Key Words:
erythema, inflammation, rosacea, telangiectasia

Introduction

Rosacea is a chronic skin disorder characterized by facial erythema, telangiectasia, inflammatory papules and pustules with intermittent episodes of exacerbation and remission. There are four generally accepted clinical subtypes, which have been described by the National Rosacea Society: erythematotelangiectatic, papulopustular, phymatous, and ocular.¹ Two variants, granulomatous and neurogenic, have also been presented.^1,2

Affecting approximately 10% of the general population, rosacea is more prevalent in women, although impacted men often have more disfiguring skin changes.³ Patients often present between 30 and 50 years of age, but manifestations can occur throughout the life course.⁴

Given that up to a third of patients have a family history of rosacea and the increased prevalence among individuals of Northern European descent, an underlying genetic predisposition may help explain these patterns.³ While the etiology of rosacea remains unclear and despite clinical heterogeneity, basic science has developed a possible unified understanding of the condition as an inflammatory disorder in the context of an altered innate immune response.⁵ It is proposed that environmental changes, which may include UV light exposure, hormone balances, and microbe challenges (by pathogens such as Demodex folliculorum), are sensed by pattern recognition receptors of the immune system. Subsequent signaling-induced effector molecules such as reactive oxygen species, cytokines, cathelicidin and chemokines may then modify dermal structure through vascular changes, collagen degeneration, lymphohistiocytic infiltration and neutrophil recruitment, which may perpetuate this response.^6,7 Given this model, it is clear why most current therapies attempt to modulate various points of this inflammatory cascade.

Furthermore, although the intricacies of the relationship between psychological factors and rosacea remains to be elucidated, 75% of affected patients report low self-esteem, with a significant odds ratio of 4.81 for a diagnosed depressive disorder in this population compared to the general population.⁸ The use of validated assessment tools has demonstrated the impact of rosacea on quality of life, and, importantly, the improvement in these psychological indices that can occur with treatment.⁹

Once rosacea is diagnosed, patients should be reassured of the benign, but chronic, nature of the condition. Counseling should be directed toward the identification and avoidance of triggers, diligent photoprotection, concealing cosmetics and proper skin care.^3,10 It is also prudent to review medications to identify, and discontinue if possible, those that may exacerbate flushing such as beta blockers.³

Treatment

Topical pharmacotherapeutic options include azelaic acid, erythromycin, metronidazole or sodium sulfacetamide 10% + sulfur 5%.¹¹ As in the management of other dermatological conditions, vehicle selection for topical rosacea preparations is an important consideration. The choice of lotion, cream, gel or foam can influence efficacy, compliance, and tolerability, which is especially relevant for these patients who often have heightened skin sensitivity, but is beyond the scope of this review.¹² In patients with moderate to severe papulopustular subtype or ocular involvement, systemic therapy is often required and includes doxycycline, erythromycin, metronidazole, minocycline, tetracycline, or, in select severe cases, low-dose isotretinoin.¹¹ Laser, light-based therapies and surgical interventions may also be warranted in select patient populations.¹³ Recent research has added low-dose doxycycline to the therapeutic armamentarium and two additional treatments, ivermectin and alpha-adrenergic receptor antagonists, hold promise for the future. This article will review the topical and systemic options for the management of cutaneous manifestations of rosacea with a focus on emerging therapies.

Topical Metronidazole

Topical metronidazole has been used in the treatment of rosacea since the 1950s. It has demonstrated greater efficacy compared to placebo in multiple trials with both statistically significant and clinically important results.¹⁴ There is no statistically significant difference between the two concentrations of topical metronidazole (0.75% or 1%) and it has also been shown to be effective in maintaining remission.¹⁴ Among available topical therapies metronidazole has also been proposed as the most costeffective regimen, which may be an important consideration for some patients.¹⁵

Topical Azelaic Acid

Azelaic acid is a naturally occurring saturated dicarboxylic acid approved for the treatment of mild to moderate rosacea. Patients using azelaic acid showed an improvement of 70-80% in their rosacea compared with 50-55% in the placebo group.¹⁴ Azelaic acid 15% gel administered once daily has demonstrated equivalent efficacy to twice daily application, although the recommended dosing is twice daily.¹⁶

Metronidazole versus Azelaic Acid

In two studies comparing topical metronidazole and azelaic acid, there was no statistically significant difference between the treatment groups with respect to patient-assessed outcomes.^17,18 However, in the split-face comparison clinical trial by Maddin, patients favored the outcome of azelaic acid.¹⁹ In both the Maddin and Elewski et al trials, the investigators were of the opinion that treatment with azelaic acid was more effective than metronidazole.^17,19

Subantimicrobial Low-dose Oral Doxycycline

Tetracyclines (pregnancy category D) have been a mainstay of rosacea therapy for more than half a century.³ However, a clear bacterial pathogen has not been implicated in the pathophysiology of rosacea.²⁰ Furthermore, standard antimicrobial dosing may affect endogenous flora and risks the development of antibiotic resistant strains. Antibiotic stewardship is advocated in all medical disciplines in hopes of preserving efficacy for the management of bacterial infections.²¹ In light of these considerations, tetracyclines also have numerous anti-inflammatory properties thought to be responsible for their efficacy in the management of rosacea. They suppress neutrophil migration and chemotaxis, inhibit angiogenesis and the activation, proliferation and migration of lymphocytes, block production of matrix metalloproteinases (MMPs), and upregulate anti-inflammatory cytokines.^22,23

