On the dark side of therapies with immunoglobulin concentrates. Theadverse events

  Peter J. Spaeth, Guido Granata, Fabiola La_Marra, Taco W. Kuijpers and Isabella Quinti

Journal Name: Frontiers in Immunology

ISSN: 1664-3224

Article type: Review Article

First received on: 31 Oct 2014

Frontiers website link: www.frontiersin.org

Primary Immunodeficiencies

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Fact Sheet 1 2

Tile of the manuscript: On the dark side of therapies with immunoglobulin 3

concentrates. The adverse events. 4 5 Submission to: Frontiers in Immunology, section Primary Immunodeficiencies, special issue on 6

“Immunoglobulin therapy in the 21st century: the dark side of the moon” 7 8 Article type: review 9 10 Number of authors: 5 11 12 Number of institutions: 3 13 14 Character counting of the abstract, spaces included: 1919 (2000 allowed) 15 16 Word counting body text: 5905 (12000 allowed) 17 18 Word counting acknowledgments: 24 19 20 Word counting legend to figures: 944 21 22 Number of tables: 3 23 24 Number of figures: 8 25 26 Number of references cited: 178 27

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On the dark side of therapies with immunoglobulin concentrates. 29

The adverse events 30

31 Peter J. Späth1, Guido Granata2, Fabiola La Marra2, Taco W. Kuijpers3 and Isabella Quinti2* 32 33 1Institute of Pharmacology, University of Berne, Berne, Switzerland, 2Dept.of Molecular Medicine, 34 Sapienza University of Rome, Rome, Italy and 3Department of Pediatric Hematology, Immunology 35 & Infectious disease, Academic Medical Centre (AMC), University of Amsterdam, Amsterdam, 36 Netherlands 37 38 39 Conflict of interest statement 40 The authors declare a potential conflict of interest and state it below. 41 PJS, none; GG, none; FLM, none; TWK, none; IQ, none 42 43 44 Running Title: Adverse events of Ig therapies 45 46 47 Correspondence 48 Isabella Quinti, MD, PhD 49 Dept.of Molecular Medicine, Sapienza University of Rome 50 Viale dell’Universita 37 51 I-00186 Rome 52 Italy 53 54 isabella.quinti@uniroma1.it 55 56 tel. and fax. +390649972007 57

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Abstract to the dark side of therapies with human immunoglobulin G concentrates 59 60 Therapy and manufacturing of human immunoglobulin G (IgG) concentrates is a success story 61 ongoing for decades showing an ever increasing demand for this plasma product. Transmission of 62 pathogens in the last decade could be entirely controlled through the antecedent introduction by 63 authorities of a regulatory network and installing quality standards by the plasma fractionation 64 industry. A cornerstone of the regulatory framework is current Good Manufacturing Practice 65 ensuring by validated steps the constant quality of an IgG concentrate. One of the more remarkable 66 steps to achieve pathogen safety was the introduction of virus filtration. Virus filtration became a 67 very versatile tool to eliminate e.g. the suspected agent of variant Creutzfeldt-Jakob disease. The 68 success of IgG concentrates on a clinical level is documented by the slowly increasing number of 69 registered indication and the more rapid increase of the off-label uses. A part of the success is the 70 adverse event profile of IgG concentrates which, even at life-long need for therapy, is excellent. 71 Adverse events (AEs) occur rarely and mainly are mild to moderate. Below we review AEs, give 72 insight in to possible mechanisms, and particularly focus on hemolysis and thrombosis. A further 73 interest of this review is the question how the introduction of plasma fractionation by ion-exchange 74 chromatography and polishing by immunoaffinity chromatographic steps might influence AE 75 profiles and efficacy of IgG concentrates. Indeed, it is not clear whether the improved recovery, 76 which can be achieved by the ion-exchange chromatography technique, leads to the expansion of 77 the same repertoire of IgG molecules in a product or whether some IgG specificities might be lost 78 while specificities otherwise absent or present in minute amounts only contribute to the improved 79 recovery. Latter might have consequences on the AE profile of a new IgG concentrate.80

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81 1. The tinge of the dark – Introduction clinical manifestations of AEs 82 83 Since the initial clinical use of immunoglobulin G (IgG) concentrates of human origin, transmission 84 of pathogens and non-infectious adverse events (AEs) were reported [1-7]. Before the mid 90ies, 85 transmission of pathogens has depended on the pool size and the fractionation methods used, 86 particularly the polishing steps of an IgG concentrate [8]. Mode of fractionation, i.e. cold ethanol or 87 ion-exchange chromatography, contaminants, route of application, i.e. intra muscular (IMIG), 88 intravenous (IVIG) or subcutaneous (SCIG), the rate of increase of the exogenous IgG in the 89 circulation of the recipient over time (Fig. 1) and incorrect handling of the concentrate are factors 90 having a role in inducing non-infectious AEs related to administration of IgG concentrates (Table 91 1). IgG concentrates represent a defined part of the adaptive immune system, are isolated form 92 pooled human plasma of at least 1000 donors, which contribute to the diversity in the final plasma-93 derived product. Therapies with IgG concentrates manufactured according to regulators 94 requirements are acknowledged to be safe in general. This does not exclude the occurrence of AEs 95 which in in their majority are rare and clinically mild to moderate. Below we like to give a few 96 insights into various aspects and possible mechanisms of AEs. 97 98 99 2. A dark and frightening environment – Pathogen safety of IgG concentrates 100 101 Modern IgG concentrates from the moment of sampling whole blood and isolation of plasma 102 thereof (recovered plasma) or the machine-supported collection of plasma (source plasma, apheresis 103 plasma) has to occur in a regulatory framework and the quality standards implemented by the 104 plasma fractionating industry (Fig. 2). The cornerstone of the regulatory framework is current Good 105 Manufacturing Practice (cGMP). The pillars of pathogen safety are validated virus inactivation and 106 virus elimination steps (Fig. 3). A hallmark of virus elimination introduced in the late 90ies in 107 Berne by the team of Christoph Kempf is the large scale virus filtration technique (formerly also 108 termed ‘nanofiltration’) [8]. Meanwhile, virus filtration became a very versatile tool to eliminate a 109 variety of pathogens, e.g. the suspected agent of variant Creutzfeldt-Jakob disease. Thanks to the 110 tightly implemented regulatory framework pathogen safety of plasma products is at a level never 111 reached before. This is well supported by the fact of missing reports of transmission by IgG 112 concentrates of emerging viruses (SARS coronavirus, West Nile Virus, MERS coronavirus and 113 others), zoonotic pathogens or the agent of variant Creutzfeldt-Jacob disease in the last decade 114 [9,10] and development of potentially specific screening techniques to eradicate transmission of 115 vCJD in the future[11]. 116 117 118 3. Some basic insights into possible mechanisms occurring in the dark 119 120 The human immune system is in charge of controlling invading organisms and provides peripheral 121 and tissue homeostasis by a variable-region connected network. The latter supports the efficient 122 removal of roughly ~1012 altered/senescent cells of the body per day. Host defense is best mediated 123 by ‘immune antibodies’, which have undergone somatic hypermutations and have narrow 124 specificities and high affinities. Antibodies, including the homeostatic ones, produced in absence of 125 an antigenic stimulation are termed ‘natural antibodies’ (NAbs). They are of germ-line 126 configuration or have undergone a few somatic hypermutations only. In general they have broad 127 specificity, are of low affinity and high avidity (with exceptions) and participate in primary host 128 defense (i.e. react best with repetitive structures as can be found on bacteria). Their homeostatic 129 functions are brought about by self-reactive antibodies which we like to term physiologic 130 autoantibodies. The immunoglobulins pools in mammals (IgM, IgG and IgA) to its smaller part 131

