Allergic reactions to mosquito bites

INTRODUCTION — Reactions to mosquito bites are caused by an immunologic response to proteins in mosquito saliva. Many people who are bitten by mosquitoes develop an immune response to these proteins. However, only a small proportion of them develop clinically relevant allergic reactions (most commonly large local reactions).

This topic briefly reviews the types of reactions that may result from mosquito bites [1]. It also focuses on large local reactions to mosquito bites and their clinical features, pathogenesis, natural history, diagnosis, differential diagnosis, treatment, and prevention. Other issues related to insect bites are reviewed separately. (See "Insect and other arthropod bites" and "Prevention of arthropod and insect bites: Repellents and other measures".)

LOCAL REACTIONS

Typical (normal) reactions — A local cutaneous reaction to a mosquito bite typically consists of an immediate wheal (swelling) with surrounding flare (redness) that peaks at approximately 20 minutes, followed by a delayed, itchy indurated (firm) papule that peaks at 24 to 36 hours and resolves over the next 7 to 10 days [2,3].

Normal immune responses — The typical clinical course of sensitization and natural desensitization to mosquito salivary allergens was described initially in the 1940s. Five stages are identified, which evolve over months or years in an individual (table 1) [4]. People who have never been exposed to a particular species of mosquito do not develop reactions to the initial bites from such mosquitoes. Subsequent bites result in the appearance of delayed local skin reactions. After repeated bites, immediate wheals develop. With further exposure, the delayed local reactions wane and eventually disappear, although the immediate reactions persist. People who are repeatedly exposed to bites from the same species of mosquito eventually also lose their immediate reactions. The duration of each of these five different stages differs, depending on the intensity and timing of mosquito exposure [5,6]. Not all patients progress through these stages even with repeated bites [6]. These typical reactions are annoying but not dangerous. The immunologic basis of sensitization and natural desensitization to mosquito bites was described in the 1990s [7,8]. Both immunoglobulin E (IgE) and immunoglobulin G (IgG), as well as lymphocytes, appear to be involved in the development of local reactions. Serum mosquito salivary gland-specific IgE and IgG levels correlated significantly with the size of the immediate skin reaction to mosquito bites, while lymphocyte proliferation to mosquito antigens correlated with the delayed reaction. (See 'Pathogenesis' below.)

Large local reactions — Large local reactions are by far the most common type of allergic reactions to mosquito bites:

●Large local reactions (sometimes referred to as "Skeeter syndrome") typically consist of an itchy or even painful area of redness, warmth, swelling, and/or induration that ranges from 2 to more than 10 cm in diameter. Large local reactions develop within hours of the bite, progress over 8 to 12 hours or more, and resolve within 3 to 10 days [9].

●Depending on the location of the bite, large local reactions can involve the entire periorbital region and much of the face or an entire extremity, especially in an infant or child. They can interfere with seeing, eating, drinking, or normal use of an extremity. Severe large local reactions can be accompanied by low-grade fever and malaise [9].

●By inspection and palpation, it can be difficult to differentiate between allergic inflammation caused by mosquito bites and inflammation caused by secondary bacterial infection (cellulitis) after scratching the bites. It is important to obtain a history of the time of onset of the red, warm swollen area at the site of a witnessed or likely mosquito bite in relationship to the time of the bite. Large local reactions typically begin within hours. Secondary bacterial infections typically begin within days.

Epidemiology — People at increased risk of allergic reactions to mosquito bites include:

●Those with a high level of exposure (ie, frequently outdoors)

●Infants and young children, once bitten and sensitized but prior to the development of natural immunity

●Newcomers or visitors to a geographic area where there are indigenous mosquitoes that they had not previously encountered, once bitten and sensitized but prior to the development of natural immunity

●Patients with primary or secondary immunodeficiency diseases who may paradoxically have elevated antibody titers to mosquito salivary gland antigen

There are also associations between immunity-related genes and mosquito bite reaction size, itch, and self-perceived attractiveness to mosquitoes [10].

