Satisfactory immune response following anaphylaxis to PCECV facilitated by the use of steroids and antihistamines

ABSTRACT

Introduction

Rabies is fatal and can cause almost certain mortality in animals and humans. Effective post-exposure prophylaxis (PEP) using the rabies vaccine remains the cornerstone for preventing disease in humans. We present the first reported case of supporting the live purified-chick-embryo-cell rabies vaccine(PCECV) administration with prophylactic high-dose corticosteroids.

Case

A 39-year-old female was at high-risk of developing rabies-like disease following a bat bite. She was commenced on PEP using PCECV. Our patient developed an anaphylactic reaction with bronchospasm and a rash following her 2^nd PCECV dose. Consequently, she received 2 days of loratadine and high-dose prednisolone prior to her final vaccination. During this administration in the emergency department, our patient completed the final PCECV dose. At a two-week follow-up, our patient had no evidence of rabies and had adequate viral neutralizing antibody levels detectable on serology.

Discussion

Type 1 hypersensitivity reactions to PCECV are rare. Only 20 anaphylactic cases have been reported from a total of 1.1million administered doses over 8 years. Individuals at higher risk of anaphylaxis include those with a prior history of allergy to either egg white, gelatin, milk, penicillin, bee venom, or beef products. Administering high dose prophylactic corticosteroids prior to vaccination can potentially induce immune tolerance and minimize subsequent risks of hypersensitivity reactions. However, data relating to its use is extremely limited to only animal and limited human case-report data from other vaccines.

Conclusion

We propose an alternative option which will require further research to manage vaccine-related anaphylaxis where immunization is an essential prophylactic requirement with the support of an immunologist and careful monitoring in an appropriate environment.

KEYWORDS:

• Rabies
• vaccine
• anaphylaxis
• corticosteroids

Rabies is a fatal zoonotic infection which can cause almost certain mortality when present in animals and humans. Therefore, effective post-exposure prophylaxis (PEP) through the use of rabies immunoglobulin (RIG) and rabies vaccines, such as the purified-chick-embryo-cell vaccine (PCECV) remains the cornerstone for preventing disease in humans. It is however unclear how to best manage individuals who have developed a severe allergic reaction to these vaccines, given the need to complete the vaccination schedule to provide effective immune protection. We present the first known case of continuing the PCECV vaccination schedule despite a prior anaphylactic episode with the support of high-dose corticosteroids and antihistamines. We hope to propose an alternative approach in managing rabies vaccine-related allergic reactions.

Case

A 39-year-old female paramedic was commenced on post-exposure prophylaxis (PEP) after a wild bat scratched her head in her house. She had no history of asthma and no prior history of any allergies. As per our routine practice, no invasive allergen screening was performed prior to commencement of PEP. As per our PEP schedule she required intramuscular human RIG on day-0 and PCECV on day-0, 3, 7 and 14 post-exposure. Our patient had no issues tolerating the intramuscular human RIG and PCECV on day-0 post-exposure. However, she developed hives and sudden onset bronchospasm within 1hour following her day-3 vaccination. Given her delay in symptom onset, she self-administered a nebulized salbutamol inhaler and 120mg fexofenadine; both of which were found at her ambulance workplace. She continued with the PCECV schedule and on advice from a general practitioner, pre-medicated herself with 120mg fexofenadine 20minutes prior to administration of her day-7 dose. Unfortunately, our patient still developed local erythema surrounding the injection-site and bronchospasm within 90minutes after vaccination. She did not report these symptoms to any medical professionals at the time, and therefore no treatment was administered. These symptoms spontaneously resolved subsequently within 1 hour. Her case was discussed between public health, infectious diseases and immunology disciplines and it was determined that she would benefit from completion of her final day-14 dose to ensure adequate immune protection, which would allow for an alternative vaccine formulation such as human-diploid-cell vaccine (HDCV) to be used should this fail. Our patient was counseled about this procedure and had given consent prior to administration. Our patient was subsequently pre-medicated with loratadine and high-dose prednisone at a dose of 50mg one day prior and 25mg on the day of PCECV administration. Whilst she was monitored in an emergency department, she developed a transient asymptomatic reduction in blood pressure with a systolic blood pressure drop from 150mmHg to 120mmHg and a rash within 1hour following the injection. There was no evidence of bronchospasm on serial peak-expiratory flow tests during her time there. Her lower blood pressure resolved within 10 minutes without any intervention and she was subsequently discharged home. Several hours later, she also developed transient severe abdominal pain and nausea. She was followed up 2weeks later with no evidence of a rabies-like disease and with adequate viral neutralizing antibodies (VNA) detected on serology 2.59 IU/ml (expected antibody levels >0.5 IU/ml). No allergy screening was performed after the patient recovered from these anaphylactic episodes nor was any specific preventative dietary or lifestyle advice provided. The patient has not developed any known allergic reactions since.

