Hypersensitivity reactions to folinic acid: mechanisms involved based on two case reports and a literature review

Two cases of immediate drug hypersensitivity are described here after the intravenous administration of FA. The reactions were initially attributed to oxaliplatin, which was administered concomitantly and has a higher frequency of HSR compared to FA [4]. After the allergy workup, HSR to FA were respectively attributed to IgE-mediated and non-IgE-mediated mechanisms.

Folates are composed of a non-reduced aromatic pteridine ring linked to para-aminobenzoic acid and one or more glutamic residues. Mean dietary intake is around 247–291 μg per day and mainly consists of the polyglutamate form of folic acid, which slowly breaks down into monoglutamates in the small intestine. The synthetic form contains only the monoglutamate form, resulting in higher bioavailability and bypassing the need for fragmentation of the polyglutamate conjugate at the brush border. In the enterocyte, monoglutamate folic acid is reduced, methylated, and released into the bloodstream as 5-methyltetrahydrofolic monoglutamate. However, these mechanisms are saturable, and unmetabolized synthetic folic acid can be detected in blood at doses as low as 200 μg [5]. Folinic acid (5-formyltetrahydrofolate) bypasses the reduction steps required for folic acid, since it is administered intravenously.

The literature describes 27 cases of HSR since 1949, mainly with oral folic acid supplement, ranging from mild anaphylactic reaction to anaphylactic shock. HSR to FA is less often described and mainly reported in patients treated for colon carcinoma. After reviewing previous case reports with HSR to FA (Table 1), we identified only 7 publications describing a total of 12 patients, mainly reported in oncology journals, without any allergy assessment except for the papers by Vermeulen et al. [6] and Ureña-Tavera et al. [7]. For the other five HSR, the involvement of FA was confirmed by the absence of symptoms after withdrawing FA from chemotherapy.

Table 1 Case reports of hypersensitivity reactions to folinic acid

HSR to carboplatin and oxaliplatin have been reported with high incidences [2]. By contrast, HSR to FA seem to be very rare. However, they could be more frequent than expected, as Ureña-Tavera et al. [7] found a prevalence of 11% (95% confidence interval: 1.98–20.74%) over a 12-month period in their population of FOLFOX- or FOLFIRI-reactive patients. In the absence of allergy assessments, the involvement of FA may be underestimated, especially since the symptoms of HSR to FA can be similar to those with oxaliplatin. As observed in Table 1, patients usually receive several further cycles of chemotherapy (up to five) with progressively more intense symptoms before the successful withdrawal of FA, because FA is rarely suspected. The complexity of regimens with multiple chemotherapeutic agents, sometimes combined with biological agents, makes the diagnosis even more difficult, which highlights the importance of publishing case reports with rare HSR.

Our first case of HSR to FA was due to an IgE-mediated reaction (elevated serum tryptase levels during the reaction and positive IDT), while the second was a non-IgE-mediated reaction. Nevertheless, both clinical situations correspond to anaphylaxis [8]. The mechanism of HSR to FA is still unclear. Serum tryptase levels are currently the best routine biomarker available to assess mast cell activation. Levels are increased with the peak between 1 and 2 h. In 2010, a consensus equation was proposed to diagnose acute mast cell activation: peak tryptase should be  > 1.2 × baseline tryptase + 2 ng/L [8].

It is important to note that HSR to FA can appear either during the first injection (two cases described by Vermeulen et al. [6] and cases 1 and 4 of Ureña et al. [7]) or after several injections (during the 10th administration in our second patient or even after the 18th cycle for case 2 of Ureña et al. [7]).

Different arguments point to an IgE-mediated mechanism. Some patients experienced symptoms such as urticaria, pruritus, hypotension, and tachycardia, suggesting an IgE-mediated anaphylaxis. In this case, tryptase levels can be elevated and skin tests positive. Benchalal et al. [9] even described a case of anaphylactic shock requiring adrenaline. In 2000, Dykewicz et al. [10] showed the existence of IgE antibodies to folate–human serum albumin complex by in-vivo and in-vitro testing. The authors suggested that in IgE-mediated reactions, folic acid, with a molecular weight of only 441 D, probably acts as a hapten by conjugation with self-proteins.

