key: cord-0721509-k3rgqwrj
authors: Bonadonna, Patrizia; Brockow, Knut; Niedoszytko, Marek; Elberink, Hanneke Oude; Akin, Cem; Nedoszytko, Boguslaw; Butterfield, Joseph H.; Alvarez-Twose, Ivan; Sotlar, Karl; Schwaab, Juliana; Jawhar, Mohamad; Castells, Mariana; Sperr, Wolfgang R.; Hermine, Olivier; Gotlib, Jason; Zanotti, Roberta; Reiter, Andreas; Broesby-Olsen, Sigurd; Bindslev-Jensen, Carsten; Schwartz, Lawrence B.; Horny, Hans-Peter; Radia, Deepti; Triggiani, Massimo; Sabato, Vito; Carter, Melody C.; Siebenhaar, Frank; Orfao, Alberto; Grattan, Clive; Metcalfe, Dean D.; Arock, Michel; Gulen, Theo; Hartmann, Karin; Valent, Peter
title: COVID-19 vaccination in mastocytosis: recommendations of the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM)
date: 2021-04-05
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2021.03.041
sha: 954f9a539b767fa13988d34e4547ff708a51a858
doc_id: 721509
cord_uid: k3rgqwrj

Mastocytosis is a neoplasm characterized by an accumulation of mast cells in various organs and increased risk for severe anaphylaxis in patients with concomitant allergies. Covid-19 is a pandemic that is associated with a relatively high rate of severe lung disease and mortality. The mortality is particularly high in those with certain comorbidities and increases with age. Recently, several companies have developed an effective vaccination against Covid-19. Although the reported frequency of severe side effects is low, there is an emerging discussion about the safety of Covid-19 vaccination in patients with severe allergies and mastocytosis. However, even in these patients, severe adverse reactions are rare. We therefore recommend the broad use of Covid-19 vaccination in patients with mastocytosis on a global basis. The only well-established exception is a known or suspected allergy against a constituent of the vaccine. Safety measures, including premedication and post-vaccination observation should be considered in all patients with mastocytosis, depending on the individual personal risk and overall situation in each case. The current article provides a summary of published data, observations and expert opinion that form the basis of these recommendations.

Introduction 100 Mastocytosis is a disease that is characterized by abnormal expansion and accumulation of 101 mast cells in i) the skin, ii) in internal organs, or iii) in both the skin and internal organs. As a result, 102 mastocytosis is diagnosed on the basis of a histologically confirmed increase and accumulation of 103 mast cells in these organs ((1),(2)). In general, mastocytosis can be divided into cutaneous 104 mastocytosis (CM) and systemic mastocytosis (SM). In patients with CM, mast cell accumulation is 105 only or primarily found in the skin. To diagnose CM, a biopsy of affected skin is often performed. The 106 pure cutaneous form of mastocytosis is usually diagnosed in (early) childhood. By contrast, most 107 patients in adulthood are diagnosed to have SM ((1), (3), (4)). 108

Symptoms of mastocytosis can result from biologically active mediators that are released 109 from mast cells (mediator-related symptoms) or from a malignant local infiltration and expansion of 110 neoplastic mast cells in various organ systems. Mast cells produce and release a large number of 111 biologically active mediators, including vasoactive mediators, coaguloactive substances, and 112 immunoregulatory molecules, such as histamine, heparin, tryptases, prostaglandins, cytokines or 113 chemokines ((2), (5), (6)). These mediators can cause a variety of symptoms, including headache, 114 fatigue, bone pain, nausea, itching, urticaria, flushing, diarrhea, abdominal discomfort and cramping, 115 hypotension, up to severe anaphylaxis with shock. Symptoms can occur in any variant of 116 mastocytosis and at any time during the course of disease ((2), (7), (8)). Patients with mastocytosis 117 are prone to recurrent severe anaphylactic reactions especially to hymenoptera venom, with an 118 incidence being much higher than in the general population ((9), (10), (11)). Fatal anaphylaxis has 119 also been described in these patients, especially after discontinuing allergen-specific immunotherapy 120 ((12)). Severe anaphylactic reactions to other triggers such as foods (3-16% of cases) and drugs (5-121 9%), have also been reported, although allergy testing may show negative results in these cases ((13), 122 (14) , (15), (16), (17), (18), (19), (20)). 123

The COVID-19 pandemic infection caused by SARS-CoV2 virus in 2019 was described first in 124

Wuhan, China and developed into a global pandemic in 2020 with a case fatality rate of up to 3.5% in 125

Europe and 1.7% in the US ( (21)). The fact that certain comorbidities confer a higher risk for a severe 126 course have raised fears and concerns also in patients with MC disorders and their physicians. 127

Initiative in Mast Cell Diseases (AIM) have recently issued an expert opinion on the risk and 129 management of patients with mastocytosis in the COVID pandemic ( (22)). Although solid data on 130 which to base recommendations are not yet available, based on their experience with CM/SM and 131 other hematologic neoplasms, and the biology of SARS-CoV-2, the experts confirmed that there is yet 132 no reason to believe that patients with mastocytosis or MCAS have a higher risk to acquire a SARS-133 J o u r n a l P r e -p r o o f CoV-2 infection. Some of these patients may even live in more or less social isolation and avoid public 134 meetings and crowded places, reducing their risk of infection compared with the general population. 135 This is supported by a study on the impact of SARS-CoV-2 infection on mastocytosis, in which 28 136 patients did neither have increased COVID-19 mortality nor clinical symptoms of MC activation. ((23)) 137