Pathogenesis — The pathogenesis of large local reactions to mosquito bites was investigated in a study of five otherwise healthy young children ages two to four years who developed large local reactions within hours of witnessed mosquito bites and five age-matched control children who developed smaller typical reactions within hours of mosquito bites [9]. All of the children with the large local reactions had been diagnosed initially with bacterial cellulitis and received systemic antibiotic treatment. In two of the children, radiographs were obtained to rule out osteomyelitis underlying the extensive soft tissue swelling.

An indirect enzyme-linked immunosorbent assay (ELISA) was used to measure IgE and immunoglobulin G 1-4 subclasses (IgG1-4), recognizing salivary gland allergens of the predominant indigenous mosquito, Aedes vexans. In the children with large local reactions, serum levels of IgE, IgG1, IgG3, and IgG4 to A. vexans salivary gland allergens were significantly elevated as compared with the levels in control children. Specific IgE and IgG concentrations were significantly higher at the end of summer as compared with levels at the end of the following winter after no exposure to mosquitoes had occurred for six months. Thus, it appears that large local reactions involve the same mechanisms (IgE and IgG antibody production) as smaller, typical reactions. Those with large local reactions mount a more robust immune response yet still eventually undergo the same natural desensitization.

Natural history — The prognosis of large local reactions to mosquito bites appears to be favorable. Children often continue to develop recurrent large local reactions to mosquito bites for several summers, after which the reactions cease to occur. However, the time to resolution varies [5,11], depending on the frequency and intensity of the patient's exposure to mosquitoes, which may be reduced by efforts to avoid mosquitoes and prevent mosquito bites.

In a study of sera from 402 children living in the region of Canada where large local reactions to mosquito bites were originally described, levels of mosquito saliva-specific IgE and IgG correlated inversely with age, peaked at one to six months of age, and decreased after five years of age [12]. In this geographic region, only 18 percent of 1059 adult blood donors had demonstrable antibodies to mosquito salivary allergens, suggesting that, in most adults, sensitization had been lost and natural desensitization had occurred.

Diagnosis — Diagnosis of large local reactions to mosquito bites is based on history and physical exam as laboratory testing is not commercially available.

History and physical exam — Diagnosis is based on the time of onset (hours) of the reaction in relationship to a witnessed or likely mosquito bite and on the physical finding of an itchy, red, warm swollen area at the site of the bite.

Laboratory testing — Skin testing or serum-specific IgE antibody testing for the presence of antibodies to mosquito saliva is not practical, because the only commercially available mosquito reagents are unstandardized whole-body extracts that contain minimal mosquito salivary allergens yet may contain irritant proteins. Obtaining pure mosquito salivary allergen for use in skin tests and in vitro tests by dissection of mosquito salivary glands or by direct collection from living mosquitoes is labor intensive and time consuming. Such allergens are not commercially available. Mosquito bite challenge tests are contraindicated because of the risk of disease transmission through a "wild" mosquito bite and the risk of causing another severe large local reaction in a susceptible patient [1,13,14]. Recombinant salivary allergens have been developed as a research tool but are not commercially available [1,15].

Differential diagnosis — The differential diagnosis of a large local reaction to a mosquito bite includes bacterial cellulitis and large local reactions to other insect bites and stings.

Bacterial cellulitis — The key information needed to distinguish a large local reaction to a mosquito bite from cellulitis is the time elapsed between a witnessed mosquito bite (or exposure to mosquitoes and a likely mosquito bite) and the appearance of an itchy, red, swollen area at the bite site. This interval is typically hours with large local reactions and days with cellulitis. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Large local reactions to other insect bites and stings — Mosquito bites are often minimally painful or painless, in contrast to painful bites from flies and other insects and painful stings from bees, wasps, yellowjackets, yellow hornets, white-faced hornets, or fire ants that cause large local reactions. (See "Insect and other arthropod bites" and "Bee, yellow jacket, wasp, and other Hymenoptera stings: Reaction types and acute management" and "Stings of imported fire ants: Clinical manifestations, diagnosis, and treatment" and "Diagnostic approach to the patient with a suspected spider bite: An overview".)

