What are Indications for Allergen-specific Immunotherapy?

Patient Presentation
A 14-year-old female came to clinic with increasing seasonal allergic rhinitis symptoms during the fall. She had increased her cetirizine to 60 mg day and nasal fluticasone to 2 puffs twice a day but still had significant symptoms. Her parents reported that she had snoring without apnea, was always mouth-breathing and had a de-nasal voice. Her running coaches had talked with her twice over the running season as they noticed that she was noticeably pale, and had more problems breathing over the course of her daily workouts. The main reason she came in was that she felt she could not breath at the end of her cross country races because she was “full of snot” and couldn’t catch her breath. “Maybe I can really run if I can breath,” she commented. The past medical history showed mild intermittent asthma with albuterol use averaging 1x/year, seasonal allergic rhinitis usually from March to November that had been resistant to fexofenadine and montelukast in the past. She also had some mild xerosis that had never needed steroid creams. She also had a history of moderate nasal stuffiness when in contact with cats. The family history was positive for mild seasonal allergic rhinitis in some family members. The review of systems was otherwise negative.

The pertinent physical exam showed a healthy female with normal vital signs and weight that was 25% and height that was 50%. She had allergic shiners and cobblestoning of her palpebral conjunctiva. Her nose showed significant edema and a bluish color. With pinching one nare at a time, where was no air movement in either nare. She also had cobblestoning of her posterior pharynx. Her lungs were clear. She had mild dry skin. The rest of her examination was negative.

The diagnosis of persistent seasonal allergic rhinitis that was not effectively treated by medications was made. She was referred to an allergist and skin testing found her to be allergic to several grass pollens, Alternaria alternata mold and cat dander. She was restarted on fexofenadine and montelukast daily and began allergen-specific immunotherapy. At her next appointment she was feeling better but it was also during the winter when she usually improved.

Allergen-specific immunotherapy (AIT) is a disease modifying treatment for allergic disease. Sometimes referred to as desensitization, the premise is to expose the patient to small but regular amounts of a specific antigen thereby building tolerance within the patient to the allergen. AIT is often underused because of safety concerns and lack of appropriately trained health care providers and facilities to safely carry out AIT treatment. There are 4 main AIT treatments options currently:

  • SCIT – subcutaneous immunotherapy
    • Allergen is injected into the subcutaneous skin
    • “Shots are effective in treating reactions to many allergens, including trees, grass, weeds, mold, house dust, dander, and insect stings.”
    • SCIT is safe when used for selected individuals and given by trained health care providers in a setting that has immediate access to treatment for anaphylaxis and resuscitation.
    • Reactions are infrequent and usually localized with erythema or hives. Rarely anaphylaxis can occur.
    • Patients with concomitant asthma have an increased risk of severe bronchospasm. Patients should also not exercise for 2 hours before or after injection.
  • SLIT – sublingual immunotherapy
    • Allergen drops or tablets are placed and held under the tongue for several minutes and then swallowed. Used for food allergies such as peanut allergy.
    • Ragweed and pollen tablets and drops used in other countries. In the US tablets for grass, ragweed and house dust mite are available.
    • Reactions are more common at the beginning of treatment with problems such as oropharyngeal pruritis and angioedema occurring
  • OIT – oral immunotherapy
    • Allergen in tablet/capsule or other measured allergy (i.e. peanut powder) is swallowed. Commonly OIT is used for milk, eggs and peanuts allergy.
  • EPIT – epicutaneous immunotherapy
    • Allergen patches are placed on the upper body and changed daily. Used for peanut allergy and has modest effects while being used but not of sustained benefit

In general, single antigens are more effective than mixtures of antigens for SCIT but may be necessary. Both SCIT and SLIT have been found to have benefit for some years after stopping therapy. Both SCIT and SLIT are safe to use. SLIT appears to have a better safety profile but there are no head to head comparisons of efficacy. “The ultimate goal of AIT safety is to completely prevent fatal reactions, but one must consider that with such treatment amounts of the causative allergen much larger than those associated to natural exposure and administered, the potential risk is unlikely to be completely eliminated.”

Food allergies affect ~4% of children and 1% of adults in the U.S. Most common allergens in the U.S. are milk, eggs, peanuts, tree nuts, soy, wheat, fish and shellfish. Milk and eggs are commonly outgrown by school age but peanut allergy is usually life-long. The LEAP study (Learning Early About Peanut Allergy – http://www.leapstudy.co.uk) found a decrease in peanut allergy at 60 months of age with early introduction of peanut foods to infants. A review can be found here along with recommendations for introduction of peanut allergy to infants.

