (Allergy, 2012).

CpG-enhanced immunotherapy

Bacterial DNA contains unmethylated CpG di-nucleotides (CpG motifs) that act as a danger signal to the vertebrate immune system and trigger protective innate and acquired immune responses.

CpGs work through toll-like receptor 9 (TLR-9) to activate monocytes, dendritic cells, B cells, and NK cells. CPGs promote Th1 and inhibit Th2 response (similar to allergen-specific SCIT). TLR9 and MyD88 play central role in protective immunity to malaria http://goo.gl/VVF07

The immune stimulatory activity of bacterial DNA can be mimicked by synthetic oligodeoxynucleotides containing CpG motifs. They can be added to a vaccine or linked to an
antigen to greatly boost the immune response.

Anti-IgE (omalizumab (Xoliar) and immunotherapy

The combination anti-IgE and allergen immunotherapy might offer advantages that
neither method can provide separately. Anti-IgE administered during the induction phase
of immunotherapy might reduce the risk of IgE-mediated anaphylaxis.

References

Allergen-specific immunotherapy for respiratory allergies: From meta-analysis to registration and beyond. JACI, 2010.

Related reading

Immunotherapy in Asthma - 11-page Medscape review http://goo.gl/KUAcA

Sublingual immunotherapy is an extremely complex issue in the U.S. AAAAI http://goo.gl/wVOKr

Timothy grass allergy immunotherapy tablets safe and effective in American children with allergic rhinitis http://goo.gl/tsKL4

Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults - it works. http://goo.gl/ePOFG

Epicutaneous allergen administration: is this the future of allergen-specific immunotherapy? Allergy, 2011.

Published: 06/27/2010

Updated: 03/15/2012

Occupational Asthma

Author: V. Dimov, M.D., Allergist/Immunologist, Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist, Assistant Professor at NSU

The workplace is a significant contributor to the burden of asthma. The majority of asthma cases probably represent what is labeled "work-exacerbated asthma". However, in a significant number of subjects, asthma is actually caused by one or more agents present in the workplace; this is occupational asthma.


Occupational Asthma (click to enlarge the image).

Occupational asthma (OA)may account for 25% or more of "de novo" adult asthma.

Two types of occupational asthma are distinguished:

1. Immunologic occupational asthma with a latency period due to high-molecular-weight agents (protein from animals, plants and food) and low-molecular-weight agents (hapten - platinum, penicillin, epoxy resin). Immunologic OA constitutes 85% of cases of OA

2. Non-immunologic occupational asthma without a latency period.

OA is caused by:

1. Immunologic OA - sensitizing agents

- high-molecular-weight agent such as a protein from biological sources
- low-molecular-weight reactive chemical such as isocyanate

Animal lab workers usually need 2 two years to develop sensitization. In contrast, flour workers need a significantly longer period for sensitization.

Allergic rhinitis usually precedes OA for HMW agents but not for LMW agents (haptens).

2. Non-immunologic OA - irritants, for example, the reactive airways dysfunction syndrome (RADS)

When evaluating patients for occupational asthma, sputum eosinophil counts at 7 and 24 hours after specific inhalation challenge have a greater sensitivity and positive predictive value than exhaled nitric oxide (eNO).

Reactive Airway Disease Syndrome (RADS)

RADS is non-allergic and non-immunologic OA. RADS occurs with a single, high dose exposure and has the following features:

- no latency
- onset within 24 hours
- persists for longer than 3 months

The major causes of RADS are soluble gases and fumes which are corrosive. An example of RADS is the World Trade Center-associated cough.

Agents implicated in RADS

Chlorine
Toluene diisocyanate
Phosgene
Sulfuric acid
Chlorine dioxide
Hydrochloric acid
Phosphoric acid
Hydrogen sulfate
Anhydrous ammonia
Sulfur dioxide

Timely removal from exposure leads to the best prognosis in OA.

Work-related asthma (WRA) has 3 phenotypes:

1. sensitizer-induced occupational asthma (OA) caused by high-molecular-weight (HMW) proteins or low-molecular-weight (LMW) chemicals

2. irritant-induced asthma

3. work-exacerbated asthma


Agents associated with occupational asthma (click to enlarge the image).

Agents associated with occupational asthma

Western Red Cedar mill
Plicatic acid

Body shop and spray paint
Isocyanates
Paints, adhesives, and plastics
Acid anhydride
Electronic soldering
Colophony, abietic acid and pimaric acid
Detergents
Alcalase
Catalytic converters
Platinum salts

Hairdressers
Ammonium persulfate

Printers, hairdressers
Gum acacia
Adhesives and epoxy resin
Phthalic anhydride
Plastics
Trimellitic anhydride
Bathtub paint, varnish, and lacquer
Toluene

Forest workers and carpenters
Wood dusts
Shellac and lacquer
Amines

Janitors
Chloramine

Hospital workers
Formaldehyde.

Related reading: One desk chair - hold the formaldehyde. If building materials had nutrition labels, you'd be scared of toxic ingredients, Google blog.

