Summary

Oryctolagus cuniculus, referred as European rabbits, are the most successful, invasive, exotic mammals, found globally. These species prefer living in herds, in interconnected underground tunnels. Rabbits are domesticated and popular lab animals. For laboratory animal care workers, laboratory animal allergy (LAA) is an important health issue. Rabbit saliva is the most potent allergen source identified, however the allergens are also found in rabbit fur, urine, hair, and dander. Inhalation is the main route of exposure to rabbit allergen, and since the size of the airborne particle is very minute, it easily penetrates through the lower respiratory tract, causing allergic symptoms. In susceptible individuals, allergic sensitization to rabbit allergens is via rabbit contact, either through its ownership, or contact in the laboratory. Allergic symptoms may include asthma, allergic rhinitis, eczema, and urticaria. Rabbit allergen, Ory c 1, is a major allergen (lipocalin family) found in the extracts of saliva, urine and fur of rabbits, that can be used for investigations of sensitivity to rabbits. Ory c 2 belongs to the family of lipocalin, that is derived from rabbit hair, fur, dust and urine. Another important allergen, Ory c 3 has shown high structural homology with cat allergen (Fel d 1), however, at amino acid level, similarity is quite low. Thus, in spite of high similarity, no cross-reactivity has been reported with Fel d 1, thus making it as a potential marker for rabbit allergy. Ory c 4 has demonstrated a degree of cross-reactivity with those of other animals, such as cat, dog and horse.

Epidemiology

Worldwide distribution

Lately, rabbit has been reported to be a significant pet allergen in the development of severe respiratory allergic diseases, due to its exposure in the household. Moreover, rabbit ownership is also on the rise. Hence, it is essential to focus on rabbit sensitization in patients allergic to this species.

Rabbit exposure in domestic environment may trigger immunoglobulin E (IgE)-mediated bronchial asthma and/or rhinitis. The development of allergic diseases such as asthma, conjunctivitis, and allergic rhinitis associated with rabbit exposure is frequently seen among researchers, laboratory animal care workers and technicians. Further, laboratory animal allergy (LAA) is an important health issue for individuals exposed to experimental animals, since it may easily lead to asthma. In a cross-sectional survey conducted in Japan (n=136), the overall prevalence of LAA was reported be 17.6%. Furthermore, the most commonly reported symptoms were found to be allergic rhino-conjunctivitis (2.4%) and asthma (3%). Among the 69 rabbit handlers, LAA was reported in 16.3%.

Individuals who are in direct contact with rabbits in laboratory and domestic settings commonly experience IgE-mediated allergic sensitization. Choi and colleagues presented a case of three individuals who developed rabbit-induced bronchial asthma and/or rhinitis, as a result of keeping rabbit as a household pet. Serum-specific IgE and IgG4 antibodies to rabbit allergens were confirmed. Further, Ory c 1 (17-kDa) glycoprotein was reported to be the major rabbit allergen. With the increase in demand for rabbits as domestic pets, allergic diseases from rabbit exposure at home or workplace have become a common scenario. Physicians should take note that exposure to rabbits may develop extreme respiratory allergic reactions even in individuals who are non-atopic.

In Japan, a large cross-sectional study was conducted wherein over 5641 laboratory animal technicians were enrolled. The prevalence of LAA was found to be 29.7% in rabbit handlers. Allergic rhinitis was the most commonly reported LAA among laboratory animal workers. In another study conducted in Korea on 401 patients with allergic symptoms, 9% were found to be sensitized to rabbits, whereas 16.7% had direct exposure to rabbits.

In a study conducted in Italy, it was demonstrated that the prevalence of sensitization to rabbits ranged between 0.62 and 4.72%. Out of 39 patients who were sensitized to rabbits, 19 individuals experienced direct rabbit contact (10 for ownership and 9 for occasional contact), and 5 individuals reported only indirect exposure through the contact with rabbit owners. Furthermore, the last 15 individuals reported neither direct nor indirect exposure. It was observed that all the monosensitized individuals domesticated rabbits as pets. Also, they were having persistent (moderate-severe) respiratory symptoms. The four (non-smokers) patients with single sensitization to rabbits reported continuous allergic rhinitis, and asthma and had a rabbit as their household pet. Hence, from the study results it has been inferred that the increased prevalence of sensitization to rabbits should not be ignored.

Risk factors

In susceptible individuals, a risk factor for the development of allergic sensitization to rabbit allergens in contact with rabbits (rabbit ownership, occasional contact, or contact in the laboratory).

In a domestic environment, direct or even indirect exposure to rabbits in susceptible individuals may result into allergic sensitization. Further, an increase in rabbit ownership may increase the risk of sensitization. Atopy status and the degree of exposure to rabbits are important determinants of sensitization to rabbits in a household environment. Sensitization to cats/dogs has been considered as a risk factor for developing allergies to other furry animals, such as rabbits.

It is presumed that the salivary allergen can spread to the rabbit’s fur by their grooming activity. Extensive spreading of allergen containing dust particles is seen in areas where the rabbit is active. Aerosolized allergens related with rabbit activities or with human activities such as handling the rabbits or cleaning-out, may result into allergen levels likely to cause sensitization or trigger symptoms in individuals who are already sensitized.

Due to high percentage of rabbit ownership, a progressive increase in rabbit sensitization has been forecasted in the future. In a study conducted in Italy, skin tests were conducted on 2,329 patients, of which 1,602 had a respiratory allergy (asthma and/or rhino-conjunctivitis). Of 1,602 individuals, 2.43% were sensitized to rabbit dander (4 monosensitized).