Patients must have confirmed skin or in vitro testing for specific antigens before any type of AIT is initiated.

Patients and families should have reasonable expectations for AIT:

  • Treatment will not be curative and symptoms may only be reduced – typically 30-40% symptom reduction for allergic rhinitis
  • Effectiveness often continues after completed treatment but it depends on the allergen and the patient
  • Families need to commit to treatment that is usually for 3 years or longer, and consider medical cost, transportation, time in the clinic and other arrangements that are necessary such as absences from school, how treatment over vacations will occur etc.
    Economic analyses find AIT to be cost effective but the amounts depend on the type of AIT and the analysis.

  • Symptom improvement may not be seen for several months

Contraindications to AIT include:

  • Absolute
    • Uncontrolled or unstable asthma
    • No initiation in patients receiving beta-blockers as these can make anaphylaxis difficult to treatment
  • Relative
    • Autoimmune disorders
    • Chronic disorders that impair tolerance to bronchospasm or hypotension
    • Immunodeficiency and immunosuppressive agent use
    • Malignancy

Indications for allergy testing and allergy referral can be reviewed here.

Learning Point
Immunotherapy indications include:

  • IgE medicated seasonal pollen induced rhinitis where patients have not responded to optimal pharmacological management especially those with moderate to severe intermittent symptoms or persistent symptoms
  • Systemic reactions to hymenoptera venom
  • Animal danger or house dust mite allergy where patients have not responded to rigorous allergen avoidance and pharmacological management

Questions for Further Discussion
1. What conditions are recommended for SLIT therapy administration?
2. How do these conditions differ from SCIT therapy administration?
3. When should skin testing versus in vivo allergy testing be used?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Allergy and Hayfever.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Frati F, Ridolo E, Fuiano N, et.al. Safety of sublingual immunotherapy in children. Expert Opin Drug Saf. 2014 Jul;13(7):947-53.

Walker SM, Durham SR, Till SJ, et.al.; British Society for Allergy and Clinical Immunology. Immunotherapy for allergic rhinitis. Clin Exp Allergy. 2011 Sep;41(9):1177-200.

Jutel M, Agache I, Bonini S, Burks AW, Calderon M, Canonica W, et.al. International Consensus on Allergen Immunotherapy II: Mechanisms, standardization, and pharmacoeconomics. J Allergy Clin Immunol. 2016 Feb;137(2):358-68.

Meltzer EO. Hot Topics in Primary Care: Sublingual Immunotherapy: A Guide for Primary Care. J Fam Pract. 2017 Apr;66(4 Suppl):S58-S63.

Pajno GB, Bernardini R, Peroni D, et.al.; Allergen-specific Immunotherapy panel of the Italian Society of Pediatric Allergy and Immunology (SIAIP). Clinical practice recommendations for allergen-specific immunotherapy in children: the Italian consensus report. Ital J Pediatr. 2017 Jan 23;43(1):13.

Berings M, Karaaslan C, Altunbulakli C, Gevaert P, Akdis M, Bachert C, Akdis CA. Advances and highlights in allergen immunotherapy: On the way to sustained clinical and immunologic tolerance. J Allergy Clin Immunol. 2017 Nov;140(5):1250-1267.

Jones SM, Burks AW. Food Allergy. N Engl J Med. 2017 Sep 21;377(12):1168-1176.

Allergy Shot Overview. American College of Allergy, Asthma, and Immunology.
Available from the Internet at http://acaai.org/allergies/treatment/allergy-shots-immunotherapy (cited 1/12/18).

Allergy Immunotherapy. American College of Allergy, Asthma, and Immunology.
Available from the Internet at http://acaai.org/allergies/allergy-treatment/allergy-immunotherapy (cited 1/12/18).

Allergy Tablets (Sublingual Immunotherapy). American College of Allergy, Asthma, and Immunology.
Available from the Internet at http://acaai.org/allergies/allergy-treatment/sublingual-immunotherapy-slit/allergy-tablets-sublingual-immunotherapy (cited 1/12/18).

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

How Do Deep Neck Infections Present?