Drug industry workers
Psyllium
Textile industry workers
Azo dyes

In a French study, physicians were asked to report newly diagnosed cases of work-related asthma and reactive airway dysfunction syndrome (RADS). 82.3% of 559 cases reported (64% males, mean age 36 yrs) involved occupational asthma, 4.7% RADS and 12.7% atypical asthma syndromes.

The most frequently suspected agents were flour (23.3%), followed by isocyanates (16.6%), latex (7.5%), aldehydes (5.5%), and persulphates (4.1%). Occupations at risk were bakers (23.9%), healthcare workers (12%), painters (9.1%), hairdressers (5.2%), wood industry workers (4.8%) and cleaners (3.5%).

Work-related Asthma - AAAAI COLA video lecture by David Bernstein, MD, 07/2012:



References

Occupational asthma: Current concepts in pathogenesis, diagnosis, and management. Mark S. Dykewicz. JACI, Volume 123, Issue 3, Pages 519-528 (March 2009)
Agents causing occupational asthma. Jean-Luc Malo et al. JACI, Volume 123, Issue 3, Pages 545-550 (March 2009)

Occupational asthma in France: a 1-yr report of the Observatoire National de Asthmes Professionnels project. Eur Respir J 2002; 19:84-89.

Hairdressers Working in Hair Salons for Women are at increased risk for occupational asthma - prevalence is 9.5% http://goo.gl/fKPDq
Occupational sensitization to soy allergens in workers at a processing facility, high molecular weight allergens Gly m 5 and Gly m 6 may be the respiratory sensitizers http://goo.gl/6oXYd

Workforce occupational asthma in New Zealand. The highest risks: printer/baker/sawmill labourer/metal processing. Ann Occup Hyg. 2010.
The new guidelines for management of work-related asthma - ERJ 2012.

Work-exacerbated asthma and occupational asthma: Do they really differ? http://buff.ly/PLajpw

Published: 05/09/2010
Updated: 10/09/2012

Interleukin-17 (IL-17)

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 NSU

IL-17 is actually not one cytokine but a family of 6 related cytokines - promote tissue damage in autoimmune diseases and play a role in defense against bacterial infections.

Differentiation and maintenance of IL-17-producing T cell subset are dependent on TGF-β, IL-23, IL-6.

There was a theme issue of JACI on IL-17 and Th17 cells (PDF).

TH17 cells produce IL-17, IL-6, TNF, and IL-22. TH17 cells are important for neutrophil recruitment and they contribute to autoimmune disorders.

T(H)17 cells are the newest member of the T(H) cell family and are characterized by their ability to produce cytokines such as:

- IL-17
- IL-17F
- IL-22
- CCL20

T(H)17 cells are also associated with the development of:

- allergic contact dermatitis
- atopic dermatitis
- asthma


T helper cells (click to enlarge the image).

Autosomal dominant hyper-IgE syndrome, a rare primary immunodeficiency disorder, is caused by mutations of signal transducer and activator of transcription 3 (STAT3), preventing T(H)17 lineage differentiation and increasing susceptibility to Staphylococcus and Candida species infections.

Anti-IL-17 Receptor Antibody Brodalumab Helps Patients with Psoriasis - NEJM, 2012. Anti–Interleukin-17 Monoclonal Antibody Ixekizumab Improves Chronic Plaque Psoriasis - NEJM, 2012.

Which cytokines promote neutrophil tissue inflammation?

(A) IL-2

(B) IL-5

(C) IL-8

(D) IL-10

(E) IL-17

Answers: IL-8 and IL-17.

References

Development and function of TH17 cells in health and disease. Louten J, Boniface K, de Waal Malefyt R. J Allergy Clin Immunol. 2009 May;123(5):1004-11.
Development and function of TH17 cells in health and disease. Louten J, Boniface K, de Waal Malefyt R. J Allergy Clin Immunol. 2009 May;123(5):1004-11.

Sarcoidosis is a Th1/Th17 multisystem disorder, Thorax 2011.
Anti-IL-17 Receptor Antibody Brodalumab Helps Patients with Psoriasis - NEJM, 2012.
Anti–Interleukin-17 Monoclonal Antibody Ixekizumab Improves Chronic Plaque Psoriasis - NEJM, 2012.

Published: 04/09/2010
Updated: 03/09/2012

Interleukin-13 (IL-13)

Author: V. Dimov, M.D., Allergist/Immunologist, Assistant Professor, University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist

Source: CD4+ T cells (TH2), NKT cells, mast cells

Receptors: Type I cytokine receptor family. Signal transduction involves Jak-STAT.

The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology.

Erythropoietin (Epo) is produced in the kidney in response to low oxygen tension. Epo works through a type I cytokine receptor that signals through Jak2-STAT5.


(click to enlarge the image)

IL-13 is homologous to IL-4. Receptor distribution more limited: endothelial cells, B-cells, mononuclear phagocytes, and basophils - NOT mast cells or T-cells.

2 cognate receptors:

- IL-13Rα1 (low affinity by itself); paired with IL-4 receptor α (high affinity, signaling)
- IL-13Rα2 ( high affinity, decoy)

IL-13–induced TGF-β–mediated fibrosis is dependent on IL-13Rα2.