Anti-inflammatory, low-dose doxycycline 40 mg capsules, formulated as 30 mg immediate-release and 10 mg delayedrelease beads and dosed once daily, provide a subantimicrobial dose that reduces the inflammatory response without producing drug concentrations required to treat bacterial diseases, thus avoiding concerns regarding selective pressures generating microbial resistance.²⁴ The efficacy of oral doxycycline 40 mg capsules once daily in the treatment of adults with rosacea was demonstrated in two large, randomized, double-blind, placebocontrolled, multicenter trials. Assessed after 16 weeks of therapy, doxycycline 40 mg provided a significantly greater reduction in the total inflammatory lesion count (primary endpoint) than placebo.²⁵ Furthermore, doxycycline 40 mg was associated with a rapid onset of action, with a significantly greater decrease in lesion count than placebo by first follow-up at 3 weeks in both studies.²⁵ Interestingly, maximum anti-inflammatory effects appear to be achieved with doxycycline 40 mg capsules once daily. In a small, randomized, double-blind trial, no additional improvement in rosacea symptoms was achieved with oral doxycycline 100 mg once daily.²⁶ The treatment was generally well-tolerated by patients; adverse events (experienced by approximately 4% of patients) were of mild to moderate intensity, with headache, nasopharyngitis and gastrointestinal side effects reported most frequently.²⁵ No photosensitivity was observed, although tetracyclines as a class of medications have been associated with this effect.²⁵ Doxycycline 40 mg capsules have been demonstrated as safe and effective monotherapy for rosacea in both males and females and in patients of all skin types.^27,28 Furthermore, patientrated measures report improvement in symptoms, reduction in the interference of symptoms with life activities, and satisfaction with treatment.²⁹ Combination therapy with doxycycline 40 mg plus either azelaic acid gel 15% or metronidazole gel 1% were also safe, efficacious and well-tolerated.^30,31

Emerging Therapies

Ivermectin cream (CD5024)

An agent currently under investigation is CD5024 1% cream, which is a new topical formulation of the acaricidal compound, ivermectin.³² Although the exact pathophysiology is yet to be elucidated, one well-known hypothesis for the etiology of rosacea is the presence of Demodex mites in the pilosebaceous unit of affected individuals.³³ Reports have been published on cutaneous demodicidosis responding to oral ivermectin and topical permethrin, but data is lacking on the topical application of ivermectin alone.³⁴

There are currently three Phase III studies ongoing, one comparing CD5024 1% cream to metronidazole cream 0.75% (ClinicalTrials.gov identifier NCT01493947) and two similar studies comparing CD5024 1% cream to azelaic acid 15% gel with an initial randomized controlled phase for 12 weeks, and a comparator extension phase for 40 weeks (ClinicalTrial.gov identifiers NCT01494467 and NCT01493687).^35-37 The projected trial completion date is August 2013.

Adrenergic Receptor Antagonists: Brimonidine and Oxymetazoline

Novel therapies to treat the erythema associated with rosacea are under development and have the potential to fill a void in the arsenal of rosacea therapeutics. The adrenergic receptor antagonists brimonidine tartrate and oxymetazoline, which have potent vasoconstrictive activity and anti-redness capabilities, are currently found in eye drops for glaucoma and a nasal decongestant spray, respectively.³⁸

Brimonidine tartrate, an alpha-2 agonist also known as CD07805/47, has been shown in a two part dose-finding Phase II study to be safe and efficacious in reducing the erythema of rosacea. A single application of the 0.5% gel reduced erythema between 30 minutes to 12 hours, as measured with an objective chromameter.³⁹ In part B of the study, two dosages (0.18% and 0.5%) of the gel was compared to vehicle over a 4 week period in 269 subjects. No tachyphylaxis, aggravation of symptoms or rebound erythema was observed. The majority of adverse effects were skin-related and mild and transient in nature. The 0.5% gel once daily was significantly more effective according to both patient and clinician assessments (≥ two-grade improvement) and is the dose that has gone forward in Phase III clinical development to confirm safety and efficacy.³⁸ Results of the Phase III randomized controlled trials are anticipated to be released in the fourth quarter of 2012.

Oxymetazoline or AGN-199201, a potent alpha-1 and partial alpha-2 receptor agonist, has been shown in case reports to be an effective agent for reducing facial erythema.⁴⁰ It has been formulated into a cream and is currently in clinical development for the treatment of erythematotelangiectatic rosacea (ClinicalTrials.gov identifier NCT 01579084).⁴¹

Other Treatments

• Available for more than 50 years, topical sodium sulphacetamide 10% + sulphur 5% has also been demonstrated to significantly reduce inflammatory lesions and facial erythema compared to vehicle.⁴² However, the quality of studies evaluating this therapy have been generally poor.¹⁴
• Systemic isotretinoin has also been used off-label in the treatment of patients with severe rosacea. A randomized, double-blind, non-inferiority trial comparing the use of different dosages of oral isotretinoin to both doxycycline or placebo found isotretinoin 0.3 mg/kg to be an effective therapy with a similar safety profile as for the treatment of acne.⁴³
• Various topical regimens including an antibiotic and tretinoin preparations have been proposed. A recent randomized, doubleblind, placebo-controlled study assessing a combination gel of clindamycin phosphate 1.2% + tretinoin 0.025% found no difference in papule/pustule count, but mild improvement in the telangiectatic component of rosacea was observed.⁴⁴
• Although not FDA approved for the management of rosacea, a randomized, double-blind, vehicle-controlled trial has demonstrated the efficacy of once daily topical benzoyl peroxide 5%/clindamycin 1% gel in patients with moderate to severe rosacea.⁴⁵ Common adverse events include pruritus, burning, and bleaching of hair/clothing.
• In a randomized, controlled, single-blind, split-face trial of patients with erythematotelangiectatic rosacea, both pulsed dye laser and intense pulsed light treatments were found to have similar efficacy and safety.^46,47
• An open-label uncontrolled trial of the calcineurin inhibitor pimecrolimus 1% cream suggests it is effective and welltolerated for mild to moderate inflammatory rosacea.⁴⁸ A small, single-centre randomized study found pimecrolimus 1% cream to be as effective as metronidazole 1% cream.⁴⁹
• The use of oral zinc sulfate has also been proposed for the management of rosacea. However, a randomized, doubleblind trial of 220 mg zinc sulfate dosed twice daily showed no difference in magnitude of improvement between subjects receiving zinc therapy versus placebo.⁵⁰
• Due to the chronic nature of the condition, patients frustrated with medical therapy may turn to marketed botanicals and herbal remedies in hopes of improved control. Although there is a paucity of data surrounding the effects of these cosmeceuticals, the prudent clinician should be aware of products that may be used by patients such as niacinamide, feverfew, turmeric, colloid.al oatmeal and quassia extract.^51,52

Conclusion

With the advent of novel therapeutic options for the treatment of rosacea such as subantimicrobial anti-inflammatory dose doxycycline, ivermectin and the alpha-adrenergic receptor antagonists, there is renewed interest in the study of this chronic inflammatory condition. There is ongoing need for well-designed, high-quality studies of widely used treatments for rosacea including isotretinoin, sodium sulphacetamide/sulphur, and light-based therapies, as well as comparative studies, given the emergence of new treatments. Lifestyle interventions such as avoidance measures for triggering factors, the use of sunscreen, dietary changes and patient education are additional areas of needed research. It would be beneficial for outcomes in future trials to be based on validated, standardized scales assessing both efficacy and improvement in quality of life. Where possible, therapeutic decision-making should take into account high-level evidence and be guided by clinical experience, individual patient characteristics and preferences until further evidence is available.

