Mosquito

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Code: i71
Latin name: Aedes communis
Source material: Whole insect
Family: Culicidae
Common names: Snow mosquito, woodland floodwater mosquito

Insect

An insect, which may result in allergy symptoms in sensitised individuals.

Allergen Exposure

The mosquitoes are a family of small, midge-like flies. A few species are harmless or even useful to humanity. However, most consume blood from living vertebrates, including humans. Various species of mosquitoes (and in particular, the females) act as vectors for a range of diseases, and transmit some of the most harmful human and livestock diseases. Mosquito habits differ; even among those that do carry important diseases, not all species carry the same diseases, or carry them under the same circumstances. Others do not routinely bite humans, but are the vectors for animal diseases.

Mosquitoes are members of the family Culicidae (stinging mosquitoes). There are more than 40 mosquito genera and more than 3 500 mosquito species worldwide. Three common mosquito species occurring globally are Culex quinquefasciatus (southern house mosquito), Aedes aegypti, and Anopheles stephensi. (1) Aedes communis is found over almost all of Europe, and in North America, Asia and Japan.

The genus Aedes contains more than 500 species distributed from the polar regions to the tropics, including North America and Europe. (2)

Aedes aegypti is the most important mosquito pest in the world, and shares many salivary allergens with other species including Culex quinquefasciatus, and with Aedes vexans, another common pest mosquito indigenous to North America. (3, 4, 5)

Mosquitoes go through four stages in their life cycle: egg, larva, pupa, and adult. In most species, adult females lay their eggs in standing water; some lay eggs near the water's edge; others attach their eggs to aquatic plants. The first three stages (egg, larva and pupa) are mostly aquatic. These stages typically last 5-14 days, depending on the species and the ambient temperature. (6) Eggs hatch to become larvae, which grow until they are able to change into pupae. The adult mosquito emerges from the mature pupa as it floats at the water’s surface. Bloodsucking mosquitoes have potential adult lifespans ranging from as little as a week to as long as several months, depending on species, gender, and weather conditions.

Species of Aedes characteristically lay their eggs either singly on the ground, on the waterline, or slightly above the waterline in tree holes or containers. These eggs hatch after flooding, and in some species they are able to survive long periods of drying. Some species have only one brood a year. Their eggs do not hatch until they have been subjected to periods of drying or cold. Other species are intermittent breeders and have several generations per year depending on rainfall or irrigation practices. Aedes species occurring in regions with cold winters pass the winter in the egg stage. (2)

Larval habitats of Aedes are extremely variable. In general, they are found in temporary pools formed by rains, melting snow, or overflows. Some species occur in coastal salt marshes that are flooded at intervals by unusually high tides. Others have become adapted to irrigation practices. A few species occur in tree holes, rock pools, and artificial containers. Practically all species of Aedes are blood-sucking. Biting habits may vary, but they attack most frequently during evening hours. However, some species bite only during the day; others bite by day or by night. (2)

The mosquito, as with all blood-feeding arthropods, has mechanisms to effectively block the haemostasis system with their saliva, which is composed of a mixture of secreted proteins. Mosquito saliva usually contains fewer than 20 dominant proteins. (7)

Allergen Description

Mosquito saliva contains many biological materials which may be classified according to their functions, as follows: (a) anticlotting and antiplatelet factors and vasodilators; (8, 9) (b) substances that affect parasite transmission by arthropod vectors; (3, 10) (c) enzymes associated with sugar feeding; (3, 11) (d) lysozyme, which may help to control bacterial growth in the meal stored in the mosquito’s crop; (12) and (e) immunomodulators. (13, 14) Most of these substances in mosquito saliva have been identified as allergens. (4, 15, 16)

Most of the proteins in mosquito saliva are allergenic in humans. (4, 16, 17, 18, 19, 20, 21) Up to 19 allergens have been found in mosquito salivary gland extracts, with molecular masses ranging from 16 to 95 kDa, (4, 18) and at least 8 proteins in the saliva of Aedes aegypti have been identified as allergens which bind to the IgE of individuals who have large local allergic reactions to mosquito bites. (4) Both species-shared and species-specific allergens exist. Among the 10 species of mosquito studied, Aedes albopictus saliva contains at least 16 allergens, Aedes vexans 12 allergens, and Aedes aegypti and Culex quinquefasciatus 8-9 allergens. (3, 4)

Limited studies have been conducted on allergens from Aedes communis, hence inference from studies on other species is in order.

