Paediatric Immunology and Infectious Diseases Flashcards
The Skin Sensitisation Theory of Allergy
The skin sensitisation theory is currently the leading theory on the origin of allergies. This theory suggests there are two main contributors to a child developing an allergy to a food:
There is a break in the infant’s skin (from eczema or a skin infection) that allows allergens, such as peanut proteins, from the environment to cross the skin and react with the immune system.
The child does not have contact with that allergen from the gastrointestinal tract, and there is an absence of GI exposure to the allergen.
The theory is that allergens entering through the skin are recognised by the immune system as being foreign and harmful proteins. The immune system reacts by becoming sensitised to that allergen, so that when it next encounters that allergen again it will launch a full immune response (an allergic reaction).
When a baby is weaned at around 6 months, if they are regularly eating foods that contain that allergen, their GI tract is regularly being exposed to that protein. The GI tract will recognise that allergen as a food and not a foreign or harmful protein, and inform the immune system that it is a safe thing to be exposed to.
The theory is that regular exposure to an allergen through food and preventing exposure to that allergen through the skin barrier can help prevent food allergies developing.
Hypersensitivity Reactions
Many conditions are a result of hypersensitivity reactions:
Asthma
Atopic eczema
Allergic rhinitis
Hayfever
Food allergies
Animal allergies
The Coombs and Gell classification is used to describe the underlying pathology of different hypersensitivity reactions:
Type 1: IgE antibodies to a specific allergen trigger mast cells and basophils to release histamines and other cytokines. This causes an immediate reaction. Typical food allergy reactions, where exposure to the allergen leads to an acute reaction, range from itching, facial swelling and urticaria to anaphylaxis.
Type 2: IgG and IgM antibodies react to an allergen and activate the complement system, leading to direct damage to the local cells. Examples are haemolytic disease of the newborn and transfusion reactions.
Type 3: Immune complexes accumulate and cause damage to local tissues. Examples are autoimmune conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis and Henoch-Schönlein purpura (HSP)
Type 4: Cell mediated hypersensitivity reactions caused by T lymphocytes. T-cells are inappropriately activated, causing inflammation and damage to local tissues. Examples are organ transplant rejection and contact dermatitis.
Investigating allergy
The most reliable information about whether a patient has an allergy is a clear and detailed history.
There are three main ways to test for allergy:
Skin prick testing
RAST testing, which involves blood tests for total and specific immunoglobulin E (IgE)
Food challenge testing
Skin prick testing and RAST testing assess sensitisation and not allergy. This is important, because it makes these tests notoriously unreliable and misleading.
Think carefully before performing an allergy test, particularly a RAST test. They often come back showing that the patient is sensitised to many of the things you have tested for, and it becomes very challenging to explain to the child or their parents that the positive test results do not mean it is unsafe for the child to eat those foods.
Foot challenge testing is the gold standard investigation for diagnosing allergy, however it requires a lot of time and resources and is only available in selected places.
Skin Prick Testing
A patch of skin is selected, usually on the patients forearm. Strategic allergen solutions are selected, for example peanuts, house dust mite and pollen. A drop of each allergen solution is placed at marked points along the patch of skin, along with a water control and a histamine control. A fresh needle is used to make a tiny break in the skin at the site of each allergen. After 15 minutes, the size of the wheals to each allergen are assessed and compared to the controls.
Patch Testing
Patch testing is the most helpful in determining an allergic contact dermatitis in response to a specific allergen. It is not helpful for food allergies. This could be for latex, perfumes, cosmetics or plants. A patch containing the allergen is placed on the patient’s skin. The patch can either contain a specific allergen, or a grid of lots of allergens as a screening tool. After 2 – 3 days the skin reaction to the patch is assessed.
RAST testing
RAST testing measures the total and allergen specific IgE quantities in the patient’s blood sample. In a patient with atopic conditions such as eczema and asthma, the results will often come back positive for everything you test.