References

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20. Mays RM, Gordon RA, Wilson JM, et al. New antibiotic therapies for acne and rosacea. Dermatol Ther. 2012 Jan-Feb;25(1):23-37.
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22. Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracyclines. Dermatol Clin. 2007 Apr;25(2):133-5, v.
23. Korting HC, Schollmann C. Tetracycline actions relevant to rosacea treatment. Skin Pharmacol Physiol. 2009;22(6):287-94.
24. McKeage K, Deeks ED. Doxycycline 40 mg capsules (30 mg immediaterelease/ 10 mg delayed-release beads): anti-inflammatory dose in rosacea. Am J Clin Dermatol. 2010;11(3):217-22.
25. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating anti-inflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007 May;56(5):791-802.
26. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008 Jun;7(6):573-6.
27. Del Rosso JQ, Preston NJ, Caveney SW, et al. Effectiveness and safety of modified-release doxycycline capsules once daily for papulopustular rosacea monotherapy results from a large community-based trial in subgroups based on gender. J Drugs Dermatol. 2012 Jun;11(6):703-7.
28. Alexis AF, Webster G, Colon LE, et al. Effectiveness and safety of doxycycline 40 mg monotherapy for the treatment of rosacea in skin type subgroups. J Am Acad Dermatol. 2012 Apr;66(4):AB50.
29. Johnson SM, LeVine P. Self-reported treatment impressions and satisfaction of papulopustular rosacea patients treated with doxycycline, USP, 40 mg capsules. J Drugs Dermatol. 2011 Dec;10(12):1376-81.
30. Del Rosso JQ, Bruce S, Jarratt M, et al. Efficacy of topical azelaic acid (AzA) gel 15% plus oral doxycycline 40 mg versus metronidazole gel 1% plus oral doxycycline 40 mg in mild-to-moderate papulopustular rosacea. J Drugs Dermatol. 2010 Jun;9(6):607-13.
31. Bhatia ND, Del Rosso JQ. Optimal management of papulopustular rosacea: rationale for combination therapy. J Drugs Dermatol. 2012 Jul;11(7):838-44.
32. UK Medicines Information. New drugs online report for ivermectin.
33. Forton FM. Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. J Eur Acad Dermatol Venereol. 2012 Jan;26(1):19-28.
34. Forstinger C, Kittler H, Binder M. Treatment of rosacea-like demodicidosis with oral ivermectin and topical permethrin cream. J Am Acad Dermatol. 1999 Nov;41(5 Pt 1):775-7.
35. Galderma. A phase 3 randomized, double blind, 12 week vehicle controlled, parallel group study assessing the efficacy and safety of CD5024 1 % cream versus vehicle cream in subjects with papulopustular rosacea, followed by a 40 week investigator blinded extension comparing the long term safety of CD5024 1% cream versus azelaic Acid 15 % gel. In: ClinicalTials.gov, Identifier: NCT01493687. Last updated June 12, 2012. Available at: http:// clinicaltrials.gov/ct2/show/NCT01493687?term=NCT01493687&rank=1. Accessed: October 2, 2012.
36. Galderma. A phase 3 randomized, double blind, 12 week vehicle controlled, parallel group study assessing the efficacy and safety of CD5024 1 % cream versus vehicle cream in subjects with papulopustular rosacea, followed by a 40 week investigator blinded. extension comparing the long term safety of CD5024 1% cream versus azelaic acid 15 % gel. In: ClinicalTials.gov, Identifier: NCT01494467. Last updated June 25, 2012. Available at: http://clinicaltrials. gov/ct2/show/NCT01494467. Accessed: October 2, 2012.
37. Galderma. Efficacy and safety of CD5024 1% cream versus metronidazole 0.75% cream in subjects with papulopustular rosacea over 16 weeks treatment, followed by a 36-week extension period (ATTRACT). In: ClinicalTrials.gov, Identifier: NCT01493947. Last updated September 5, 2012. Available: http:// clinicaltrials.gov/ct2/show/NCT01493947?term=NCT01493947&rank=1. Accessed: October 2, 2012.
38. Fowler J, Jarratt M, Moore A, et al. Once-daily topical brimonidine tartrate gel 0.5% is a novel treatment for moderate to severe facial erythema of rosacea: results of two multicentre, randomized and vehicle-controlled studies. Br J Dermatol. 2012 Mar;166(3):633-41.
39. Galderma. Randomized, double-blind, parallel-group, vehicle-controlled, dose-finding study investigating the pharmacodynamics and safety of three concentrations of CD07805/47 topical gel (0.07%, 0.18%, and 0.50%), applied in subjects with moderate to severe erythematotelangiectatic rosacea. In: ClinicalTrials.gov, Identifier: NCT00989014. Last updated July 24, 2012. Available at: http://clinicaltrials.gov/ct2/show/NCT00989014. Accessed: September 25, 2012.
40. Shanler SD, Ondo AL. Successful treatment of the erythema and flushing of rosacea using a topically applied selective alpha1-adrenergic receptor agonist, oxymetazoline. Arch Dermatol. 2007 Nov;143(11):1369-71.
41. Bikowski J. Rosacea therapy: current approaches and future directions. Pract Dermatol. 2012 Jul:31-2.
42. Korting HC, Schollmann C. Current topical and systemic approaches to treatment of rosacea. J Eur Acad Dermatol Venereol. 2009 Aug;23(8):876-82.
43. Gollnick H, Blume-Peytavi U, Szabo EL, et al. Systemic isotretinoin in the treatment of rosacea – doxycycline- and placebo-controlled, randomized clinical study. J Dtsch Dermatol Ges. 2010 Jul;8(7):505-15.
44. Chang AL, Alora-Palli M, Lima XT, et al. A randomized, double-blind, placebocontrolled, pilot study to assess the efficacy and safety of clindamycin 1.2% and tretinoin 0.025% combination gel for the treatment of acne rosacea over 12 weeks. J Drugs Dermatol. 2012 Mar;11(3):333-9.
45. Breneman D, Savin R, VandePol C, et al. Double-blind, randomized, vehiclecontrolled clinical trial of once-daily benzoyl peroxide/clindamycin topical gel in the treatment of patients with moderate to severe rosacea. Int J Dermatol.2004 May;43(5):381-7.
46. Neuhaus IM, Zane LT, Tope WD. Comparative efficacy of nonpurpuragenic pulsed dye laser and intense pulsed light for erythematotelangiectatic rosacea. Dermatol Surg. 2009 Jun;35(6):920-8.
47. Kassir R, Kolluru A, Kassir M. Intense pulsed light for the treatment of rosacea and telangiectasias. J Cosmet Laser Ther. 2011 Oct;13(5):216-22.
48. Kim MB, Kim GW, Park HJ, et al. Pimecrolimus 1% cream for the treatment of rosacea. J Dermatol. 2011 Dec;38(12):1135-9.
49. Koca R, Altinyazar HC, Ankarali H, et al. A comparison of metronidazole 1% cream and pimecrolimus 1% cream in the treatment of patients with papulopustular rosacea: a randomized open-label clinical trial. Clin Exp Dermatol. 2010 Apr;35(3):251-6.
50. Bamford JT, Gessert CE, Haller IV, et al. Randomized, double-blind trial of 220 mg zinc sulfate twice daily in the treatment of rosacea. Int J Dermatol. 2012 Apr;51(4):459-62.
51. Emer J, Waldorf H, Berson D. Botanicals and anti-inflammatories: natural ingredients for rosacea. Semin Cutan Med Surg. 2011 Sep;30(3):148-55.
52. Ferrari A, Diehl C. Evaluation of the efficacy and tolerance of a topical gel with 4% quassia extract in the treatment of rosacea. J Clin Pharmacol. 2012 Jan;52(1):84-8.

