Molluscum Contagiosum

About this topic

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All ages

This guidance covers the management of molluscum contagiosum.

This guidance does not cover the management of other viral skin infections (e.g. warts).

There is a separate CKS topic on Warts (including verrucas).

The target audience for this guidance is healthcare professionals working within the NHS in England, who are providing first-contact or primary health care. Patient information from NHS Direct is intended to be printed and given to people, or parents of children, with this condition, and the Shared decision making sections are designed to provide a focus for discussion during the consultation about the treatment options.

Changes

Version 1.0.0, revision planned in 2010.

Last revised in January 2007

July–September 2006 — reviewed. Validated in December 2006 and issued in January 2007.

This guidance has been reviewed, restructured and updated following a full literature review.There have been no major changes to the guidance. An overview on management is given. Practical advice on avoidance has also been incorporated. An evidence section has been added to support the recommendations given.

Previous changes

November 2002 — written. Validated in June 2003 and issued in July 2003.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 March 2007.

HTAs (Health Technology Assessments)

No new HTAs since 1 March 2007.

Economic appraisals

No new economic appraisals relevant to England since 1 March 2007.

Systematic reviews and meta-analyses

No new systematic review or meta-analysis since 1 March 2007.

Primary evidence

No new high quality randomized controlled trials since 1 March 2007.

New policies

No new national policies or guidelines since 1 March 2007.

New safety alerts

No new safety alerts since 1 March 2007.

Changes in product availability

No changes in product availability since 1 March 2007.

Concise knowledge for clinical scenarios

Molluscum contagiosum

Which therapy?

• Watchful waiting and reassurance should be considered as first-line management of molluscum contagiosum.
• Advice on prevention and limiting the spread is needed but no restriction from school, work, or swimming pools is necessary.
• If treatment is needed, consider physical destruction:
• Squeezing of individual lesions using gloved fingers or tweezers (after bathing) to express white core material. Limit to only a few lesions at a time, as the process can be painful. Allow 1–2 weeks for resolution of traumatized lesions. Normally, an area of redness surrounding the lesion will suggest an immune response and clearance.
• Piercing of lesions with an orange stick or a clean needle (after bathing) to express white core material.
• Cryotherapy, giving one brief freeze of 5–10 seconds to allow a halo of ice to form over lesion and 1–2 mm of surrounding skin. Repeat at 2–3-weekly intervals until clearance. Improve accuracy by using a cotton-tip applicator or a disposable ear speculum (small end held over the lesion), directing the freeze onto the lesion.

Should I refer or investigate?

Refer?

• Refer:
• Anyone who is HIV-positive who has extensive lesions to an HIV specialist, as extensive molluscum contagiosum is a marker that the person might be severely immunocompromised
• People with ocular and lid-margin lesions and associated red eyes (suggestive of conjunctivitis) to an ophthalmologist, as lesions around the eyes can rarely cause a chronic keratoconjunctivitis
• Consider referring to a dermatologist if:
• Uncertain of the diagnosis
• The person is known to be immunocompromised
• Depending on local policy and guidelines, consider referral if:
• There are extensive, painful, inflamed lesions — but remember that itchy lesions can be suggestive of resolution and self-destruction, so might not need referral (see How do I manage associated eczema? and How do I manage lesions that look inflamed or infected?)
• Not responding to primary care management
• Consider referring adults with anogenital molluscum contagiosum to a genito-urinary medicine clinic for screening for sexually transmitted infections.

Investigate?

• Consider the possibility of immunocompromise in anyone with extensive or atypical lesions. Investigate (in particular, to exclude HIV) and refer appropriately.

Follow-up advice

• Follow-up is not usually necessary.

Prescriptions

Drug rationale

• No prescriptions are included because lesions usually resolve without treatment.

Shared decision making

• Molluscum contagiosum usually clears without treatment within 18 months. Therefore it is usually best to leave it alone.
• Some people want treatment for cosmetic reasons. The best options are ‘squeezing’ or ‘freezing’ the molluscum lumps.
• Other treatments such as acid or silver nitrate are sometimes used, but success is not guaranteed. Also:
• These treatments can be painful.
• Some treatments have a risk of burning the surrounding skin.
• All treatments have a small risk of scarring the skin.
• Children with molluscum contagiosum can mix normally with others and should not be barred from swimming.

Detailed knowledge about this topic

Goals and outcome measures

Goals

• To offer appropriate reassurance and management until natural resolution occurs
• To identify and refer individuals who might be immunocompromised

Background information

What is it?

• Molluscum contagiosum is a viral skin infection caused by molluscum contagiosum virus (MCV), a member of the the Poxviridae family.
• There are four distinct subclasses of MCV, with MCV1 being the most common cause of molluscum contagiosum.
• Transmission occurs by close personal contact, or indirectly via fomites (contaminated surfaces) such as shared towels and flannels.
• The incubation period is between 2 weeks and 8 weeks.
• Replication of the virus in infected cells causes hyperplasia and development of the characteristic flesh-coloured, umbilicated papules.

[Bhatia, 2005; Crowe, 2005]

How common is it?

• Molluscum contagiosum is common, but the exact prevalence is uncertain as many people never seek medical care and most studies have looked at selected populations, such as people attending genito-urinary medicine clinics or dermatology outpatient departments.
• A large UK general practice-based survey of patients' records [Pannell et al, 2005] found that:
• The annual incidence of new presentations of molluscum was 261/100,000.
• The annual incidence of new presentations of molluscum in children aged under 15 years was 1265/100,000.
• Over 80% of reported cases occurred in children aged under 15 years, with the maximum incidence in preschool children aged 1–4 years.
• In a general practice population of 10,000 people, about 24 new cases of molluscum contagiosum would present each year.
• Molluscum contagiosum is said to disproportionately affect children with atopic eczema, although there is little evidence to support this [Sladden and Johnston, 2004].
• Molluscum contagiosum occurs more commonly in people who are immunocompromised. For example, in people with HIV the prevalence of molluscum contagiosum is reported to range between 5% and 33%, the prevalence increasing with decreasing CD4 counts [Schwartz and Myskowski, 1992; Crowe, 2005].

How do I know my patient has it?

• Diagnosis is based on the characteristic appearance of the lesion.
• Investigations are usually not necessary unless the diagnosis is uncertain or if immunosuppression is suspected.

History

• Lesions do not usually cause symptoms.
• Itching and occasionally pain can occur if:
• The lesions become inflamed or infected
• Eczematous patches develop around the lesions (this occurs in 10% of people and is especially likely to occur in people with a history of atopy [Kakourou et al, 2005; van der Wouden et al, 2006]
• There may be a history of other members of the family or partners being affected.
• The diagnosis should be particularly considered in people who are immunocompromised (e.g. HIV infection, transplant patients) or who are using topical immunosuppressants such as steroids or tacrolimus [Lerbaek and Agner, 2004; Wilson and Reid, 2004; Bhatia, 2005; Crowe, 2005].

Examination

• The following are typical features of molluscum contagiosum [Lowy, 1999]:
• Discrete, smooth, flesh-coloured, pinkish or pearly white papules.
• There may be a central umbilication or depression, particularly in mature lesions.
• A white curd-like material can often be expressed by squeezing mature lesions.
• Lesions grow over several weeks to a size ranging from 1 mm to 5 mm in diameter (but they can be much larger if the person is immunocompromised).
• An eczematous reaction can occur around the lesions.
• Lesions can become irritated and inflamed (this seems to be particularly common prior to spontaneous resolution).
• If bacterial superinfection occurs, spreading erythema, oedema, crusting, or pus might be seen.
• On average, the number of lesions is no more than 20 (but there can be hundreds, particularly if the person is immunocompromised) [Lynch and Minkin, 1968; Rosenberg and Yusk, 1970; Hellier, 1971].
• Lesions can occur anywhere on the body, except on the palms of the hands and soles of the feet [Owens, 2005].
• In children, they commonly occur in flexures and anogenital regions, but this does not imply sexual abuse (unless other factors suggest this).
• In adults, lesions also often involve the genitalia, pubis, thighs, and lower abdomen, as a result of sexual transmission.
• In people who are immunocompromised, lesions are often widespread.
• Rarely, lesions can occur on the oral mucosa and on the eyelids (which can lead to chronic keratoconjunctivitis) [Laxmisha et al, 2003; Redmond, 2004].
• Lesions are usually clustered in one or two areas, but can be widely scattered.
• For images, see www.dermis.net.