Food Challenge
A food challenge should be performed in a specialised unit with very close monitoring. The child is gradually given increasing quantities of an allergen to assess the reaction, starting with almost non-existent quantities diluted further in other foods, for example mixing a small amount of peanut into a bar of chocolate. Children are monitored very closely after each exposure. This can be very helpful in excluding allergies for reassurance.
Managing allergy
Establishing the correct allergen is essential
Avoidance of that allergen
Avoiding foods that trigger reactions
Regular hoovering and changing sheets and pillows in patients that are allergic to house dust mites
Staying in doors when the pollen count is high
Prophylactic antihistamines are useful when contact is inevitable, for example hayfever and allergic rhinitis
Patients at risk of anaphylactic reactions should be given an adrenalin auto-injector
In certain cases, specialist centres may initiate a lengthy process of gradually exposing the patients to allergens over months, called immunotherapy, with the aim of reducing their reaction to certain foods or allergens.
Following exposure to an allergen
Treatment of allergic reactions are with:
Antihistamines (e.g. cetirizine)
Steroids (e.g. oral prednisolone, topical hydrocortisone or IV hydrocortisone)
Intramuscular adrenalin in anaphylaxis
Antihistamines and steroids work by dampening the immune response to allergens. Close monitoring is essential after an allergic reaction to ensure it does not progress to anaphylaxis.
Anaphylaxis
Anaphylaxis is a life-threatening medical emergency. It is caused by a severe type 1 hypersensitivity reaction. Immunoglobulin E (IgE) stimulates mast cells to rapidly release histamine and other pro-inflammatory chemicals. This is called mast cell degranulation. This causes a rapid onset of symptoms, with airway, breathing and/or circulation compromise.
The key feature that differentiates anaphylaxis from a non-anaphylactic allergic reaction is compromise of the airway, breathing or circulation.
Presentation of anaphylaxis
Patients present with a history of exposure to an allergen (although it can be idiopathic). There will be rapid onset of allergic symptoms:
Urticaria
Itching
Angio-oedema, with swelling around lips and eyes
Abdominal pain
Additional symptoms that indicate anaphylaxis are:
Shortness of breath
Wheeze
Swelling of the larynx, causing stridor
Tachycardia
Lightheadedness
Collapse
Managing anaphylaxis
Anaphylaxis requires immediate medical attention and management. It should be managed by an experienced paediatrician. Call for help early. Refer to the resuscitation guidelines for full management guidelines.
Initial assessment of acutely unwell child is with an ABCDE approach, assessing and treating:
A – Airway: Secure the airway
B – Breathing: Provide oxygen if required. Salbutamol can help with wheezing.
C – Circulation: Provide an IV bolus of fluids
D – Disability: Lie the patient flat to improve cerebral perfusion
E – Exposure: Look for flushing, urticaria and angio-oedema
Once a diagnosis of anaphylaxis is established, there are three medications given to treat the reaction:
Intramuscular adrenalin, repeated after 5 minutes if required
Antihistamines, such as oral chlorphenamine or cetirizine
Steroids, usually intravenous hydrocortisone
After anaphylaxis
All children should have a period of assessment and observation after an anaphylactic reaction, as biphasic reactions can occur, meaning they can have a second anaphylactic reaction after successful treatment of the first. Children should be admitted to the paediatric unit for observation.
Anaphylaxis can be confirmed by measuring the serum mast cell tryptase within 6 hours of the event. Tryptase is released during mast cell degranulation and stays in the blood for 6 hours before gradually disappearing.
Education and follow-up of the family and child is essential. They need to be educated about allergy, how to avoid allergens and how to spot the signs of anaphylaxis. Parents should be trained in basic life support. Specialist referral should be made in all children with anaphylaxis for diagnosis, education, follow up and training in how to use an adrenalin auto-injector.
TOM TIP: Remember to measure mast cell tryptase within 6 hours of an anaphylactic reaction. This is a common exam question and also something that will impress senior colleagues if it is part of your management plan when managing children with anaphylaxis.