Patient Presentation
A 7-year-old female came to clinic with a 2 day history of general fatigue. Initially she had a low grade fever of 100.5°F but this had increased over time to 101.8°F. She also was now drinking less and hadn’t urinated in 6 hours. Her father noted over the day she seemed to be having neck stiffness and was only wanting to hold her head tilted to the right. On her way to the clinic she complained of a minor sore throat. There was strep throat circulating in her school. The past medical history was non-contributory and she was fully immunized. The review of systems showed no rash, emesis/diarrhea, cough, dysphonia, difficulty opening/closing her mouth, or ear or neck pain.

The pertinent physical exam showed a moderately ill-child. Her temperature was 101.7°F, respiratory rate of 22, pulse of 124, and she had a normal blood pressure. She was fatigued and fussy but would cooperate with examination. She had full range of motion in her neck but did have a preference of a right head tilt. Her ears were normal. Her pharynx showed 2-3+ tonsils that were red without exudates or palatal petechiae. There was no asymmetry of the tonsillar pillars or uvula. No bulging was noted in the posterior pharynx. Her lips were slightly tacky. Her teeth showed no pain with tapping. Her neck had no obvious asymmetry and she had some anterior and posterior cervical shotty lymph nodes. Her neck had no palpable tenderness. Her heart, lungs and abdomen were negative. She had no rashes and her capillary refill was 3 seconds

The work-up of a rapid strep test in the office was negative. The child appeared sicker out of proportion to her history and was mild-moderately dehydrated, so the patient was transferred to the emergency room. The attending and resident in the clinic felt that the patient may have a viral syndrome that would improve with fluids, viral meningitis, or less likely, a head and neck abscess. In the emergency room, the laboratory evaluation showed a white blood cell count of 18,600/mm2 with a 20% left shift in neutrophils. She had a C-reactive protein of 4.6 mg/dL. Intrvenous fluids were started and she felt better. Her head tilt continued so a head computed tomogram was performed and the diagnosis of a left parapharyngeal abscess was made.

The patient’s clinical course showed that Otolaryngology was consulted and the patient admitted. She was given intravenous antibiotics and on day 2 had surgical drainage. She was discharged on day 5 and completed 2.5 weeks of antibiotics in total. She was having no problems at followup at 2 weeks post-op.

Case Image

Figure 122 – Axial image from a CT scan of the neck performed with intravenous contrast demonstrates a left sided parapharyngeal abscess with a low density, round, fluid-filled center. There was some associated mass effect on the airway.


Deep neck space infections (DNSI) are not very common (estimated to be 4.6/100,000) but extremely important to have a high index of suspicion for.
The anatomy of DNSs is complex and covered by substantial amounts of superficial soft tissue making diagnosis difficult.
Additionally, children often cannot give more precise or accurate histories and can be difficult to examine> Most infections in children are in those < 6 years.
Lying within or adjacent to the DNS are numerous bones, blood vessels, nerves and other soft tissues. The spaces communicate between each other and therefore spreading can also occur including into the chest.

Complications of DNSI include:

  • Airway compromise
  • Jugular vein thrombosis (Lemierre’s syndrome)
  • Mediastinitis
  • Neural dysfunction
  • Osteomyelitis
  • Sepsis
  • Vascular erosion

In pediatric patients, the usual cause is pharyngitis or tonsillitis, whereas in adult patients the usual cause is odontogenic. However it is important to note that there are substantial numbers of cases (20-50%) that the etiology is not identified. Fortunately, DNSIs are less common because of antibiotics for treatment of respiratory illnesses and odontogenic problems.

Other causes of DNSIs include:

  • Cervical lymphadenitis
  • Congenital anomalies
    • Branchial cleft
    • Thyroglossal duct cysts
  • Foreign body
  • Trauma
  • Instrumentation – bronchoscopy, esophagoscopy
  • Intravenous drug use
  • Salivary gland obstruction or infection
  • Laryngopyocele
  • Mastoiditis
  • Thyroiditis
  • Malignant node or mass with necrosis/suppuration

The spread from the initial location can be from direct spread, lymphatic system, lymphadenopathy suppuration, or from communication with other DNSs. Peritonsillar abscesses (also known as quinsy) are the most common. Retropharyngeal and parapharyngeal abscesses generally are the next most common but their order depends on the study. Submandibular, buccal, and mixed infections (including Ludwig’s angina) are less common.

