Yellow fever is a disease caused by a Flavivirus, and transmitted by a mosquito vector. Although most cases are asymptomatic, 15% of patients will develop severe illness, which can involve multiorgan dysfunction and hemorrhagic symptoms, and which is fatal in 20%–50%. Treatment is supportive; therefore, vaccination remains the most important strategy against yellow fever. Many countries require proof of vaccination to permit entry by travelers.
The live-attenuated yellow fever vaccine (YFV) is safe and highly effective, providing long-term immunity in >95% of recipients after a single dose. YFV contains ovalbumin, and the quantity varies by brand and is not published by the manufacturer. Stamaril (United Kingdom) has been reported to contain 0.067–0.306 µg of ovalbumin per 0.5 mL dose (mean 0.105 µg/0.5 mL), while YF-VAX was found to contain 1.215–2.21 µg per dose (mean 1.56 µg/0.5 mL). YF-VAX also contains gelatin, another potential allergen.1 YFV has been reported to induce a reaction in a patient with allergy to cooked but not raw egg.2 This is explained by the fact that the vaccine is not heated during manufacturing, and may contain heat-labile proteins. The rate of anaphylaxis to YFV is 0.76 cases per 100,000 doses, though the proportion of these cases occurring in patients with egg allergy is not known.1
Hypersensitivity to egg is a contraindication to receipt of YFV in the manufacturer’s product information. Some guidelines advise that YFV is contraindicated in patients with any egg allergy, while others restrict this to only anaphylaxis, and recommend skin prick testing (SPT), intradermal testing (IDT), graded dosing or desensitization under specialist guidance for patients with mild egg allergy. A small number of authors have documented safe administration of YFV to egg-allergic patients, including to those with anaphylactic egg allergy, with the majority of reported patients being adults.3–9 We present our experience in 2 Australian tertiary pediatric hospitals, which, to our knowledge, is the largest case series of yellow fever vaccination in egg-allergic children.
We reviewed clinic records from the Specialist Immunization Clinics at 2 Australian tertiary pediatric hospitals between January 2011 and September 2019, identifying children with egg allergy requiring yellow fever vaccination. Patients were included if they had a documented positive SPT result to egg as well as history of a clinical reaction. Patients were identified by searching departmental databases. We reviewed demographic details and medical history, including comorbidities and results of previous allergy testing. We then reviewed the approach to skin testing and vaccine dosing used in our clinics, and reviewed outcomes including adverse events. The decision to perform skin testing or use graded dosing was at the discretion of the clinician. A mean wheal diameter of 3 × 3 mm2 was considered a positive SPT or IDT result. The study was approved by the Sydney Children’s Hospital Network Human Research Ethics Committee, Sydney, Australia (HREC/18/SCHN/424).
Eleven egg-allergic children (11 months to 13 years of age) presented for yellow fever vaccination, and their clinical history, vaccination protocol and outcomes are presented in Table 1. All had a clinical history consistent with an IgE-mediated reaction to egg, and 3 were consistent with anaphylaxis. The management of YFV in these 11 egg-allergic children was based on the treating clinicians decision. Of the 11, 7 patients underwent SPT with undiluted YFV (Stamaril, Sanofi Aventis), which was negative in all cases. One of these patients also underwent IDT with 1:100 dilution of the vaccine, which was negative. All 7 patients proceeded to a graded 2-dose protocol whereby 10% of the dose was given, and after a 30- to 60-minute observation period, the remaining 90% was given, followed by an hour of observation. In 1 patient, a faint erythematous rash on the neck and face was reported 20 minutes after the 90% dose, which resolved spontaneously. In another patient, the 10% dose was given subcutaneously, following which a 10-cm area of erythema appeared surrounding the injection site. At the discretion of the treating clinician, an antihistamine was given, and a further 20% of the dose given subcutaneously after an hour, with a smaller area of erythema developing around the injection site, which resolved spontaneously. After an hour, the remaining 70% of the dose was given intramuscularly with no further adverse events. The remaining 4 patients were vaccinated without skin testing; 3 patients followed the 2-dose protocol described above, and 1 was given the full dose in a single administration. All patients received the full dose of YFV, and no serious adverse events were reported.
Raw egg allergy is common, with a prevalence of 8.9% in Australian infants.10 The maximum dose of ovalbumin that can be administered in a vaccine to egg-allergic patients is unknown. Influenza vaccines contain up to 1.6 µg/dose of ovalbumin and are routinely given to egg-allergic patents without prior skin testing.11,12 Skin testing and graded dosing were shown to be unnecessary for influenza vaccine after numerous large studies confirmed that vaccination of egg allergic patients was safe. The exact ovalbumin quantity in currently available YFVs is not known for each brand and appears to vary significantly.
Within our cohort of 11 patients, there was variation between practitioners in skin testing and dosing protocols, reflecting the lack of consensus on how to manage these patients. Published protocols for yellow fever vaccination in egg-allergic patients vary widely.3,5–9 The most cautious approach involves SPT to neat vaccine and IDT to 1:10 or 1:100 dilution, though some authors advise against IDT in young children since it is painful.4,5 The requirement for skin testing limits the availability of vaccine challenge to areas where specialist supervision is available. Fractional intradermal dosing of YFV is immunogenic, with as little as 0.1 mL given intradermally providing at least 12 months of protection; therefore, even partial intradermal vaccination may be beneficial.13
Skin testing is seldom performed to evaluate vaccine hypersensitivity, and is often negative. Cheung et al14 demonstrated that the vast majority of children who have had an immediate reaction to a prior dose of a vaccine will safely tolerate further doses via 2-step graded challenge and only recommend skin testing for those with a history of anaphylaxis. This approach could be adapted for children with hypersensitivity to a vaccine component, and a 2-dose graded challenge without skin testing may be a safe approach to vaccinate children with mild egg allergy.
There were no serious adverse events in our case series. One patient developed a transient localized erythematous rash on the face and neck, and another had local erythema around the injection site of his 10% challenge dose, which had been given subcutaneously. Local erythema is common following subcutaneous injections.
Seven studies which together included 166 egg-allergic patients (and together including 11 children) who received YFV reported that the vast majority of patients tolerated the full dose with no adverse events.3–9 Of these 166 patients, generalized urticaria and local angioedema were reported in 1 patient, and localized urticaria or erythema were reported in further 3 patients.
Limitations of our case series include its retrospective nature, as a result of which we had limited data, including the nature and recency of the index reactions to egg, which could have confirmed currency of the allergy at the time of vaccination. Another limitation is the use of only a single brand of YFV.
Current expert guidelines vary on how to vaccinate egg-allergic patients with YFV, creating inconsistencies in practice as demonstrated in the literature and in our case series. Skin testing and graded dosing provide avenues to provide lifelong protection against yellow fever even for those with anaphylactic egg allergy. Egg allergy is common, and there is growing evidence that vaccination with YFV is safe in this population. We propose that skin testing may not be required for patients with mild (non-anaphylactic) egg allergy who require YFV, and that a 2-step graded challenge under medical supervision is a safe alternative.
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