Investigation

• Investigations are rarely required, as the diagnosis can usually be made clinically.
• In cases of diagnostic uncertainty, the following investigations might be carried out in secondary care:
• Smears of individual lesions (with either light microscopy to look for characteristic intracytoplasmic inclusion bodies or electron microscopy to look for poxvirus-like particles)
• Skin biopsy

[Scott, 2001; Smolinski and Yan, 2005]

What else might it be?

• The differential diagnosis of multiple lesions includes:
• Warts
• Milia — white keratinous cysts on the face, most frequent around the eyes
• Lichen planus (uncommon) — an inflammatory pruritic disease characterized by distinctive, usually purplish papules
• Syringomata (uncommon) — small pale papules, usually around the eyes
• Cutaneous cryptococcosis — umbilicated papules not uncommon on the face, found in patients with immunosuppression (especially HIV)
• Solitary molluscum can be difficult to diagnose, and it might be best to refer for diagnosis, particularly in the older age group. A solitary molluscum can resemble:
• Pyogenic granuloma — small, usually solitary, sessile or pedunculated, raspberry-like, friable granulation tissue; they occur most often in children
• Keratoacanthoma — a rapidly growing papule that develops into a skin-coloured nodule with a smooth crater and a central keratin plug
• Basal-cell carcinoma — a tumour composed of a waxy semitranslucent nodule, forming around a central depression that can be ulcerated, crusted, or bleeding
• Intradermal naevus (mole) — a papule that varies in colour from normal skin colour to brown or black
• Sebaceous gland hyperplasia — single or multiple yellowish papules on the face; more common in people who are chronically immunocompromised
• Spitz naevus (epithelial naevus) — a smooth-surfaced, raised, round, slightly scaly, firm papule with a pink, yellow-brown, brownish-red, or purplish-red colour

[Arnold et al, 1990]

Complications and prognosis

Complications

• Complications from molluscum contagiosum are uncommon, but the following can occur:
• Emotional and psychological distress arising from the cosmetic appearance [Tyring, 2003].
• Scarring if lesions become inflamed or infected, or due to treatment. More likely to occur in areas of adipose tissue (such as the thighs).
• Bacterial superinfection, especially in people with atopic eczema or impaired immune function [Lowy, 1999; Tyring, 2003].
• Conjunctivitis and keratitis can complicate lesions around the eyelid (rare) [Lowy, 1999; Redmond, 2004].

Prognosis

• Spontaneous resolution usually occurs within 18 months, but this can take from 6 months to 5 years [Tyring, 2003].
• The mean duration of each lesion is 8 months, but autoinoculation leads to new lesions [Sladden and Johnston, 2004].
• One study found that 16% of people had spontaneous clearance at 1 year.
• In people who are immunocompromised, individual molluscum contagiosum lesions can persist for 5 years or longer [Crowe, 2005].
• Once molluscum contagiosum has cleared completely, recurrence is rare [Ginsburg, 1986].

Management issues

Overview of management

Molluscum contagiosum is contagious; exclusion from school, gym, or swimming is not necessary, but consider simple to reduce the risk of transmission to others. Most lesions resolve spontaneously in 18 months and do not recur. No treatment should be recommended first-line. If intervention is decided on, consider simple trauma to the lesions by squeezing, piercing, or cryotherapy/diathermy. Consider referring if uncertain of the diagnosis or if the person is immunosuppressed. In adults with anogenital molluscum contagiosum, exclude other sexually transmitted diseases.

What advice should I give about reducing the risk of spread?

• Lesions are contagious until the last one has gone [HPA, 2003].
• No exclusion from school, gym, or swimming pools is necessary [HPA, 2003].
• It is sensible to consider measures to reduce the risk of transmission to others. Although there is no evidence on the effectiveness of such measures [Smolinski and Yan, 2005]:
• Keeping affected areas covered with clothing (where practical) will help to prevent spread of the virus.
• Avoid sharing towels and clothing, as molluscum contagiosum can be caught via fomites (contaminated objects).
• Avoid sharing baths.
• In adults with anogenital lesions, advise on the use of a condom and screen for any other sexually transmitted diseases. However, latex condoms will only offer partial protection. The molluscum virus does not need mucous membrane for transmission, so other skin areas that are not protected will allow spread of infection (i.e. thighs, anus). Also, after treatment, people should be aware of recurrence and the risk of further transmission [Tyring, 2003].
• Limit personal spread by not scratching the lesions, as this will lead to autoinoculation at other sites and persistence of infection.

Does molluscum contagiosum need to be treated?

• The decision on whether or not to treat molluscum contagiosum should be taken on an individual basis, and the discussion should involve the following points:
• There is a strong case for no treatment:
• Lesions do not usually cause symptoms.
• Individual lesions usually resolve within a few months, with complete clearance of all lesions within 1–2 years.
• Treatments can be painful and are often poorly tolerated by children.
• Treatments can cause scarring, but scarring rarely occurs if lesions are allowed to resolve spontaneously.
• There is little available evidence regarding the effectiveness of treatments.
• The presence of molluscum contagiosum should not limit activities such as sport, swimming, school, or work.
• Treatment might be preferred if:
• Lesions are cosmetically unsightly (although treatments can themselves result in unsightly scarring)
• Lesions are uncomfortable, itching, or bleeding
• Lesions are persistent, recurrent, or extensive
• Although treatment is often advocated to prevent autoinoculation or transmission to close contacts, there is no evidence to support this.

What treatments are available in primary care?

• The evidence regarding treatments for molluscum contagiosum is very limited, and no evidence-based recommendations can be made.
• The best management is to leave the lesions alone and await spontaneous resolution, particularly as treatment can be painful and lead to scarring.
• If treatment is decided on, the following are most commonly used in a primary care setting:
• Simple trauma, either by squeezing or piercing individual lesions, to evoke an immune response to initiate resolution.This can be carried out by patients, parents, or a care-giver. This process can be painful and the most sensible children might not cooperate. There is no clear guidance on the optimal method and frequency needed:
• Squeezing the lesions between the fingernails (ideally while wearing gloves to limit spread of the virus) or with tweezers, to remove the white core material is best carried out after a bath, when the lesions are softer. Limit treatment to a few lesions at a time. Discard white curd-like material carefully (contains infective virus). Leave 1–2 weeks for resolution [Crowe, 2005; NHS direct, 2006].
• Another option is to pierce the lesions with an orange stick to express the white core.
• Cryotherapy or diathermy:
• This is poorly tolerated by young children, so is usually only appropriate for older children or adults.
• The pain associated with cryotherapy or diathermy can be reduced by the application of a topical anaesthetic (such as lidocaine/prilocaine cream) 1 hour before treatment. This is particularly useful if a cluster of lesions is being treated.
• If only a few lesions are being treated with cryotherapy, then the use of a topical anaesthetic might not be necessary. Diathermy is generally a more painful procedure and topical anaesthesia is usually necessary.
• Cryotherapy with liquid nitrogen should be applied once for 5–10 seconds directly to lesions to achieve a halo of ice over the lesion and 1–2 mm of the surrounding skin. Repeat 2–3-weekly until the lesion has gone. Use of a cotton-tip applicator chilled in liquid nitrogen or a disposable ear speculum (with the small end held over the lesion and spraying into the funnel end) can help make the freezing more accurate [Crowe, 2005; Smolinski and Yan, 2005].
• If cotton buds are used, reduce possible transmission of viruses by decanting liquid nitrogen into a separate disposable container (from a Dewar flask), use one cotton bud for each patient, disregard leftover liquid nitrogen, and keep the Dewar flask cleaned and full [Jones and Darville, 1989].
• Other treatments are generally carried out in secondary care but are sometimes carried out in primary care, depending on the experience of the practitioner.