Discussion

Anaphylaxis to PCECV is extremely uncommon and has potentially only been documented in 20cases from over 1.1million dose administrations across 8 years spanning from 1997 to 2005.¹ Most of these episodes have occurred within 1 hour of receiving either the first or third PCECV dose. The PCECV formulation is derived from a fixed-virus strain and is propagated in a purified-chick-embryo-cell culture and inactivated using β-propiolactone. PCECV contains trometamol, disodium edetate, monopotassium glutamate, polygeline and sucrose.² The vaccine may also contain several micrograms of egg and gelatin due to the manufacturing process.²

Individuals at higher risk of anaphylaxis to PCECV include those with known allergies to either egg white, gelatin, milk, penicillin, bee venom, or beef products.¹ Type 1 hypersensitivity reactions however can potentially be minimized by using the same formulation throughout a rabies vaccination schedule.³ However the CDC recommends people with a serious hypersensitivity to the components of rabies vaccine to be revaccinated with caution.³ The risk of failing to complete a rabies vaccination course may translate into inadequate immune protection and the potential for developing disease.

One proposed strategy to provide optimal immunity after an anaphylaxis is to use an alternative rabies vaccine formulation.¹ Despite these measures, according to a large rabies vaccine registry two cases still developed mild anaphylactic episodes of itch, chest tightness and increased secretions. One of these reported patients developed an anaphylactic episode after changing from the HDCV to PCECV formulation.¹

An alternative option is to use corticosteroids prior to vaccination to induce immune tolerance and minimize subsequent risks of hypersensitivity reactions. Previous experimental animal studies on this subject have revealed mixed results. Whilst one study involving mice revealed that a single dose of corticosteroids prior to vaccination did not affect antibody formation;⁴ other mouse and rabbit models failed to demonstrate an immune response to vaccination whilst receiving corticosteroids.^5,6 However, the limited evidence in humans has largely been supportive for the use of adjunctive corticosteroids. There are however no prior reports of corticosteroid use to support PCECV immunization following anaphylaxis.

In support of corticosteroid use, Huang et al described a case of an anaphylaxis following the first HDCV dose.⁷ The patient was administered a total of 8mg dexamethasone in the first two days post anaphylaxis; in comparison, our patient had received a higher corticosteroid dose exposure. The immunization regimen continued without change in vaccine formulation or delay. No further corticosteroids were administered nor were any further allergic reactions noted. However adequate VNA concentrations were noted on day14 post the initial vaccine dose. In our case, VNA titers were tested at 1 month following initial dose and were above the lower limit threshold.

A similar adequate immune response to PCECV was noted in one case where corticosteroids were required in response to secondary acute disseminated encephalomyelitis.⁸ This notion has been supported by prospective vaccination studies in immunosuppressed individuals on long-term corticosteroids. Kubiet demonstrated a similar curbed immune response to influenza vaccination in corticosteroid-treated patients; this effect was not however observed to be corticosteroid-dose dependent.⁹

It is important to note that it is unclear at present what role alternative agents such as montelukast or omalizumab may play in preventing recurrent anaphylactic episodes in those with a prior vaccine-related allergy. This case also demonstrates the importance of timely notification to health authorities of adverse events following immunization to facilitate optimal management.

Conclusion

Post exposure prophylaxis is the cornerstone of preventing fatal outcomes in potential rabies exposure. We report the first-case of supporting ongoing PCECV immunization following an episode of anaphylaxis with an extremely-limited course of corticosteroids. This has been supported in only a handful of prior cases of vaccination-related anaphylaxis. It is however unclear what duration or dose of corticosteroids would be appropriate in this setting given the potential of impairing the required immune response to provide protection. This case postulates an alternative approach to managing vaccine-related anaphylaxis where immunization is an essential prophylactic requirement with the involvement of immunology and an appropriate environment to supervise administration. Further research is required to determine if this recommendation can be universally endorsed.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.