Skin Centre for Dermatology and Skin Laser Clinic, Peterborough, ON, Canada

ABSTRACT

The incidence of nonmelanoma skin cancer continues to increase. While surgical excision remains the mainstay of treatment, growing demand from patients for effective, tissue-sparing approaches with good cosmetic results has led to the development of novel therapeutic agents. Several studies have reported on the safety and efficacy of topical ingenol mebutate gel, a derivative of the plant Euphorbia peplus, in the treatment of actinic keratosis and superficial basal cell carcinoma. An understanding of the history, mechanism of action, and recent trial evidence for this emerging therapy can assist physicians in counseling patients on available treatment options and in selecting appropriate therapy.

Key Words:
actinic keratosis, ingenol mebutate, PEP005

Introduction

Nonmelanoma skin cancer is the most common type of cancer in humans.¹ While burgeoning incidence in North America has been partially attributed to improved skin cancer surveillance and detection, increased outdoor activity and sun exposure along with changing clothing styles are also implicated in this growing burden of disease.² Although surgical excision remains the mainstay of treatment, there exists demand from patients for medical alternatives that will remove the lesion while achieving a good cosmetic outcome.³ Despite increasing recognition of the role of prevention, including sun avoidance and sun protection through appropriate clothing and use of sunscreen, there remains a need for treatment of existing lesions. It has been recognized that actinic keratoses may occur as a single lesion or affect an entire region of skin (field cancerization).⁴ These lesions can progress to squamous cell carcinoma (SCC) but risk for individual lesions cannot be stratified clinically, supporting a role for active management of actinic keratoses in addition to that of basal cell, intraepidermal, and squamous cell carcinomas.⁴

This search for non-surgical and tissue-sparing treatments has led to the development of novel, non-invasive modalities. Further, with increasing mainstream media attention advocating the use of botanical extracts in both the cosmetic and pharmaceutical industries, the availability of controlled clinical trials is an important consideration in providing education and treatment selection for patients.⁵ Awareness of the history, mechanisms, and evidence for ingenol mebutate, formerly known as PEP005, as an emerging therapy for nonmelanoma skin cancer can assist physicians in counseling patients on available treatment options and in selecting appropriate therapy.

History

Ingenol mebutate (ingenol-3-angelate) is an extract from the plant Euphorbia peplus (E. peplus). More commonly known as the Spurge family, E. peplus belongs to the Euphorbiaceae, one of the most important medicinal families of plants with a long tradition.⁶ Comprised of over 3000 species within 200 genera, Euphorbiaceae is one of the largest families of flowering plants with species distributed over most of the globe.⁶ All euphorbias contain a natural irritant latex, which has been used for medicinal purposes since the time of recorded history.⁶ In more recent history, case reports have documented the use of wild E. peplus in the treatment of basal cell carcinoma,⁷ and participants in an Australian community survey of skin cancer and solar keratosis using naturopathic home remedies unanimously considered E. peplus to be an effective treatment for these lesions.⁸ This long experience of community use with few documented side-effects elicited the initiation of clinical trials assessing the potential of topical E. peplus for nonmelanoma skin cancer.⁹

Mechanism of Action

Several mechanisms have been identified to explain the chemotherapeutic effects of ingenol mebutate, a hydrophobic diterpene ester. Preclinical electron microscopy showed that treatment of a murine model with ingenol mebutate, both in vitro and in vivo, rapidly caused swelling of mitochondria of dysplastic keratinocytes and cell death by primary necrosis.¹⁰ Importantly, by induction of primary necrosis, it is unlikely to have its activity compromised by the development of apoptosis resistance in tumor cells.¹¹

Also of note, ingenol mebutate was observed to promote healing as well as restoration of normal clinical and histologic morphology.¹⁰ The inflammatory response generated by topical application, a predominantly neutrophilic infiltration, has been attributed to protein kinase C activation, and this activity may contribute to effective wound healing.^10,12,13 Protein kinase Cmediated neutrophilic cutaneous infiltrates are the response to the chemokine milieu generated by activated keratinocytes.¹⁴ The neutrophil infiltrate helps prevent relapse of the treated tumor by mediating antibody-dependent cellular cytotoxicity against residual tumor cells.^15,16 The immunostimulatory properties of ingenol mebutate have also been demonstrated to produce regression of smaller, distant untreated tumors.¹⁵

