Correspondence to ‘Hypersensitivity Reactions to Human Albumin—A Case Series and Diagnostic Algorithm’

We read with great interest the article by Basu et al. [1] proposing a diagnostic algorithm for hypersensitivity reactions to human serum albumin (HSA). This review summarises the rare cases of HSA hypersensitivity reported in the literature and outlines the steps allergists should consider. During manufacturing, stabilising agents, such as caprylic acid, are added to preserve the albumin molecule. Excessive concentrations of these excipients may increase its immunogenicity, as reported by Ring et al. [2]. Immunoglobulin E–mediated hypersensitivity to modified commercial HSA has been described previously [3]. The objective of this correspondence is to refine the diagnostic algorithm with a focus on batch-specific immunogenicity and batch variability. This refinement follows a case of a 53-year-old patient admitted to the intensive care unit with severe thermal burns who received a 20% HSA infusion (Vialebex, LFB) [4]. Within 1 h of the second administration, he developed a grade II reaction (Ring and Messmer). He recovered rapidly with epinephrine and corticosteroids. Tryptase kinetics were consistent with mast cell degranulation. Batch 1 (the implicated batch) and batch 2 (the control batch) were tested using skin prick testing (SPT), intradermal testing (IDT) and a basophil activation test (BAT), following the recommendations of the FlowCast kit (Bühlmann). Caprylic acid concentration was quantified using gas chromatography–mass spectrometry, revealing a 26-fold higher concentration in Batch 1 compared to Batch 2. IDT (1:100, 1:1000) and BAT (1:1; 1:10; 1:100; 1:1000; 1:10,000) were positive for Batch 1, whereas Batch 2 yielded negative results. These results suggest that anaphylaxis was triggered by the batch with elevated caprylic acid, which increased the immunogenicity of HSA in this batch. LFB did not provide information on excipient variability. We propose refining the diagnostic algorithm outlined by Basu et al. [1], taking into account new decision points (Figure 1). The stepwise approach, progressing from the least risky to the riskiest test, is preserved. If available, the implicated batch must be tested (Figure 1, white box). When the suspected batch is no longer available, we suggest testing two different HSA batches to improve diagnostic accuracy and reduce the risk of false negatives (Figure 1, blue box). If at least one test yields a positive result, HSA hypersensitivity, modified or not, is confirmed. It can be excluded if the tests on the implicated batch or the two different batches yield negative results. For patients with a history of severe reactions, a histamine release test (HRT) or BAT may serve as a safer alternative to titrated IDT when selecting the batch prior to intravenous provocation. There are some limitations: intravenous provocation are recommended in centres with experience and in vitro tests (BAT and HRT) are not routinely available in all clinical settings. This approach aligns with current recommendations for food allergy diagnostics [5]. To go further in the investigation of potential immunologic mechanisms and therapeutic alternatives, a control batch, a commercial HSA of other manufacturers and/or human plasma can be tested. An HSA batch with negative tests findings may be considered as a therapeutic alternative on a case-by-case basis, guided by the individual benefit–risk assessment. Testing therapeutic alternatives could help to identify the immunisation mechanism. Ring et al. [2] and Moreno Lozano et al. [3] previously demonstrated that four patients developed anaphylactic reactions to caprylate-modified HSA (SPT positives), but tolerated native monomeric albumin or human plasma (SPT and IDT negatives). Structural or chemical modifications occurring during albumin purification or stabilisation may generate neoepitopes, leading to a specific IgE-mediated immune response against the modified albumin rather than the native plasma protein. Other chemical modifications have been described, such as ethylene oxide (ETO), which causes neoantigens capable of triggering hypersensitivity reactions [6]. In conclusion, a practical experience has shown the importance of: (1) testing the implicated batch or at least two batches due to variability in excipient effects; (2)using in vitro testing in the diagnostic strategy in cases of severe reaction; and (3) investigating HSA immunisation origins with the help of a reference laboratory to propose therapeutic alternatives. These findings could be reinforced by improving the accuracy of pharmacovigilance reports by including all information. Interdisciplinary collaboration between pharmacovigilance specialists, clinicians and immunologists is essential to properly investigate this type of hypersensitivity. J.C., M.S., A.G. and J.G. reported the case report. J.C., J.B. and M.D. performed the laboratory tests. J.C., J.B. and J.G. interpreted the data and drafted the manuscript. M.S., A.G., J.B., M.D., M.B.-D. and C.P. contributed substantially to the analysis of the data and revised the manuscript. All authors approved the final version to be published. We would like to thank the teams at the Immunology and Pharmacology Laboratory at Bordeaux University Hospital for their invaluable assistance with the basophil activation test and the gas chromatography–mass spectrometry analysis, particularly Margaux Cabagni, Loïc Morand, Kamal Echchelh, Dominique Ducint and Dr. Stéphane Boucher. The English in this document has been checked by at least two professional editors, both of whom are native English speakers. For a certificate, please see: http://www.textcheck.com/certificate/6GQhEk. This study was funded by the laboratory's own funds. The authors declare no conflicts of interest. This article is linked to Basu et al. paper. To view this article, visit https://doi.org/10.1111/all.15971. The data that support the findings of this study are available from the corresponding author upon reasonable request.