IL-13 binds to a low-affinity IL-13Ra2 subunit and a high-affinity complex comprised of IL-13Ra1 and IL-4Ra. Binding to this high-affinity complex leads to the phosphorylation-dependent activation of JAK1, JAK2 and STAT6.

IL-3 effects: IL-3 promotes the growth and development of mast cells from bone marrow.

IL-3 is a basophil differentiating cytokine vs. stem cell factor (c-Kit ligand) which is a mast cell growth factor.

IL-13 effects

- B cells: isotype switching to IgE
- Epithelial cells: increased mucus production
- Fibroblasts: increased collagen synthesis
- Macrophages: increased collagen synthesis

Medications

There are 3 humanized mAbs in phase I or phase II human clinical trials.

CAT-354 well tolerated in phase I trial, phase II trial is underway.

Genentech Pipeline: Lebrikizumab is a humanized monoclonal antibody that bind specifically to IL-13.

STAT6

STAT6 is the common transcription factor for both IL-4 and IL-13 signaling.

Therapeutic target via:

- a dominant-negative peptide
- anti-sense RNA-based approaches

References

Asthma Phenotypes and Interleukin-13 - Moving Closer to Personalized Medicine - NEJM, 2011.

Interleukin-13 Signaling and Its Role in Asthma, WAO Journal, 2011.

http://www.medimmune.com/pipeline/pipeline_phase2_detail.asp, Wynn, T. A. IL-13 effector functions. Annu. Rev. Immunol. 21, 425–456 (2003).

Andrews, A. L. et al. IL-13 receptor 2: a regulator of IL-13 and IL-4 signal transduction in primary human fibroblasts. J. Allergy Clin. Immunol. 118, 858–865 (2006).

Grunig, G. et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 282, 2261–2263 (1998).

Bree, A. et al. IL-13 blockade reduces lung inflammation after Ascaris suum challenge in cynomolgus monkeys. J. Allergy Clin. Immunol. 119, 1251–1257 (2007).

McCusker, C. T. et al. Inhibition of experimental allergic airways disease by local application of a cell-penetrating dominant-negative STAT6 peptide. J. Immunol. 179, 2556–2564 (2007).

Popescu, F. D. Antisense- and RNA-interference-based therapeutic strategies in allergy. J. Cell Mol. Med. 9, 840–853 (2005).

Published: 04/09/2010
Updated: 09/09/2011

Interleukin-12 (IL-12)

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

IL-12 family cytokines are immunological playmakers that mediate surprisingly diverse functional effects (Nature, 2012 http://buff.ly/PE2xeG).

Source: Macrophages, dendritic cells

Crystal structure of human IL-12, Wikipedia, public domain.

IL-12 effects

- T cells: TH1 differentiation
- NK cells and T cells: IFN-γ synthesis, increased cytotoxic activity

IL-12 is the main cytokine that activates STAT4.

IL-12 consists of two subunits - p35 and p40.

IL-12 binds to a type I receptor, composed of β1 and β2 subunits:

- p35 binds to β2 receptor, leading to Jak 2 activation and STAT4

- p40 binds to β1 receptor, leading toTyk 2 activation and STAT4

IL-12 sends a powerful signal to naive T cells, directing their differentiation to TH, shifting immune response towards cell-mediated immunity. In asthma, production of IL-12 by blood cells and expression in airway is impaired.

IL-18 is synergistic with IL-12.

Trials

Injection of rh IL-12 reduces circulating eosinophils in asthma. Treatment was not well tolerated: flu-like symptoms, abnormal LFTs and arrhythmias. Not actively developed as a therapy.

References

Bryan, SA, O'Connor, BJ, Matti, S, et al. Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000; 356:2149.

Related reading

IL-12 in Wikipedia.

Ustekinumab is a Strong Option for Moderate to Severe Psoriasis - anti-IL12/23 monoclonal antibody with NNT of 2 http://goo.gl/gbXSJ

Published: 04/09/2010
Updated: 08/09/2011

Interleukin-10 (IL-10)

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

Source: Macrophages, T cells (mainly regulatory T cells)

IL-10 binds to a type II cytokine receptor, with Jak1 and Tyk2, Janus family kinases, which induce STAT3 signaling molecule.


(click to enlarge the image)

IL-10 effects

Macrophages, dendritic cells: inhibition of IL-12 production and expression of costimulators and class II MHC molecules

IL-10 has numerous functions:

- Inhibits eosinophil survival
- Inhibits IL-4 induced IgE synthesis
- Enhances IgG4 isotype switching
- Main inhibitory cytokine produced by T-reg cells in SCIT

Trials

In normal volunteers, IL-10 decreases CD4+ and CD8+ T cells, T-cell proliferation and endotoxin-driven TNF and IL-1beta production.

References

Recombinant human IL-10 currently being tested in RA, IBD, psoriasis, transplantation and hepatitis C. Chernoff, A. E. et al. A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J. Immunol. 154, 5492–5499 (1995).