Indications for an Adrenalin Auto-Injector
Epipen, Jext and Emerade are trade names for adrenalin auto-injector devices.
They are given to all children and adolescents with anaphylactic reactions. They may also be considered in children with generalised allergic reactions (without anaphylaxis) with certain risk factors:
Asthma requiring inhaled steroids
Poor access to medical treatment (e.g. rural locations)
Adolescents, who are at higher risk
Nut or insect sting allergies are higher risk
Significant co-morbidities, such as cardiovascular disease
How to Use an Adrenalin Auto-Injector
The first step is to confirm the diagnosis of anaphylaxis.
Prepare the device by removing the safety cap on the non-needle end. There is a blue cap on EpiPen and a yellow cap on Jext.
Grip the device in a fist with the needle end pointing downwards. The needle end is orange on EpiPen and black on Jext. Do not put your thumb over the end, because if the device is upside down you will inject your thumb with adrenalin and could risk losing it.
Administer the injection by firmly jabbing the device into the outer portion of the mid thigh until the device clicks. This can be done through clothing. EpiPen advise holding it in place for 3 seconds and Jext advise 10 seconds before removing the device.
Remove the device and gently massage the area for 10 seconds.
Phone an emergency ambulance. A second dose may be given (with a new pen) after 5 minutes if required.
TOM TIP: You may be asked to show a parent or child how to use an adrenalin auto-injector, either in exams or in clinical practice. It is worth familiarising yourself with a Jext and EpiPen device. The drug companies often provide dummy devices that are usually lying around the paediatric wards. Check the draws and shelves in the doctors office and ask a friendly senior nurse. They are useful to help you get familiar with the device and practice explaining to your peers.
Allergic rhinitis
Allergic rhinitis is a condition caused by an IgE-mediated type 1 hypersensitivity reaction. Environmental allergens cause an allergic inflammatory response in the nasal mucosa. It is very common and can significantly affect sleep, mood, hobbies, work and school performance and quality of life.
Allergic rhinitis may be:
Seasonal, for example hay fever
Perennial (year round), for example house dust mite allergy
Occupational, associated with the school or work environment
Presentation of allergic rhinitis
Allergic rhinitis typically causes:
Runny, blocked and itchy nose
Sneezing
Itchy, red and swollen eyes
Allergic rhinitis is associated with a personal or family history of other allergic conditions (atopy).
Diagnosis is usually made based on the history. Skin prick testing can be useful, particularly testing for pollen, animals and house dust mite allergy.
Allergic rhinitis triggers
Tree pollen or grass allergy leads to seasonal symptoms (hay fever)
House dust mites and pets can lead to persistent symptoms, often worse in dusty rooms at night. Pillows can be full of house dust mites.
Pets can lead to persistent symptoms when the pet or their hair, skin or saliva is present
Other allergens lead to symptoms after exposure (e.g. mould)
Managing allergic rhinitis
Avoid the trigger. Hoovering and changing pillows regularly and allowing good ventilation of the home can help with house dust mite allergy. Staying indoors during high pollen counts can help with hay fever symptoms. Minimise contact with pets that are known to trigger allergies.
Oral antihistamines are taken prior to exposure to reduce allergic symptoms:
Non-sedating antihistamines include cetirizine, loratadine and fexofenadine
Sedating antihistamines include chlorphenamine (Piriton) and promethazine
Nasal corticosteroid sprays such as fluticasone and mometasone can be taken regularly to suppress local allergic symptoms.
Nasal antihistamines may be a good option for rapid onset symptoms in response to a trigger.
Referral to an immunologist may be necessary if symptoms are still unmanageable.
Nasal Spray Technique
The aim when administering a nasal spray is to get a good coating throughout the nasal passage. Hold the spray in the left hand when spraying into the right nostril and vice versa. Aim to spray slightly outward, away from the nasal septum. Do NOT sniff at the same time as spraying, as this sends the mist straight to the back of the throat. The patient should not taste the spray at the back of the throat. If they do, that means it has gone too far.