In laboratories, the laboratory animal workers are at risk of sensitization, and it has been reported that up to one-third will have symptomatic asthma. An atopic background and the intensity of exposure are further risk factors.

Route Of Exposure

Main

Airway inhalation is the main route of exposure to rabbit allergen. The characteristic feature of this allergen is that it can easily penetrate through the lower respiratory tract and cause allergic symptoms since the size of the airborne particle obtained from rabbits is very minute.

Secondary

Direct skin and eye contact are considered as a secondary route of allergen exposure. It has been reported, that, on rare occurrences, laboratory animal workers allergic to an experimental animal may experience an anaphylactic reaction from either an animal bite or through contaminated needle punctures.

Clinical Relevance

Exposure or contact to rodents, in general, have long been identified as a risk factor for the development of allergic symptoms in sensitized individuals. In occupational settings, the association between laboratory animal allergy or occupational asthma and rodent exposure is well documented. It is estimated that between 11% and 44% of people working with laboratory animals will develop allergies related to their occupation. Symptoms may include rhinitis, eczema, urticaria, and asthma. Cases are often identified using disease surveillance methods, and exposure reduction may be achieved by the use of respiratory protection or by reassignment to a job where exposure is minimized. Medication may also be required.

Severe anaphylaxis

Two case studies were conducted that reported severe allergic reactions such as anaphylaxis among individuals who were exposed to rabbits. In one case study, an atopic girl experienced symptoms such as coughing, itching, rhinorrhea, breathlessness, reverse sneezing, and sensation of swelling in the throat, after inhalant exposure to a rabbit. Her serum-specific IgE to rabbit epithelium and fur was raised and her skin prick test was found to be positive to rabbit epithelium. In the other case study, a 32-year-old male physician incidentally got a minor injury from a needle that had been used on the rabbit tissue. A serious anaphylactic reaction developed within 15 minutes of its use, and the physician was hospitalized. Serum IgE antibodies were elevated (16.2 U/ml), however, other antibody titers were reduced.

Allergic rhinitis

In a case of a 6-year-old girl with a 3-year history of allergic rhinitis and asthma, worsening of both these symptoms was reported in-home setting and upon exposure to outdoor pollen. Upon interrogation, it was revealed that the family owned a pet rabbit. The laboratory findings revealed positive results for rabbit epithelium (8.43 kIU/L). The family was advised to avoid going out during pollination and keep the rabbit away from home, as it could be a potential trigger aggravating the child’s symptoms.

Asthma

It is often seen that rabbits are associated with allergic asthma, of insidious onset. However, it can sometimes result in severe, continuous asthma of rapid onset.

A cross-sectional study was conducted in school children in Kuwait that assessed the relationship between keeping rabbits as pets and the development of allergic symptoms. According to the results, it was reported that exposure to rabbits was statistically significantly related to asthma symptoms, such as current dry cough at night (adjusted prevalence ratios [aPRs] 1.18), ever-doctor diagnosed asthma (aPR 1.30), and asthma in the last 12 months (aPR 1.38).

Atopic Dermatitis

In a cross-sectional study, significant association between rabbit keeping as a pet and atopic dermatitis was found. According to the results, it was reported that exposure to rabbits was statistically significantly associated with severe eczema symptoms (aPR 1.94) and ever-diagnosed eczema i.e. study-defined current eczema (aPR 1.45).

Prevention And Therapy

Prevention strategies

Avoidance

In symptomatic animal care handlers, the use of personal protective equipment can help in reducing the exposure of allergen. Equipment such as laminar flow cage, and protective measures such as regular wet washing of containers and routine maintenance of ventilation systems can decrease the exposure of these allergens to a good extent.

All laboratory animal handlers should undergo regular medical screening with allergic skin testing. Further, they should also be given training on how to reduce personal exposure.

Cross-Reactivity

The importance of cross-reactivity between furry animal sensitization is strengthened by the fact that greater numbers of patients having cat and dog sensitivity report rabbit sensitivity, with no obvious history of rabbit exposure.

Ory c 3 is a lipophilin having high structural homology to Fel d 1 (cat allergen). In a study including a group of patients sensitized to rabbit, the prevalence of IgE to Ory c 3 was found to be 77%. In spite of high structural homology, the sequence identity has been reported to be very low, and no cross-reactivity has been found between Ory c 3 (rabbit) and Fel d 1 (cat) allergen. In the case of Ory c 4, high sequence identity has been observed between Ory c 4 (rabbit) and dog (Can f 6), cat (Fel d 4) and horse (Equ c 1) allergens, suggesting high probability of IgE cross-reactivity.

Further, a case of a 17-year-old female patient was reported who had sensitization to rabbit products (urine, serum, and epithelium) during childhood. The symptoms worsened during adolescence and the female patient developed anaphylaxis with severe bronchospasm, secondary to ingestion of rabbit meat. It was demonstrated that the 60-kDa albumin was accountable for the cross-reactivity between rabbit epithelium and meat.

Some allergens belonging to lipocalin family have reported high amino acid sequence identity among them (up to 60%), thus explaining the cross‐reactivity between these allergens. These include - Ory c 4 (rabbit), Fel d 4 (cat), Can f 6 (dog), Equ c 1 (horse), Mus m 1 (mouse), and Rat n 1 (rat).

Although not dominant, however cross-reactivity has been observed between rabbit allergen, 15 kDa and IgE antibodies in deer-allergic individuals.