These IgE-mediated reactions are similar to those observed with oxaliplatin, where patients receive several doses before the appearance of the first symptoms, and even more when chemotherapy is interrupted and then resumed again, giving the time for sensitization.

IgE-mediated HSR can also occur on the first exposure to a given drug, as shown for cetuximab in which preexisting IgE antibodies, acquired through tick bites, cause these reactions [11]. It was suggested by Dykewicz et al. [10] that folic acid contained in food could be the sensitizer with clinical cross-reactivity to FA during the first intravenous administration. This hypothesis is ruled out for our first case: the cross-reactivity to folic acid was not confirmed by the SPT and OPT.

Nevertheless, most patients develop non-specific symptoms with lower back pain and chills as well as unelevated serum tryptase levels, and these can sometimes even occur during the first exposure. These reactions are not explained by IgE-mediated HSR.

IgE-independent mechanisms of anaphylaxis include IgG-mediated anaphylaxis, complement activation, direct activation of mast cells by drugs that interact with receptors such as MRGPRX2 and cytokine-mediated mechanisms [12].

Complement activation has been well described with HSR to taxanes. Most patients (80%) reacted after the first or second exposure to taxanes despite the use of standard premedication, with atypical symptoms such as back pain or abdominal pain occurring in around 40% of patients. These reactions are attributed to complement activation by the surfactants used in their formulation (Cremophor EL for paclitaxel and polysorbate 80 for docetaxel) [13]. Cremophor EL promotes the generation of biologically active complement products such as C3a and C5a [14]. These products can activate mast cells resulting in release of histamine, leukotrienes and prostaglandins that can induce flushing, hypoxia, hives and hypotension [15]. However, this mechanism is unlikely since there is no excipient in FA to be incriminated.

Another possible pathway for non-IgE-mediated HSR is the activation of mast cells through MRGPRX2, a new member of the Mas-related G protein-coupled subfamily of receptors, which is present in mast cells and potentially in basophils and eosinophils. MRGPRX2 activation is very effective in activating mast cells, especially with the intravenous administration of drugs at sufficient concentrations to stimulate the receptor and containing structural patterns known as tetrahydroisoquinoline (THIQ). These or similar motifs are found in members of the neuromuscular blocking agents (e.g., cisatracurium) and fluoroquinolone drug family [16]. FA has a relatively similar structure and may activate this receptor, which could explain non-IgE-mediated reactions. Since its first description in 2015 [17], the hypothesis of non-IgE-mediated mast cell activation through MRGPRX2 has been appealing, even if the pathophysiology is not yet completely understood. Nevertheless, it seems that this activation could release more tryptase and less histamine compared to an IgE-mediated activation [18].

IgG-mediated reactions are another possible pathway. IgG-antigen complexes can activate the macrophage and neutrophil low-affinity receptor (FcγRIII) and stimulate platelet-activating factor (PAF). This factor promotes platelet aggregation and release of thromboxane A2 and serotonin, increasing vascular permeability and can lead to hypotension, cardiac dysfunction and smooth muscle contraction. This anaphylaxis has been demonstrated in murines, and it has been hypothesized that in humans IgG antibodies can mediate systemic anaphylaxis if there are large numbers of both IgG and antigen present, which can be the case with parenterally administered drug [19].

Finally, anaphylaxis can be caused by cytokine-release reactions (CRRs), usually triggered by chimeric, humanized or human mAbs and chemotherapeutic agents. The release of proinflammatory mediators such as tumor necrosis factor alpha (TNF-α), IL-1β and IL-6 are responsible for chills, fever and pain, symptoms compatible with the second case-report. It should be mentioned that a mixed reaction can be observed during chemotherapy combining IgE-mediated reactions (redness, pruritus, urticaria, wheezing) and CRRs symptoms (chills, fever, malaise), thereby making it impossible to differentiate between mechanisms [12]. The mixed reaction is probably the most attractive explanation for the first patient.

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