In addition to this induced neutrophilia, the protein kinase C pathway activation of ingenol mebutate also targets and damages the subepidermal intrinsic tumor vasculature.¹⁷ Further preclinical murine modeling has demonstrated that, through P-glycoprotein-mediated absorptive drug transport, ingenol mebutate can pass the stratum corneum barrier and penetrate to exert its pharmacological effects in the dermis and hypodermis.¹⁷

Efficacy

Several controlled studies have shown ingenol mebutate to be effective in the treatment of nonmelanoma skin cancer. Ramsay and colleagues evaluated the efficacy of E. peplus sap, containing approximately 100-300 µg mL^-1 ingenol mebutate.⁹ Patients in this phase I/II clinical study had at least one histologically confirmed basal cell carcinoma (BCC), intraepidermal carcinoma (IEC), or squamous cell carcinomas (SCC). The inclusion criteria accepted patients who were deemed unsuitable for surgical treatments (due to nature or site of lesion, age, or anticoagulant use) or who had failed previous treatments (including surgery, fluorouracil 5% cream, and/or liquid nitrogen) and refused surgical treatment. Thirty-six patients with a total of 48 lesions were treated topically once-daily for 3 consecutive days. The complete clinical response rate, defined as the absence of tumor on clinical exam 1 month following treatment, was 82% (n=28) for BCC, 94% (n=16) for IEC, and 75% (n=4) for SCC.⁹ Most common treatment site reactions included dry skin desquamation, patchy moist desquamation, and/or erythema. In over 60% of patients these skin reactions returned to normal within 1 month, with only mild erythema persisting for an average of 4 months in the remaining patients. Pain was rated from none to mild by 80% of participants receiving treatment with ingenol mebutate. This clinical study affirming the community experience with E. peplus sap provides support for further clinical development of ingenol mebutate for the treatment of basal cell, intraepidermal, and squamous cell carcinomas.

In a phase IIa randomized, double-blind, vehicle-controlled study conducted by Siller and colleagues, the safety of two applications of ingenol mebutate gel was investigated.¹⁸ In 58 patients with biopsy-confirmed actinic keratoses, lesions were treated with ingenol mebutate gel 0.0025%, 0.01% or 0.05%, or vehicle gel. No significant difference in tolerability was found between the gels with active ingredient or with application on days 1 and 2 as compared to days 1 and 8. There were no treatment-related serious adverse events. Local skin reactions consisting of mild to moderate erythema, flaking/scaling/dryness, and scabbing/ crusting were common but returned to baseline within 1 month of treatment cessation. There were no cases of scarring or abnormal lesion proliferation. Although this study also suggested a favorable clinical outcome with the treatment group, due to the limitations of small sample size, this efficacy data should be interpreted with caution.¹⁸

Anderson and colleagues conducted a phase IIb randomized, double-blind, vehicle-controlled study to further explore safety, efficacy, and tolerability.¹⁹ The trial compared ingenol mebutate 0.025% gel applied once-daily for 3 consecutive days or 0.05% gel applied once-daily for 2 or 3 consecutive days as field-directed therapy for an area containing 4-8 clinically typical, discrete actinic keratoses. The severity of local skin reactions in the active treatment groups followed a dose-dependent pattern, peaked between days 3 and 8, and largely resolved by day 15. Compared to vehicle, assessment at day 57 showed a statistically significant difference in partial clearance (56.0% to 75.4% from lowest to highest dosage) and for complete clearance (40.0% to 54.4% from lowest to highest dosage) with ingenol mebutate gel.¹⁹

Phase III trials have recently been undertaken evaluating topical ingenol mebutate gel at 0.05% for the treatment of actinic keratoses located on the trunk and extremities, and 0.015% for the face and scalp, although this data is not yet available.^20-23

Ingenol mebutate is also in clinical development as a short-course treatment for superficial basal cell carcinoma (sBCC). A phase IIa study conducted by Siller and colleagues evaluated the safety of two applications of topical ingenol mebutate gel at concentrations of 0.0025%, 0.01%, or 0.05% on histologically confirmed sBCC.²⁴ Of the 60 patients, adverse effects were low with no serious events. Four patients experienced severe local skin reactions resulting in only one application of medication for two patients and a delay in second application by 1 week for an additional two patients. Although the study population was small, histological clearance rates favored the treatment groups and served as a secondary endpoint.²⁴ A current phase II study will further assess safety and efficacy of ingenol mebutate in the treatment of sBCC.²⁵

Safety and Adverse Events

Available clinical data studying ingenol mebutate over the course of weeks to months has shown a favorable safety profile and has not demonstrated any severe adverse events. Mild to severe local skin reactions have been the most common treatment-related events and are not unexpected given the mechanism of action of both primary necrosis and concurrent inflammation.^9,18,19,24

However, case reports have documented side-effects from accidental ocular exposure to the sap of E. peplus.^26,27 Initial symptoms of ocular exposure were generally stinging pain with blurred vision. Clinical findings varied from mild epithelial keratoconjunctivitis to a severe keratitis, but with supportive management, all signs and symptoms resolved by 1-2 weeks.²⁶ Although such effects of ingenol mebutate gel have not been widely reported, caution with ocular exposure is likely warranted.

Conclusion

While not fully established, the efficacy of ingenol mebutate appears to be comparable with other non-surgical modalities.^28-30 Its use is associated with low toxicity, it is relatively well tolerated by patients, and resultant cosmesis is advantageous. Further, the 2-3 day course of therapy is likely to be viewed favorably by patients in terms of a shorter overall treatment time compared to other available topical therapies and this may show benefits with respect to enhancing adherence. Further data regarding efficacy and direct comparison to currently available therapies will be important in the assessment of ingenol mebutate gel and its role in the treatment of actinic keratoses and nonmelanoma skin cancer. Longitudinal studies will also be needed to confirm clinical cure over time, identify recurrence risk, and elucidate longer-term safety data.