When should I refer somebody with molluscum contagiosum?

• Molluscum contagiosum can usually be managed in primary care.
• Refer:
• Anyone who is HIV-positive with extensive lesions to an HIV specialist, as extensive molluscum contagiosum is a marker that the person could be severely immunocompromised
• People with lid-margin or ocular lesions and associated red eyes (suggestive of conjunctivitis) to an ophthalmologist, as lesions around the eyes can rarely cause a chronic keratoconjunctivitis
• Consider referring to a dermatologist if:
• Uncertain of the diagnosis
• The patient is known to be immunocompromised
• Depending on local policy and guidelines, consider referral if:
• Extensive, painful, inflamed lesions — but remember that itchy lesions are suggestive of resolution and self-destruction, so might not need referral.
• Not responding to primary care management
• Consider referring adults with anogenital molluscum contagiosum to a genito-urinary medicine clinic for screening for sexually transmitted infections.

[Scott, 2001; Centre for Change & Innovation, 2005]

What treatments are available in secondary care?

• For people referred to secondary care, treatments other than simple trauma to the lesions, cryotherapy, or diathermy might be considered (see Table 1).
• The evidence regarding these treatments is very limited, and the choice of treatment is usually based on the personal experience of the treating physician.

Table 1. Some treatments for molluscum contagiosum that might be considered in secondary care.

Treatment	Comments
Surgical treatments
Curettage and cautery	Curettage is commonly used. A Cochrane review was unable to find any studies evaluating its effectiveness [van der Wouden et al, 2006]. Experience suggests that it is effective, although there is a risk of scarring. Topical anaesthesia is usually necessary [de Waard-van der Spek et al, 1990].
Pulsed dye laser	Case reports suggest effectiveness (over 90% clearance with one treatment), but cost, availability, and high recurrence rates (65%) limit its use in the UK [Smolinski and Yan, 2005].
Topical treatments
Phenol ablation	One small study found an increased risk of scarring compared with simply squeezing the lesions, with no difference in cure rates (1 month after treatment, complete resolution had occurred in 75% of lesions treated with phenol and in 77% of lesions treated by squeezing) [Weller et al, 1999].
Podophyllin/podophyllotoxin	A randomized controlled trial compared the effectiveness of two different strengths of podophyllotoxin cream (0.5% and 0.3%) and placebo in 150 people with predominantly genital lesions [Syed et al, 1994]. After 12 weeks of treatment, 92% of the 0.5% cream group were cured, compared with 52% of the 0.3% cream group and 16% of the placebo group (p <>
Retinoids	There have been a number of case reports of success with topical tretinoin 0.05% [Smolinski and Yan, 2005].
Imiquimod 5%	A number of uncontrolled studies suggest that imiquimod cream (an immunomodulatory drug) might be a safe and effective treatment [van der Wouden et al, 2006]. A case series, follow-up trial of 15 children showed that after 4 months 5% imiquimod led to complete clearance in two children and a partial clearance (average 65% of lesions cleared) in a further seven children [Bayerl et al, 2003]. A randomized, placebo-controlled trial of 100 people with thigh or genital lesions found that after 4 weeks' treatment, 82% of people treated with imiquimod 1% cream were cured, compared with 16% of those treated with placebo cream (p < class="cit">[Syed et al, 1998].
Benzoyl peroxide 10%	A small randomized controlled trial found that benzoyl peroxide 10% cream was more effective than tretinoin 0.05% cream (after 6 weeks of treatment, 92% of the benzyol peroxide group were lesion-free, compared with 45% of the tretinoin group; p = 0.02) [Saryazdi, 2004].
Silver nitrate paste	An uncontrolled study found that silver nitrate paste cleared molluscum contagiosum in over 90% of people after 1 month of treatment [Niizeki and Hashimoto, 1999]. However, it is rarely used because of the risk of silver tattooing.
Potassium hydroxide solution 10%	A small randomized controlled trial (n = 20) comparing potassium hydroxide 10% solution with a saline palcebo showed clearance of molluscum with topical potassium hydroxide in 6/10 children at 90 days' follow-up; 2/10 children reported 'no change' in the potassium hydroxide group, compared with 8/10 children in the control group (though this difference did not reach statistical significance). Recognized stinging and postinflammatory pigmentary changes were recorded [Short et al, 2002].
Cantharidin	A large retrospective study (n = 300) involving children showed 90% clearance of molluscum after two applications of topical cantharidin, with limited adverse effects. Not suitable for use on the face [Smolinski and Yan, 2005].

How do I manage associated eczema?

• Molluscum contagiosum is often seen in children who have eczema.
• If eczema is troublesome, this should generally be managed in the usual manner, irrespective of whether molluscum lesions are present or not (see the CKS topic on Eczema — atopic). Leaving eczema untreated could result in further scratching and spread of the virus.
• Use the least potent topical steroid that is effective.
• Some experts recommend avoiding application of topical steroid to the immediate vicinity of molluscum lesions, because of concerns about allowing proliferation of the virus (due to local immunosuppression). We could find no evidence to support this concern.
• Eczematous patches often develop around molluscum lesions, without evidence of eczema elsewhere [DeOreo et al, 1956; Crowe, 2005].
• This is thought to be an immune response to the molluscum virus.
• Anecdotal experience suggests that this reaction often precedes clearance of the virus.
• Treatment is not usually required but, if necessary, emollients and a mild topical steroid can be used.

How do I manage lesions that look inflamed or infected?

• It is common for individual lesions to become inflamed, and it can be difficult to distinguish between a normal host immune response, trauma, and infection.
• Prior to molluscum contagiosum resolving, lesions can become mildly inflamed, with redness and irritation. It is thought that this represents the development of a cellular immune response, and no treatment is required.
• Individual lesions also commonly become inflamed following treatment — if mild and with no evidence of infection, then no action is needed.
• If lesions become inflamed, with evidence of infection (such as spreading erythema, oedema, crusting, or pus), antibiotics are recommended. The decision on whether to prescribe a topical or a systemic antibiotic depends on the severity of the clinical signs.

[Smolinski and Yan, 2005]

What issues do I need to consider in a person with anogenital lesions?

• The treatment of molluscum contagiosum lesions in the anogenital area is the same as for lesions elsewhere on the body.
• Increasingly, treatments for genital warts, such as podophyllotoxin 0.5% cream and imiquimod 5% cream, are being used to treat genital molluscum. There is encouraging evidence to support this. These treatments would usually only be used in a genito-urinary medicine clinic.
• In adults with anogenital lesions, screening for sexually transmitted infections (STIs) is recommended [Scott, 2001; Ting and Dytoc, 2004]. Contact tracing of partners is not required unless an STI is diagnosed [Scott, 2001].
• In children, lesions are commonly seen in the genital and perineal areas (14%) but referral for suspected sexual abuse should only be arranged if there is other evidence to suggest this [Highet, 1992].

What issues do I need to consider in a person who has HIV?

• People infected with HIV who have molluscum contagiosum often require management in secondary care.
• Lesions can be atypical (e.g. giant lesions), multiple, and in unusual locations [Ficarra and Gaglioti, 1989; Petersen and Gerstoft, 1992; Schwartz and Myskowski, 1992].
• Lesions can mimic other cutaneous diseases (e.g. cutaneous cryptococcosis), and a biopsy might be required for diagnosis [Rico and Penneys, 1985].
• Molluscum contagiosum can be a sign of significant immunocompromise, the severity of the infection varying inversely with the CD4 count [Schwartz and Myskowski, 1992].
• Although the treatment options are similar to those in people without HIV infection, molluscum contagiosum is usually more resistant to treatment.
• In people with severe immunodeficiency, molluscum contagiosum is usually progressive and resistant to conventional treatments [Schwartz and Myskowski, 1992; Gottlieb and Myskowski, 1994].
• The new immune modulators such as cidofovir (systemic and topical), topical imiquimod, intralesional interferon, and topical streptococcal antigen OK-432 can be useful in such individuals [Crowe, 2005].
• Widely disseminated molluscum contagiosum can improve with antiretroviral therapy as the CD4 count improves [Calista et al, 1999].