Cytokine Receptors

Neonatal BCG vaccination induces IL-10 production by CD4(+) CD25(+) T cells. http://goo.gl/grZJ

Published: 04/09/2010
Updated: 08/09/2010

Interleukin-9 (IL-9)

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

Source: Th2 cells.

Receptors: Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked SCID.


(click to enlarge the image)

IL-9 effects

Stimulates cell proliferation and prevents apoptosis.

Trials

Blocking IL-9 reduces airway hyperresponsiveness in mice. Phase I trials of IL-9 mAb (MEDI-528) completed. Phase II trials in progress for treating moderate to severe, persistent asthma.

References

http://www.medimmune.com/pipeline/pipeline_phase2_detail.asp. 'Byrne, P. et al. A single dose of MEDI-528, a monoclonal antibody against interleukin-19, is well tolerated in mild and moderate asthmatics in the phase II trial MI-CP-138. Chest 132, 478 (2007).

Published: 04/09/2010
Updated: 08/09/2010

Interleukin-7 (IL-7)

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

IL-7 is a Type I family cytokine secreted by stromal cells in many tissues.

IL-7 stimulates survival and expansion of immature precursors committed to the B and T lymphocyte lineages.

IL-7 receptor consists of α chain associated with the γc chain (part of the receptors for IL-2, IL-4, and IL-15)

γc mutations lead to X-linked SCID. Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked

SCID.

Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).

Lack of a signal through which cytokine receptor accounts for the lack of T cell maturation in X-linked SCID?

A. IL-2

B. IL-7

C. IL-9

D. IL-15

E. IL-5

Answer: B.

References

Pending.

Published: 04/09/2010
Updated: 09/09/2010

Interleukin-5 (IL-5)

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

Source: CD4+ T cells (TH2).

Receptor: IL-5R heterodimer induces Jak2 and STAT 3 signaling pathway. The receptors for IL-3, IL-5, and GM-CSF share a common β chain. All 3 cytokines stimulate the development of eosinophils.

The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology.


(click to enlarge the image)

IL-5 effects

- Eosinophils: activation, increased production
- B cells: proliferation, IgA production

IL-5 is the key regulator of eosinophil proliferation.

Mepolizumab (Bosatria)

Humanized mAb against IL-5. Promising results in hypereosinophilic syndrome and eosinophilic esophagitis. Larger trials ongoing. Disappointing early clinical trials in asthma. 2 asthma studies published in NEJM in March 2009.

Emerging appreciation of asthma heterogeneity. Identification of "eosinophilic asthma" with tissue eosinophils, greater airway remodeling, more exacerbations.

Three concepts in NEJM studies:

1. inhibition of IL-5 reduces eosinophilic inflammation

2. not all asthma is eosinophilic

3. reduction in eosinophils associated with a decreased rate of exacerbations

Unlike previous studies of anti-IL-5, the NEJM trials included patients highly eosinophilic asthma (sputum eosinophils gerater than 3%, 16% in one group).

Eosinophilic asthma occurs in less than 5% of adult-onset asthma.

Average age at asthma onset was the mid-to-late 20s. Screened hundreds to get 20 in one study. Reduction of eosinophils had no effect on FEV1, symptoms, and asthma control.

Mepolizumab and Exacerbations of Refractory Eosinophilic Asthma, NEJM 2009

RCT, 61 subjects, sputum eosinophils greater than 3% despite high-dose ICS. Infusions of mepolizumab (29) or placebo (32) monthly for 1 year. Primary outcome: number of severe exacerbations. Secondary outcomes: symptoms, AQLQ (1-7), FEV1, airway hyperresponsiveness,eosinophils - blood and sputum.

Fewer severe exacerbations (2.0 vs. 3.4 per subject; relative risk, 0.57; P=0.02). Improvement in AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; P=0.02). Lower eosinophil counts in the blood (P lower than 0.001) and sputum (P=0.002). No significant differences: symptoms, FEV1, airway hyperresponsiveness.

Haldar P, Brightling CE, Hargadon B, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973-984.

Mepolizumab for Prednisone-Dependent Asthma with Sputum Eosinophilia, NEJM 2009

RCT, persistent sputum eosinophilia (greater than 3%) and symptoms despite oral CS. Less than 3% of the 800 adult patients with severe asthma in the practice (McMaster University, Hamilton, ON, Canada). 9 patients received mepolizumab (5 monthly infusions), 11 placebo.

12 asthma exacerbations in 10 placebo patients. Only one mepolizumab patient had an exacerbation, not associated with sputum eosinophilia (P=0.002). Mepolizumab patients able to reduce prednisone dose by a mean of 84% of their maximum possible dose, as compared with 48±40.5% in placebo (P=0.04). Improvements in eosinophil numbers, asthma control, FEV1 for 8 weeks after last infusion.

Small pilot study.

Severe limitations:

- higher sputum eosinophil count at baseline in the mepolizumab group (16.6 vs 4)
- no significant difference in final prednisone doses in the two study groups
- most on LABAs: did not retest for albuterol reversibility or methacholine in all patients
- some investigators aware of study-group assignments - aware of sputum-cell counts

Nair P, Pizzichini MMM, Kjarsgaard M, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009;360:985-993

Receptors for each of the following cytokines share the common gamma chain except which one?