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provides defense and to its larger part homeostasis. Human IgG has a role in both. Thus, 132 infusion/injection of IgG concentrates inevitably results in recognition of occasional pathogens, 133 toxins or superantigens and concomitantly in a wide array of variable-region (V-region) 134 interactions. V-region recognitions are interactions of the self-reactive antibodies of the many 135 donors in the IgG concentrate with the recipients’ body/immune system and vice versa. A 136 bewildering wide range of possible reactions can occur which primarily are dependent on the 137 immunologic status of the recipient at the time of therapy and to a smaller part on the IgG 138 concentrate(s). The therapeutic effect achieved depends on the disease treated, and can depend on 139 the concentration reached locally, i.e. can have agonistic or antagonistic effects [11,12]. In 140 summary, it is our opinion that IgG concentrates always provide more or less the same ‘bouquet’ of 141 IgG specificities (similarity). Each time, the recipient’s actual immune condition decides from 142 which part of the IgG the patient’s derailed immune system is profiting (diversity). 143 144 Parameters leading to adverse events (AEs) related to infusion/injection of IgG concentrates are: (i) 145 the content in the product of biologically highly active likely beneficial ingredient that have to be 146 kept under control (e.g. content of ‘dimers’ devoid of remarkable complement activation in vivo; 147 see below), and the content in unwanted active ingredient that have to be discarded during 148 manufacturing (alloantibodies); (ii) impurities such as IgA (anaphylactoid reaction); (iii) activated 149 coagulation and contact activation factors (thromboembolic events) and; (iv) excipients such as 150 sucrose (osmotic nephrosis). Here, we like to add an additional parameter: the sum of potentially 151 beneficial V-region connected reactions. In case they overshoot they might add to processes leading 152 to AEs. In summary, the intensity of the resulting AEs is depending on the immune status of the 153 recipient, the infusion rate, e.g. how rapidly the active ingredients (the various IgG specificities), 154 the impurities and the excipients reach the circulation of the recipient. Thus, the i.v. application has 155 the highest chance for the occurrence of adverse events. 156 157 In the early days of IVIG therapy, complement-mediated ‘anaphylactoid’ (i.e. immediate) and 158 ‘phlogistic’ (i.e. inflammatory) AEs were distinguished [13,14]. The complement-mediated AEs 159 were considered to be caused by aggregates in the product (‘spontaneous complement activation’ or 160 anti-complementary activity or ACA) or by in vivo formation of immune complexes (patient’s 161 condition related; e.g. subclinical infections or the unnoticed presence of anti-IgA antibodies) and 162 therefore only IgG concentrates with low or absent ACA is accepted by authorities for human use. 163 Below, we present one instructive case of each type of reaction. 164 165 166 3.1. The rapid onset of darkness – The immediate adverse events 167 168 The first reports of AEs concerned either the application of complement-activating fractions in an 169 IgG concentrate or the in vivo formation of complement-activating immune complexes [2-4]. A 170 very rare but potentially fatal condition is the formation of IgA/anti-IgA complexes in patients 171 being initiated on replacement therapy and having serum IgG antibodies against infused IgA not 172 recognized before the start of the IVIG infusion [15]. Prerequisite for the presence of anti-IgA 173 antibodies is the most common primary immunoglobulin defect, i.e. selective IgA deficiency 174 (sIgAD) or IgAD associated with diminution of other immunoglobulin classes. IgA deficiency is 175 defined by serum levels of <0.05 g/L or <0.07 g/L (depending on laboratories). A marked 176 diminution of serum IgA consistent with IgAD in various ethnic groups is estimated being 1:155 to 177 1:18,550 [16]. The mean frequency in Caucasians is approximately 1:700 [17]. Up to 40% of 178 patients with IgAD have been reported having anti-IgA antibodies in the serum with titers ranging 179 between 1:4 and 1:262,144. In approximately 10% of patients with common variable 180 immunodeficiency, and occasionally in patients with other primary immunodeficiency diseases 181 measurable anti-IgA can be detected [18,19]. These antibodies are predominantly of the IgG class, 182

