Hypersensitivity Reaction to Equine Rabies Immunoglobulin with Confirmed Positive Rechallenge in Category III Dog Bite Exposure: A Comprehensive Case Report

Abstract

Background: Equine rabies immunoglobulin (ERIG) constitutes the cornerstone of category III rabies post-exposure prophylaxis (PEP) in resource-limited settings, yet acute hypersensitivity reactions complicate 5-46% of administrations. Deliberate positive re challenge re-administration post-reaction to confirm causality remains exceptionally rare in published literature, precluding definitive risk-benefit analyses. Case Presentation: A healthy 17-year-old male (55 kg) manifested severe multisystem hypersensitivity (nausea, emesis, Grade II local reaction, vertigo) 30 minutes following 40 IU ERIG for right forefinger dog bite. Temporary de challenge yielded partial resolution, while deliberate re challenge produced attenuated but confirmatory recurrence (Naranjo score: 8, "Probable"; WHO-UMC: "Probable/Likely"). Complete recovery ensued upon permanent discontinuation, permitting unhindered ARV completion. Conclusions: This meticulously documented re challenge case delineates ERIG's acute Type I hypersensitivity profile, informing premedication strategies, HRIG substitution criteria, and pharmacovigilance imperatives in India's 20 million annual Category II/III exposures.

Keywords

Introduction

Rabies exacts a devastating toll in India claiming approximately 18,000-20,000 lives annually while generating over 20 million Category II/III animal bite exposures necessitating post-exposure prophylaxis (PEP). The National Rabies Control Programme mandates combined active-passive immunization for Category III bites (transdermal injuries with bleeding): intradermal rabies vaccine (ARV) plus rabies immunoglobulin (RIG). ^{7 9 10}

While human RIG (HRIG) exhibits superior safety, equine RIG (ERIG) purified from hyper immune horse serum predominates due to 10-fold cost disparity (?2,000 vs ?20,000 per dose). ERIG hypersensitivity manifests across a spectrum: immediate Type I IgE-mediated (anaphylaxis, urticaria: 1-6%), Type III immune complex (serum sickness: 20-46%), and late cutaneous reactions. ^{4 6 11} Therapeutic re challenge post-initial reaction administering full/standard dose to confirm causality represents the gold standard for ADR attribution yet encounters ethical/practical barriers, yielding sparse primary documentation.^{3  5 11 12}  This report chronicles deliberate ERIG re challenge in an otherwise healthy adolescent, achieving Naranjo score 8 ("Probable ADR") through temporal association, de challenge improvement, and reaction recurrence. The case illuminate’s diagnostic nuances, management algorithms, and pharmacovigilance contributions within India's high-burden context.

CASE PRESENTATION

Patient Profile: A 17-year-old male (initials: NNK; weight: 55 kg; no known drug/food allergies or atopy) sustained a Category III dog bite to the right forefinger mid-second phalanx from a stray dog on January 1, 2026 (~2 hours’ pre-presentation). The 1.5 × 0.8 cm laceration exhibited punctate bleeding and adherent dirt.

Initial Management at VDGMC Latur:

Wound preparation: Surgical debridement, copious irrigation (20% soap solution), high-pressure jet lavage

Closure: Primary suturing under 1% lignocaine infiltration

PEP per NACO 2024 guidelines:

ARV: VaxiRab N (Serum Institute India) 0.1 mL ID × 8 sites (2 deltoids, 2 thighs, 4 gluteals)

Tetanus prophylaxis: TT 0.5 mL IM (deltoid)

ERIG: Equine rabies immunoglobulin 40 IU total—20 IU local wound infiltration (palmar/radial margins) + 20 IU deep IM (gluteus)

Detailed Clinical Timeline

Table 1: Detailed Clinical Timeline

Physical Examination Findings

Local reaction: Grade II (induration >5 cm, erythema without blistering) per WHO ADR grading ⁷

Systemic: Acute gastrointestinal (emesis), vertigo; excluded vasovagal (prolonged symptoms), sepsis (afebrile)

Wound: Clean, minimal exudate, no crepitus/ cellulitis

Investigations: Deferred due to clinical stability, low serum sickness/anaphylaxis pretest probability, and resource constraints.

Causality Assessment

Table 2: Causality Assessment

Naranjo Adverse Drug Reaction Probability Scale (Score: 8 = Probable) ^{3 5}

WHO-UMC Causality: Probable/Likely (clear temporal sequence + de/rechallenge consistency) ⁷

Follow-up and Outcome

PvPI Reporting: Individual Case Safety Report submitted via umc.pvpi.in (acknowledgment pending).

Consent: Written guardian consent obtained for anonymized publication and data use.

DISCUSSION

Pathophysiology: ERIG hypersensitivity reflects equine heterologous protein immunogenicity. Type I (immediate) reactions involve IgE cross-linking  mast cell degranulation (histamine, leukotrienes), explaining gastrointestinal (emesis via 5HT3 agonism), cutaneous (edema), and vestibular (histamine H1-mediated) manifestations. Rechallenge attenuation suggests partial tachyphylaxis or antihistamine prophylaxis effect.^{1 6 11}

Literature Context:

Acute ERIG ADRs: 6% incidence (anaphylaxis <1%) vs serum sickness (21-46%, days 7-14)

Rechallenge precedent: Rare; one Thai series (n=3) documents graded dosing post-reaction without recurrence

India-specific: ERIG dominates 92% RIG market; Maharashtra reports 1.2 lakh Category III bites annually.