Evaluation usually includes some type of radiological imaging to rule out other entities and to better define the DNSI. Computed tomography is often used as it is usually available and quick to complete. Magnetic resonance imaging has better soft tissue visualization but may not be available and usually takes longer which may require sedation. Ultrasound has been used in some cases.

Patients are treated with broad spectrum antibiotics especially for mixed, polymicrobial infections with aerobic and anaerobic organisms. Streptococcus and Staphylococcus are more commonly cultured. Surgical treatment is considered primary treatment and used initially or after a period of antibiotics. Some patients have resolution without surgical intervention.

Learning Point
As noted above children may have minimal signs and symptoms for DNSI. Parapharyngeal abscesses can be difficult as they can have no obvious swelling, and little or no pain or trismus. Poor oral intake, fever and upper respiratory tract infection symptoms such as rhinorrhea or cough are common and can look like many common pediatric illnesses. Fever, sore throat and dysphagia are also common symptoms of presenting DNSI patients.

Other possible signs of DNSIs include:

  • Fever
  • Neck swelling or mass, particularly with asymmetry
  • Fluctuance
  • Lateral pharyngeal wall displaced medially
  • Posterior pharyngeal wall displaced anteriorly
  • Tachypnea or shortness of breath
  • Trismus (due to pterygoid muscle inflammation)
  • Voice change
  • Referred pain – ear pain, headache, neck pain
  • Neural deficits – especially cranial nerves such as Horner syndrome, or vocal cord paralysis and hoarseness
  • Torticollis (due to inflammation of paraspinal muscles)

Questions for Further Discussion
1. What are indications for referral to otorhinolaryngology?
2. What antibiotics would you choose for empiric treatment of DNSIs?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Abscess

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Raghani MJ, Raghani N. Bilateral deep neck space infection in pediatric patients: review of literature and report of a case. J Indian Soc Pedod Prev Dent. 2015 Jan-Mar;33(1):61-5.

Lawrence R, Bateman N. Controversies in the management of deep neck space infection in children: an evidence-based review. Clin Otolaryngol. 2017 Feb;42(1):156-163.

Corte FC, Firmino-Machado J, Moura CP, Spratley J, Santos M. Acute pediatric neck infections: Outcomes in a seven-year series. Int J Pediatr Otorhinolaryngol. 2017 Aug;99:128-134.

Hah YM, Jung AR, Lee YC, Eun YG. Risk factors for transcervical incision and drainage of pediatric deep neck infections. J Pediatr Surg. 2017 Jun 27. pii: S0022-3468(17)30396-2.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa

What is the Besinger Score?

Patient Presentation
The residents were discussing a 7-year-old female who was currently in the pediatric intensive care unit with muscle weakness. The resident taking care of her said, “The neurologists think she may have myasthenia gravis, but her autoantibodies are negative. Apparently this happens more with young kids. They are going to do a Tensilon® test this afternoon so I get to watch them do that. She’s having a lot of problems controlling her secretions so we’re monitoring her respiratory status closely.” One of the other residents asked about how she presented. “We’ll initially we thought this was Guillian-Barre, but once we got more history it didn’t seem to be an ascending paralysis, but was more generalized weakness, plus there was a history of her eyes being droopy when she would get sick. Plus this time when she got an ear infection and a bad cold, she had a lot of problems swallowing and parents thought she was really tired. Turns out she was really weak,” he recounted. The attending said that she had seen a Tensilon test performed when she was a resident, “I don’t remember if the patient had myasthenia or not, but I remember the neurology fellow trying to push the child’s eyes open to determine if weakness was improving with the Tensilon. I know there is a specific protocol for doing the test, plus I think there’s another specific test for monitoring patients. It’s been a long time since I looked up myasthenia though.”

Myasthenia gravis (MG) is a rare disease in the pediatric population. The incidence depends on the population studied but is estimated at 1-9/1 million/year. It was first described by William Heinrich Erb in 1879. The cause is autoantibodies against components of the post-synaptic membrane of the neuromuscular junction, usually against the acetylcholine binding receptor (AChR).

It can occur at any age but is more common in the adult population. Juvenile patients (0-19 years) are divided into prepubertal (12 years) who have disease presentations similar to the adult population. In adults there are 5 grades: ocular symptoms, mild, moderate, severe and very severe.