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but anti-IgA antibodies of other immunoglobulin classes have been described as well [20,21]. The 183 reason for their emergence remains unknown. 184 185 Taken the above numbers the infusion of human derived products containing IgA resulting in severe 186 anaphylactoid type AEs should be considerable. This is not the case [22]. Questions about the 187 clinical relevance of above numbers emerge as soon as (i) blood banks estimate the theoretical risk 188 of IgA anapyhlactic reactions [15]; (ii) assess relation of severe IgAD with presence or absence of 189 anti-IgA antibodies [23]; (iii) screen donors for very low IgA levels in order to become able to 190 provide blood and plasma derived products free of IgA and find a considerably lower frequency 191 than expected [24]; (ii) when a more close look to ‘anti-IgA’ gives ‘unexpected’ results, including 192 ‘anti-IgA’ in blood donors with normal serum IgA level or ‘anti-IgA’ that cannot be neutralized 193 with purified IgA [25]; (iv) or when blood products containing proven anti-IgA do not elicit severe 194 AEs [26]. 195 196 Among patients on replacement therapy those with CVID may rarely develop severe AEs [15]. The 197 discrepancy between anti-IgA positive patients and frequency of AEs raises the question about the 198 nature of the many reported anti-IgA antibodies and also raises the question about the immunologic 199 condition which allows the formation of anaphylactoid anti-IgA antibodies. There might be some 200 logic in supposing, anaphylactoid anti-IgA cannot evolve at IgA levels otherwise fulfilling the 201 definition of IgAD. Such a condition would constantly generate immune complexes which in turn 202 could activate complement, react with immune cells and be deposited in lung and kidney. Indeed, 203 Horn et al. found anti-IgA antibodies in CVID patients missing IgA+ B cells and presenting with 204 IgA levels <0.0009 g/L, a level which is more than 50 to 70 fold lower than the threshold for IgAD 205 [27]. 206 207 The kinetics of anti-IgA after infusion of blood products have been studied in a few cases. In these 208 patients, a fall in anti-IgA titers has been noticed followed by an increase during subsequent weeks 209 or months. This suggests that at appropriate proportions, IgA of the infused material and anti-IgA 210 present in the patients’ serum combine with each other to form immune complexes, activate 211 complement, and are eliminated by macrophages. The increase in anti-IgA titers over time indicates 212 that the infused IgA-containing product has a booster effect [19,20,28]. Such boosting effect 213 together with the presence of anti-IgA before the application of an IgG concentrate can be taken as 214 the ultimate confirmation of a supposed IgA/anti-IgA (Fig. 4). 215 216 A non-complement-mediated anaphylactoid reaction was ascribed to the unforeseen release of 217 elastase and other pro-inflammatory substances from neutrophils activated by the formation of in 218 vivo IgA/anti-IgA complexes. Complement-activation or mast cell-dependent release of vasoactive 219 substances were excluded as pathogenic mechanisms. Although the IgA/anti-IgA complexes usually 220 do not cause clinically relevant neutrophil degranulation within the circulation, the presence of a 221 rare genotype encoding a novel gain-of-function IgG receptor on neutrophils may provoke 222 premature degranulation by these complexes. This phenomenon was only relevant in 223 hypogammaglobulinemic patients in the presence of in vivo IgA/anti-IgA complexes [29]. The low 224 prevalence of this genotype combined with an IgAD or CVID may explain the rarity of serious 225 anaphylactoid reactions in newly IVIG-treated patients. 226 227 228 3.2. Insight into the phlogiston of the dark – The pro-inflammatory cytokines 229 230 In the early days of Ig-therapy the nature of the ‘phlogistic’ AEs was obscure. However, it was 231 already known that initial sings of AE can be overcome when the patient receives a dose of IVIG 232 his immune system can cope with, than infusion is stopped for several hours, where after infusion 233

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can be restarted at high rates without further problems (Fig. 5). One of the authors had a particular 234 opportunity to get an insight into what a “phlogistic reaction” might be. At the occasion of a 235 voluntary infusion of an investigational liquid IVIG, he encountered a severe flu-like AE of more 236 than 12 hours duration. Before injection, the investigational liquid preparation had passed all release 237 criteria for human use, including spontaneous complement activation assessed by ACA and was 238 free of prekallikrein activator. In those days assays for cytokines in biological samples just began to 239 become available and were included into the parameters assessed in the study. Infusion was stopped 240 after one hour because of a drop of pulse rate and heavy discomfort provoking the laconic comment 241 by the proband’s chief technician who was taking samples: “you look green”. The infusion was 242 continued after another 90 minutes when the heart rate had almost normalized. The infusion could 243 be completed within an additional 3.25 hours (0.4g/kg b.w.) without further aggravation of malaise. 244 The leukocyte count transiently had dropped to a nadir of 40% at 2 hours followed by a 245 leukocytosis peaks at 8 hours. Complement activation, as assessed by generation of 246 C3a/C3a[desArg] and the formation of the terminal complement complex C5b-9, apparently did not 247 occur: the C3a/C3a[desArg] value reached a maximum of 260 ng/mL (norm: <200 ng/mL) at 7 248 hours while the C5b-9 value never moved outside the normal range. Instead, a sequence of rapid 249 transient massive increases of pro-inflammatory cytokines was seen: (i) TNF� started to increase 250 30 min post initiation of infusion from a value of 20 pg/mL to a peak value at two hours which was 251 above the calibration range of the test kit of 1500 pg/mL; (ii) IL-8 increase started after 1 hour from 252 29 pg/mL and peaked at 2.5 hours with 4400 pg/mL post initiation of infusion; (iii) IL-6 secretion 253 started after 1 hour with an undetectable level and peaked at 4 hours with 345 pg/mL. All pro-254 inflammatory cytokines fell sharply while the second part of the infusion was still ongoing. The day 255 after infusion, the pro-inflammatory cytokine profiles were back to normal and the flu-like 256 syndrome was gone. In contrast, IL-1ra values started increasing at 1.5 hours (300pg/mL), peaked at 257 4 hours (>32000 pg/mL) and decreased slowly to reach a value of 10500 pg/mL 24 hours after 258 initiation of the infusion. 259 260 A series of further experiments with investigational and marketed IVIGs was performed. All IgG 261 concentrates were analyzed for their molecular weight (MW) distribution. The most remarkable 262 differences emerged in the MW range of dimers while the presence of minute amounts of higher 263 oligomers could not be excluded with certainty. Below we will use the term ‘dimers’ for that 264 fraction of IgG with higher MW. Subsequent findings indicated that levels of ‘dimers’ >12% were 265 responsible for complement-independent cell activation and cytokine release. The TNF peaks 266 assessed at 2.5 hours post initiation of infusions correlated with ’dimer’ content of the IVIGs and 267 mirrored a clinical score of AEs [30-32]. 268 269 A few years before a complement-independent induction of a hypotensive factor by IgG di- and 270 oligomers was reported in animal experiments [33]. A key role for macrophages in the generation of 271 the hypotensive lipid factor was identified as platelet-activating factor, being induced by dimers and 272 polymers [34,35]. Several years later, the dimer-mediated AEs in animal experiments were 273 confirmed [36,37]. Yet, at the same time, the dimer content of IVIG apparently correlated with the 274 clinical efficacy in a murine ITP model [38,39]. Variables such as ‘infusion rate’, ‘genetic 275 background’, ‘endogenous immunoglobulin levels’, or ‘proportional fraction of polymers versus 276 dimers’ may impact on the balance between the phlogiston (being cytokines, active lipid 277 substances, or a combination of factors) and the therapeutic efficacy (blocking IgG receptors on 278 liver/spleen macrophages to prevent clearance of ‘opsonized’ material such as platelets in ITP). As 279 of today, reports on release of cytokines in humans in association with AEs or tolerability toward 280 dimers remain scarce and to the best of our knowledge studies in humans of causative 281 factors/fraction in an IgG concentrate has not been adequately addressed [40-43]. 282 283