Prevention — Prevention of large local reactions consists of mosquito avoidance and prophylaxis with an oral nonsedating H1 antihistamine.

Mosquito avoidance — Written information about insect repellents and environmental control measures to reduce mosquito populations near the home should be provided for patients who have experienced large local reactions and for parents and caregivers of children who have experienced such reactions. Key points are reviewed briefly here and discussed in greater detail elsewhere. (See "Prevention of arthropod and insect bites: Repellents and other measures".)

●Activities should be modified to avoid mosquito bites. Measures might include staying indoors at dawn and dusk and avoidance of wetlands.

●Standing water should be eliminated around the home or other immediate environment in order to reduce breeding areas for mosquitoes. Screens on windows and doors should be well maintained.

●The insecticide permethrin is suitable for application to fabrics (for example, camp tents, sleeping bags, and clothing) but not for direct application to human skin. Permethrin-impregnated clothes (eg, shirts) are available commercially.

●Different insect repellents are available in a variety of formulations and concentrations. The most effective repellents are DEET (N,N-diethyl-3-methylbenzamide) and picaridin [16,17].

•Humans attract mosquitoes by their body odor, skin temperature, and exhaled carbon dioxide. DEET-containing products provide excellent protection against bites. The higher the DEET concentration, the longer lasting the protection. DEET in a concentration of 10% can be applied safely to the skin of children over two months of age. DEET is potentially neurotoxic if applied in high concentrations to abraded or sunburned skin or if unintentionally ingested or inhaled. DEET is also a plasticizer, and, as such, it can dissolve mosquito nets, spandex, rayon, and leather, as well as plastic eyeglass frames and watches. (See "Prevention of arthropod and insect bites: Repellents and other measures", section on 'DEET'.)

•Picaridin blocks insects' ability to locate human skin by forming a barrier on the skin. It is odorless, leaves no residue, and has long-lasting efficacy (between 8 to 10 hours). Overall, in comparison with DEET, it is more effective against mosquitoes and less potentially toxic to humans. Picaridin can be applied safely to the skin of children over two months of age. (See "Prevention of arthropod and insect bites: Repellents and other measures", section on 'Picaridin'.)

•Other agents, such as citronella and lemon eucalyptus oil, are less effective and relatively short acting. For example, citronella may be effective for only 20 minutes, and eucalyptus oil may be effective for only two hours.

Antihistamines — We suggest to patients that a nonsedating antihistamine be taken on a regular daily basis when mosquito exposure is inevitable and that such antihistamines should also be used to treat itching, redness, and swelling that occur at mosquito bite sites.

In randomized, double-blind, placebo-controlled trials of patients bitten by mosquitoes in laboratory and field settings, prophylactic oral administration of a second-generation H1 antihistamine, such as cetirizine, loratadine, fexofenadine, or rupatadine (not available in the United States or Canada), relieved itching in the early-phase allergic reaction and reduced the late-phase reaction (redness, swelling, and induration) [18-20].

Treatment — Treatment of large local reactions involves antihistamines and, for severe reactions, glucocorticoids.

Antihistamines — Second-generation H1 antihistamines, such as cetirizine, loratadine, fexofenadine, or rupatadine (not available in the United States or Canada), can be administered to relieve itching in association with large local reactions.

Glucocorticoids — Glucocorticoids are used to treat the allergic inflammation associated with large local reactions to stinging insects [21]. This approach has been extrapolated to the treatment of large local reactions to mosquito bites.

●To relieve itching, redness, warmth, and swelling, a moderately potent topical corticosteroid cream may be applied twice daily for 5 to 10 days (table 2).

●For severe, large local reactions that are distressing and/or interfere with normal vision, ingestion of liquid or food, or ambulation, an oral glucocorticoid such as prednisone 1 mg/kg to a maximum of 50 mg may be given for five to seven days.

Antibiotic treatment is not indicated for large local reactions that develop within hours of mosquito bites, because it is unlikely that bacterial infection would develop this rapidly.