Therefore, in those with CM and ISM the risk may be comparable to those without mastocytosis, and 138 may be more dependent on other co-existing risk factors such as age, obesity, and cardiovascular 139 disease ((22)). However, in patients with advanced SM (aggressive SM, SM with an associated 140 hematologic neoplasm, or MC leukemia), the risk may be increased because these patients may have 141 an impaired immune system that is further suppressed by some antineoplastic drugs such as 142 cladribine or glucocorticoids, whereas no (further) immunosuppression is introduced by the KIT-143 targeting drugs used in advanced SM. There is no evidence to suggest that antiviral drugs and drugs 144 used to treat SARS-CoV-2 infection induce or aggravate MC activation in patients with allergies, 145 patients with mastocytosis ((24)). 146

The cooperation between the scientific community and the pharmaceutical industry has 147 resulted in the fast development of many vaccines with different mechanisms of action, which 148 stimulate the immune system and protect from the potentially deadly COVID-19 infection ((25), (26), 149 (27), (28)). The first months of the vaccination with currently approved vaccines (primarily using 150 mRNA based technologies) resulted in several reports of severe allergic reactions including 151 anaphylaxis ((26), (29)). These reports led to a degree of concern among patients with mastocytosis 152 and their physicians whether vaccination to COVID 19 can be safely administered in this population 153 and whether there is an increased risk for reactions due to vaccination in patient with mast cell 154 disorders. The aim of the current paper is to help medical staff managing the COVID-19 immunization 155 program on how to deal with patients suffering from mastocytosis needing vaccination. 156

Recommendations given in this paper are based on expert opinion. Although evidence to provide 157 recommendations is still limited at this time, the authors see the need to evaluate the potential risk 158 of vaccination in mastocytosis patients. 159

A recent work report of the American Academy of Allergy Asthma and Immunology on 160 adverse reactions to drugs and biologics in patients with clonal mast cell disorders ( (19)) Based on the risk related to the SARS-CoV-2 infection and the data reviewed above, members 176 of the ECNM and AIM analyzed the risk-benefit ratio, concluding that there is presently no evidence 177 that the incidence and severity of reactions to available vaccines is higher in patients with 178 mastocytosis and against believing that patients suffering from mastocytosis are at comparable risk 179 to the general population from COVID-19. Thus, they should be offered vaccination to SARS-CoV-2 180 COVID-19. COVID -19 vaccination is effective to reduce the risk of a potentially fatal infection and 181 available data so far suggests an overall low risk of anaphylaxis in the general population, even 182 though the risk is higher as compared to other vaccines. However, since these subjects have a higher 183 risk of non-specific release of mediators, it is suggested to proceed with caution both in order not to 184 exclude them from vaccination and to reduce the risk of any adverse reactions. 185 The role of premedication to avoid adverse reactions to medications, such as radiocontrast 210 media, hymenoptera immunotherapy or anesthetics has not been evaluated in controlled studies but 211 is currently best clinical practice. Earlier studies on the use of pre-medications for patients with 212 severe contrast media reactions were successful at tenfold lowering the rate of reactions with re-213 exposures and paved the way for the current pre-medication protocols ((35), (36), (37), (38)). 214

Whether pre-medications can protect from anaphylaxis in IgE-mediated reactions has not be 215 evaluated and no controlled studies are available to provide evidence of protection from reactions to 216 vaccines. There is a general consensus among experts about the use of pre-medications in 217 mastocytosis patients at high risk for anaphylaxis and H1-antihistamines taken 30-60 minutes before 218 vaccination are the preferred drugs. Corticosteroids, H2-antihistamines and montelukast are also 219 considered; however, there is concern that corticosteroids may influence vaccination efficacy. The 220 benefit of premedication with H2-antihistamines and montelukast has been even less well 221 documented. Currently premedication with an H1-antihistamine is recommended in patients with 222 mastocytosis at high risk for anaphylaxis, whereas the addition of other prophylactic drugs such as 223 H2-antihistamines or montelukast can be considered on a case-by-case basis, once risk stratification 224 is done. 225

Many mastocytosis patients are treated with anti-mediator-type drugs, including 226 antihistamines, antileukotrienes, cromones, and omalizumab (anti-IgE) ( (39)). There is no reason to 227 suggest that these drugs exert immunosuppressive effects or would reduce the efficacy of the 228 vaccination, even when used over several years. Therefore, patients on anti-mediator-based 229 treatment should continue their therapy during vaccination. Omalizumab is effective in preventing 230 anaphylaxis and improving chronic MC mediator-related symptoms in patients with anaphylaxis, 231 insufficiently controlled by conventional therapy and should not be discontinued ((39)). Patients on 232 omalizumab may receive a dose 1 week prior to vaccination for sufficient omalizumab levels during 233 the procedure. 234 235 Emergency awareness and equipment for anaphylaxis treatment in the vaccination center 236 J o u r n a l P r e -p r o o f As hypersensitivity reactions can occur to any vaccine in any patient and the reaction severity 237 to known triggers for anaphylaxis is often more severe in mastocytosis patients, they should be 238 vaccinated in a health care facility equipped and experienced with the treatment of anaphylaxis with 239 resuscitation equipment readily available (see Figure 1 and Table 1) . 240