References

1. Galiczynski EM, Vidimos AT. Nonsurgical treatment of nonmelanoma skin cancer. Dermatol Clin 2011 Apr;29(2):297-309.
2. Patel RV, Frankel A, Goldenberg G. An update on nonmelanoma skin cancer. J Clin Aesthet Dermatol 2011 Feb;4(2):20-7.
3. Madan V, Lear JT, Szeimies RM. Non-melanoma skin cancer. Lancet 2010 Feb 20;375(9715):673-85.
4. Fuchs A, Marmur E. The kinetics of skin cancer: progression of actinic keratosis to squamous cell carcinoma. Dermatol Surg 2007 Sep;33(9): 1099-101.
5. Reuter J, Merfort I, Schempp CM. Botanicals in dermatology: an evidencebased review. Am J Clin Dermatol 2010;11(4):247-67.
6. Appendino G, Szallasi A. Euphorbium: modern research on its active principle, resiniferatoxin, revives an ancient medicine. Life Sci 1997;60(10):681-96.
7. Weedon D, Chick J. Home treatment of basal cell carcinoma. Med J Aust 1976 Jun 12;1(24):928.
8. Green AC, Beardmore GL. Home treatment of skin cancer and solar keratoses. Australas J Dermatol 1988;29(3):127-30.
9. Ramsay JR, Suhrbier A, Aylward JH, et al. The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers. Br J Dermatol 2011 Mar;164(3):633-6.
10. Ogbourne SM, Suhrbier A, Jones B, et al. Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death. Cancer Res 2004 Apr 15;64(8):2833-9.
11. Ivanov VN, Bhoumik A, Ronai Z. Death receptors and melanoma resistance to apoptosis. Oncogene 2003 May 19;22(20):3152-61.
12. Serova M, Ghoul A, Benhadji KA, et al. Effects of protein kinase C modulation by PEP005, a novel ingenol angelate, on mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling in cancer cells. Mol Cancer Ther 2008 Apr;7(4):915-22.
13. Lee WY, Hampson P, Coulthard L, et al. Novel antileukemic compound ingenol 3-angelate inhibits T cell apoptosis by activating protein kinase Ctheta. J Biol Chem 2010 Jul 30;285(31):23889-98.
14. Wheeler DL, Ness KJ, Oberley TD, et al. Protein kinase Cepsilon is linked to 12-O-tetradecanoylphorbol-13-acetate-induced tumor necrosis factor-alpha ectodomain shedding and the development of metastatic squamous cell carcinoma in protein kinase Cepsilon transgenic mice. Cancer Res 2003 Oct 1;63(19):6547-55.
15. Le TT, Gardner J, Hoang-Le D, et al. Immunostimulatory cancer chemotherapy using local ingenol-3-angelate and synergy with immunotherapies. Vaccine 2009 May 18;27(23):3053-62.
16. Challacombe JM, Suhrbier A, Parsons PG, et al. Neutrophils are a key component of the antitumor efficacy of topical chemotherapy with ingenol-3- angelate. J Immunol 2006 Dec 1;177(11):8123-32.
17. Li L, Shukla S, Lee A, et al. The skin cancer chemotherapeutic agent ingenol- 3-angelate (PEP005) is a substrate for the epidermal multidrug transporter (ABCB1) and targets tumor vasculature. Cancer Res 2010 Jun 1;70(11): 4509-19.
18. Siller G, Gebauer K, Welburn P, et al. PEP005 (ingenol mebutate) gel, a novel agent for the treatment of actinic keratosis: results of a randomized, doubleblind, vehicle-controlled, multicentre, phase IIa study. Australas J Dermatol 2009 Feb;50(1):16-22.
19. Anderson L, Schmieder GJ, Werschler WP, et al. Randomized, double-blind, double-dummy, vehicle-controlled study of ingenol mebutate gel 0.025% and 0.05% for actinic keratosis. J Am Acad Dermatol 2009 Jun;60(6):934-43.
20. A multi-center, randomized, parallel group, double-blind, vehicle-controlled study to evaluate the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.05%, in patients with actinic keratoses on non-head locations (region-Ib). In: ClinicalTrials.gov NLM Identifier: NCT00942604. Available from: http://clinicaltrials.gov/ct2/show/NCT00942604. Accessed: August 31, 2011.
21. A multi-center, randomized, parallel group, double-blind, vehiclecontrolled study to evaluate the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.015% in patients with actinic keratoses on the head (face or scalp) (region-IIa). In: ClinicalTrials.gov NLM Identifier: NCT00916006. Available from: http://clinicaltrials.gov/ct2/show/NCT00916006. Accessed: August 31, 2011.
22. A multi-center, randomized, parallel group, double-blind, vehiclecontrolled study to evaluate the efficacy and safety of PEP005 (ingenol mebutate) gel, 0.015% in patients with actinic keratoses on the head (face or scalp) (region-IIb). In: ClinicalTrials.gov NLM Identifier: NCT00915551. Available from: http://clinicaltrials.gov/ct2/show/NCT00915551. Accessed: August 31, 2011.
23. A multi-center, open-label study to evaluate the safety and efficacy of PEP005 (ingenol mebutate) gel, 0.05% in patients with actinic keratoses on non-head locations (trunk and extremities). In: ClinicalTrials.gov NLM Identifier: NCT00917306. Available from: http://clinicaltrials.gov/ct2/show/ NCT00917306. Accessed: August 31, 2011.
24. Siller G, Rosen R, Freeman M, et al. PEP005 (ingenol mebutate) gel for the topical treatment of superficial basal cell carcinoma: Results of a randomized phase IIa trial. Australas J Dermatol 2010 May;51(2):99-105.
25. PEP005 Gel – Evaluation of the safety and efficacy of ingenol mebutate gel on a superficial basal cell carcinoma on the trunk or extremities. In: ClinicalTrials.gov NLM Identifier: NCT01325688. Available from: http://clinicaltrials.gov/ct2/show/NCT01325688. Accessed: August 31, 2011.
26. Eke T, Al-Husainy S, Raynor MK. The spectrum of ocular inflammation caused by euphorbia plant sap. Arch Ophthalmol 2000 Jan;118(1):13-6.
27. Lam TSK, Wong OF, Leung CH, et al. A case report of ocular injury by Euphorbia plant sap. Hong Kong J Emerg Med 2009 Oct;16(4):267-270.
28. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol 1992 Jun;26(6):976-90.
29. Thissen MR, Neumann MH, Schouten LJ. A systematic review of treatment modalities for primary basal cell carcinomas. Arch Dermatol 1999 Oct; 135(10):1177-83.
30. Love WE, Bernhard JD, Bordeaux JS. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. Arch Dermatol 2009 Dec;145(12):1431-8.

¹Skin Centre for Dermatology and Skin Laser Clinic, Peterborough, ON, Canada

ABSTRACT

The common bedbug (Cimex lectularius) is increasingly prevalent and a source of concern and questions for patients. In addition to a range of cutaneous presentations and potential for serious sequelae, bedbug bites cause significant psychological distress and create an economic burden associated with infestation control. Recognition of characteristic entomology, clinical presentation, diagnostic features and differential diagnosis can support expedient identification of patients exposed to infestations and support their appropriate management.

Key Words:
bedbugs, Cimex lectularius, infestation, pest control

Introduction

The common bedbug, Cimex lectularius (C. lectularius), is a hematophagus arthropod. A pest to mankind for centuries, bedbug populations in industrial nations declined steadily with the advent of novel pesticides, improved sanitation practices, and economic conditions.¹ In contrast, infestations in developing countries have persisted.² However, pest control companies in Canada and the United States are reporting overwhelming increases in the number of new bedbug encounters compared with 10 years ago.³ This recent bedbug resurgence has been attributed to evolving pesticide resistance coupled with increased rates of international trade and travel, as travellers can bring the insects home in their clothing and luggage.^4,5 Bedbugs have since established more widespread infestation of environments serving transient populations such as hotels, dormitories, hospitals, cruise ships, and homeless shelters.^6-9 In addition to this increased prevalence, bedbugs are also widely discussed in popular media and may be presented as a concern by patients.¹⁰ Awareness of the entomology, diagnosis, and management of bedbugs can assist physicians in detecting affected individuals and providing concerned patients with education on this topic.

Epidemiology

Bedbugs can be introduced to an environment from either local or distant sites. Local transmission occurs by “active dispersal” as the insects walk short distances to find a source for feeding. This is the predominant means of infestation in multi-unit dwellings as the bedbugs travel through ductwork, crevices in drywall, or electrical outlets. Infestation from distant sites occurs via “passive dispersal” when bedbugs travel on clothing, luggage, or shipped furniture.¹¹ As such, poorly maintained living conditions, overcrowding and transitory populations can confer increased risk of bedbugs.¹² Local public health departments often have limited resources to combat this problem, and municipal regulatory bodies struggle to assign responsibility of high eradication costs to landlords or transient tenant populations. ¹³

Entomology

Bedbugs are broad, oval-shaped, flat, wingless insects.¹⁴ Adults are red-brown in color and typically measure 4-7 mm; they are often likened to apple seeds in their appearance.¹¹ Patients may describe a distinctive, characteristic ‘sweet’ odor associated with the insects. While they may be difficult to detect early in the course of infestation, the bedbug life cycle can result in an exponential increase in numbers during the first month. The typical lifespan in temperate climates averages from 6 to 24 months, and an adult female could lay 200-500 eggs during this time.¹⁵ Nymphs hatch after 4 to 10 days and are pale and translucent. To reach full maturity they must molt four times, which can only occur with a blood meal. If a host is available they will feed every 3 to 7 days.¹⁵ However, adding to their resilience, bedbugs can survive 12 months without feeding, and even more than 2 years in cooler environments.¹¹

Hosts are typically bitten at night on exposed skin and an insect will feed for 10 to 20 minutes until completely engorged.¹⁵ The proboscis, an elongated feeding organ, is composed of two tubules. The first tubule secretes several substances, including an anesthetizing compound (producing a painless bite that may be undetectable for hours), proteolytic enzymes, anticoagulants (such as factor-X inhibitor), and vasodilatory substances (such as nitric oxide).¹⁶ This collection of substances can contribute to the subsequent local hypersensitivity reactions.¹¹ The second tubule simultaneously extracts the blood meal.

Bedbugs do not stay on the body of the host after feeding. Unable to fly or jump, they have six legs with which they are able to travel into crevices and evade detection at ambient temperatures.¹⁷ While they are most active in temperate environments, bedbugs exhibit incredible tolerance for temperature extremes and have been demonstrated to require 1 hour of exposure to temperatures lower than -16°C or greater than 48°C in order to be killed.^18,19

Psychological Consequences

The social and psychological impact of bedbugs can be devastating for affected individuals. Infestation can be stigmatizing due to the misconception that bedbugs are related to poor housekeeping or inadequate hygiene. In reality, bedbugs are attracted to carbon dioxide and body heat and they are nourished by blood, not excrement or waste.⁶ Minimizing clutter can thus reduce hiding places where insects may remain undetected, but patients can be reassured that they are not to blame. In addition to the stresses of identifying and controlling bedbugs in the home or workplace, some patients suffer anxiety due to fears of reinfestation even after the insects have been eliminated.²⁰ Extreme cases can result in delusions of parasitosis and in these situations a referral to psychiatry can be helpful.²¹

Cutaneous Manifestation

The bites of bedbugs can closely resemble those of other arthropods; however, they tend to be clustered on skin that is freely exposed when sleeping, such as the face and distal extremities. Bites may follow a linear path, or characteristically, appear in a group of three to five (colloquially known as ‘breakfast, lunch, and supper’).^22,23 In non-sensitized individuals, pruritic, erythematous macules may be the only cutaneous evidence of bedbug bites.²⁴ Bite sites typically appear as pruritic papules and wheals, which form in response to components of the saliva injected by the bedbug. The lesions often have a hemorrhagic punctum in the centre. Exaggerated local reactions, such as wheals, vesicles and bullae, may occur in patients whom have previously been bitten or have been sensitized to other insects.^25-27 Papular eruptions that mimic urticaria have been associated with IgG antibodies to C. lectularius proteins.^28,29 However, compared with other causes, urticaria from bedbugs has been found to last longer and blanches less easily.²⁹ In contrast, it is IgE that mediates the occasionally-manifested bullous allergic hypersensitivity.²² Although rare, cases of asthma exacerbations, type I hypersensitivity allergic cutaneous reactions, and severe anemia secondary to bedbug bites have been reported.^25,30

Diagnostic Considerations

Differential Diagnosis

Insect bite reactions are often non-specific and, as such, are susceptible to misdiagnosis. In the absence of typical presentation or evidence of infestation, bedbug bites can be challenging to differentiate from those of other arthropods. Further, in addition to the common bedbug C. lectularius, the tropical bedbug Cimex hemipterus and bat bug Cimex pipistrelli cause similar clinical symptoms.³¹ Bites from bedbugs have been incorrectly diagnosed and documented as:⁴