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In IgG preparations, various forms of dimers might be present: formed through covalent binding 284 [44] by denaturation, hydrophobic interactions of the Fc-parts and by idiotype/anti-idiotype 285 interactions, as part of the V-connected network of peripheral immune homeostasis [45]. For a 286 commercially viable fractionation process, pooling of donated plasma is mandatory in order to 287 obtain a volume of starting material large enough to cover ever increasing costs for documentation, 288 in-process and batch-release testing as it is required by cGMP. Pooling also intends to smoothing 289 the batch-to-batch differences in antibody titres, a goal apparently difficult to achieve to levels as 290 theory might imply [46]. Consequences of pooling are on the one hand an enrichment of 291 public/common immune antibodies while diluting out individual specificities; on the other hand, the 292 antibodies of the immune network of an individual donor are exposed to those of many other 293 donors. The more individuals contribute to the pool, the more complex the possible ‘immune-294 network’ interactions will become. The subsequent fractionation process has far-reaching effects on 295 immunoglobulins from a given pool: only trace amounts of IgA and IgM are retained in the final 296 product, i.e. IgG is deprived of its counterparts of the V-connected immune network. The ‘naked’ 297 IgG molecules of the homeostatic network can interact with each other at a ’random combining site-298 interactions of single donor-derived monomeric IgG’ [47], otherwise not existing in vivo. This 299 interaction is largely reversible. With increasing numbers of donors included into the pool, the 300 immune network recognition among the ‘naked’ IgG molecules of the V-connected network 301 becomes more and more complex, and the dimer and lower oligomer content in the resulting IgG 302 concentrate increases [48-50]. In lyophilized IgG concentrates, the dimer formation is ‘frozen’ at a 303 low level while in liquid preparations an equilibrium between monomers and dimers is achieved 304 over time reaching a dimer content of 12% or more if not hampered by stabilizers. Specificities, as 305 far as they have been addressed, in the dimer fraction considerably differ from the monomeric 306 fraction [51-55]. In conclusion, the immunomodulatory efficacy of IgG concentrates in part depends 307 on the capacity and extent to form ‘dimer’ fractions devoid of remarkable complement activation in 308 vivo. The ‘art’ of manufacturing a liquid IgG concentrate is not to eliminate the monomeric IgG 309 having potential for ‘dimer’ formation but to inhibit extensive ‘dimerization’. In summary, AEs 310 might be associated with the induction of pro-inflammatory cytokines in absence of measurable 311 complement activation in vivo where all regulatory mechanisms and removal processes of a body 312 are at disposition. At reasonable infusion rates in the open system of the human body, clinically 313 relevant systemic complement activation apparently needs oligomers formed of three or more IgG 314 molecules. 315 316 317 4. The missing oxygen on the dark side - Immunoglobulin-induced hemolysis 318 319 There are multiple reports of Ig-induced hemolytic anemia (HA) in patients receiving high doses of 320 IVIG [56-91] (Table 2 and Fig.6; (www.adrreports.eu). By spontaneous reporting, risk factors 321 recognized for Ig-induced hemolysis include beside high doses (more than 100 g IVIG over 2-4 322 days), female gender and histo-blood group type A, B or AB of recipients. 323 324 A significant proportion of patients receiving IVIG develop a positive direct antiglobulin test 325 (DAT) detectable after 24 hours for up to 10 days after the IVIG infusion [92,93]. However, it 326 should be underlined that the DAT positivity due to the factors mentioned above [94-95] is not 327 sufficient per se to diagnose hemolysis and DAT positivity does not necessarily imply the presence 328 of active hemolysis. DAT-positive mild hemolytic reactions can be easily missed and the true 329 incidence of such reactions is difficult to document without careful clinical and laboratory follow-330 up. 331 332

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In the majority of reports on HA, intravascular RBC destruction via complement activation or 333 extravascular RBC sequestration and removal by the reticulo-endothelial system was proposed to 334 result from IgG alloantibodies with specificity for RBC antigens A, B, D or C. 335 HA induced by high-dose IVIG has an average incidence of 5.8% [96]. Low dose IgG replacement 336 therapy is considered universally as safe, and only few cases of hemolysis following low-dose IVIG 337 SCIG administration have been described [63,78,93]. A baseline white and red blood cell count 338 prior to IVIG initiation and a close clinical and laboratory follow up was suggested as a useful tool 339 for early diagnosis and treatment. A possible work up might be to check hemoglobin (Hb) level 340 prior and 48-78 hours after Ig infusion. In case of a drop of Hb, the presence of DAT, an increase in 341 unconjugated bilirubin, lactate dehydrogenase (LDH), and reduced haptoglobin level, followed by a 342 rise in reticulocyte count should be assessed (Fig.7). We systematically reviewed case reports 343 related to IVIG-induced hemolysis from 1987 to 2014 and identified 29 articles containing reports 344 of 109 patients. Baseline characteristics of the patients are shown in Table 2. When available, blood 345 group, DAT, Hb drop and outcome are indicated. All reports showed positive DAT, except for a 346 case of Yin et al [59]; in this case, DAT was performed 10 days after IVIG administration and the 347 DAT negativity might have been due to a rapid removal of sensitized RBCs. 348 349 In the majority of patients, the outcome was positive: 106 out of 109 patients recovered with or 350 without packed RBC transfusions; three patients died after HA, with the hemolytic episode 351 representing a precipitating factor of a severe underlying condition. Elution experiments were 352 performed and the search for blood group antibodies revealed anti-A and anti-B specificity in the 353 majority of cases; anti-D specificity was assessed in 4 reports, often associated with other 354 specificities [78,89,93]. A search for other specificities such as anti-band 3 or anti-Gal was not 355 performed. Only one report detected anti-C specificity in three patients; in one of them associated 356 with anti-D irregular antibodies [93]. Although studies were restricted to blood group antibodies, 357 this finding demonstrated that polyvalent IgG preparations might contain clinically significant non-358 blood group antibodies, which are not part of the lot-release criteria in that their titration is not yet 359 required by the European Pharmacopoeia. Antibodies in HA such as anti-C may have unexpected 360 hemolytic consequences [97-101]. Beside passive transfer of alloantibodies, IgG administration 361 also has been demonstrated to lead to unspecific enhanced erythrocyte sequestration, in particular in 362 patients with underlying inflammatory disorders [102-103]. In 2009, the Canadian IVIG hemolysis 363 Pharmacovigilance group elaborated criteria to define an ‘IVIG-induced hemolysis’ [66]. They 364 included a reduction of Hb levels ≥ 1 g within 10 days after Ig administration, with appearance of a 365 positive DAT and, at least, two of the following criteria: increase in the reticulocyte count, elevation 366 of lactate dehydrogenase (LDH) and unconjugated bilirubin serum levels, low haptoglobin, 367 hemoglobinuria, hemoglobinemia, presence of significant spherocytosis, in the absence of 368 alternative causes of anemia. The passive transfer of IgG alloantibodies through IgG concentrates is 369 difficult to explain as polyvalent IgG is prepared from plasma of thousands of donors. Since 370 immunization to RBC alloantigens can occur because of past transfusions or pregnancy, the 371 hypothetical numbers of alloimmunized plasma donors should be rather low. Recently, other 372 mechanisms underlying alloimmunization related to molecular mimicry have been demonstrated 373 [104]. The mechanism of high-dose IVIG-induced HA is complex and it might vary from patient to 374 patient. IVIG cause hemolysis due to: (i) disease-associated pre-coating of RBCs; (ii) IgG with 375 hemolysis triggered by passive transfer of IgG binding to blood group antigens; (ii) transfer of high 376 levels of alloantibodies to RBC pre-coated at a low level only; or (iv) transfer of clinically tolerable 377 levels of isoagglutinins plus transfer of additional RBC-reacting physiological autoantibodies. 378 Indeed, hemolytic reactions could not be related exclusively to transfer of alloantibodies. Hence, 379 antibodies other than histo-blood group alloantibodies (pre-)coated to RBCs might contribute to 380 hemolysis in IgG recipients need to be identified. In addition, hemolytic episodes may possibly be 381 precipitated by some sort of complexed/denatured IgG that co-purify with other IgG in the product 382 [58,102,103,105]. Recently, a two hit mechanism for IVIG-induced hemolysis has been proposed: 383

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the passive transfer of alloantibodies through IVIG representing the first hit and the underlying 384 inflammatory state representing the second hit. [106]. Nowadays, all commercial Ig products have 385 to undergo anti-A and anti-B testing and regulatory requirement ask for respective IgG antibody 386 titers of ≤1:64 at 5% solution strength (w/v) [86,87]. Nevertheless, hemolysis might occur even in 387 recipients of IgG products that meet these specifications [58]. Consequently, it has been suggested 388 that IgG recipients should be monitored for clinical signs and symptoms of hemolysis [107]. 389 390 391 4.1. Reasoning in the dark about the consequences of the struggle to stay on the sunny side – 392 Measures to overcome elevated frequencies of hemolysis. 393 394 With the detection of the immunomodulatory potential of IgG concentrates, their clinical use has 395 continuously increased [108]. To cover the need, at a first glance, an increase of the volume of 396 plasma fractionated seems to be the most convenient option. However, this might economically not 397 be viable because plasma products are interconnected [109] and before increasing output of one 398 product (e.g. IVIG) the market absorbance of the other products as well (e.g. albumin) must be 399 ascertained. On a longer-run, a more viable option is to improve recovery. Considering recovery, 400 the cold ethanol fractionation apparently has reached its limits. As of today, four manufactures have 401 invested into a ‘modern’ fractioning technique on the basis of ion-exchange chromatography. Ion-402 exchange chromatography allows elevated recovery at high purity. As of today, five IVIGs, one 403 SCIG and one anti-D concentrate are fractionated by ion-exchange chromatography. 404 Pharmacovigilance has shown that all of them, more or less prominently, show a tendency for 405 elevated frequencies of hemolytic AEs. Anti-A and anti-B alloantibody titers are now lot release 406 criteria (see above) as they constitute the major risk parameter for hemolytic reactions mediated by 407 IgG concentrates. To stay on the sunny side, two manufacturers have taken measures to reduce anti-408 A and anti–B titers in their IgG products. One measure chosen was adsorption of the alloantibodies 409 by affinity chromatography [110]. Reported reduction in both alloantibodies was significant and 410 levels were similar to those in cold-ethanol fractionated immunoglobulins [111]. The other measure 411 chosen was reduction in anti-A using an automated indirect agglutination test for donor screening 412 and exclusion of high-titre donations (approx. 5.1%) from plasma pooling and fractionation [112]. 413 This measure reduced anti-A in the IgG concentrate by one titer step. To ensure staying on the safe 414 and sunny side, the manufacturer has announced the introduction of an alloanti-A and alloanti-B 415 immune-affinity chromatography step into the manufacturing process [113]. Preliminary results 416 indicate depletion in anti-A and anti-B by >80% in investigational lots. Subsequently we want to 417 discuss possible consequences of (extensive) removal of antibodies reacting with histo-blood group 418 antigens A and B. 419 420 421 4.1.1. Struggling to stay on the sunny side – Reduction of histo-blood group A and B 422 alloantibodies in IgG concentrates 423 424 Three facts have initiated our thinking about possible consequences of removal of histo-blood group 425 A and B reacting antibodies from IgG concentrates. (I) in collaboration with Hans U. Lutz, formerly 426 Biochemistry ETH Zurich, we have observed the non-intended removal of natural anti-C3 427 autoantibodies regulating complement activation by large-scale immune-affinity adsorption of IgA 428 from an IgG concentrate [114]. Anti-C3 antibodies belong to the family of ‘natural antibodies’ 429 (NAbs) and have a particular role in homeostasis: they control activation of complement, among 430 others, in the frame of NAb-mediated opsono-phagocytosis of altered or senescent cells, including 431 RBCs [115-117]. Thus, the intention to target one particular antibody by affinity chromatography 432 might reduce that antibody specificity but at the same time affect other specificities as well. (II) it 433 should be kept in mind that the blood groups A and B are in fact ‘histo-blood group’ antigens, i.e. 434

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they are also found on white blood cells, T lymphocytes and proteins and also can be found in 435 soluble form [118]. Alloantibodies reacting with histo-blood group antigens A and B thus have 436 much broader tissue recognition than RBCs only. In addition, alloanti-A and alloanti-B belong to 437 the population of NAbs recognizing non-self and most likely participate in primary host defense 438 [119]. (III) in contrast to cold-ethanol fractionation, where low titers of alloanti-A and alloanti-B 439 are achieved on basis of their isoelectric points (IEPs), the (extensive) immune affinity removal 440 might affect a much wider IEP range, thereby removing broadly reacting antibodies and impairing 441 some desirable functions of the IgG concentrate. 442 443 444 4.1.2. Possible consequences of the struggle to stay on the sunny side - Antibodies reacting 445 with the terminal di- tri- and tetra-saccharides of histo-blood group antigens A and B 446 447 Histo-blood group A and B epitopes in terminal position are tetrasaccharides. Alloantibodies to 448 these tetra-saccharides are found in plasma of healthy individuals depending on the blood group 449 they have. Research of antibodies other than the alloantibodies reacting with ‘blood group’ A or B 450 has been performed using the corresponding terminal di- or tetra-saccharides for isolation [120-451 122]. The antibodies reacting with terminal di-, tri- and tetra-saccharides of histo-blood groups A 452 and B belong to the large family of human natural anti-glycan immunoglobulins (anti-glycan 453 NAbs). Recently, the repertoire and epitope specificity of such immunoglobulins was addressed in 454 depth [123,124]. It proved that serum of healthy individuals contain respectable amounts of di- or 455 tri-saccharide-reacting NAbs. These pseudo-anti-A and pseudo-anti-B NAbs are not reacting with 456 the tetra-saccharide of histo-blood groups A and B. In contrast alloanti-A and –B antibodies able to 457 react with tetrasaccharides are reacting with corresponding terminal di- and tri-saccharides as well. 458 Understanding the biological role of these ‘high-titer and population conservative’ anti-glycan 459 NAbs needs further investigations and those reacting with histo-blood group A- and B-like 460 structures are of particular interest. A population of the anti-glycan NAbs are the anti-αGal NAbs 461 which recognize Galα1-3Gal and Galα1-3(Fucα1-2)Gal epitopes. Anti-αGal NAbs have been 462 described being xenoreactive, recognizing bacterial Galα1-3Gal [125] and having tissue 463 homeostatic function. The daily removal of altered/senescent cells of the body is ~1012. Removal is 464 mainly mediated by apoptosis (no inflammation, no necrosis). Removal of RBCs with a daily 465 turnover of ~2 x 1011, corresponding to ~20 g cell mass, is effectuated in absence of apoptosis 466 because of the missing nuclei. Instead, in parallel of their age, RBC encounter increasing 467 cumulative oxidative stress, which causes increased exposure of otherwise cryptic structures such as 468 spectrin, band 3 or αGal epitopes. These exposed structures are recognized by low affinity, high 469 avidity NAbs, which promote their efficient removal of RBCs [126]. Immunoaffinity adsorption of 470 Gal by trisaccharides might have a Janus effect. Directing to the sunny side of the moon, 471 adsorbing Gal NAbs reacting with altered and senescent self on RBC might prevent an increase in 472 the IgG load of RBCs of individuals with inflammatory diseases eventually facilitating hemolysis. 473 Directing to the dark side of the moon, such adsorption of tissue homeostatic antibodies might 474 deprive an IgG concentrate of beneficial antibodies relevant for some infectious diseases. 475 When choosing affinity resins for immunoadsorption, there might be another aspect of impact on 476 IgG concentrate worth to consider. Although they are NAbs, alloanti-A and –B antibodies can be 477 induced by feeding bacteria bearing the corresponding carbohydrate epitopes [119] and are 478 considered to participate in primary host-defence. A complete removal by immunoaffinity might 479 influence some effector function of an IgG concentrate. Other antibodies possibly involved in 480 primary host defense are the anti-Gal NAbs. They show a broad specificity and can react with a 481 number of related αGal-terminated oligosaccharides, including those on bacteria [127]. Again, 482 immunoadsorption might diminish the potential of an IgG concentrate to mediate primary host 483 defense. 484 485