In a recent study saliva-specific IgE to 5 mosquito species were measured in serum of 14 individuals who had systemic reactions to mosquito bites. (47) Eleven of these individuals had a positive IgE response to Aedes albopictus saliva, a species which was previously reported to contain the highest number of allergens of 10 species studied, (4) while 5-8 individuals had raised serum-specific IgE to saliva from each of the remaining 4 species (Aedes vexans, Aedes aegypti, Culex quinquefasciatus and Anopheles sinornata), suggesting that Aedes albopictus has the highest number of species-shared allergens. IgE antibodies against 35.5, 32.5, and 22.5 kDa allergens in Culex quinquefasciatus saliva were found in 22 (41%), 15 (28%), and 13 (24%) respectively of 54 individuals with a history of mosquito bite allergy. The 22.5 kDa allergen was found mainly in children. (22) It is therefore apparent that a heterogenous response to allergens in the population can be expected, which may differ between age groups.

Although the common cause of hypersensitivity reactions is as a result of ‘mosquito bites’, mosquito-derived allergens and/or fragments which are present in air might serve as important inhalant allergens in type-I allergic respiratory disorders. (1, 23, 24, 25)

Immunoblot analysis showed unique individual IgE-binding patterns and suggested that both genus- and species-specific mosquito allergens exist. (26)

Four proteins in the saliva of A. communis with molecular weights of 22, 30, 36, and 64 kDa have been found to be antigenic by immunoblotting studies. (21) The most frequent IgE binding has been reported to occur to the 36 kDa protein, (21) although most people with immediate skin reactivity to A. communis mosquito bites have IgE that recognise the 36 kDa and 22 kDa antigens. (21, 27) The response to the 36 kDa antigen appears to be shared with A. aegypti. (17) A 37 kDa major antigen protein was isolated and cloned (28) from the adult female salivary glands of A. aegypti and appears to be shared by Aedes species distributed world-wide, (5) and perhaps also by other Diptera species. Another protein, Aed a 1, a 68 kD apyrase, has also been characterised as an important allergen in the saliva of Aedes aegypti. (29)

No allergens from A. communis have been characterised. However, a range of proteins and allergens have been isolated and characterised from A. aegypti, and may be representative of those in A. communis.

Table. Aedes aegypti salivary proteins

Protein name

Allergen name

Molecular weight (kDa)

Biological functions

Reference

alpha-Amylase 1

 

81.5

Unknown

 (3)

Apyrase

Aed a 1

68

Antiplatelet

(3, 30, 31)

alpha-Glucosidase (maltase-like 1)

Aed a 4

67

Sugar digestion

(3, 30)

Esterase

 

65

Unknown

(3)

Anticoagulant-factor Xa

 

54

Anticoagulant

(30)

Aed a X1

Aed a X1 ?

44

Unknown

(30)

Aed a X2

Aed a X2 ?

37

Unknown

(30)

Female-specific protein, D7

Aed a 2

37

Unknown

(3, 30, 32)

 

Aed a 3

30

Unknown

(3, 30, 33)

Sialokinins

 

1.4

Vasodilator

(30)

Antitumour necrosis factor

 

Unknown

Antitumour

(30)

Lysozyme

 

Unknown

Bacteriolysis

(30)

Modified from Peng and Simons (30)

 

Potential Cross-Reactivity

Cross-reactivity within the family Culicidae seems to be extensive, and there may be a certain degree of cross-reactivity with other families. Cross-reactivity with Anopheles (malaria) mosquito has been shown. (34)

That species-specific and cross-reactive allergens are present is illustrated by a study that demonstrated that an allergen similar to Aed a 2 of A. aegypti was found in 7 of the 11 mosquito species studied (Ochlerotatus triseriatus, Culex quinquefasciatus, and all five Aedes species (A. communis, A. aegypti, A. vexans, A. albopictus, A. togoi), but not in the remaining four species (Culex pipiens, Culex tarsalis, Anopheles sinensis and Culiseta inornata). The data indicated that the proteins in other mosquito species, especially in the Aedes genus, share common antigenic structures with Aed a 1 and Aed a 2 of A. aegypti. The authors suggested that Aed a 4, an alpha-glucosidase, may also be a cross-reactive allergen, since alpha-glucosidase was found in other mosquito species. (3)

