Changes

August 2024 — minor update. Details of updated NICE quality standards have been added to this topic.

Update

Goals

To support primary healthcare professionals to:

• Make a diagnosis of angio-oedema and anaphylaxis.
• Determine the cause/trigger of angio-oedema and anaphylaxis, where possible.
• Manage a person with angio-oedema and/or anaphylaxis, including arranging admission or referral (where necessary) and following up the person after emergency treatment for suspected anaphylaxis.

Outcome measures

Audit criteria

QOF indicators

QIPP - Options for local implementation

NICE quality standards

Anaphylaxis

• People who are prescribed an adrenaline auto-injector after emergency treatment for anaphylaxis are given training in how and when to use it before being discharged. 
• People who have received emergency treatment for anaphylaxis are referred to a specialist allergy service. 
• People who have a systemic reaction to wasp or bee stings are referred to a specialist allergy service to assess whether venom immunotherapy would be suitable. 
• People who have received treatment for anaphylaxis are retrained on the use of their adrenaline auto-injector each time it is represcribed.

[NICE, 2024]

What is it?

• Angio-oedema is swelling of deep dermis, subcutaneous, or submucosal tissue, often affecting the face (lips, tongue, and eyelids), genitalia, hands, or feet. Less commonly, submucosal swelling affects the bowel and airway.
  • Angio-oedema most commonly occurs with urticaria (a superficial swelling of the epidermis and mucous membranes that results in a red, raised, and intensely itchy rash [or weals]), but may occur in isolation. For more information, see the CKS topic on Urticaria.
  • Angio-oedema can be classified:
    • According to its duration as chronic (symptoms persist for 6 weeks or longer) or acute (symptoms last for less than 6 weeks).
    • According to its cause as allergic angio-oedema, non-allergic drug reaction, idiopathic angio-oedema, hereditary C1 esterase inhibitor (C1-INH) deficiency (or hereditary angio-oedema), and acquired C1-INH deficiency (or acquired angio-oedema). See the section on Causes/trigger factors for more information.
• Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction that is characterized by rapidly developing airway and/or breathing and/or circulation problems usually associated with skin and mucosal changes. 
• The mechanism for angio-oedema and anaphylaxis is the same, as both histamine and/or bradykinin are involved. However, in anaphylaxis the reaction is more marked, resulting in an increase in vascular permeability and subsequent circulatory collapse.

[Resuscitation Council UK, 2021a; BMJ Best Practice, 2022; BMJ, 2016; DermNet NZ, 2022]

What are the causes/trigger factors?

• The causes/trigger factors of angio-oedema depend on the type of angio-oedema [BMJ, 2016; DermNet NZ, 2022].
  • Acute allergic angio-oedema is usually mast cell-mediated (typically immunoglobulin E [IgE]-mediated) and histamine-induced. It almost always occurs with urticaria within 1–2 hours of exposure to the allergen, which includes certain foods (especially nuts, shellfish, milk, and eggs), certain drugs (including non-steroidal anti-inflammatory drugs [NSAIDs], penicillin, and vaccines), insect bites, latex, and contrast media for radiological investigations. 
  • Non-allergic angio-oedema is usually caused by increased bradykinin levels and includes non-allergic drug reactions, hereditary angio-oedema (HAE), and acquired angio-oedema (AAE).
    • Non-allergic drug reaction occurs days to months after taking the eliciting drug, most commonly angiotensin-converting enzyme (ACE) inhibitors. 
    • HAE is a rare and potentially life-threatening genetic abnormality. It is usually inherited in an autosomal-dominant manner, but about 25% of cases are thought to be due to new mutations (with no previous family history) [BMJ, 2016]. In type 1 HAE (the most common form), there is a deficiency of the plasma protein C1 inhibitor (C1-INH), leading to the overproduction of bradykinin and a subsequent abrupt increase in vascular permeability. Type 2 HAE is characterized by the presence of normal or elevated levels of dysfunctional C1-INH, and type 3 (a very rare form) affects coagulation factor XII [ASCIA, 2022]. Most attacks occur spontaneously, but mild trauma (for example dental work), viral illness, cold exposure, stress, pregnancy, or ingestion of certain foods and drugs are possible triggers (or aggravating factors).
    • AAE, characterized by acquired deficiency of C1-INH, is even rarer than HAE and is usually secondary to lymphoma or a connective tissue disorder, such as systemic lupus erythematosus (SLE [which destroys the function of C1-INH]). Unlike HAE (where 50% of cases present in childhood), AAE usually presents in adults [Primary Care Dermatology Society, 2021]. The precipitating and aggravating factors of AAE are similar to those of HAE. 
  • Idiopathic angio-oedema is usually a chronic and relapsing angio-oedema with an unknown cause. Many cases are thought to be autoimmune in nature, and about 30–50% of cases are associated with other autoimmune conditions (including SLE). 
• Anaphylaxis can be triggered by any of a very broad range of triggers, most commonly foods, drugs, and venom (including wasp and bee stings) [Resuscitation Council UK, 2021b], but in many cases no cause can be identified and a significant number of cases are idiopathic [Pflipsen, 2020].
  • Food is a common factor in children; drugs are much more common triggers in adults. 
  • Any food or class of drug can cause anaphylaxis. However, nuts are the most common food cause, and anaesthetics, antibiotics (especially penicillin and cephalosporins), NSAIDs, and aspirin are the most commonly implicated drugs.
  • Rarely, anaphylaxis may be triggered by exercise (2%) [Pflipsen, 2020]. 
  • A 2018 analysis of data from the European Anaphylaxis Registry identified a greater risk of severe anaphylaxis in those of a higher age, or with concomitant mastocytosis (odds ratio 3.1, CI 2.6-3.7) [Worm, 2018].

How common is it?

• Angio-oedema is common. 
  • It occurs with urticaria in around 40% of cases [Marzano, 2015; BMJ, 2016], and about 10% of people experience only angio-oedema without urticaria [Sanchez-Borges, 2021].
  • Angiotensin-converting enzyme (ACE) inhibitor-related angio-oedema occurs in about 0.1-0.7% of people taking this drug and is more common in black people than in white people [BMJ, 2016].
  • Hereditary angio-oedema is rare, with estimates of prevalence ranging from 1 in 10,000 to 1 in 150,000 people and there are no known ethnic or sex differences [ASCIA, 2022].
  • Acquired angio-oedema is even more rare, with crude estimated prevalence ranging from 1 in 100,000 to 1 in 500,000 people [BMJ, 2016]. It usually occurs in adulthood. 
• The true incidence and prevalence of anaphylaxis are difficult to establish. 
  • Based on results from a number of international epidemiological studies, the overall frequency of episodes of anaphylaxis is estimated to be between 1–761 cases per 100,000 persons per year, and the lifetime prevalence is between 50–2000 episodes per 100,000 persons (or 0.05–2.0%) [Lieberman, 2006; Resuscitation Council UK, 2021b].
  • This is in line with UK primary care data which indicated a lifetime age-standardized prevalence of a recorded diagnosis of anaphylaxis of 75.5 per 100,000 in 2005. Based on these data, it is estimated that about 1 in 1333 of the English population has experienced anaphylaxis at some point in their lives [Resuscitation Council UK, 2021b].
  • The latest NHS Digital figures show that hospital admissions for children and young people under 18 years of age has risen by 70% during the 5 years to 2019 [NHS Digital, 2019].

What are the complications?

• Angio-oedema may have a detrimental effect on a person's quality of life and psychological well-being, especially if it is persistent [Radonjic-Hoesli, 2018]. Respiratory distress and death may occur if there is severe laryngeal swelling [Powell, 2015]. 
• Anaphylaxis causes around 20 deaths each year in the UK, although this may be an underestimate [Resuscitation Council UK, 2021a].
  • Approximately 50% of fatalities are due to circulatory collapse (shock), and the rest are due to respiratory failure (asphyxia) [Resuscitation Council UK, 2021a].
  • Death usually occurs shortly after contact with the trigger. Evidence from a case-series showed that [Pumphrey, 2000]:
    • Fatal food reactions cause respiratory arrest typically after about 30 minutes.
    • Insect stings cause collapse from shock after about 15 minutes.
    • Deaths caused by intravenous medication occur most commonly within 5 minutes.
    • Death never occurred more than 6 hours after contact with the trigger.

What is the prognosis?

• The prognosis of angio-oedema depends on the type.
  • Acute allergic angio-oedema is self-limiting in most cases and will resolve in 1–3 days, but relapses are common and unpredictable [DermNet NZ, 2022]. Where the cause/trigger can be identified and avoided, angio-oedema can be prevented (or the risk of an attack reduced).
  • Idiopathic angio-oedema often has a chronic and relapsing course.
  • Angiotensin-converting enzyme (ACE) inhibitor-related angio-oedema can become more severe if the drug is not discontinued, and in 20% of cases it can be life-threatening [Kaplan, 2008].
  • Hereditary angio-oedema usually requires lifelong treatment, and the prognosis of acquired angio-oedema depends on the treatment of the underlying disorder.
• With prompt treatment, the overall prognosis of anaphylaxis is good, with a case fatality ratio of less than 1% reported in most population-based studies [Resuscitation Council UK, 2021a].
  • Resuscitation Council (UK) estimates that there are about 20 anaphylaxis deaths reported each year in the UK, although this may be a substantial underestimate [Resuscitation Council UK, 2021a]. The risk of death is increased if there is pre-existing asthma (especially if it is poorly controlled) and in those asthmatics who fail to use (or delay treatment with) adrenaline.
  • People with previous reactions are at higher risk for recurrence, but the severity of the previous reaction does not necessarily predict the severity of a subsequent reaction [BMJ Best Practice, 2022]. The risk of a person suffering a recurrent anaphylactic reaction is estimated at 1 in 12 per year [Resuscitation Council UK, 2021a].
  • The risk of recurrence also depends on the cause of anaphylaxis and the quality of management provided [Ewan, 2016].

How do I diagnose angio-oedema?

• Take a careful history. Ask about:
  • Details of the current episode, including:
    • When the swelling started and how long it has been present for.
    • Whether the swelling is itchy or painful.
    • Any known causes/trigger factors, such as certain foods, drug treatments, and insect bites or stings.
    • If there is associated urticaria.
  • Any past episodes. 
  • Family history of angio-oedema. 
  • Past medical history (including autoimmune conditions or lymphoma).
  • Any co-existing medical conditions, such as previous or current allergies or autoimmune conditions.
  • Any gastrointestinal symptoms (swelling of the lining of the intestinal tracts may cause gastrointestinal pain and cramps).
  • Features of anaphylaxis (past or present).
• Examine the person. 
  • The clinical features of angio-oedema may vary slightly between the different types. In general:
    • The surface of the skin may appear normal or there may be weals or other rashes.
    • Skin swelling is less well defined than in urticaria and can affect the eyes, lips, genitalia, hands, and/or feet.
    • The swellings are often more painful than itchy and can take up to 72 hours to resolve.
    • See the section on Assessing the cause of angio-oedema for more information.
  • Assess for respiratory symptoms (such as stridor, wheeze, or breathlessness) or signs of circulatory collapse. If present, consider the diagnosis of anaphylaxis. See the section on Diagnosis of anaphylaxis for more information.

How should I assess the cause of angio-oedema?

• For people with angio-oedema with urticaria:
  • Suspect an allergic cause when angio-oedema is transient (hours or days) and occurs within 1–2 hours of exposure to a known allergen.
    • Common allergens include certain foods (especially nuts, shellfish, milk, and eggs), drugs (such as penicillin), latex, and insect bites and stings. Symptoms may persist if there is continuous exposure to the allergen.
    • If symptoms recur or persist and the cause cannot be clearly identified, refer to a dermatologist or immunologist for assessment of the cause. Do not try to confirm an allergic cause by deliberate exposure to a suspected allergen, as this may cause a severe allergic reaction.
  • Suspect idiopathic angio-oedema when the person has recurrent episodes of angio-oedema and urticaria and an allergic cause cannot be identified.
    • Idiopathic angio-oedema is more common in people with autoimmune disorders, such as systemic lupus erythematosus (SLE) and autoimmune thyroiditis. Look for clinical features of these conditions if they have not been previously diagnosed. Consider the following investigations to screen for autoimmune conditions: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and an autoantibody screen, including thyroid autoantibodies.
    • If idiopathic angio-oedema is suspected, refer to an immunologist or dermatologist for confirmation of the diagnosis.
• For people with angio-oedema without urticaria, a non-allergic cause is likely.
  • Suspect a non-allergic drug reaction if the person is taking an angiotensin-converting enzyme (ACE) inhibitor.
    • The diagnosis is confirmed if symptoms resolve and do not recur after withdrawing the drug. Episodes may persist for several months after stopping the drug.
  • Suspect hereditary angio-oedema (HAE) if there is a history of a parent being affected.
    • HAE usually presents after puberty and is characterized by recurrent oedema of the limbs, trunk, face, and genitals. The swellings (which are non-itchy, non-pitting, and painless) typically take 24 hours to peak, and resolve over 48–72 hours (or longer). Gastrointestinal symptoms (abdominal pain, nausea, vomiting, abdominal distention, diarrhoea, and/or constipation) are common and can mimic an acute abdomen. Upper airway swelling is a much less frequent manifestation and may affect the oropharynx (tongue, soft palate) or the larynx. Laryngeal swelling can cause death from asphyxiation. 
    • If HAE is suspected, refer to an immunologist or dermatologist for confirmation of the diagnosis. The diagnosis is confirmed by finding low serum levels of complement C1 inhibitor in a person with a family history of angio-oedema.
  • Suspect acquired angio-oedema (AAE) if the person is known to have lymphoma (usually splenic villous lymphoma) or a connective tissue disorder (for example SLE) and no family history of angio-oedema. The clinical features are similar to those of HAE.
    • If AAE is suspected, refer to an immunologist or dermatologist for confirmation of the diagnosis. The diagnosis is confirmed by finding low serum levels of complement C1 inhibitor in a person with a known cause for the condition.