What issues do I need to consider in a person with lid-margin or ocular lesions?

• Molluscum contagiosum on the eyelids can rarely cause a chronic keratoconjunctivitis.
• It is unclear whether asymptomatic lid-margin or ocular molluscum contagiosum routinely requires treatment [Margo and Katz, 1983].
• If the child develops eye symptoms thought to be secondary to molluscum contagiosum (e.g. red or sticky eyes), seek advice from an ophthalmologist [Redmond, 2004].

Supporting evidence

Evidence for treating non-genital molluscum contagiosum

In most people, molluscum contagiosum is a mild condition which resolves completely within a year or two without leaving scarring, and watchful waiting and reassurance of patients and parents is often the preferred management. If treatment is thought to be indicated, there is a lack of good-quality data to guide choice. In particular, there is very limited information on the effectiveness and safety of the commonly used 'destructive' treatments, such as cryotherapy and curettage. There is evidence from one small trial that simple trauma to the lesions by squeezing is as effective as the more aggressive treatment of phenol ablation, with less risk of scarring. However, even squeezing increased the risk of scarring, with 65% of lesions leaving scars on healing.

• A Cochrane review (search date to March 2004) evaluated the evidence for treatments for molluscum contagiosum (five randomized controlled trials [RCTs], n = 137) [van der Wouden et al, 2006].
• Most of the studies identified could not be included in the review because they were uncontrolled case series. Such studies are open to significant biases, and results are particularly difficult to evaluate for molluscum contagiosum due to the high rate of spontaneous resolution.
• Only five RCTs suitable for inclusion in the review were identified.
• Three RCTs examined the use of topical treatments and two examined the use of systemic treatments (one of oral cimetidine, the other of a homeopathic remedy).
• All of these studies were small and had methodological problems.
• Only one study, which compared 5% sodium nitrite applied daily with 5% salicylic acid under occlusion with 5% salicylic acid alone, found a statistically significant effect, but this finding is difficult to interpret as there was no placebo arm in this study.
• No studies on curettage were found.
• One study was found that compared two types of cryotherapy for cutaneous skin lesions (but only 10 participants had molluscum contagiosum).
• One study was found that compared physical expression (squeezing) with phenol ablation, but this was non-randomized and lesions were the unit of treatment and analysis [Weller et al, 1999]. Cure rates at 1 month were 75% for physical expression and 77% for phenol ablation, which is higher than would be expected from natural resolution. Phenol ablation was associated with more scarring (80%), but squeezing lesions also resulted in scarring (65%).
• The authors of the review concluded that, at present, no reliable evidence-based recommendations can be given for the treatment of non-genital molluscum contagiosum in immunocompetent people, and until robust evidence emerges for effective and safe treatment, clinicians should consider expectant management (i.e. waiting for spontaneous resolution of the molluscum lesions).
• A number of alternative/complementary therapies are promoted for the treatment of molluscum, but their effectiveness is unproved.
• In addition to the trial of a homeopathic remedy included in the Cochrane review, we found a small RCT of an essential oil [Burke et al, 2004]. Results from this trial suggest that application of essential oil of Australian lemon myrtle might be an effective treatment, but further research is needed.

Evidence for treating anogenital molluscum contagiosum

The treatment options for anogenital molluscum contagiosum are similar to those for non-genital molluscum, although there is little evidence regarding effectiveness specifically in people with anogenital molluscum. There is limited evidence that treatments commonly used for the treatment of genital warts (podophyllotoxin and imiquimod) are also effective for the treatment of genital molluscum contagiosum — such treatments would usually only be offered in a genito-urinary medicine clinic.

• Podophyllotoxin:
• A randomized controlled trial (RCT) (n = 120) of people with mainly genital molluscum contagiosum compared treatment with podophyllotoxin 0.5% cream, podophyllotoxin 0.3% cream, and placebo [Syed et al, 1994].
• Patients self-administered the cream to their lesions twice daily for three consecutive days per week for up to 4 weeks. Cure was defined as total clearance of the lesions.
• After 1 month, cure was achieved in 92% of the podophyllotoxin 0.5% group, in 52% of the podophyllotoxin 0.3% group, and in 16% of the placebo group (p <>
• Imiquimod:
• An RCT (n = 100) of people with thigh or genital molluscum contagiosum compared treatment with 1% imiquimod cream with placebo cream [Syed et al, 1998].
• Patients self-administered the cream to their lesions three times daily for five consecutive days per week. Cure was defined as total clearance of the lesions.
• After 4 weeks' treatment, 82% of the imiquimod group were cured, compared with 16% of the placebo group (p <>
• Among 49 cured patients, three had relapses after 10 months.

References

NHS staff in England can link, free of charge, from references to the full-text journal articles by clicking on [NHS Full-text]. You will need an NHS Athens password to access these resources. Click here for Athens registration.

All references with links to [Free Full-text] are freely available online to users in England and Wales. This includes the full text of Department of Health papers and Cochrane Library reviews.