• Mosquito bites
• Spider bites
• Scabies
• Drug eruption
• Food allergy
• Staphylococcus infection
• Varicella

Unfortunately, misdiagnosis can result in inappropriate or unnecessary therapeutic and investigative interventions. While bedbugs characteristically affect skin that is exposed during the night, the furrows of scabies are more often found in covered areas, such as the periumbilical region, scrotum, and axillae.¹⁴ There is a broad differential in which histology may distinguish other conditions that produce similar-appearing skin lesions, including dermatitis herpetiformis, transient acantholytic dermatosis, urticarial dermatoses, or prodromal bullous pemphigoid. ^14,32

Histology

In the event of biopsy, bedbug reactions are similar histologically to other arthropod bite reactions. Tissue demonstrates dense eosinophil-predominant perivascular infiltrate of both superficial and deep dermis with minimal spongiosis. Subepidermal vesiculation and edema of the papillary dermis may also be seen.^14,29,32

Disease Transmission

In addition to cutaneous and possible allergic reactions to bedbugs, the risk of disease transmission via bites has also been raised as a concern.³³ There is both historical and experimental laboratory data supporting the Hepatitis B virus as a candidate for bedbug transmission.³⁴ Further, a recent case report details the isolation of both vancomycin-resistant Enterococcus faecium (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) bacterial colonies from bedbugs.³⁵ However, although the question of the hematogphagus bedbug vectorial capacity is compatible with logic and these parasitic insects have been found to carry > 40 different microorganisms, they have not been identified as transmitting human disease.^11,26

Management

Uncomplicated bedbug bites usually resolve within 1-2 weeks and are self-limited. Although the evidence base is weak, management is otherwise symptomatic. Topical or oral antipruritic agents combined with an intermediate corticosteroid can bring some relief. For some patients, having prescription topicals compounded with menthol and camphor can be soothing. Superinfection can occur, especially in cases with significant excoriation, and can be treated with topical or oral antibiotics.¹⁶

Systemic reactions to bedbug bites are treated with intramuscular epinephrine, antihistamines, and oral corticosteroids, as in insect-induced anaphylaxis.¹⁶

In tandem with the control of symptoms, eliminating the infestation must be aggressively pursued to prevent further bites. Goddard et al. (2009) have outlined several steps that are useful in successful eradication of bedbugs:¹⁶

1. Proper identification of the bedbugs species
2. Education of the patient, other dwelling occupants, and landlord, as applicable
3. Thorough inspection of both infested and other nearby areas
4. Implementation of pesticide and non-chemical control measures
5. Follow-up to ensure control of the infestation

Conclusion

Bedbug infestation is increasingly prevalent and generates much anxiety in patients, which is fuelled by media coverage of this issue. As such, bedbug bites are a prudent component of a differential diagnoses if arthropod bites are suspected or history is suspicious for infestation. Confirmation of infestation may be necessary to establish the diagnosis in light of the often equivocal constellation of clinical symptoms. In addition to the cutaneous discomfort of bites and potentially serious sequelae, such as anaphylaxis, bedbug bites can cause significant psychological distress. Controlling symptoms through corticosteroids and anti-pruritics is helpful for patient comfort. However, ultimately, eradication of the offending insect and the prevention of further bites is the goal of therapy for these patients.

References

1. Berg R. Bed bugs: the pesticide dilemma. J Environ Health 72(10):32-5 (2010 Jun).
2. Gbakima AA, Terry BC, Kanja F, et al. High prevalence of bedbugs Cimex hemipterus and Cimex lectularis in camps for internally displaced persons in Freetown, Sierra Leone: a pilot humanitarian investigation. West Afr J Med 21(4):268-71 (2002 Oct-Dec).
3. Benac N. Bedbug bites becoming bigger battle. CMAJ 182(15):1606 (2010 Oct 19).
4. Doggett SL, Russell R. Bed bugs – What the GP needs to know. Aust Fam Physician 38(11):880-4 (2009 Nov).
5. Romero A, Potter MF, Potter DA, et al. Insecticide resistance in the bed bug: a factor in the pest’s sudden resurgence? J Med Entomol 44(2):175-8 (2007 Mar).
6. Krause-Parello CA, Sciscione P. Bedbugs: an equal opportunist and cosmopolitan creature. J Sch Nurs 25(2):126-32 (2009 Apr).
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23. Stibich AS, Carbonaro PA, Schwartz RA. Insect bite reactions: an update. Dermatology 202(3):193-7 (2001).
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25. Cestari TF, Martignago BF. Scabies, pediculosis, bedbugs, and stinkbugs: uncommon presentations. Clin Dermatol 23(6):545-54 (2005 Nov-Dec).
26. Fletcher CL, Ardern-Jones MR, Hay RJ. Widespread bullous eruption due to multiple bed bug bites. Clin Exp Dermatol 27(1):74-5 (2002 Jan).
27. Liebold K, Schliemann-Willers S, Wollina U. Disseminated bullous eruption with systemic reaction caused by Cimex lectularius. J Eur Acad Dermatol Venereol 17(4):461-3 (2003 Jul).
28. Abdel-Naser MB, Lotfy RA, Al-Sherbiny MM, et al. Patients with papular urticaria have IgG antibodies to bedbug (Cimex lectularius) antigens. Parasitol Res 98(6):550-6 (2006 May).
29. Scarupa MD, Economides A. Bedbug bites masquerading as urticaria. J Allergy Clin Immunol 117(6):1508-9 (2006 Jun).
30. Pritchard MJ, Hwang SW. Cases: Severe anemia from bedbugs. CMAJ 181(5):287-8 (2009 Sep 1).
31. Davis RF, Johnston GA, Sladden MJ. Recognition and management of common ectoparasitic diseases in travelers. Am J Clin Dermatol 10(1):1-8 (2009).
32. Cohen PR, Tschen JA, Robinson FW, et al. Recurrent episodes of painful and pruritic red skin lesions. Am J Clin Dermatol 11(1):73-8 (2010).
33. Goddard J. Bed bugs bounce back – but do they transmit disease? Infect Med 20(10):473-4 (2003 Oct).
34. Silverman AL, Qu LH, Blow J, et al. Assessment of hepatitis B virus DNA and hepatitis C virus RNA in the common bedbug (Cimex lectularius L.) and kissing bug (Rodnius prolixus). Am J Gastroenterol 96(7):2194-8 (2001 Jul).
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