How should I diagnose anaphylaxis?

The Working Group of the Resuscitation Council (UK) advises that the Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) approach (summarized below) is used to recognize (and manage) people with suspected anaphylaxis. For detailed information on this approach, see Appendix 1 of the Emergency treatment of anaphylactic reactions: Guidelines for healthcare providers available on the Resuscitation Council (UK) website (www.resus.org.uk).

• Anaphylaxis is likely when all of the following 3 criteria are met:
  • Sudden onset and rapid progression of symptoms.
    • The person will feel and look unwell.
    • Most reactions occur over several minutes. Rarely, reactions may be slower in onset.
    • The time of onset of an anaphylactic reaction will depend on the type of trigger. For example, an intravenous trigger will cause a more rapid onset of reaction than stings, which tend to cause a more rapid onset than orally ingested triggers.
    • The person will appear anxious and can experience a 'sense of impending doom'.
  • Life-threatening Airway and/or Breathing and/or Circulation problems.
    • Airway problems include airway swelling (for example throat and tongue swelling [pharyngeal/laryngeal oedema]), difficulty in breathing and swallowing (and a feeling of the throat closing up), hoarse voice, and stridor (a high-pitched inspiratory noise caused by upper airway obstruction).
    • Breathing problems include shortness of breath (increased respiratory rate), wheeze, tiredness, confusion (caused by hypoxia), cyanosis (the person appears blue; this is usually a late sign), peripheral capillary oxygen saturation (SpO₂) less than 92%, and respiratory arrest.
    • Circulatory problems include signs of shock (pale, clammy), increased pulse rate (tachycardia), low blood pressure (feeling faint, dizziness, collapse), decreased level (or loss) of consciousness, and cardiac arrest. Anaphylaxis can also cause myocardial ischaemia and electrocardiograph (ECG) changes even in people with normal coronary arteries.
    • These Airway, Breathing, and Circulation problems can alter the person’s neurological status (Disability problems) because of decreased brain perfusion, and there may be confusion and agitation.
  • Skin and/or mucosal changes.
    • These should be assessed as part of the Exposure when using the ABCDE approach.
    • They are often the first features, present in over 80% of anaphylactic reactions, and can be subtle or dramatic.
    • There may be erythema (a patchy or generalized red rash), urticaria, or angio-oedema.
• The diagnosis of anaphylaxis is supported by the person's exposure to a known allergen.
• Be aware that:
  • Skin changes without life-threatening airway, breathing, or circulation problems do not signify an anaphylactic reaction. Most people who have allergic skin changes do not go on to develop an anaphylactic reaction.
  • Skin and mucosal changes can be subtle or absent in up to 20% of reactions. Some people may present with only a decrease in blood pressure (a circulation problem).
  • There may also be gastrointestinal symptoms (such as vomiting, abdominal pain, and incontinence).
  • Occasionally a biphasic anaphylactic reaction may occur.
    • This is a potentially life-threatening recurrence of symptoms after the initial presentation, without re-exposure to the trigger. The infrequent nature of these reactions makes them difficult to predict.
    • Biphasic reactions are less likely among people with food-induced anaphylaxis, but people who present with hypotension or have idiopathic anaphylaxis may be at increased risk. 

What else could it be?