MG symptoms include:

  • Ocular symptoms are common
    • Ptosis – uni- or bilateral, children may tilt head to see
    • Ophthalmoplegic facial weakness – lid twitch, strabismus
  • Facial/bulbar weakness
    • Masked facies
    • Chewing and swallowing problems
    • Speech problems
    • Coughing and coughing insufficiency
  • Respiratory symptoms
    • Respiratory insufficiency
  • Peripheral symptoms (proximal symmetrical weakness)
    • Exercise intolerance
    • Fatigability
    • Difficulty with climbing stairs, rising from seated position, personal hygiene
  • Worsening of symptoms with
    • Exercise
    • Fever or infection
    • Elevated temperature
    • Medication

Symptoms often improve with rest such as sleeping with improved symptoms at night or early in the day. Prepubertal children usually present with ocular symptoms (which can wax/wane) such as ptosis, blurred or double vision. Generalized muscle weakness is rare. Ocular symptoms are common and may precede the other generalized symptoms by 2-3 years or they may not develop.

MG can be confused with other entities such as Guillain-Barre or brain stem encephalitis. Evaluation includes a strong history and physical examination (note that the physical examination may be falsely normal as patients may be resting more before the appointment). Autoantibodies to AChR, muscle-specific kinase and Titin are often positive in adults but frequently negative in children particularly younger children. Nerve stimulation testing can also be helpful. Intravenous edrophonium or Tensilon testing is also used. Edrophonium inhibits acetylcholine esterase and therefore the acetylcholine is in contact with the AChR for longer. Therefore patient symptoms improve with the administration of the drug. This is only carried out in an intensive care setting as side effects include hypotension and bradycardia. Edrophonium testing can improve MG symptoms but can also be positive in a number of other conditions.

Treatment in children usually begins with pyridostigmine which is an acetylcholine esterase inhibitor. Immunomodulators and immunosuppressive medications are also sometimes used especially if pyridostigmine is not effective. Sometimes plasma exchange or intravenous immunoglobulin is used. Thymectomy improves many patient symptoms and potentially patient remissions. There is a higher remission rate using thymectomy within 1 year after symptom onset. Spontaneous remission is common in prepubertal children with ocular symptoms only.

A review of causes of ptosis can be found here.
A review of hypotonia in infants can be found here.
A review of muscle weakness can be found here.

Learning Point
Drs. Besinger, Toyka, Homberg, Heininger, Hohlfeld, and Fateh-Moghadam first proposed a score for clinical severity for MG patients in 1983. Since that time the scoring system has been further developed and validated and is called the Quantitative Myasthenia Gravis (QMG) test that can be reviewed here. Components currently include:

  • Ocular symptoms – double vision, ptosis
  • Facial/bulbar symptoms – eyelid closure, swallowing, speech
  • Muscle weakness – head lift, hand grip, arm lift, leg lift
  • Respiratory weakness – forced vital capacity

The Myasthenia Gravis Foundation of American also has other instruments such as activities of daily living and quality of life available here.

Questions for Further Discussion
1. What is the difference between hypotonia and muscle weakness?
2. What are indications for treating a patient in the intensive care setting?
3. What are transient neonatal myasthenia gravis and congenital myasthenic syndromes?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Myasthenia Gravis

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Besinger UA, Toyka KV, Homberg M, Heininger K, Hohlfeld R, Fateh-Moghadam A. Myasthenia gravis: long-term correlation of binding and bungarotoxin blocking antibodies against acetylcholine receptors with changes in disease severity. Neurology. 1983 Oct;33(10):1316-21.

Barnett C, Katzberg H, Nabavi M, Bril V. The quantitative myasthenia gravis score: comparison with clinical, electrophysiological, and laboratory markers. J Clin Neuromuscul Dis. 2012 Jun;13(4):201-5.

Liew WK, Kang PB. Update on juvenile myasthenia gravis. Curr Opin Pediatr. 2013 Dec;25(6):694-700.

Della Marina A, Trippe H, Lutz S, Schara U. Juvenile myasthenia gravis: recommendations for diagnostic approaches and treatment. Neuropediatrics. 2014 Apr;45(2):75-83.

Sanders DB, Wolfe GI, Benatar M, et.al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016 Jul 26;87(4):419-25.

Myasthenia Gravis Foundation of America. Clinical Overview of MG. Available from the Internet at: http://myasthenia.org/HealthProfessionals/ClinicalOverviewofMG.aspx(cited 12/12/17)

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa