Transfusion and Allergy: What is it, and what is it not? Prof. Olivier GARRAUD INTS, Paris Université de Lyon/Saint-Etienne France

The commonest picture of Allergy Allergy is commonly sensed as an Antibody (Ab) mediated immune response specific to a unique or more frequently a panoply of crossreactive antigenic epitopes, that manifest with a variety of symptoms (cutaneous, respiratory, digestive ) that are either minor or severe, and evenly lethal Allergy commonly happens in individuals presenting with genetically transmissible susceptibility, referred to as atopy

Allergy is frequently mediated by Abs that are IgE in nature (but not exclusively) IgE Abs bing IgE-receptors and especially high affinity FceRs (FceRI), that are constitutionally expressed by certain cells (of which mast cells, basophils, ); IgE also binds FceRII (CD23), expressed on B cells, eosinophils, platelets and alveolar macrophages Besides, there is a tightly regulated loop involving IgE, CD21 (EBV-R, C3d-R = CR2) and CD23

The Allergen \ specific IgE (or another type of Ab) / FceR \ Mast (or other) cell Signals the cell Activates it Degranulates it (provided that there are granules) Mast cells thus may release: Histamin Serotonin Tryptase Ca++, ADP, ATP

The diagnosis is usually complex and tedious because the majority of reagents are labile and in small sometimes infinitesimal amounts Direct diagnosis: IgE, Allergen Indirect diagnosis: Granule content Specific amounts of IgE are produced in very low quantities that may all be all be absorbed in the reaction and thus, no longer available for labwork testing

The diagnosis is often made indirectly, because of the reoccurrence of symptoms after introduction/re-introduction of a panel of crossreacting antigens and because of the clinical expression of symptoms such as Eczema, urticaria, rashes, Asthma Oedema and because patients respond favourably to Targeted symptomatic and emergency treatment Prevention Ag eviction Anti-allergic drugs

Allergy in general: Definitions and basic mechanisms Allergic diseases including allergic asthma, allergic rhinitis/conjunctivitis and allergic urticarial are common, and potentially dangerous diseases caused by an IgE-mediated reaction by the mast cells. Allergic diseases affecting 10-30% of the world population are characterized by genetic predisposition, antigenic sensitization and exposure leading to clinically significant reactions. Clinical allergy is seen as acute attacks and/or chronic situation with persistent symptoms. The allergic sensitization leading to this reaction is an immediate type I immunological hypersensitivity based on IgE sensitization to a specific allergen, leading to immediate degranulation of mast cells or basophils upon re-exposure; crossreactions to allergens displayed by distinct bearing are not uncommon. Sensitized individuals may react severely, locally and/or simultaneously in more organ systems, leading to anaphylactic shock, although milder reactions such as urticaria, oedema and flushing/pruritus are the commonest manifestations). A cytokinemediated late-phase reaction (gene transcription dependant) may follow some hours after type-i allergic reaction. Complement activation may cause mast cells to degranulate, mimicking allergic reactions, due to IgG-receptor activation, hyperosmolarity, or other mechanisms (opioids). O Garraud & M Bagge-Hansen, EDQM/GTS, in progress

What about Transfusion?

Epidemiology of Adverse Transfusion Reactions in PC transfusion (source: ANSM, France, 2011)

Allergy in Transfusion: frequency and mechanisms of recipient reactions Active clinical surveillance studies have reported immediate allergic transfusion reactions (ATR) to have the same clinical pattern as other allergic reactions and to follow 0.15-3.7% of transfusions with different blood components, most frequently platelets. Reduction in plasma content and/or washing of platelets reduces reaction frequency, and allergy is generally thought to be linked to plasma, although platelets may play a direct role. Known mechanisms include: 1) passive transfer of donor IgE to sensitize recipient mast cells and elicit reaction upon allergen exposure; 2) recipient allergy to plasma proteins (IgA, BSA, haptoglobin) following sensitization due to transfusions, BSA exposure or pregnancies; 3) recipient allergy by allergens transferred by donor blood. Atopic predisposition is associated with increased frequency of ATR, and some studies suggest that allergic individuals mast cells may be more prone to cause ATR. In many cases of ATR, the mechanism is unclear, and e.g. direct transfer of mast cell products (histamine, tryptase or other) or platelet products are also possible causes; a 2-step mechanism has also been proposed O Garraud & M Bagge-Hansen, EDQM/GTS, in progress

Hypotheses 1) Passive transfer of donor IgE to sensitize recipient mast cells and elicit reaction upon allergen exposure; 2) Recipient allergy to plasma proteins (IgA, BSA, haptoglobin) following sensitization due to transfusions, BSA exposure or pregnancies; 3) Recipient allergy by allergens transferred by donor blood

But! What about sentization? What about genetic predisposition? What about evidence of IgE mediation?