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In summary, the principles of avoiding co-fractionation through cold-ethanol fractionation [128] 486 versus immune-affinity removal of histo-blood group alloantibodies can have an impact on the 487 presence of homeostatic and first-line defense antibodies. According to present knowledge, only 488 resins coated with the corresponding tetra-saccharides can ascertain the selective removal of histo-489 blood group alloantibodies presumably involved in HA. Resins coated with the corresponding di- 490 and tri-saccharides might also remove blood group alloantibodies, however not selectively. Such 491 resins in addition might remove a broad range of NAbs present in IgG concentrates at relative high 492 amounts. In the literature, the use of tri-saccharide coated resin was reported [129-131]. We have 493 found no information available in the public domain indicating which type of resin is/will be used 494 for reduction of the histo-blood group alloantibodies in large scale fractionation of IgG. 495 Furthermore, we suggest that the effect of reduction of anti-A and ant-B reacting antibodies by 496 immune-affinity on the antibody repertoire of IgG concentrates can only be assessed by e.g. using 497 pathogens/commensals, which share the saccharide epitopes, that have been used to coat the affinity 498 resins or alternatively by exposing senescent RBCs stripped off the IgGs coated in vivo. Finally, 499 techniques are required, which allow detection of low affinity, high avidity NAbs. 500 501 502 5. Falling deep into a dark lunar crater – Thrombosis 503 504 IVIG-administration related AEs, including thrombosis, have been extensively described [132]. 505 Thrombotic AEs are severe AEs and patients with risk factors require a special care. Reported 506 average incidence of IVIG induced thrombosis ranges from 3 to 13% [133]. Recognized risk factors 507 for IVIG-induced thrombosis include male gender; age > 60; diabetes; renal insufficiency, 508 dyslipidemia; hypertension; immobility; coronary disease; pre-existing vascular disease, family 509 history of early thromboembolic disease; atrial fibrillation, high-dose and high-speed IVIG 510 infusions. IVIG-induced thrombosis is reported both as venous events such as thrombosis stroke, 511 pulmonary embolism (PE), deep venous thrombosis (DVT) and arterial ischemia events such as 512 myocardial infarct and stroke. The mechanisms leading to IVIG-associated thrombosis are still not 513 completely clear; three main mechanisms have been proposed, emphasizing the role of an increased 514 blood viscosity causing a hypercoagulable state [134], the role of anticardiolipin antibodies 515 passively transferred through IVIG [135] and the role of factor XIa or other biologically highly 516 active factors passively transferred via IgG concentrates, such as PKA. Avoiding activated 517 coagulation factors in IgG concentrates starts with appropriate anticoagulation of donated 518 blood/plasma, i.e. careful mixing of anticoagulant and sample over the whole donation process. 519 Alterations in an established manufacturing process neglecting appropriate controls can also lead to 520 increased risk of transmission of activated coagulation factors. High molecular weight proteins 521 passively transferred by IVIG are probably responsible for this phenomenon [136]. In patients with 522 other risk factors, such as vascular disease, this increase in blood viscosity can precipitate 523 thromboembolic events. As elderly individuals are prone for such AEs, we like to point to the 524 possibility of elevated altered/senescent self-reacting with infused homeostatic NAbs being a 525 possible factor facilitating thrombotic events. A relationship between IVIG administration and 526 cerebral vasospasm has also been suggested by Sztajzel et al [137]; blood viscosity is a determinant 527 for oxygen delivery to the tissues, and changes in viscosity can lead to a reduction in cerebral or 528 myocardial perfusion. 529 530 We systematically reviewed case reports related to IVIG-induced thrombosis from 1986 to 2014 531 (Fig. 8). Literature search identified 35 articles containing reports concerning 65 patients [133,138-532 168]. When data were available, diagnosis, risk factors, the number of IVIG infusion prior to 533 thrombosis event and outcome have been indicated. Baseline characteristics of the patients are 534 shown in Table 3. High-dose IVIG induced thromboembolic events in 59 patients low to medium 535 IVIG doses. Mary et al. observed that the frequency and type of arterial events was inversely related 536

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to the time elapsed from IVIG infusion; almost 50% (23 vs 21 reports) of arterial ischemic events 537 occurred in 12 hours following IVIG, while about 75% of venous thrombosis occurred after more 538 than 24 hours. No correlation between number of infusions and occurrence of adverse event was 539 observed. The main risk factors observed in this review were hypertension (19 cases, 33% of 540 prevalence), previous vascular disease (18%), and dyslipidemia (17%). Average mortality for 541 thrombotic events was 10% (arterial ischemia 9% vs venous thrombosis 11%, pulmonary embolism 542 representing the main venous fatal event). Predicting IVIG induced thrombosis is difficult. Risk 543 factors should be assessed for each patient including instrumental exams when needed. Doppler 544 ultrasound can be useful as early diagnostic tool for thrombosis or to detect the presence of 545 abnormal blood flow especially after prolonged immobility. IVIG should be administered at low 546 infusion rate to reduce the risk. The administration of antiplatelet or anticoagulant prophylaxis was 547 suggested in patients with several risk factors [147]. However, thrombotic events have been 548 reported even after several previous uncomplicated courses of treatment. In such cases, patients 549 should be examined for signs and symptoms of thrombosis during each courses of IVIG. 550 551 IgG concentrates are widely acknowledged to offer a safe, high-dose, long-term therapy option for a 552 variety of diseases. Adverse events occur rarely and mainly are mild to moderate. Deviations from 553 this rule of thumb are addressed by authorities and the plasma fractionation industry to achieve 554 corrections. Above we have reviewed two types of AE which have shown elevated frequency in the 555 near past. We tried to give some insights which might help in reducing frequencies of AEs bed side. 556 557 558 Acknowledgments 559 560 Authors are deeply grateful to Hans-Hartmut Peter, Freiburg, Germany, for his careful reading of 561 the manuscript, the valuable comments and the correction of English. 562