It is prudent and not demanding to extend the general observation period in mastocytosis patients to 241 at least 30 minutes, and potentially even longer in those with an increased risk to develop 242 anaphylaxis with recognition of logistic limitations in larger vaccination centers. 243

In the vaccination center, the equipment and drugs for the management of anaphylactic 244 events should be available ( (40) Pulse oximeter Medical latex free gloves, alcohol swabs oxygen -it should be possible to give flow of 6-8 ml/min 100% using a non-rebreather mask Needles or catheters with a wide-bore cannula (14-

Prevalence of allergy and anaphylactic symptoms in 210 adult and 327 pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis 328 (REMA)

Anaphylaxis in patients with mastocytosis: a study on 331 history, clinical features and risk factors in 120 patients

Drug allergy in mast cell disease

High prevalence of anaphylaxis in patients with 337 systemic mastocytosis -a single-centre experience

How much specific 340 is the association between hymenoptera venom allergy and mastocytosis? Allergy

Clinical 344 presentation and management practice of systemic mastocytosis. A survey on 460 Italian 345 patients

Adverse 348 reactions to drugs and biologics in patients with clonal mast cell disorders: A Work Group 349 Report of the Mast Cells Disorder Committee

Low Frequency of IgE-Mediated Food Hypersensitivity in 353

Risk and 357 management of patients with mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) 358 pandemic: Expert opinions

COVID-19 361 infection in patients with mast cell disorders including mastocytosis does not impact mast cell 362 activation symptoms

Maintaining Safety with SARS-CoV-2 Vaccines

Safety and Efficacy of 368 the BNT162b2 mRNA Covid-19 Vaccine

Food and Drug Administration. Moderna COVID-19 vaccine

Food and Drug Adinistration, Vaccines and Related Biological Products 372 Advisory Committee

Efficacy and Safety of the 374 mRNA-1273 SARS-CoV-2 Vaccine

Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination

Reports of Anaphylaxis After Receipt of mRNA COVID-19

Vaccination management in 386 children and adults with mastocytosis

Vaccination and allergy: 389 EAACI position paper, practical aspects. Pediatr Allergy Immunol

mRNA COVID-19 vaccine is well tolerated in patients with 392 cutaneous and systemic mastocytosis with mast cell activation symptoms and anaphylaxis

Evaluation of 396 vaccination safety in children with mastocytosis

Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested 400 Approach

Efficacy of antihistamine 403 pretreatment in the prevention of adverse reactions to Hymenoptera immunotherapy: A 404 prospective, randomized, placebo-controlled trial

Practice Parameters for 408 Diagnosing and Managing Iodinated Contrast Media Hypersensitivity

The prevention of immediate generalized reactions to 411 radiocontrast media in high-risk patients

Stratified premedication 415 strategy for the prevention of contrast media hypersensitivity in high-risk patients

Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: Efficacy 420 and safety observations

-Patients without previous anaphylaxis or anaphylaxis to a well-defined trigger (e.g. hymenoptera venom) and no reactions to medications containing polyethylene glycol Routine vaccination in outpatient setting with emergency awareness and emergency medication available for resuscitation Supervision for 30 minutes after vaccination Patient carries unexpired adrenaline autoinjector at the vaccination site Premedication with sedating or non-sedating H1 antihistamine may be considered 30-60 minutes prior to vaccination.

-Patients with prior anaphylactic reactions with triggers or without known triggers (idiopathic anaphylaxis), but not to polyethylene glycol -Patients with previous reactions (e.g. local redness, fever, generalized malaise) to other vaccines, but no anaphylaxis Routine vaccination in outpatient setting with emergency awareness and emergency medication available for resuscitation Supervision for 30-60 minutes after vaccination Patient carries unexpired adrenaline autoinjector to the vaccination site Premedication with sedating or non -sedating H1 antihistamine should be considered 30-60 min prior to vaccination.

-Patients with Brighton consensus anaphylactic reaction grade 1 and 2 to the first dose of COVID -19 vaccine -Patients with known or suspected allergy to polyethylene glycol or polysorbate 80/20 -Patients with previous anaphylaxis to vaccination -Unstable patients with mastocytosis and severe uncontrolled MCAS symptoms Allergy evaluation recommended prior to vaccination Skin test to PEG and polysorbate 80/20 and vaccine o avoidance of vaccines containing PEG if positive skin test o vaccination in hospital setting recommended with resuscitation capabilities, emergency awareness if negative skin tests. Supervision for 60 minutes after vaccination Patient carries non expired adrenaline autoinjector to the site of vaccination Premedication with sedating or non -sedating H1 antihistamine should be done 30-60 min prior to vaccination