A. IL-2

B. IL-7

C. IL-9

D. IL-15

E. IL-5

Answer: E.

References

Flood-Page P, Swenson C, Faiferman I, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med 2007;176:1062-1071.

Sally E. Wenzel, M.D. Eosinophils in Asthma — Closing the Loop or Opening the Door? NEJM, Volume 360:1026-1028, March 5, 2009, Number 10.

Monoclonal antibody reslizumab improves lung function in asthma subtype with eosinophilic airway inflammation - ACAAI, 2010. http://goo.gl/UJJHG

Anti-IL5 Antibody Reslizumb (mAb) Looks Promising for Severe Eosinophilic Asthma http://goo.gl/mlGkL

Azithromycin Inhibits IL-5 Production of T Helper Type 2 Cells from Asthmatic Children. http://1.usa.gov/171oIN

Published: 04/09/2010
Updated: 06/09/2011

Interleukin-4 (IL-4)

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

Source: CD4 T cells (TH2), mast cells.

The 3 established T(H)2 cytokines, IL-4, IL-5, and IL-13, each play a nonredundant role in allergic disease pathology.

Receptors: Type I cytokine receptor family which signals through the Jak-STAT pathway (STAT6). Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked SCID.


(click to enlarge the image)

IL-4 effects

- B cells: isotype switching to IgE
- T cells: TH2 differentiation, proliferation
- Macrophages: inhibition of IFN-gamma-mediated activation

- Mast cells: proliferation (in vitro)

IL-4 is the key cytokine for the IgE isotype switch.

Induction of VCAM -1, promotion of eosinophil migration, mucus production.

Th2 lymphocyte differentiation with subsequent release of additional IL-4, IL-5, and IL-13.

IL-4 and GATA3

IL-4 activates STAT6, which then engages the transcription factor GATA3, leading to secretion of IL-4. GATA3 is pivotal for Th2 maturation.

T-bet (also called TBX21 or T-box 21) is pivotal for Th1 maturation. T-bet inhibits IL-4, IL-5, and IL-17 secretion. T-bet may also inhibit Th2 differentiation by preventing GATA3 from interacting with its target DNA. T-bet is a bridge between innate and adaptive immunity (http://buff.ly/1aD6h8s).

Oral synthesis inhibitors of IL-4

Suplatast tosilate inhibits the production of IL-4 and IL-5. In a study of asthmatic patients, there was an improvement in airway hyperresponsiveness, symptoms, and PEFR, and decreased IgE.

Soluble IL-4 receptor

Altrakincept is a recombinant, human IL-4 receptor - the extracellular portion. A small proof-of-concept trials of inhaled altrakincept in asthma showed promise but 2 larger trials failed to confirm efficacy - did not invalidate IL-4 as a target - there were concerns over the bioavailability of altrakincept in those trials.

IL-4Ra receptor antagonist (antibody)

AMG-317 is a fully human mAb antagonist to the IL-4Ra receptor - inhibits both IL-4 and IL-13 signaling). Developed by Amgen (hence the name "AMG") for treatment of allergic asthma.

AMG-317 (AAAAI abstract, March 09): 12-wk RCT, double-blind, 260 subjects with uncontrolled asthma, FEV1 50-80%. Randomized to 12 weekly injections of AMG 317 (75mg, 150mg, 300mg) or placebo. Primary endpoint was improvement in ACQ score.

At week 12, mean improvements in ACQ scores were: placebo (0.48), AMG 317 75mg (0.33), 150mg (0.56), and 300mg (0.65) (p=NS for all). Median improvement in total serum IgE was significantly greater in the 300mg AMG 317 group vs placebo. No AMG 317 treatment-related SAEs were reported.

Aerovant INH and Aeroderm IV

IL-4 mutein that inhibits the effects of both IL-4 and IL-13 through its ability to block IL-4Ra.

Aerovant (Pitrakinra) INH

Aerovant INH: Phase IIa, 30-patient study met its primary endpoint of reducing the severity of late asthmatic response by 72% percent (p lower than 0.001), BID for 27 days. Started in 2009: Phase IIb clinical trial of inhaled dry powder Aerovant in patients with uncontrolled asthma.

http://www.aerovance.com/press_132007.html
http://www.aerovance.com/press_030209.html

Aeroderm IV

PEGylated recombinant human IL-4 variant, block IL-4Ra.

Phase Iia in 24 patients with atopic dermatitis using a non-PEGylated form of the molecule (AER 001). Future studies will be in severe atopic eczema patients using the PEGylated form (AER 003).

http://www.aerovance.com/aeroderm.html

References

Hwang ES; Szabo SJ; Schwartzberg PL; Glimcher LH. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 2005 Jan 21;307(5708):430-3.

Tamaoki J, Kondo M, Sakai N, Aoshiba K, Tagaya E, Nakata J, et al. Effect of suplatast tosilate, a Th2 cytokine inhibitor, on steroid-dependent asthma: a double-blind randomised study. Lancet 2000;356:273-8.