1. Arnold, H., Odam, R.B. and James, W.D. (Eds.) (1990) Andrews’ diseases of the skin: clinical dermatology. 8th edn. Philadelphia: Saunders.
2. Bayerl, C., Feller, G. and Goerdt, S. (2003) Experience in treating molluscum contagiosum in children with imiquimod 5% cream. British Journal of Dermatology 149(Suppl 66), 25-29.
3. Bhatia, A. (2005) Molluscum contagiosum. eMedicine. WebMD. www.emedicine.com [Accessed: 03/10/2006]. [Free Full-text]
4. Burke, B.E., Baillie, J.-E. and Olson, R.D. (2004) Essential oil of Australian lemon myrtle (Backhousia citriodora) in the treatment of molluscum contagiosum in children. Biomedicine & Pharmacotherapy 58(4), 245-247.
5. Calista, D., Boschini, A. and Landi, G. (1999) Resolution of disseminated molluscum contagiosum with highly active anti-retroviral therapy (HAART) in patients with AIDS. European Journal of Dermatology 9(3), 211-213.
6. Centre for Change & Innovation (2005) Dermatology. Molluscum contagiosum patient pathway. Scottish Executive. www.cci.scot.nhs.uk [Accessed: 11/08/2006]. [Free Full-text]
7. Crowe, M.A. (2005) Molluscum contagiosum. eMedicine. WebMD. www.emedicine.com [Accessed: 03/10/2006]. [Free Full-text]
8. DeOreo, G.A., Johnson, H.H. and Binkley, G.W (1956) An eczematous reaction associated with molluscum contagiosum. Archives of Dermatology 74(4), 344-348.
9. de Waard-van der Spek, F.B, Oranje, A.P., Lillieborg, S. et al. (1990) Treatment of molluscum contagiosum using a lidocaine/prilocaine cream (EMLA) for analgesia. Journal of the American Academy of Dermatology 23(4), 1-8.
10. Ficarra, G. and Gaglioti, D. (1989) Facial molluscum contagiosum in HIV-infected patients. International Journal of Oral & Maxillofacial Surgery 18(4), 200-201.
11. Ginsburg, C.M. (1986) Management of selected skin and soft tissue infections. Pediatric Infectious Disease 5(6), 735-740.
12. Gottlieb, S.L. and Myskowski, P.L. (1994) Molluscum contagiosum. International Journal of Dermatology 33(7), 453-461.
13. Hellier, F.F. (1971) Profuse mollusca contagiosa of the face induced by corticosteroids. British Journal of Dermatology 85(4), 398.
14. Highet, A.S. (1992) Molluscum contagiosum. Archives of Disease in Childhood 67(10), 1248-1249.
15. HPA (2003) Guidelines on the management of communicable diseases in schools and nurseries: Molluscum contagiosum. Health Protection Agency. www.hpa.org.uk [Accessed: 25/09/2002]. [Free Full-text]
16. Jones, S.K. and Darville, J.M. (1989) Transmission of virus particles by cryotherapy and multi-use caustic pencils: a problem to dermatologists? British Journal of Dermatology 121(4), 481-486.
17. Kakourou, T., Zachariades, A., Anastasiou, T. et al. (2005) Molluscum contagiosum in Greek children: a case series. International Journal of Dermatology 44(3), 221-223.
18. Laxmisha, C., Thappa, D.M. and Jaisankar, T.J. (2003) Clinical profile of molluscum contagiosum in children versus adults. Dermatology Online Journal 9(5). [Free Full-text]
19. Lerbaek, A. and Agner, T. (2004) Facial eruption of molluscum contagiosum during topical treatment of atopic dermatitis with tacrolimus. British Journal of Dermatology 150(6), 1210-1211.
20. Lowy, D.R. (1999) Molluscum contagiosum. In: Freedberg, I.M., Eisen, A.Z., Wolff, K. et al. (Eds.) Fitzpatrick's dermatology in general medicine. 5th edn. London: McGraw-Hill. 2478-2481.
21. Lynch, P.J. and Minkin, W. (1968) Molluscum contagiosum of the adult. Probable venereal transmission. Archives of Dermatology 98(2), 141-143.
22. Margo, C. and Katz, N.N. (1983) Management of periocular molluscum contagiosum in children. Journal of Pediatric Ophthalmology & Strabismus 20(1), 19-21.
23. NHS direct (2006) Molluscum contagiosum. NHS Direct. www.nhsdirect.nhs.uk [Accessed: 03/10/2006]. [Free Full-text]
24. Niizeki, K. and Hashimoto, K. (1999) Treatment of molluscum contagiosum with silver nitrate paste. Pediatric Dermatology 16(5), 395-397.
25. Owens, T.A. (2005) Molluscum contagiosum. Medline Plus. U.S. National Library of Medicine. http://medlineplus.gov [Accessed: 03/10/2006]. [Free Full-text]
26. Pannell, R.S., Fleming, D.M. and Cross, K.W. (2005) The incidence of molluscum contagiosum, scabies and lichen planus. Epidemiology & Infection 133(6), 985-991.
27. Petersen, C.S. and Gerstoft, J. (1992) Molluscum contagiosum in HIV-infected patients. Dermatology 184(1), 19-21.
28. Redmond, R.M. (2004) Molluscum contagiosum is not always benign. British Medical Journal 329(7462), 403. [Free Full-text]
29. Rico, M.J. and Penneys, N.S. (1985) Cutaneous cryptococcosis resembling molluscum contagiosum in a patient with AIDS. Archives of Dermatology 121(7), 901-902.
30. Rosenberg, E.W. and Yusk, J.W. (1970) Molluscum contagiosum. Eruption following treatment with prednisone and methotrexate. Archives of Dermatology 101(4), 439-441.
31. Saryazdi, S. (2004) The comparative efficancy of benzoyl peroxide 10% cream and tretinoin 0.05% cream in the treatment of molluscum contagiosum. Abstract 10th World Congress on Pediatric Dermatology. Pediatric Dermatology 21(3), 399.
32. Schwartz, J.J. and Myskowski, P.L. (1992) Molluscum contagiosum in patients with human immunodeficiency virus infection. A review of twenty-seven patients. Journal of the American Academy of Dermatology 27(4), 583-588.
33. Scott, G (2001) 2001 national guideline for the management of molluscum contagiosum. Association for Genitourinary Medicine and the Medical Society for the Study of Venereal Diseases. www.bashh.org [Accessed: 22/04/2005]. [Free Full-text]
34. Short, K.A., Fuller, L.C. and Higgins, E.M. (2002) Double-blind randomized placebo-controlled trial of the use of topical potassium hydroxide in the treatment of molluscum contagiosum. Abstract PAD-11. British Journal of Dermatology 147(Suppl 62), 95.
35. Sladden, M.J. and Johnston, G.A. (2004) Common skin infections in children. British Medical Journal 329(7457), 95-99. [Free Full-text]
36. Smolinski, K.N. and Yan, A.C. (2005) How and when to treat: Molluscum contagiosum and warts in children. Pediatric Annals 34(3), 211-221. [NHS Athens Full-text]
37. Syed, T.A., Lundin, S. and Ahmad, M. (1994) Topical 0.3% and 0.5% podophyllotoxin cream for self-treatment of molluscum contagiosum in males. A placebo-controlled, double-blind study. Dermatology 189(1), 65-68.
38. Syed, T. A., Goswami, J., Abbas Ahmadpour, O. and Seyed, Ali Ahmad (1998) Treatment of molluscum contagiosum in males with an analog of imiquimod 1% in cream : a placebo-controlled, double-blind study. Journal of Dermatology 25(5), 309-313.
39. Ting, P.T. and Dytoc, M.T. (2004) Therapy of external anogenital warts and molluscum contagiosum: a literature review. Dermatologic Therapy 17(1), 68-101.
40. Tyring, S.K. (2003) Molluscum contagiosum: the importance of early diagnosis and treatment. American Journal of Obstetrics and Gynecology 189(Suppl 3), S12-S16.
41. van der Wouden, J.C., Menke, J., Gajadin, S. et al. (2006) Interventions for cutaneous molluscum contagiosum (Cochrane Review). The Cochrane Library. Issue 2. Chichester, UK: John Wiley and Sons, Ltd. www.thecochranelibrary.com [Accessed: 11/08/2006]. [Free Full-text]
42. Weller, R., O'Callaghan, C.J., MacSween, R.M. and White, M.I. (1999) Scarring in molluscum contagiosum: comparison of physical expression and phenol ablation. British Medical Journal 319(7224), 1540. [Free Full-text]
43. Wilson, L.M. and Reid, C.M. (2004) Molluscum contagiosum in atopic dermatitis treated with 0.1% tacrolimus ointment. Australasian Journal of Dermatology 45(3), 184-185.

Initial Evaluation and Management of Patients Presenting with Acute Urticaria or Angioedema

From American Academy of Emergency Medicine

Clinical Practice Guideline

Posted 03/06/2007

Michael Winters, MD
Author Information

Position Statements

AAEM statements are not to be construed as dictating an exclusive course of action nor are they intended to replace the medical judgment of healthcare professionals. The unique circumstances of individual patients and environments are to be taken into account in any diagnosis and treatment plan. AAEM statements reflect clinical and scientific advances as of the date of their publication and are subject to change.

Clinical Practice Guideline: Initial Evaluation and Management of Patients Presenting with Acute Urticaria or Angioedema

Reviewed and approved by the AAEM Clinical Practice Guidelines Committee

Scope of Application
This guideline is intended for use by physicians working in community and hospital-based emergency departments.

Inclusion Criteria
This clinical guideline is intended for patients presenting with a chief complaint of acute urticaria and/or angioedema.

Exclusion Criteria
Excluded from this clinical guideline are patients with chronic urticaria.