Cow’s milk protein allergy
Cow’s milk protein allergy is a condition typically affecting infants and young children under 3 years. It involves hypersensitivity to the protein in cow’s milk. This may be IgE mediated, in which case there is a rapid reaction to cow’s milk, occurring within 2 hours of ingestion. It can also be non-IgE medicated, with reactions occurring slowly over several days.
This is different to lactose intolerance and cow’s milk intolerance. People with cow’s milk protein allergy do not have an allergy to lactose. Lactose is a sugar, not a protein. Cow’s milk intolerance is not an allergic process and does not involve the immune system.
Cow’s milk protein allergy is more common in formula fed babies and those with a personal or family history of other atopic conditions.
Presentation of cow’s milk protein allergy
Cow’s milk protein allergy usually presents before 1 year of age. It may become apparent when weaned from breast milk to formula milk or food containing milk. It can present in breastfed babies when the mother is consuming dairy products.
Gastrointestinal symptoms:
Bloating and wind
Abdominal pain
Diarrhoea
Vomiting
General allergic symptoms in response to the cow’s milk protein:
Urticarial rash (hives)
Angio-oedema (facial swelling)
Cough or wheeze
Sneezing
Watery eyes
Eczema
Rarely in severe cases anaphylaxis can occur.
Managing cow’s milk protein allergy
The diagnosis is made based on a full history and examination. Skin prick testing can help support the diagnosis but is not always necessary. Avoiding cow’s milk should fully resolve symptoms:
Breast feeding mothers should avoid dairy products
Replace formula with special hydrolysed formulas designed for cow’s milk allergy
Hydrolysed formulas contain cow’s milk, however the proteins have been broken down so that they no longer trigger an immune response. In severe cases infants may require elemental formulas made of basic amino acids (e.g. neocate).
Most children will outgrow cow’s milk protein allergy by age 3, often earlier.
Every 6 months or so, infants can be tried on the first step of the milk ladder (e.g. malted milk biscuits) and then slowly progress up the ladder until they develop symptoms. Over time they should gradually be able to progress towards a normal diet containing milk.
Cow’s Milk Intolerance versus Cow’s Milk Allergy
Cow’s milk intolerance is different from cow’s milk protein allergy. It is important not to get these mixed up. Cow’s milk intolerance presents with the same gastrointestinal symptoms as cow’s milk allergy (bloating, wind, diarrhoea and vomiting), however it does not give the allergic features (rash, angio-oedema, sneezing and coughing).
Infants with cow’s milk allergy will not be able to tolerate cow’s milk at all, as it causes an allergic reaction, whereas infants with cow’s milk intolerance will be able to tolerate and continue to grow and develop, but will suffer with gastrointestinal symptoms whilst having cow’s milk.
Infants with cow’s milk intolerance will grow out of it by 2 – 3 years. They can be fed with breast milk, hydrolysed formulas and weaned to foods not containing cow’s milk. After one year of age they can be started on the milk ladder.
Most children with recurrent infections have a normal immune system. Other features associated with recurrent infections may make you consider investigating further for immunodeficiency and other pathology. Children with these features should be referred to a specialist for further assessment.
Chronic diarrhoea since infancy
Failure to thrive
Appearing unusually well with quite a severe infection, for example afebrile with a large pneumonia
Significantly more infections than expected, particularly bacterial lower respiratory tract infections
Unusual or persistent infections such as cytomegalovirus, candida and pneumocystis jiroveci
Investigating recurrent infections in children
Full blood count: low neutrophils suggest a phagocytic disorder and low lymphocytes suggest a T cell disorder
Immunoglobulins: abnormalities suggest a B cell disorders
Complement proteins: abnormalities suggest a complement disorder
Antibody responses to vaccines, specifically pneumococcal and haemophilus vaccines
HIV test if clinically relevant
Chest xray for scarring from previous chest infections
Sweat test for cystic fibrosis
CT chest for bronchiectasis
Severe combined immunodeficiency
Severe combined immunodeficiency (SCID) is the most severe condition causing immunodeficiency. Children with SCID have almost no immunity to infections. It is a syndrome caused by a number of different genetic disorders that result in absent or dysfunctioning T and B cells.