Horiguchi T, Tachikawa S, Handa M, Hanazono K, Kondo R, Ishibashi A, et al.Effects of suplatast tosilate on airway inflammation and airway hyperresponsiveness. J Asthma 2001;38:331-6.

Yoshida M, Aizawa H, Inoue H, Matsumoto K, Koto H, Komori M, et al. Effect of suplatast tosilate on airway hyperresponsiveness and inflammation in asthma patients. J Asthma 2002;39:545-52.

Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al. Efficacy of soluble IL-4 receptor for the treatment of adults with asthma. J Allergy Clin Immunol 2001;107:963-70

Borish, LC, Nelson, HS, Lanz, MJ, et al. Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med 1999; 160:1816.

Wenzel, S, Wilbraham, D, Fuller, R, et al. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 2007; 370:1422.

J. Corren, W. Busse, E. Meltzer3, L. Mansfield4, G. Bensch5, Y. Chon6, M. Dunn6, H. Weng6, S. Lin. Efficacy and Safety of AMG 317, an IL-4Ra Antagonist, in Atopic Asthmatic Subjects: A Randomized, Double-blind, Placebo-controlled Study. JACI, Volume 123, Issue 3, Page 732 (March 2009).

Published: 04/09/2010
Updated: 08/09/2010

Interleukin-2 (IL-2)

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

Source: T cells, mostly CD4 T cells.

Receptor: IL-2 receptor is composed of 3 proteins: IL-2Rα, IL-2Rβ, γc. The receptor engages the Jak3-STAT5 signal transduction pathway. Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked

SCID.

Cytokine receptors (click to enlarge the image).

IL-2 effects

- T cells: proliferation, increased cytokine synthesis; potentiates Fas-mediated apoptosis; promotes regulatory T cell development, survival
- NK cells: proliferation, activation
- B cells: proliferation, antibody synthesis (in vitro)

Activation of Th2 cells by allergen leads to production of IL-2 and its receptor IL-2Ra.

Binding of IL-2 to Th2 cells expressing IL-2Ra leads to proliferation of that clone of specifically sensitized Th2 cells.

IL-2 promotes proliferation and survival of antigen specific T-cells, hence its old name “T-cell growth factor”.

Medications

Daclizumab (anti-CD25/IL-2Ra)

Humanized mAb approved for prevention of renal allograft rejection that binds to the alpha chain (CD25) of the IL-2 receptor on T cells. Inhibits IL-2–induced proliferation and reduces TH2 and TH1 cytokines from activated T cells. Humanized IL-2Ra or daclizumab (Zenapax) is used for prophylaxis of acute organ rejection in renal transplant patients.

Daclizumab was well tolerated in trials of asthma and was associated with clinical improvment. However, IL-2 has pleiotropic effects and caution is warranted in targeting this key cytokine.

Chimeric IL-2Ra or basiliximab

Chimeric IL-2Ra or basiliximab (Simulect) is used for prophylaxis of acute organ rejection in renal transplant patients.

Recombinant IL-2 (Proleukin)

Recombinant IL-2 (Proleukin) is used in the management of metastatic renal cell carcinoma and metastatic melanoma.

Suited to a T: Interleukin-2 as Therapy for Graft-versus-Host Disease - NEJM, 2011.

References

Busse, WW, Israel, E, Nelson, HS, et al. Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial. Am J Respir Crit Care Med 2008; 178:1002.

Desensitization protocols may overcome incompatibility barriers in renal transplantation, NEJM, 2011.

Published: 04/09/2010
Updated: 11/30/2011

Transforming Growth Factor-β (TFG-β)

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

TGF-β was discovered as a tumor product that promoted the survival of cells.

Some regulatory T cells produce TGF-β, and the same cells may also produce IL-10, which also has immunosuppressive activities.

TGF-β inhibits the proliferation and effector functions of T cells and the activation of macrophages. Acts on neutrophils and endothelial cells to counteract the effects of pro-inflammatory cytokines.

TGF-β stimulates production of IgA by inducing B cells to switch to this isotype.

References

Cellular and Molecular Immunology, Abbas et al, 2009.

Published: 04/09/2010
Updated: 04/09/2010

Cytokine Receptors

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

Cytokine Receptors include the following types:

- Type I (hematopoietin receptors - IL-3 and Epo)
- Type II
- IL-1 family receptors - they share Toll-like/IL-1 receptor (TIR) domain
- TNF receptors
- Seven-transmembrane α-helical receptors


(click to enlarge the image)

Type I Cytokine Receptors

Type I are hemopoietin receptors, contain a domain with two cysteine residues and a sequence of tryptophan-serine-X-tryptophan-serine (WSXWS), where X is any amino acid. Bind cytokines that fold into four α-helical strands - type I cytokines.

All type I and type II cytokine receptors engage Jak-STAT signaling pathways.

Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked SCID.

Type II Cytokine Receptors

Type II are similar to type I (two extracellular domains with conserved cysteines) but do not contain the WSXWS motif. These receptors consist of one ligand-binding polypeptide chain and one signal-transducing chain.

All type I and II cytokine receptors engage Jak-STAT signaling pathways.