Methodology
A MEDLINE search for articles published between January 1996 and April 2006 was performed for urticaria and angioedema. Key words consisted of urticaria, angioedema, angio-neurotic edema, antihistamines, corticosteroids, nasopharyngolaryngoscopy, angiotensin converting enzyme inhibitor, angiotensin receptor blocker, and hereditary angioedema. The bibliographies of individual articles were also searched for additional references, some of which were published prior to 1996. Articles were reviewed and analyzed by the lead author and then scored for strength according to the following levels of evidence:

I Evidence obtained from at least one properly designed, randomized controlled trial

II-i Evidence obtained from well designed controlled trials without randomization

II-ii Evidence obtained from well designed cohort or case-control analytic studies, preferably more than one center or research group

II-iii Evidence obtained from multiple time series with or without intervention. Dramatic results in uncontrolled experiments could also be regarded as this type of evidence

III Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees

IV Evidence inadequate owing to problems of methodology (e.g. sample size, or length or comprehensiveness of follow up or conflicts of evidence)

Recommendations were then made according to the following grading system:

A. There is good evidence to support the use of the procedure

B. There is fair evidence to support the use of the procedure

C. There is poor evidence to support the use of the procedure

D. There is fair evidence to support the rejection of the procedure

E. There is good evidence to support the rejection of the procedure

Introduction
Up to 25% of the United States population will experience an episode of urticaria or angioedema during their lifetime.^[1,2]Each year, over one million patients present to a physician for evaluation and treatment of urticaria and/or angioedema.^[3] Many of these patients arrive at local emergency departments seeking treatment. For emergency physicians, the evaluation and management of patients with urticaria or angioedema can be challenging. Both disorders can be caused by a number of immunologic and non-immunologic mechanisms. As a result, the list of potential etiologies is extensive. Aside from the history and physical examination, there is little that the emergency physician can rely on to aid in discovering a cause. With the exception of hereditary angioedema, routine laboratory studies such as a complete blood count, basic metabolic panel, electrolytes, liver function tests, or urinalysis have been shown to be of no utility in the evaluation of acute urticaria and angioedema. Management is often dependent upon the etiology and severity of clinical presentation. For some causes, treatment, as well as patient disposition, remains controversial. In order to provide effective and efficient care, it is imperative to understand current concepts and controversies in the management of urticaria and angioedema.

This clinical guideline focuses on the evaluation and treatment of emergency department patients with acute urticaria and/or angioedema. Specific emphasis is placed on the importance of the history of present illness, the role of laboratory testing, angiotensin converting enzyme (ACE) inhibitor angioedema, indications for antihistamines and corticosteroids, indications for nasopharyngolaryngoscopy, and patient disposition.

Are the lesions consistent with urticaria or angioedema?
Urticaria is described as generalized, erythematous, pruritic papules that are localized to the papillary dermis.^[4] Lesions are typically discrete with raised borders, round or oval in shape, range in size from several millimeters to a few centimeters, and blanch with pressure.^[2,4] Occasionally, urticarial lesions may appear irregular, serpiginous, or gyrate.^[2]

Mechanisms of urticaria can be classified into one of four categories: immune-mediated, complement-mediated, non-immune mediated, and autoimmune-mediated.^[4] Regardless of the etiology, all mechanisms cause degranulation of the dermal mast cell. Mast cell release of preformed mediators results in endothelial activation, vasodilatation, and increased vascular permeability. Vasoactive mediators implicated in urticaria include histamine, prostaglandin D 2 , cysteinyl leukotrienes C 4 and D 4 , platelet activating factor, anaphylotoxins, histamine releasing factor, cytokines, and chemokines.^[2,4,5] Immune-mediated urticaria results from the cross-linking of IgE located on the surface of mast cells and basophils. Examples of immune-mediated urticaria include medications (penicillin), foods, and hymenoptera venom.^[4] Complement-mediated urticaria is caused by the direct activation of mast cells by complement proteins, most notably the anaphylatoxins C3a, C4a, and C5a. Antibody-antigen complexes, seen in serum sickness and transfusion reactions, directly activate the complement cascade and can result in urticaria. Non-immune mediated urticaria results from the direct activation of mast cells by non-IgE mechanisms. Examples of non-immune mediated etiologies include physical stimuli, alcohol, radiocontrast dye, and medications such as opiates, vancomycin, non-steroidal anti-inflammatory drugs, and aspirin.^[4] Degranulation of mast cells by circulating auto-antibodies defines autoimmune-mediated urticaria.

Angioedema commonly accompanies urticaria. Approximately 50% of patients present with both urticaria and angioedema.^[6] Clinically, angioedema is characterized by the abrupt onset of non-pitting, non-pruritic swelling that involves the reticular dermis, subcutaneous, and submucosal layers.^[5,7,8] Lesions are typically asymmetric in distribution, well defined, and located in non-dependent areas. Common locations include the face, especially the lips and periorbital area; the extremities; genitalia; and abdominal viscera.^[5] In contrast to urticaria, angioedema typically lasts anywhere from 24 to 96 hours. There is no fundamental difference between the lesions of urticaria and angioedema.^[5] Both result from local vasodilatation and increased vascular permeability.

Etiologies of angioedema are divided into mast cell mediated and non-mast cell mediated. Patients with mast cell mediated angioedema present with urticaria and angioedema. The mechanisms are identical to that of isolated urticaria and are discussed above. Isolated angioedema, which occurs in approximately 10% of patients, is due to non-mast cell mediated mechanisms. The two most common mechanisms of non-mast cell mediated angioedema are abnormalities in the bradykinin pathway and abnormalities of the complement system.^[6] ACE inhibitor angioedema and hereditary angioedema are examples of etiologies that present with isolated angioedema.

Patient Management Recommendations:

Lesions should be consistent with the definitions of urticaria or angioedema.

Strength of Evidence: III
Recommendation Grade: A

What are the key elements of the history of present illness in patients with acute urticaria and/or angioedema?
History is the most important component of the evaluation of patients with urticaria and/or angioedema.^[4] The history should begin with an assessment of symptom duration. Six weeks has arbitrarily been chosen to divide patients between acute and chronic urticaria/angioedema. Time distinction is important, as etiologies and the evaluation of acute and chronic urticaria/angioedema are different. In contrast to chronic urticaria, acute urticaria and/or angioedema are more likely to have an identifiable etiology. The most common causes of acute urticaria and/or angioedema are medications, foods, infections, insect venom, contact allergens (latex sensitivity), and radiocontrast media.^[2,8,9] Medications known to cause urticaria and/or angioedema include antibiotics (penicillins, sulfonamides, vancomycin), ACE inhibitors, angiotensin receptor blockers (ARB), non-steroidal anti-inflammatory drugs (NSAID), aspirin, opiates and narcotics, ß-blockers, and hormonal treatments (contraceptives and hormone-replacement therapy).^[10-14] Urticaria and angioedema are also associated with numerous vitamin supplements and herbal products. Patients should be directly questioned regarding alternative medicine treatments, as most will not consider these products to be medications.^[10] Common food allergens that cause urticaria and angioedema include nuts, eggs, milk, fish (scombroid), and shellfish.^[9] Viral infections are a common cause of acute urticaria.^[2] Although controversial, other infections reported to cause urticaria and/or angioedema include sinus infections, dental abscesses, cholecystitis, andHelicobacter pylori gastric infections.

Additional etiologies of acute urticaria and/or angioedema include physical and environmental triggers. Dermatographism, in which mast cell degranulation is caused by minor skin trauma, is the most common physical trigger.^[10] Environmental triggers include exposure to heat, cold, sun, and water. Similar to alternative medicine treatments, patients should be asked about the use of topical products. Herbal soaps, lotions, hair dyes, nail products, detergents, and toiletries can cause urticaria and, in rare cases, angioedema.^[10] Endocrine disorders (thyroid), paraneoplastic syndromes, and autoimmune conditions more commonly cause chronic urticaria and are usually suggested by findings from the review of systems.