Cross-reactivity has been demonstrated between C. quinquefasciatus, A. aegypti and A stephensi, with evidence that 30 and 33 kDa proteins are shared among these 3 mosquitos. (1)

Mosquito salivary allergens may cross-react with allergens from other biting insects (chironomids) and from crustaceans. (35, 36, 37, 38, 39) Moreover, there are rare reports of cross-reactivity with allergens in Hymenoptera venom, attributed to the presence of hyaluronidase. (40, 41)

Appreciating which allergens are cross-reactive may influence diagnoses, as illustrated by a study which detected a 25 kDa protein in the serum of a 14-year-old boy with seasonal rhinoconjunctivitis and an immediate local reaction to a mosquito bite. He had raised serum IgE to a number of arthropod species, including Chironomus thummi (3.2 kU/l), A. communis (12.7kU/l), D. pteronyssinus (3.2 kU/l); yet he had had no contact with chironomids and was asymptomatic outside springtime. Immunoblot testing demonstrated that a similar 25 kDa protein was present in all three, postulated to be a glutathione S-transferase enzyme. (42) This was similarly alluded to in a second study by the same authors, (38) who also reported a patient who demonstrated cross-reactivity between A. communis, Culex pipiens and red midge larvae (Chironomus). (43)

A Spanish study reported that 31% of patients with reactions to mosquito bite were sensitised to A. communis, and 53% of this group were also sensitised to other arthropods, probably due to cross-reactivity. (44)

Clinical Experience

a. IgE-mediated reactions

Throughout the world, allergic reactions to mosquito bites are of clinical concern. Reactions may vary from being mild, and simply a skin irritation, to local allergic reactions, but may also result in life-threatening reactions. (23, 24, 25, 30, 45) Although cutaneous reactions are seen most often, systemic reactions, including generalised urticaria and angioedema have been reported. (46, 47, 48, 49, 50) Severe local reactions such as ‘Skeeter Syndrome’ have also been described. (51) Respiratory allergy, including rhinitis, conjunctivitis, and/or asthma (caused by inhalation of mosquito fragments containing allergens), has been reported. (23)

Mosquito bite-sensitive subjects frequently have circulating IgE and IgG4 antibodies to Aedes mosquito saliva proteins. (19, 21, 26, 27, 52) Typically the levels are highest in children, and slowly decrease over time. (53) However, IgE-mediated and T-lymphocyte-mediated hypersensitivities are involved in the development of mosquito allergy. (5, 19, 21, 46, 54, 55) A study on people living in Finnish Lapland revealed that seasonal exposure to mosquito bites leads to an increased IgE, IgG4 and IgG1 antibody response, a phenomenon similar to that occurring in (for example) pollen allergy. (56)

Cutaneous reactions following mosquito bites range from immediate wheal-and-flare reactions to delayed bite papules. Typical local cutaneous reactions to mosquito bites consist of small immediate wheals and flares peaking at 20 minutes, and delayed pruritic indurated papules peaking at 24-36 hours, then diminishing over several days or weeks. (52, 57) Large local reactions to mosquito bites consist of itchy, red, warm swellings appearing within minutes of the bites, and itchy papules and ecchymotic, vesiculated, blistering, bullous, haemorrhagic or even Arthus reactions, appearing 2-6 hours after the bites and persisting for days or weeks. (51, 58, 59, 60, 61, 62) Only those reactions which cause large or atypical (ecchymotic or vesiculated) local reactions or systemic reactions are considered to be ‘mosquito allergy’. (3)

A study of 14 individuals with a history of acute systemic allergic reactions to mosquito bites – defined as the presence of one or more of the following: urticaria, angioedema, wheezing, dyspnea, hypotension, and decrease or loss of consciousness – is illustrative. Ten individuals were from the United States and one each from Canada, Germany, Japan, and Switzerland. Testing was conducted for specific IgE and IgG antibodies to saliva from 5 common mosquito species with different geographic distributions: mosquito saliva-specific IgE levels to all 5 species were significantly increased in the individuals with systemic allergic reactions, compared with the control subjects. 11 individuals had positive results to A. albopictus and up to 4 additional species; 3 individuals had positive results to only one species. (47)