Meanwhile! Certain donors are prone to discomfort while any transfusion episode

Plus! The reduction of plasma alleviates the allergictype symptomatology But some plasma remains, in much larger amounts than trace!

Is all type of allergic-type manifestation in transfusion, allergy?

Blood component transfusion and Febrile, Non Haemolytic, Transfusion Reaction or FNHTR Well documented with Platelet Component Transfusion Reactions: the role of soluble CD40-Ligand (and its polymorphisms) References: the Blumberg et al. group, the Garraud et al. group etc. Along with the role of soluble Ox40-Ligand and interleukin-27 References: Hamzeh-Cognasse et al, 2013; Nguyen et al, 2014 General references: Garraud et al, Crit care, 2013

Most recent evidence: the cytokine pattern being produced by stored platelets drive the clinical manifestation of FNHTR PLOS ONE www.plosone.org 13 May 2014 Volume 9 Issue 5 e97082

There are distinct clinical presentations which also vary with the age of PCs at delivery time -Youger PCs are more commonly associated with allergic-type reactions -Older PCs are more frequently associated with FNHTRs

This is probably one of the first demonstrations that certain cytokines and BRMs associate with clinical symptoms of serious adverse events after the transfusion of platelets; the age of platelet component further influences the level of secreted BRM

Recapitulation This indicates that Allergic type Reactions following Platelet Component Transfusions are frequently cytokine/chemokine and Biological Response Modifier due-fnhtrs But some manifestations seem linked with either or resemble severe allergy (oedema etc.)

.a-granule platelet content This indicates that Allergic type Reactions following Platelet Component Transfusions are frequently cytokine/chemokine and Biological Response Modifier due FNHTRs But some manifestations seem linked with Is there room for the d platelet granule, either linked that comprise to plasma of the or very resemble same factors severe allergy (oedema etc.) That trigger typical allergic symptoms (Histamin, Serotonin, Tryptase, Ca++, ADP, ATP )

Conclusions

Diagnosing ATR Acute ATR must not be ignored; occurrences or strong suspicions should be reported according to IHN/ISBT standards. Diagnosis may be supported by tryptase measurements (immediate tryptase level increase within 2 hours vs baseline level). Plasma protein allergy may be diagnosed by specific anti-protein IgE/IgG-measurements, skin prick test, recipient polymorphisms/synthesis defects leading to low levels or complete absence of the protein. Nevertheless, laboratory investigation to identify allergy is difficult in general and disappointing in transfusion in particular. Reactions to methylene blue should be suspected and diagnosed if the agent is used for viral inactivation. Recently, food allergens (at least peanut) have been shown to be transferred via a blood component and cause anaphylaxis in a (peanut-) allergic recipient; this may warrant future measures, pending a risk analysis. O Garraud & M Bagge-Hansen, EDQM/GTS, in progress

Prophylaxis of ATR Avoiding transfer of donor-ige by excluding all donors with history of severe allergic reactions (asthma, angioedema, anaphylaxis, systemic reactions) and donors with allergy (regardless of severity) specifically against medicine, latex, food and insects works well and is reasonable due to the well-established cause-effect mechanism. Non-allergic asthma or rhinitis is not known to pose a risk to the recipient, but massive systemic medication or unstable condition may warrant donor exclusion. Individual recipients with allergy specific to plasma proteins should be diagnosed after one or more allergic reactions to blood components or infusion with blood derivatives. IgA-deficient donors are preferable for recipients with anti-iga, when possible. Plasma reduction is known to reduce ATR, but may not be feasible. Pre-transfusion antihistamines have not proven effective in RCT s and is not recommended, whereas they may be used in manifest allergic reactions. O Garraud & M Bagge-Hansen, EDQM/GTS, in progress

Transfusion Allergy is still questioned A working group has been set up at the EDQM (Council of Europe), GTS group to focus on this hazard and to compare declared occurrences, analysis, prevention and eventually treatment in the different European and Observatory countries The role of Platelet secreted Biological Response Modifiers and especially from the a granules responsible for FNHTR must, however, not be ignored.

Thank you \ Danke schön / Grazie mille / Merci! (ogarraud@ints.fr)