IL-1 family receptors

IL-1 family receptors share a cytosolic sequence, called the Toll-like/IL-1 receptor (TIR) domain.

TNF receptors

TNF receptors are part of a large family of proteins (some of which are not cytokine receptors) with trimeric, cysteine-rich extracellular domains.

G protein-coupled receptors

Seven-transmembrane α-helical receptors are also called serpentine receptors, because their transmembrane domains "snake" back and forth through the membrane. Also called G protein-coupled receptors because their signaling pathways involve guanosine triphosphate (GTP)-binding proteins (G proteins). Involved in many types of cellular responses and typically produce a rapid and transient response.

References

Cellular and Molecular Immunology, Abbas et al., 2009.

Published: 04/09/2010
Updated: 08/14/2010

Interferon-gamma

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

Source: T cells (TH1, CD8+ T cells), NK cells

Interferon-gamma effects

- Macrophages: activation (increased microbicidal functions)
- B cells: isotype switching to opsonizing and complement-fixing IgG subclasses
- T cells: TH1 differentiation
- Various cells: increased expression of class I and class II MHC molecules, increased antigen processing and presentation to T cells

Interferon-gamma suppresses TH2-cell-mediated allergic inflammation and suppresses allergic airway inflammation in animal models. It is induced during SCIT.

What is T-bet?

T-bet (also called TBX21 or T-box 21) is pivotal for Th1 maturation. STAT4 activates the transcription factor T-bet, which induces the secretion of IFN-gamma. T-bet promotes Th1 development by direct induction of IFN-gamma and IL-12Rbeta2 chain gene transcription. IFN-gamma acts an amplifier by binding to its receptor on Th1 cells and activating STAT1, which then engages T-bet. T-bet is a bridge between innate and adaptive immunity (http://buff.ly/1aD6h8s).

T-bet inhibits IL-4, IL-5, and IL-17 secretion. T-bet may also inhibit Th2 differentiation by preventing GATA3 from interacting with its target DNA.

Potential treatment targets

T-bet: CpG antisense oligodeoxynucleotides

GATA3: GATA3-specific DNAzyme and CpG antisense oligodeoxynucleotides

Interferon-gamma therapy in asthma

Early studies of recombinant human IFN gamma gamma SQ in asthma were disappointing. One small study showed a reversal of the TH2-cell cytokine profile in severe asthma.

IFN beta therapy in asthma

Epithelial cells from asthmatics have an impaired protective IFNb response to infection with the common cold virus. Trials of recombinant human IFNb by inhalation to prevent severe virus-induced asthma exacerbations.

What is IGRA?

Interferon Gamma Release Assay (IGRA): used in any evaluation for TB infection (active or latent). It is more specific than TSTs (PPD), which may be positive with previous BCG or exposure to non-TB Mb. A positive test indicates TB infection. A negative test excludes TB in immunocompetent patients.

References

Hwang ES; Szabo SJ; Schwartzberg PL; Glimcher LH. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 2005 Jan 21;307(5708):430-3.

Boguniewicz, M. et al. The effects of nebulized recombinant interferon-γ in asthmatic airways. J. Allergy Clin. Immunol. 95, 133–135 (1995).

Simon, H. U., Seelbach, H., Ehmann, R. & Schmitz, M. Clinical and immunological effects of low-dose IFNα treatment in patients with corticosteroid-resistant asthma. Allergy 58, 1250–1255 (2003).

Wark, P. A. et al. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J. Exp. Med. 201, 937–947 (2005).

Contoli, M. et al. Role of deficient type III interferon-λ production in asthma exacerbations. Nature Med. 12, 1023–1026 (2006).

Holgate, S. T. Exacerbations: the asthma paradox. Am. J. Respir. Crit. Care Med. 172, 941–943 (2005).

Prognostic Value of a T-Cell–Based, Interferon- Biomarker in Children with Tuberculosis Contact Mustafa Bakir, MD; Kerry A. Millington, DPhil; Ahmet Soysal, MD; Jonathan J. Deeks, PhD; Serpil Efee; Yasemin Aslan, SRN; Davinder P.S. Dosanjh, DPhil; and Ajit Lalvani, DM. Annals of Int Med, 2 December 2008 | Volume 149 Issue 11 | Pages 777-786.

Neonatal BCG vaccination induces IL-10 production by CD4(+) CD25(+) T cells. http://goo.gl/grZJ

Related reading

Protective effect of BCG vaccination: time to reconsider the vaccination threshold? Thorax, 2010. http://goo.gl/nztVL

BCG vaccination: 90 years on and still so much to learn - Thorax http://goo.gl/2tyRj

Interferon regulatory factor 8 (IRF8) Mutations and Human Dendritic-Cell Immunodeficiency. NEJM, 2011.

Published: 04/09/2010
Updated: 04/09/2011

Cytokines

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

What is the difference between cytokine, interleukin and chemokine?

Cytokines (Greek cyto-, cell; and -kinos, movement) are substances secreted by cells of the immune system which carry signals locally between cells. They are proteins, peptides, or glycoproteins.