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Legends to the figures 564 565 Figure 1: Provoking the dark. Administration of an IgG concentrate inevitably results in the 566 interactions of the exogenous IgG with the various parts of the immune system of the recipient and 567 vice versa. The rate of increase over time of exogenous IgG in the circulation of the recipient is a 568 key parameter for intensity of these interactions and eventual AEs. IgG in the circulation over 569 time (insert) is dependent on infusion rate together with the strength of the solution applied and 570 the mode of application, i.e. intravenous (solid and dashed line) or subcutaneous (dashed-dotted 571 line). From the patient’s side the threshold for a clinically noticeable AE (dotted line) might depend 572 on factors such as levels of primed cells, the efficiency of control mechanism and the metabolism of 573 e.g. mediators of inflammation. Although the area under the curve of generated e.g. complement 574 activation products and/or pro-inflammatory mediators might be the same for low (dashed line) and 575 high (solid line) infusion rates, at high infusion rate, the system might be not be able to cope with 576 the acute onset of reactions. At low infusion rates (dashed line) all the events might remain below 577 the threshold of clinically observable AE. Indeed, in several dozen of infusions using a marketed 578 IVIG in all cases except one, a more or less pronounced increase of TNF was measured at 2.5 579 hours post initiation of infusion. The only person in the cohort not showing a measurable TNF 580 increase was a woman caring at home for her brother to with full blown AIDS [170]. 581 Subcutaneously applied IgG concentrate reaches the circulation slowly (dashed-dotted line) and 582 systemic AEs are less frequent than with IVIG but they are not absent [171-177] (the case of 583 inappropriate use of SCIG is not considered). In contrast local mild to moderate AEs are more 584 frequent with SCIG [178]. 585 586 Figure 2: Staying within a network is helpful for staying at the sunny side of the moon - from 587 blood/plasma collection to blood/plasma products. Handling of blood/plasma products to obtain 588 therapeutic goods has to be performed within a regulatory framework. Manufacturing of stable 589 blood product has strictly to adhere to current Good Manufacturing Practice (cGMP). Not following 590 cGMP can lead to withdraw of a plasma product from the market from one to the other day. At 591 collection of blood/plasma screening for high titre anti-A has been introduced for one IgG 592 concentrate [112]. 593 594 Figure 3: Active measures to stay on the sunny side of the moon - possible sites for introducing 595 validated pathogen reduction and/or inactivation measures (*) along the various fractionation 596 methods. One manufacturer has already introduced an immunoaffinity chromatographic step to 597 reduce anti-A and anti-B titres in its product and another manufacturer has announced the 598 introduction of such a step to its manufacturing process [110-113] 599 600 Figure 4: An individual’s slithering into the dark. A female patient has been suffering from 601 recurrent airway infections since adolescence, occasionally complicated by pneumonia. At age 34, 602 selective IgA deficiency was diagnosed. Ten years later, she was hospitalized with pneumonia. 603 Within these 10 years her serum IgG had dropped from 7 g/L to 0.87 g/L (dashed line) and IgA was 604 undetectable. The diagnosis was changed into CVID, and IVIG replacement therapy was initiated. 605 Events on the day of infusion between 8:38 a.m. and 8:30 p.m. were as follows: two minutes after 606 the start of the infusion, having received 8 drops of a 3% IgG solution (IgA <1.2 g/L; 3% solution), 607 she experienced a flush, back pain, rigors, difficulty in breathing, and hypotension. The infusion 608 was immediately stopped. After approximately one hour the reaction has weaned, and two hours 609 later the patient felt well again, and the infusion of total 6 g IgG could be continued without further 610 complications. The patient repeatedly assured having never received any blood or plasma products 611 in the past. Notwithstanding, a serum sample drawn before the initiation of the infusion 612 demonstrated the presence of anti-IgA (full line). The follow-up of anti-IgA titers confirmed a true 613 anaphylactoid reaction mediated by anti-IgA, as the anti-IgA became undetectable immediately 614

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after the infusion and showed a rebound phenomenon after one month. True anaphylactoid reaction 615 was also confirmed by follow-up of total complement hemolytic activity (CH50) on the day of 616 infusion (dashed-dotted line). Interestingly enough the CH50 value reached its nadir at the end of 617 the infusion when the patient had no complains. 618 619 Figure 5: Clinical signs of the ‘phlogiston’ of the dark. A CVID patient received his firs infusion of 620 IVIG (a 3% solution). Despite the start of the infusion at an infusion rate (IR) of only 10 drops per 621 min which was incrementally increased by 5 drops all 30 min, rise of heart rate (HR, Panel A), and 622 of body temperature (BT, Panel B) after 2 hours of the initiation of infusion indicated the onset of a 623 ‘phlogistic’ reaction and infusion was stopped. Stop of the infusion for 30 min immediately let drop 624 HR and BT. Restarting the infusion showed some negative effect. The first day a total of 9 g IgG 625 was infused. The next day the rapid infusion of additional 9g of IgG was without consequence on 626 BT and HR, indicating silencing of cells releasing mediators of inflammation. 627 628 Figure 6. The missing oxygen on the dark side: Ig-induced hemolysis in patients on Ig treatment. 629 Black bars indicate the number of patients with a given clinical condition 630 631 Figure 7. Monitoring for evidence for oxygen missing at the dark side. Diagnostic algorithm for Ig-632 induced hemolysis according to criteria elaborated by the Canadian Group [66]. 633 634 Figure 8. Falling deep into a dark lunar crater while being on Ig treatment. Black bars indicate the 635 number of patients with a given clinical condition and Ig-mediated thrombosis. 636

637

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