Following symptom duration, determine the duration of individual lesions. Urticarial lesions last less than 24 hours and resolve without skin change.^[8] For lesions that last longer than 24 hours, alternative diagnoses should be considered. One of the most important alternative diagnoses to consider is urticarial vasculitis. The lesions of urticarial vasculitis are painful rather than pruritic, do not blanch, are located predominantly in the lower extremities, and typically leave a permanent pigmentary change.^[2] Skin biopsy is required for a definitive diagnosis of vasculitis. Other disorders to consider in the patient with urticarial lesions that exceed 24 hours are erythema multiforme minor, discoid lupus, morbilliform drug eruption, dermatitis herpetiformis, and bullous pemphigoid.^[9] Angioedema characteristically lasts 1 to 3 days. For patients with lesions that last longer than 96 hours consider dermatomyositis, superior vena cava syndrome, photodermatitis, Crohn's disease of the mouth and lips, facial cellulitis, Ascher syndrome (recurrent swelling of the eyelids), and Melkersson-Rosenthal syndrome (granulomatous swelling of the lips).^[5]

In patients with isolated angioedema, consider medications and abnormalities of C1 esterase inhibitor (C1INH). Abnormalities in C1INH can either be acquired or hereditary. Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent bouts of angioedema primarily affecting the extremities, gastrointestinal tract, and genitalia. Suspect HAE in the patient with a family history of first degree relatives with similar symptoms. Medications known to cause isolated angioedema include ACE inhibitors, ARBs, NSAIDS, fibrinolytics, and estrogen.^[5]

Patient Management Recommendations:

Review medications, foods, and exposure to insect venom, contact allergens, and radiocontrast media in patients with acute urticaria and/or angioedema. Consider medications (namely ACE inhibitors), hereditary angioedema, and acquired abnormalities in C1INH in patients with isolated angioedema. Consider alternative diagnoses in patients with presumed urticaria whose lesions last longer than 24 hours.

Strength of Evidence: III
Recommendation Grade: A

Are routine laboratory studies indicated in the evaluation of acute urticaria and angioedema?
Unless hereditary angioedema is suspected from the history and physical examination, there is no role for laboratory studies in the evaluation of acute urticaria and/or angioedema.^[15] Acute urticaria or angioedema is self-limited. Laboratory testing is deferred until at least 6 weeks of persistent symptoms.^[10] For patients whose symptoms are longer than 6 weeks in duration, it is recommended to obtain a complete blood count, urinalysis, erythrocyte sedimentation rate, and liver function tests. However, the utility of these labs, even in patients with chronic symptoms, remains controversial. In a recent comprehensive meta-analysis that included over 6400 patients with chronic urticaria or angioedema, screening laboratory analysis detected unsuspected diagnoses in only 1.6% of patients.^[16]

Patient Management Recommendations:

Routine laboratory studies are not indicated in the evaluation of patients with acute urticaria and angioedema.

Strength of Evidence: III
Recommendation Grade: B

What is the role of ACE inhibitors in isolated angioedema?
Introduced in 1981 for the treatment of hypertension and congestive heart failure, ACE inhibitors have become one of the most largely prescribed medications worldwide.^[5,17] Currently, as many as 40 million patients are taking an ACE inhibitor.^[18] Angioedema is a well-recognized side effect of these medications. The reported incidence of ACE inhibitor angioedema ranges from 0.1% to 1.0%.^[19] For African Americans, the risk is 4.5 times higher than Caucasians.^[18,20] It is important to recognize that ACE inhibitor angioedema is a class effect and is not dose-dependent.^[5] Symptoms can occur anywhere from a few hours up to 10 years after the initial dose. In fact, up to 40% of patients with ACE inhibitor angioedema present months to years after their initial dose.^[19] Unfortunately, many physicians remain unaware of the delayed onset of ACE inhibitor angioedema.^[17] A recent study demonstrated an average delay of 10 months between the initial episode of angioedema and the eventual withdrawal of the medication.^[21] Continuing an ACE inhibitor after an initial episode of angioedema increases patient morbidity.^[22]

The pathophysiology of ACE inhibitor angioedema remains controversial. Most theories center on the decreased degradation of bradykinin, a potent vasodilator that increases vascular permeability. Only a small percentage of patients, however, develop angioedema while taking an ACE inhibitor. It is likely that other humoral factors such as nitric oxide, interleukin-1, and tumor necrosis factor are involved.^[19,23] Defects in C1INH, carboxyalkyldipeptide N, and urinary kallikrein have also been proposed as mechanisms for ACE inhibitor angioedema.^[19,24]

Clinically, ACE inhibitor angioedema presents without urticaria. Up to 68% of cases of isolated angioedema are due to an ACE inhibitor.^[25-28] Edema is often localized to the head, neck, lips, mouth, tongue, larynx, pharynx, and subglottal regions.^[5] In rare cases, involvement of the abdominal viscera can occur, resulting in sudden abdominal pain, nausea, vomiting, and diarrhea.^[5,19]

Treatment of patients with ACE inhibitor angioedema focuses on discontinuation of the drug, airway management, and supportive care. Careful airway management is crucial. Immediately intubate patients with stridor, accessory muscle use, or drooling of saliva. Additional indications for intubation, based upon retrospective series, include tongue edema and edema of the floor of the mouth.^[25,26,29] For patients presenting with angioedema and complaints of odynophagia, hoarseness, voice change, or dyspnea, fiberoptic nasopharyngolaryngoscopy (NPL) can be an invaluable tool. Any patient with laryngeal edema by NPL requires admission to the intensive care unit (ICU) for airway monitoring. The role of medications in ACE inhibitor angioedema is controversial. Epinephrine, antihistamines, and corticosteroids can be given to these patients; however, there are no controlled studies that demonstrate the efficacy of the medications in this setting.^[8,18,30]

Patient Management Recommendations:

Discontinue ACE inhibitors in any patient presenting with isolated angioedema. Intubate patients presenting with respiratory distress, stridor, drooling, tongue edema, or significant edema of the floor of the mouth. Antihistamines and corticosteroids can be given; although, there is no evidence supporting their efficacy.

Strength of Evidence: II-iii
Recommendation Grade: B

Do ARBs cause angioedema?
Introduced in 1995, angiotensin receptor antagonists (ARB) are gaining widespread use in the treatment of hypertension, heart failure, and renal disease. ARBs primarily act by blocking the angiotensin type I receptor, which mediates the vasoconstrictive effects of angiotensin II.^[19] Since the mechanism of action is different from ACE inhibitors, ARBs, theoretically, should not be associated with the same side effects. Angioedema, however, does occur with ARBs. There is increasing evidence that ARBs also activate angiotensin type II receptors, producing vasodilatation and increased vascular permeability through nitric oxide pathways.^[19]

The true incidence of ARB angioedema remains unknown; however, it does appear to be less than angioedema caused by ACE inhibitors.^[19] Patients with ARB angioedema often have a prior history of ACE inhibitor angioedema. Warner et al, found that 32% of patients with angioedema due to an ARB had a prior episode of angioedema attributed to an ACE inhibitor.^[31] ARBs should not be considered a safe alternative for patients who have experienced ACE inhibitor angioedema.^[19] The management of patients with ARB angioedema is identical to that of patients with ACE inhibitor angioedema.

Patient Management Recommendations:

Patients with a history of ACE inhibitor angioedema should not be prescribed an ARB. Treatment of ARB angioedema is identical to that of ACE inhibitor angioedema.

Strength of Evidence: II-iii
Recommendation Grade: B

What is the role of fiberoptic NPL in the evaluation of patients with angioedema?
Emergency physicians recognize that angioedema involving the upper airway can be life-threatening. Fiberoptic NPL provides the emergency physician the ability to evaluate the severity of laryngeal compromise. Laryngeal edema is considered an ominous finding indicative of severe disease. All patients with laryngeal edema require admission to the ICU. Based upon recent studies, patients who complain of dyspnea, hoarseness, voice change, odynophagia, or have stridor on examination are likely to have laryngeal edema.^[32,33] These patients should undergo NPL. For emergency physicians without access to a nasopharynoscope, otolaryngology consultation for NPL should be obtained. Based on current literature, no patient with a normal larynx on NPL has progressed to require emergent airway intervention.^[32]

Patient Management Recommendations:

Perform NPL on patients presenting with dyspnea, hoarseness, voice change, or odynophagia. Admit all patients with laryngeal edema to the ICU.