Individuals at increased risk of severe reactions to mosquito bites include those with: a) a high level of exposure, for example, outdoor workers; (46) b) weak natural immunity, for example, infants and young children; (51, 63) c) no previous exposure to indigenous mosquitoes, for example, immigrants or visitors; and d) primary or secondary immune deficiency such as AIDS, malignancies (64) or Epstein-Barr virus-associated lymphoproliferative diseases. (30, 65) However, severe anaphylactic reactions to mosquito stings are surprisingly rare with regard to the worldwide distribution of mosquitos. (4) Possibly, naturally-acquired immunity by repeated exposure is crucial. (53, 57)

‘Skeeter Syndrome’ is defined as a mosquito-induced large local inflammatory reaction sometimes accompanied by low-grade fever that is often misdiagnosed as cellulitis. Systemic reactions following mosquito bites include angioedema, generalised urticaria, nausea, vomiting, wheezing and other anaphylaxis manifestations. (23, 35, 40, 46, 47)

Clinical observations of the natural history of sensitisation and subsequent desensitisation to the saliva injected by mosquito bites have been classified into five stages. (66 cited in 3, 67 cited in 3) Individuals who have never been exposed to a specific species of mosquito do not get a reaction from the initial bites (stage I), but following subsequent bites, delayed cutaneous lesions appear (stage II). After repeated bites, immediate wheals develop (stage III). With further exposure, delayed reactions are no longer observed, and only immediate wheals are noted (stage IV). Individuals repeatedly exposed to thousands of bites from the same species of mosquito eventually lose the immediate reactions (stage V). These 5 stages have also been documented in a study in which stages II and IV appeared to be transient. (57)

Naturally-acquired desensitisation to mosquito saliva has also been confirmed in several cross-sectional studies. (3) Indeed, immunotherapy using injections of mosquito whole-body extracts has been reported to prevent allergic reactions to subsequent bites. (46, 60, 68)

As a result of species-specific and common allergens, diagnosis may be problematical; as illustrated in the case report of a 19-year-old man who presented with persistent pruriginous lesions several hours after being bitten by a mosquito. Prick tests to commercial extract of whole-body extracts (Culex pipiens) were negative; however, the intradermal test was positive. Specific mosquito (A. communis) IgEs were raised (1.06 kIU/L). Specific immunotherapy with a whole-body extract of C. pipiens was successful. (69) The basophil activation test has been successfully utilised in certain instances. (48)

The relevance of species-specific and common allergens is also illustrated by a study evaluating the prevalence of IgE and IgG4 class antibodies to the saliva of A. communis and A. aegypti mosquitoes in the sera of three groups of exposed children. The frequencies of IgE antibodies to the major 36 kDa A. communis and A. aegypti saliva antigens ranged from 82 to 90% in the 20 Finnish, 17 Kenyan, and 20 Mexican children. The corresponding IgG4 antibody frequencies were 85, 41, and 20%, respectively. The Finnish children abnormally sensitive to mosquito bites frequently had IgE and IgG4 antibodies to the 22 kDa A. communis saliva antigen, suggesting that these antibodies play a role in the pathogenesis of immediate cutaneous mosquito bite reactions. In contrast to this, no increase was found in the frequency of A. aegypti antibody in the Kenyan and Mexican children with papular urticaria, suggesting that humoral immune response to A. aegypti saliva was not involved in the development of this disorder. (27)

Cutaneous reactivity to mosquito bites was examined in 27 adult volunteers exposed to A. communis mosquitoes. Twenty-three subjects experienced a combination of immediate whealing and delayed bite-papules, two subjects each experienced only immediate or delayed cutaneous reactions, and two were non-responsive to the bites. The mean size of whealing and the mean score of pruritus was similar in 19 non-atopic and in eight atopic volunteers. The authors concluded that the results confirmed that normal subjects exhibit different stages of sensitisation to mosquito bites. (70)

A girl aged 14 years, who showed local skin lesions and generalised reactions such as fever, hepatosplenomegaly, hypergammaglobulinaemia and pancytopenia following mosquito bites, was shown to have specific IgE antibody against mosquito antigens after being evaluated with various immunological methods. (24)

Although mosquito allergy has been reported world-wide, few prevalence studies have been conducted.