Diagnostic Nuances:

• Temporal consistency (<30 min onset both episodes)
• Dose-response (severe → attenuated)
• Excludes: ARV (cell-culture vaccine, <0.01% ADR), tetanus toxoid (separate site/timing), wound infection (afebrile course)

Management Lessons:

Premedication: Antihistamine ± low-dose dexamethasone 30 min pre-ERIG warrants RCT evaluation

Graded challenge: 0.1 mL test dose → incremental over 30 min (vs full 40 IU rechallenge)

?Substitution: HRIG for age <18 years, prior equine exposure, atopic

Monitoring: 2-hour observation post-ERIG mandatory

Pharmacovigilance Impact: PvPI integration tracks regional ERIG-ADR epidemiology, informing policy (Schedule H1 compliance). This rechallenge case elevates signal strength for hypersensitivity risk communication.

CONCLUSION

This Naranjo score 8, rechallenge-confirmed ERIG hypersensitivity exemplifies the delicate PEP balance: absolute rabies prevention versus manageable acute ADR burden. Indian practitioners must operationalize premedication protocols, HRIG rationing algorithms, and universal PvPI reporting to safeguard millions confronting canine rabies annually.

AUTHOR CONTRIBUTIONS

All authors were involved in the conceptualization and methodological planning of the case report. They participated in literature search, clinical data collection, evaluation of adverse drug reaction causality, analysis and interpretation of findings, and preparation of the initial draft. Critical revisions were undertaken by all authors, who also reviewed and approved the final manuscript.

DATA AVAILABILITY STATEMENT

Information supporting the conclusions of this case report may be obtained from the corresponding author upon justified request. Public sharing of the data has been restricted to protect patient confidentiality and comply with ethical considerations.

FINANCIAL SUPPORT AND SPONSORSHIP

This study did not receive any financial assistance from public, commercial, or non-profit funding agencies.

CONFLICTS OF INTEREST

The authors report no financial or personal relationships that could have influenced the work presented in this manuscript.

CONSENT FOR PUBLICATION

Written informed consent obtained from the patient's legally authorized representative for publication of this case report and any accompanying images/tables. A copy remains with corresponding author.

REFERENCES

1. Suwansrinon, K., Jaijareonsup, W., Wilde, H., Benjavongkulchai, M., Sriaroon, C., & Sitprija, V. (2007). Sex- and age-related differences in rabies immunoglobulin hypersensitivity. Transactions of the Royal Society of Tropical Medicine and Hygiene, 101(2), 206–208. https://doi.org/10.1016/j.trstmh.2006.04.009
2. Ushakumari, A., Kanchana, B. M., Suresh, R., Krishnan, J., & Abraham, S. (2024). Adverse Events Following Equine Rabies Immunoglobulin Administration among Category 3 Animal Bite Exposures. Preventive Medicine: Research & Reviews, 2(3), 111–113. https://doi.org/10.4103/PMRR.PMRR_111_24
3. Sudarshan, M. K., Ashwath Narayana, D. H., & Ravish, H. S. (2011). Is the skin sensitivity test required for administering equine rabies immunoglobulin? The National medical journal of India, 24(2), 80–82. https://pubmed.ncbi.nlm.nih.gov/21668049/
4. Rajagopal, J., M. R., M., B. R., H., & Swamy, P. (2019). Clinical safety profile of Premi-Rab a new indigenous equine rabies immunoglobulin for cat III animal bite victims at anti rabies clinic of a tertiary care hospital, Karnataka. International Journal Of Community Medicine And Public Health, 6(3), 1197–1200. https://doi.org/10.18203/2394-6040.ijcmph20190610
5. Sudarshan, M. K., Kodandaram, N. S., Venkatesh, G. M., Mahendra, B. J., Ashwath Narayana, D. H., & Parasuramalu, B. G. (2007). Evaluation of a new premedication protocol for administration of equine rabies immunoglobulin in patients with hypersensitivity. Indian journal of public health, 51(2), 91–96. https://pubmed.ncbi.nlm.nih.gov/18240468/
6. Purcell RH, Wunner WH, Doherty RL. Purified equine rabies immune globulin: safety and clinical use. Bull World Health Organ. 1987;65(3):375–383.
7. WHO Expert Committee on Rabies (13th Report). World Health Organization Technical Report Series. 2018.
8. Centers for Disease Control and Prevention (CDC). Rabies Post-Exposure Prophylaxis Guidelines, 2025 update.
9. APCRI Expert Consultation on Rabies Immunoglobulins (2025 Report). Association for Prevention & Control of Rabies in India.
10. National Rabies Prophylaxis Guidelines (India). Ministry of Health & Family Welfare (2025).
11. Saramma Abraham et al. Allergic manifestations to equine rabies immunoglobulin  a case series. APCRI Journal. 2023;25(2):8–10.
12. Banyai S, Inthawong T, Wilde H. Rabies immunoglobulins: comparative effectiveness and safety between human and equine sources. Vaccine. 2021;39(15):2025–2031.