Interleukins are a group of cytokines first found to be expressed by white blood cells (leukocytes). The name is a misnomer since interleukins are produced by a wide variety of cells, not only leukocytes.

Chemokines (Greek -kinos, movement) are a family of small cytokines, or proteins secreted by cells. The name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines.

What is the number of FDA-approved immunomodulators for asthma as of April 2010?

One. Omalizumab (Xolair ®) (exclusing SCIT, of course).

What is a "classic" cytokine inhibitor that you use very often?

Glucocorticoids are potent transcriptional inhibitors and have been available for many years. Many effects of glucocorticoids: inhibition of NF-kB, adhesion molecule expression, arachidonic acid metabolism, metalloproteinase production, etc.

Related reading

Tumor necrosis factor (TNF)

Interferon-gamma

Transforming Growth Factor-β (TFG-β)

Interleukin-2 (IL-2)

Interleukin-4 (IL-4)

Interleukin-5 (IL-5)

Interleukin-7 (IL-7)

Interleukin-9 (IL-9)

Interleukin-10 (IL-10)

Interleukin-12 (IL-12)

Interleukin-13 (IL-13)

Interleukin-17 (IL-17)

Published: 04/09/2010
Updated: 04/22/2010

Treatment of 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 NSU

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

Allergic Rhinitis and its Impact on Asthma (ARIA): Achievements in 10 years and future needs. ARIA has reclassified AR as mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. http://buff.ly/QL1eYI

This is a very brief summary that will be updated.

Asthma classification and treatment for each stage.


Immunomodulators for allergic disorders, basic mind map.


Immunomodulators for allergic disorders, complete mind map.


Cytokine targets for immunomodulators for allergic disorders.

One of the changes between the asthma guidelines from 1997 (Second Expert Panel Report EPR2, 1997) and 2007 (Third Report, EPR3, 2007) is the concept of risk for future asthma.

Patients should continue their controller medications to reduce their future risk.

References

Immunomodulators for allergic respiratory disorders. Casale TB, Stokes JR. J Allergy Clin Immunol. 2008 Feb;121(2):288-96; quiz 297-8.


Asthma Inhalers - Factoring the Cost (click to enlarge the image).

Inhaled corticosteroid (ICS)

Relative binding affinity for glucocorticoid receptor (GR): mometasone > fluticasone > budesonide > triamcinolone.

Relative anti-inflammatory potency: mometasone = fluticasone > budesonide = beclomethasone > triamcinolone.

Related Reading

Pharmacotherapy of Mild Persistent Asthma - comprehensive review, 2011.

The Goals of Asthma Management. Dr. Neil Kao Allergy and Asthma Website, 2010.
Timeline of Major Advances in Treatment of Asthma from 1812 through 2012 - NEJM, 2012.

Published: 04/04/2010
Updated: 10/04/2012

Hypereosinophilic syndrome (HES)

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

Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by:

- persistent blood eosinophilia greater than 1.5 x 10(9)/L
- absence of a secondary cause
- eosinophil-associated pathology

A 2009 analysis showed that 11% of patients with HES were Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) mutation-positive, and 17% had an aberrant or clonal T-cell population.

Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% of patients with most remaining on maintenance doses (median, 10 mg prednisone daily for 2 months to 20 years).

Hydroxyurea and IFN-alpha were also effective, but their use was limited by toxicity. Hydrea and interferon are equally effective for idiopathic HES ( about 30%) (AAAAI, 2012).

Imatinib was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%).

Mepolizumab (anti-IL-5 mAb) is awaiting FDA approval.

References:

Hypereosinophilic syndrome: A multicenter, retrospective analysis of clinical characteristics and response to therapy. Ogbogu PU, Bochner BS, Butterfield JH, Gleich GJ, Huss-Marp J, Kahn JE, Leiferman KM, Nutman TB, Pfab F, Ring J, Rothenberg ME, Roufosse F, Sajous MH, Sheikh J, Simon D, Simon HU, Stein ML, Wardlaw A, Weller PF, Klion AD. J Allergy Clin Immunol. 2009 Nov 10.

Published: 11/17/2009
Updated: 02/17/2012

Interleukins

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

Interleukins are a group of cytokines (signaling molecules) that were first found to be expressed by white blood cells (leukocytes). The name is a misnomer since interleukins are produced by a wide variety of body cells, not only leukocytes.

Interleukin-1 (IL-1)

Interleukin-2 (IL-2)

Interleukin-3 (IL-3)

Interleukin-4 (IL-4)

Interleukin-5 (IL-5)

Interleukin-6 (IL-6)

Interleukin-7 (IL-7)

Interleukin-9 (IL-9)

Interleukin-10 (IL-10)

Interleukin-12 (IL-12)

Interleukin-13 (IL-13)

Interleukin-17 (IL-17)

Interleukin 18 (IL-18)

Interleukin 33 (IL-33)

Related reading

Interleukin. Wikipedia.

IL-22 is a possible target for control of autoimmune diseases

IL-27 is expressed in chronic eczematous skin and stimulates keratinocytes

Published: 08/25/2009
Updated: 08/21/2010