Presentation of SCID
SCID will present in the first few months of life with:
Persistent severe diarrhoea
Failure to thrive
Opportunistic infections that are more frequent or severe than in healthy children, for example severe and later fatal chickenpox, Pneumocystis jiroveci pneumonia and cytomegalovirus
Unwell after live vaccinations such as the BCG, MMR and nasal flu vaccine
Omenn syndrome (see below)
Causes of SCID
More than 50% of cases are caused by a mutations in the common gamma chain on the X chromosome that codes for interleukin receptors on T and B cells. This has X-linked recessive inheritance.
There are many other gene mutations that can lead to SCID including:
JAC3 gene mutations
Mutations leading to adenosine deaminase deficiency
Omenn Syndrome
Omenn syndrome is a rare cause of SCID. It is the result of a mutation in the recombination-activating gene (RAG 1 or RAG 2) that codes for important proteins in T and B cells. It has autosomal recessive inheritance.
The syndrome is caused by abnormally functioning and deregulated T cells that attack the tissues in the fetus or neonate. This leads the classic features of Omenn syndrome:
A red, scaly, dry rash (erythroderma)
Hair loss (alopecia)
Diarrhoea
Failure to thrive
Lymphadenopathy
Hepatosplenomegaly
Selective Immunoglobulin A Deficiency
This is the most common immunoglobulin deficiency. Patients have low levels of IgA and normal levels of IgG and IgM.
IgA is present in secretions of the mucous membranes, such as saliva, respiratory tract secretions, GI tract secretions, tears and sweat. IgA protects against opportunistic infections of these mucous membranes.
Selective IgA deficiency is a mild immunodeficiency. Patients are often asymptomatic and never diagnosed. Patients have a tendency to recurrent mucous membrane infections, such as lower respiratory tract infections, and autoimmune conditions.
TOM TIP: The place you are likely to come across IgA deficiency is when testing for coeliac disease. The blood tests for coeliac disease are the IgA levels of anti-TTG and anti-EMA antibodies. When you test for these antibodies, it is important to also test for total immunoglobulin A levels. If the total IgA is low due to an IgA deficiency, the coeliac test will be negative, even when they have coeliac disease. In this circumstance, you can test for the IgG version of anti-TTG or anti-EMA antibodies or simply do an endoscopy with biopsies.
Common Variable Immunodeficiency
Common variable immunodeficiency is caused by a genetic mutation in the genes coding for components of B cells. The result is deficiency in IgG and IgA, with or without a deficiency in IgM. This leads to recurrent respiratory tract infections, typically leading to chronic lung disease over time. Patients are unable to develop immunity to infections or vaccinations. They are also prone to immune disorders such as rheumatoid arthritis, and cancers such as non-Hodgkins lymphoma. Management is with regular immunoglobulin infusions and treating infections and complications as they occur.
X-linked Agammaglobulinaemia
X-linked agammaglobulinaemia is also known as Bruton’s agammaglobulinaemia. This is an X-linked recessive condition. It results in abnormal B cell development and deficiency in all classes of immunoglobulins. It causes similar issues to common variable immunodeficiency.
DiGeorge Syndrome
DiGeorge syndrome, also called 22q11.2 deletion syndrome, results from a microdeletion in a portion of chromosome 22 that leads to a developmental defect in the third pharyngeal pouch and third branchial cleft. One of the consequences of this is incomplete development of the thymus gland. An underdeveloped thymus gland results in an inability to create functional T cells.