Strength of Evidence: II-iii
Recommendation Grade: B

What medications are first-line treatment for the patient with acute urticaria and angioedema?
Emergency department treatment of the patient with acute urticaria and/or angioedema centers on antihistamines and corticosteroids. For patients presenting with anaphylaxis, respiratory distress, or severe laryngeal edema, administer epinephrine intramuscular or subcutaneously in a dose of 0.3 mg every 10 minutes (0.3 ml of 1:1000 dilution).^[15]

H₁-blocking antihistamines are the cornerstone of therapy in patients with acute urticaria and angioedema. In addition to relieving pruritus, these agents reduce the number, size, and duration of lesions.^[34] First-generation H₁ antihistamines such as diphenhydramine and hydroxyzine are effective; however, sedation is a significant side effect. As a result, second-generation H₁ antagonists (loratadine, cetirizine, desloratadine, fexofenadine) are considered the agents of choice for outpatient therapy.^[4] These medications have poor central nervous system penetration, thereby producing less sedation. There are currently no controlled trials that demonstrate the superiority of any first- or second-generation H₁ antagonist.^[35] Many dermatologists prescribe a combination of two H₁ antagonists; a non-sedating agent during the day combined with a sedating H₁ antihistamine at night. This regimen has not been proven in randomized, placebo-controlled trials.^[34] Doxepin hydrochloride, a tricyclic antidepressant with potent H₁ and H₂ antagonist properties, is recommended as an alternative to treatment with antihistamines. This medication, however, has significant side effects of severe sedation, dry mouth, and weight gain. For these reasons, it should not be considered first line treatment for acute urticaria and angioedema.

For patients whose symptoms are not controlled with an H₁ antagonist, the addition of an H₂ antagonist may be beneficial.^[2] Approximately 15% of histamine receptors in the skin are of the H₂ subtype. The combination of H₁ and H₂ antagonists has been demonstrated to be beneficial to patients with urticaria.^[2] H₂ antagonists used alone, however, are not effective.

Corticosteroids are indicated for patients with anaphylaxis, laryngeal edema, and severe symptoms unresponsive to antihistamines.^[10] Corticosteroids exhibit an anti-inflammatory effect by preventing the formation of leukotrienes and prostaglandins.^[10] In addition, these agents also suppress multiple facets of the cellular and humoral immune system.^[10] Recommended doses for patients with severe symptoms range from 0.5 - 1.0 mg/kg/day, with or without a taper.^[4] Antileukotrienes do not have a role in the management of patients with acute urticaria and angioedema.

Patient Management Recommendations:

Administer intramuscular or subcutaneous epinephrine to patients with respiratory distress. Administer an H1 antagonist to patients with acute urticaria and angioedema. For patients whose symptoms are not controlled with an H1 antagonist, add an H2 antagonist to the treatment regimen. Patients with severe symptoms, laryngeal edema, or anaphylaxis should receive corticosteroids.

Strength of Evidence: I
Recommendation Grade: A

What medications must be avoided in patients with acute urticaria and angioedema?
Regardless of whether an etiology is discovered, patients should avoid drugs that exacerbate urticaria or angioedema. Aspirin, NSAIDs, and opiates should be discontinued, as these medications can worsen urticaria.^[8,9] ACE inhibitors must be stopped in anyone presenting with isolated angioedema. As discussed, emergency physicians should not switch patients with ACE inhibitor angioedema to an ARB. In addition to medications, patients should avoid alcohol, as this can also aggravate symptoms.

Patient Management Recommendations:

Alcohol, NSAIDS, aspirin, opiates, and ACE inhibitors should be avoided in patients with acute urticaria and/or angioedema.

Strength of Evidence: III
Recommendation Grade: B

What is the treatment for patients with HAE?
HAE is a rare, autosomal dominant disorder affecting approximately 1:50,000 individuals.^[5,36] HAE occurs as a result of either an inherited or acquired abnormality in C1INH. Currently, there are three types of HAE. Type I accounts for 80% to 85% of cases and is due to decreased production of C1INH. Type II comprises 15% to 20% of cases and occurs as a result of a functionally impaired C1INH. Type I and Type II HAE occur in all races with no sex predilection. Type III has only recently been described where both C1INH levels and function are normal. To date, Type III has only been reported in women and the clinical significance is unknown.^[37] Interestingly, there is an increased frequency of autoimmune diseases in patients with HAE. Depending on the study, up to 12% of patients with HAE have an autoimmune disorder.^[38] Systemic lupus erythematosus, thyroiditis, glomerulonephritis, and inflammatory bowel disorders are reported to occur with greater frequency in patients with HAE.^[36]

Patients with HAE typically first manifest symptoms during the second decade of life.^[36] The majority of patients are able to identify a potential trigger. Common triggers include minor trauma, dental procedures, vigorous exercise, emotional stress, infections, oral contraceptive use, and alcohol consumption.^[5,36,39] Attacks of HAE typically last 2 to 5 days before spontaneously resolving.^[36] The main sites of edema include the face, extremities, and genitalia.^[5] Gastrointestinal involvement can occur presenting with severe cramps, nausea, vomiting, and diarrhea. Episodes of gastrointestinal tract HAE usually last 12 to 24 hours.^[36,40]

Diagnosis of HAE requires laboratory investigation. During acute attacks, complement proteins C4 and C2 are consumed, thereby producing low levels. A C4 level below 50% suggests the diagnosis. If C4 levels are low, a quantitative and functional measurement of C1INH activity is performed. A normal C4 level during an acute episode essentially rules out HAE.^[5] For the emergency physician, C4 and C1INH levels are not routine laboratory requests. If HAE is suspected from the history and physical examination, the emergency physician should obtain a C4 level. The result will not return during the patient's emergency department visit. Therefore, promptly refer patients to an immunologist or dermatologist for clinical and laboratory follow up. C1INH levels are performed as part of the outpatient evaluation. Interestingly, up to 25% of patients with HAE have no family history of disease.^[36] Thus, a negative family history should not be used to exclude HAE when clinical suspicion is high.

Acute episodes of HAE typically do not respond to antihistamines, corticosteroids, or epinephrine.^[5,36,41] As stated, symptoms spontaneously resolve in the majority of cases. For patients with severe attacks, the treatment of choice is C1INH concentrate. However, C1INH concentrate is not available in the United States . There are several reports on the successful use of fresh frozen plasma (FFP) for acute exacerbations of HAE.^[41] FFP contains C1INH, as well as other complement proteins. There is a theoretical concern that episodes may be worsened by FFP. As such, many physicians recommend that FFP not be used in patients with HAE. A recent review of the literature, however, found no case reports of HAE exacerbated by the administration of FFP.^[41] Androgens, as well as antifibrinolytics, have been used for prophylaxis against attacks; however, they have no role in the acute management of HAE.

Patient Management Recommendations:

Obtain a C4 level in patients with suspected HAE. Consider FFP for acute, severe episodes of HAE.

Strength of Evidence: III
Recommendation Grade: B

Which patients with angioedema require admission?
Disposition of the patient with angioedema can be challenging for the emergency physician. As discussed, any patient with laryngeal edema by NPL should be admitted to the ICU for airway monitoring. In addition, ICU admission is also indicated for non-intubated patients with tongue edema or edema of the floor of the mouth. Indications for non-ICU admission include patients who present with severe symptoms (without laryngeal edema), unreliable patients, or those with disease progression in the emergency department. Patients with isolated cutaneous swelling may be observed in the emergency department and discharged home. Although 6 hours is the recommended period of observation, there is currently no literature to support this recommendation.

Patient Management Recommendations:

Admit intubated patients and those with laryngeal edema, edema of the floor of the mouth, or tongue edema to the ICU. Patients who are unreliable, or those who have disease progression while in the ED, should be admitted to a non-ICU bed provided there is no laryngeal edema. Patients with isolated cutaneous swelling can be observed for 6 hours in the emergency department and, if there is no disease progression, discharged home.

Strength of Evidence: II-iii
Recommendation Grade: B

Flow chart (PDF)