OTHER TYPES OF REACTIONS

Systemic allergic reactions — Systemic allergic reactions to mosquito bites include acute generalized urticaria and, rarely, anaphylaxis [22]. A patient with systemic mastocytosis and recurrent anaphylaxis associated with mosquito bites has also been described [23].

Respiratory allergy — Some patients with allergic rhinitis and asthma are sensitized (ie, have formed specific IgE) to airborne mosquito allergens [24]. These allergens may be present in the bodies of mosquitos and may be different than the salivary allergens that cause bite reactions [25]. One airborne allergen has been identified as a tropomyosin and may cross-react with tropomyosins from arthropods [26]. Immunotherapy with whole-body mosquito extract has been reported to improve respiratory symptoms in sensitized patients [27].

Unusual forms of large local reactions — Sometimes large local reactions develop an ecchymotic appearance or form blisters, vesicles, or bullae in association with Epstein-Barr virus (EBV), Wells syndrome (eosinophilic cellulitis), or hematologic malignancies [28-32].

SUMMARY AND RECOMMENDATIONS

●Possible reactions to mosquito bites – Possible reactions to mosquito bites include normal reactions, large local reactions, and systemic reactions:

•A normal cutaneous reaction to a mosquito bite consists of an immediate localized swelling with surrounding redness that peaks at approximately 20 minutes, followed by a delayed, itchy indurated papule that peaks in 2 to 3 days and resolves over the next 7 to 10 days. Many people who are bitten by mosquitoes become sensitized to mosquito salivary allergens, but few develop mosquito allergy. (See 'Typical (normal) reactions' above.)

•Large local reactions to mosquito bites are itchy, red, warm swellings that develop within hours of bites and resolve with or without treatment over 3 to 10 days. Large local reactions to mosquito bites are most common in young children and typically cease to occur within a few years. (See 'Large local reactions' above.)

In middle-aged and older adults, large local reactions that develop an ecchymotic appearance or form blisters, vesicles, or bullae have been noted in association with Epstein-Barr virus (EBV), Wells syndrome (eosinophilic cellulitis), or hematologic malignancies. (See 'Epidemiology' above and 'Natural history' above.)

•Systemic allergic reactions to mosquito bites include acute generalized urticaria and, rarely, anaphylaxis. (See 'Systemic allergic reactions' above.)

●Diagnosis – The diagnosis of large local reactions to mosquito bites is made clinically. The key information needed is the time elapsed, measured in hours (not days) between a witnessed mosquito bite or exposure to mosquitoes and a likely mosquito bite and the appearance of an itchy, red, warm, swollen area at the bite site. Prompt recognition and appropriate treatment helps avoid unnecessary diagnostic procedures and unnecessary antibiotic treatment. (See 'Diagnosis' above.)

●Large local reactions versus cellulitis – Large local reactions to mosquito bites are frequently misdiagnosed as bacterial cellulitis. However, large local reactions to mosquito bites typically develop within hours of a bite, and bacterial cellulitis typically develops a few days later, after bite sites have been scratched and excoriated. (See 'Differential diagnosis' above.)

●Prevention – Environmental measures to limit mosquito breeding habitats and repellents to prevent bites are the primary means of preventing large local reactions in patients with a history of past reactions. If mosquito exposure is predictable or inevitable, we recommend a nonsedating H1 antihistamine taken before spending time outdoors (Grade 1B). (See 'Prevention' above.)

●Management – Treatment of large local reactions to mosquito bites is symptomatic (see 'Treatment' above):

•For patients with bothersome itching, we recommend an oral nonsedating H1 antihistamine (Grade 1B).

•For patients with swelling and induration several centimeters in diameter, we suggest a moderate-potency topical corticosteroid cream (Grade 2C), applied twice daily for 5 to 10 days (table 2).

•For patients with extensive periorbital swelling that interferes with vision, lip swelling that interferes with liquid or food ingestion, or extensive limb swelling that interferes with movement, we suggest a short course of an oral glucocorticoid, such as prednisone (eg, 1 mg/kg to a maximum of 50 mg) once daily for five to seven days (Grade 2C).

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges F Estelle R Simons, MD, FRCPC, who contributed to earlier versions of this topic review.