A cross-sectional descriptive study of children from 11 public elementary schools in the metropolitan area of Monterrey, Mexico, reported that 76% of respondents had experienced adverse effects to mosquito bite in the preceding 12 months, of which itching (75%) and rash (72%) were the most frequent symptoms. (71)

An Indian study evaluating 3 389 consecutive patients attending an allergy clinic over a period of 5 years found that around 58% of children and 60% of adults were skin-prick test-positive for mosquito (species not specified). (72)

Cross-reactivity may play a role in prevalence studies. In previous studies conducted on young adults in Reykjavik, Iceland, 6-9% were shown to be sensitised to house dust mite Dermatophagoides pteronyssinus. However, only negligible amounts of HDM and HDM allergens were detected in their homes. Of those with specific IgE against D. pteronyssinus, 75% had detectable IgE antibodies to cross-reactive allergens, compared with none in the control group: Lepidoglyphus destructor (67%), shrimp (58%), cockroach (33%), mosquito (17%), tropomyosin (17%) and blood worm (4%). (73)

Similarly, a skin-prick study of 131 Taiwanese patients found that 71% had positive skin reactions to D pteronyssinus, 69% to D. farinae, 44% to Blomia tropicalis, 37% to American cockroach, 36% to German cockroach, 4% to dog dander, 8% to cat dander, and 29% to mosquito (species not specified). (74)

A study of 100 Norwegian families (426 subjects) of 7- to 35-year-old sibling-pairs with asthma and their parents, evaluated for sensitisation to common local inhalant allergens, reported that 31 subjects (7.5%) were sensitised (5 monosensitised) to cockroach (27 by skin-prick test and seven by IgE antibody, all with additional inhalant allergy), and co-sensitisation was most common to grass (in 61%), cat (48%), dog (48%) and mites (42%). Of the cockroach-sensitised patients, 5 were sensitised to mosquito (species not identified) compared to none of the 393 in the non-sensitised group. (75)

Authors have suggested, as commercially-available mosquito allergen preparations are made from whole-body extracts (which may contain little salivary protein and many non-salivary proteins), that these may cause new sensitisation and other side effects. (76) In a study, a serum-specific IgE test in which a mosquito whole-body extract was used as the capture antigen was compared to a mosquito saliva-capture ELISA in the diagnosis of individuals with systemic or severe local reactions to mosquito bites. (77) The mosquito saliva-capture ELISA was more sensitive and specific (less likely to give false-negative and false-positive results) than the serum-specific IgE assay in the diagnosis of mosquito allergy. The positivity rate was 56% for the saliva-capture ELISA and 25% for the serum-specific IgE test in mosquito-allergic individuals, versus 5% in the negative controls. The results suggest that mosquito saliva proteins should be used in the diagnosis of mosquito allergy. (3)

Immunotherapy using injections of mosquito whole-body extracts has been shown to prevent allergic reactions to subsequent bites. (46, 60, 68, 69) In a study of 20 mosquito-allergic individuals treated with A. communis whole-body extract for 18 months, the treated individuals reported the disappearance of severe local reactions and symptoms of allergic rhinitis, which was statistically correlated with improvement of symptom and medication consumption scores and decreased allergic reactivity in nasal provocation tests with mosquito extract. (68)

However, it has been suggested that because current commercially-available mosquito whole-body extracts contain few mosquito-saliva proteins and many non-salivary proteins, these may be ineffective in down-regulating the specific immune responses to mosquito salivary allergens and may cause additional sensitisation. (76) In the future, the production of recombinant allergens may facilitate diagnosis and desensitisation. (30, 33)

b. Other reactions

It has been suggested that hypersensitivity to mosquito bites is associated with chronic Epstein-Barr virus (EBV) infection and natural killer (NK) cell leukaemia/lymphoma. (78, 79)

A previously healthy 25-year-old female patient developed hypersensitivity pneumonitis following repeated exposure to the smoke of mosquito coils. (80)

Airline flights departing from certain locations, in particular where malaria is prominent, are fumigated with pyrethroids. Only anecdotal reports of adverse responses among passengers or crew have been received. A description of pyrethroid allergy in an individual exposed to this chemical is described. (81)

Compiled by Dr Harris Steinman, harris@allergyadvisor.com

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As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.