Features of DiGeorge syndrome can be remembered with the CATCH-22 mnemonic:
C – Congenital heart disease
A – Abnormal facies (characteristic facial appearance)
T – Thymus gland incompletely developed
C – Cleft palate
H – Hypoparathyroidism and resulting Hypocalcaemia
22nd chromosome affected
Purine Nucleoside Phosphorylase Deficiency
Purine nucleoside phosphorylase (PNP) deficiency is an autosomal recessive condition. PNPase is an enzyme that helps breakdown purines. Without this enzyme, a metabolite called dGTP builds up. This metabolite is exclusively toxic to T cells. Increased levels of dGTP causes low levels of T-lymphocytes. There are normal levels of B cells and immunoglobulins. Clinically, patients immunity to infection gradually gets worse. They become increasingly susceptible to infections, particularly viruses and live vaccines.
Wiskott-Aldrich Syndrome
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive condition with a mutation on the WAS gene. It causes abnormal functioning of T cells. Other features include:
Thrombocytopenia
Immunodeficiency
Neutropenia
Eczema
Recurrent infections
Chronic bloody diarrhoea
Ataxic Telangiectasia
Ataxic telangiectasia is an autosomal recessive condition affecting the gene coding for the ATM serine/threonine kinase protein on chromosome 11. This protein is important in several functions of DNA coding, meaning that a mutation in this gene leads to problems coding for many other genes.
There are various features of the condition:
Low numbers of T-cells and immunoglobulins, causing immunodeficiency and recurrent infections.
Ataxia: problems with coordination due to cerebellar impairment
Telangiectasia, particularly in the sclera and damaged areas of skin
Predisposition to cancers, particularly haematological cancers
Slow growth and delayed puberty
Accelerated ageing
Liver failure
Complement disorders
Complement disorders affect the complement proteins that make up the complement system, which helps destroy pathogenic cells. Complement proteins are most important in dealing with encapsulated organisms, such as:
Haemophilus influenza B
Streptococcus pneumonia
Neisseria meningitidis
Complement Deficiencies
Deficiencies in complement proteins result in a vulnerability to certain infective organisms, leading to recurrent infections with these organisms. Complement deficiencies make children particularly susceptible to infections of the respiratory tract, ears and throat. Complement deficiencies are also associated with immune complex disorders, such as systemic lupus erythematous, as an incomplete complement cascade leads to immune complexes building up and being deposited in tissues, leading to chronic inflammation. C2 deficiency is the most common complement deficiency.
Vaccination against encapsulated organisms is very important in patients with complement deficiencies.
C1 Esterase Inhibitor Deficiency (Hereditary Angioedema)
Bradykinin is part of the inflammatory response. It is responsible for promoting blood vessel dilatation and increased vascular permeability, leading to angioedema. Part of the action of C1 esterase is to inhibit bradykinin. An absence of C1 esterase causes intermittent angioedema in response to minor triggers, such as viral infections or stress, or without any clear trigger at all.
Angioedema often affects the lips or face but can occur anywhere on the body, including the respiratory and gastrointestinal tract. The swelling can last several few days before self resolving. Angioedema can occur in the larynx and compromise the patients airway. Patients can be treated with intravenous C-1 esterase inhibitor as prophylaxis before dental or surgical procedures or in response to acute attacks of angioedema.
TOM TIP: A key test for hereditary angioedema (C1 esterase inhibitor deficiency) is to check the levels of C4 (compliment 4). C4 levels will be low in the condition. The exam question describe a patient with episodes of unexplained lip swelling and ask what test to perform. The answer is C4 levels.
Mannose-Binding Lectin Deficiency
Deficiency in mannose-binding lectin is relatively common in the general population. A deficiency leads to inhibition of the alternative pathway of the complement system. In otherwise healthy individuals, it seems to be relatively unimportant and does not seem to cause major immunodeficiency. In patients who are otherwise susceptible to infection (e.g. cystic fibrosis) this can lead to a more severe variant of their existing disease.