• Differential diagnoses of angio-oedema include:
  • Acute contact dermatitis — a person may have a history of contact with a sensitizing agent, with associated intense itching. For more information, see the CKS topic on Dermatitis - contact.
  • Cellulitis — acute onset of red, painful, hot, swollen, and tender skin often associated with fever. For more information, see the CKS topic on Cellulitis - acute.
  • Connective tissue disorders — systemic lupus erythematosus is characterized by a butterfly rash on the face and features of systemic involvement.
  • Erysipelas — caused by Group A beta Streptococcus and presents with a facial rash which is well-defined and not fleeting, with associated tenderness and fever.
  • Idiopathic scrotal oedema in children — unknown aetiology but the swelling is limited to the scrotum.
  • Lymphoedema — chronic thickening of tissue, unlike the acute stretching seen in angio-oedema.
  • Rosenthal–Melkersson syndrome — a rare neurological disorder of unknown aetiology which causes recurrent non-resolving facial oedema, peripheral facial nerve palsy, and fissuring of the tongue.
  • Surgical abdomen — sometimes presents similarly to hereditary or acquired angio-oedema.
• Differential diagnoses of anaphylaxis include:
  • Angio-oedema. 
  • Asthma — a chronic respiratory condition associated with airway inflammation and hyper-responsiveness. For more information, see the CKS topic on Asthma.
  • Acute anxiety (globus hystericus or panic attack). For more information, see the CKS topic on Generalized anxiety disorder.
  • Breath-holding episode in a child.
  • Foreign body aspiration.
  • Hypoglycaemia (low blood glucose) — the main adverse effect of insulin treatment, generally defined as being present when blood glucose levels decrease to less than 3.5 mmol/L. For more information, see the sections on hypoglycaemia in the CKS topics on Insulin therapy in type 1 diabetes or Insulin therapy in type 2 diabetes.
  • Pulmonary embolism — a condition in which one or more emboli, usually arising from a blood clot formed in the veins (or, rarely, in the right heart) are lodged in and obstruct the pulmonary arterial system. For more information, see the CKS topic on Pulmonary embolism.
  • Urticaria. For more information, see the CKS topic on Urticaria.
  • Vasovagal episode — transient loss of consciousness that resolves quickly. There is usually no evidence of airway symptoms.
  • Other conditions, including:
    • Mastocytosis — a rare condition caused by an excess number of mast cells gathering in the body's tissues.
    • Carcinoid syndrome — a collection of symptoms experienced by some people when a carcinoid tumour (usually one that has spread to the liver) releases hormones (such as serotonin) into the bloodstream.
    • Scombroid poisoning (from contaminated fish).
    • Seizure disorder.
    • Septic shock.

Scenario: Angio-oedema without anaphylaxis

From birth onwards.

Scenario: Anaphylaxis with or without angio-oedema

From birth onwards.

What are the recommended emergency drug doses?

CKS recommends prescribers should check the manufacturer's SPC guidance for the individual self-administration tool being used for specific dosing information. 

Table 1. Doses of emergency drugs for anaphylaxis and angio-oedema.

• • A 25 mm needle is best and is suitable for all ages.
  • In pre-term or very small infants, a 16 mm needle is suitable for IM injection.
  • In some adults, a longer length (38 mm) may be needed.
• Give the IM injection with the needle at a 90° angle to the skin, which should be stretched not bunched.
• Note: antihistamines and corticosteroids are no longer recommended for routine emergency treatment for anaphylaxis, although they are recommended for angio-oedema without anaphylaxis. See the sections on Management of anaphylaxis with or without angio-oedema and Management of angio-oedema without anaphylaxis for more information.

[Resuscitation Council UK, 2021a]

Non-sedating antihistamines when there is no airway involvement

What do I need to know about prescribing oral corticosteroids?

• Be aware that:
  • Frequent or prolonged use of systemic corticosteroids is associated with serious adverse effects, including growth retardation in children, diabetes mellitus, high blood pressure, and osteoporosis. However, these are unlikely to be a problem with a single course of prednisolone.
  • It is not necessary to taper the dose when stopping a one-week course of prednisolone.
• For detailed prescribing information on oral corticosteroids, including contraindications and cautions, adverse effects, and drug interactions, see the CKS topic on Corticosteroids - oral.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of angio-oedema and anaphylaxis.

Search dates

October 2017 - September 2022

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

• exp Angioedema/, angio-oedema.tw., exp Anaphylaxis/

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.