The Potential of Low Molecular Weight Heparin to Mitigate Cytokine Storm in Severe COVID‐19 Patients: A Retrospective Cohort Study

On March 11, 2020, the World Health Organization declared its assessment of coronavirus disease 2019 (COVID‐19) as a global pandemic. However, specific anti‐severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) drugs are still under development, and patients are managed by multiple complementary treatments. We performed a retrospective analysis to compare and evaluate the effect of low molecular weight heparin (LMWH) treatment on disease progression. For this purpose, the clinical records and laboratory indicators were extracted from electronic medical records of 42 patients with COVID‐19 (21 of whom were treated with LMWH, and 21 without LMWH) hospitalized (Union Hospital of Huazhong University of Science and Technology) from February 1 to March 15, 2020. Changes in the percentage of lymphocytes before and after LMWH treatment were significantly different from those in the control group (P = 0.011). Likewise, changes in the levels of D‐dimer and fibrinogen degradation products in the LMWH group before and after treatment were significantly different from those in the control group (P = 0.035). Remarkably, IL‐6 levels were significantly reduced after LMWH treatment (P = 0.006), indicating that, besides other beneficial properties, LMWH may exert an anti‐inflammatory effect and attenuate in part the “cytokine storm” induced by the virus. Our results support the use of LMWH as a potential therapeutic drug for the treatment of COVID‐19, paving the way for a subsequent well‐controlled clinical study.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Our results strongly suggest low molecular weight heparin (LMWH) as an effective strategy in a therapeutic or combination therapy against coronavirus disease 2019 (COVID‐19).

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ LMWH exerts an anti‐inflammatory effect by means of reducing IL‐6 and increasing lymphocyte%. We, therefore, favor the use of LMWH as a potential therapeutic drug for the treatment of COVID‐19.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ A new therapeutic approach for COVID‐19 was proposed based on the non‐anticoagulant properties of LMWH.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ In view of the COVID‐19 pandemic, our study will be of pronounced interest to a broad spectrum of clinicians and scientists of several disciplines focusing on translational and basic aspects related to COVID‐19 and virology in general.

On March 11, 2020, the World Health Organization (WHO) declared its assessment of coronavirus disease 2019 (COVID‐19) as a global pandemic. Severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) is characterized by a long incubation period, high infectivity, and multiple routes of transmission. ¹ , ² However, no effective medicines are currently available, so patients are treated symptomatically. A better understanding of the mechanisms of pathological changes will help to screen potential drugs out of the currently available medications.Several clinical studies revealed that cytokine storms are important mechanisms underlying disease exacerbation and death of patients with COVID‐19. ³ , ⁴ , ⁵ Particularly, IL‐6 levels in severely ill patients were significantly higher than in mild cases. ⁶ IL‐6 is one of the core cytokines, ⁷ contributing to many of the key symptoms of cytokine storm, such as vascular leakage, activation of the complement, and coagulation cascades, inducing disseminated intravascular coagulation. ⁸ , ⁹ Reducing the levels of IL‐6 and decreasing its activity may prevent or even reverse the cytokine storm syndrome, ¹⁰ thereby improving the condition of patients with COVID‐19.Substantial studies have reported that low molecular weight heparin (LMWH) has various non‐anticoagulant properties that play an anti‐inflammatory role by reducing the release of IL‐6. ¹¹ , ¹² , ¹³ However, the anti‐inflammatory effects of LMWH in COVID‐19 are currently unknown. By analyzing the effect of LMWH in patients with COVID‐19, our retrospective cohort study demonstrates, for the first time, the significant beneficial effect of LMWH in controlling cytokine storm and delaying disease progression (Figure 1 ).Open in a separate windowFigure 1Possible mechanism of anti‐inflammatory effects of low molecular weight heparin (LMWH) in patients with coronavirus disease 2019 (COVID‐19). Under conventional antiviral treatment regimens, LMWH improves hypercoagulability, inhibits IL‐6 release, and attenuates IL‐6 biological activity. It has potential antiviral effects and helps delay or block inflammatory cytokine storms. LMWH can increases the lymphocyte% in the patients. The multiple effects of LMWH encourages its application for the treatment of patients with COVID‐19. HSPG, heparin sulfate proteoglycan; SARS‐CoV‐2, severe acute respiratory syndrome‐coronavirus 2.     

抗Ⅹa活性检测在抗凝治疗中的临床应用现状与前景

随着检测技术的进步,临床中各种疾病伴随血栓的检出率越来越高.普通肝素和低分子量肝素是目前临床应用较多的注射用抗凝剂,其中普通肝素的半衰期短、无肾毒性、有拮抗剂;低分子量肝素半衰期较长,需在一些特殊人群如儿童、孕妇、老人中进行监测.口服抗凝剂中,除华法林等传统药物外,靶向活化凝血因子Ⅹa的抗凝药物如利伐沙班亦越来越多地应...     

Heparin‐associated thrombocytopenia in 24 401 patients with venous thromboembolism: findings from the RIETE Registry1

Summary. Background: Whether the treatment of venous thromboembolism (VTE) with unfractionated heparin (UFH) confers a higher risk of thrombocytopenia than does treatment with low molecular weight heparin (LMWH) remains controversial, and very few data are available from routine clinical practice. Objectives: We assessed the incidence, risk factors and prognosis of heparin‐associated thrombocytopenia (HAT) according to the type of heparin therapy, UFH or LMWH. Patients/Methods: Data were obtained from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE), which included 25 369 patients with confirmed VTE until February 2009. Among them, 24 401 patients were treated either with UFH or with LMWH, and had available information about the 6‐month occurrence of confirmed thrombocytopenia, defined as a platelet count ≤ 150 000 mm^–3. Results: One hundred and forty‐one patients receiving UFH and/or LMWH developed thrombocytopenia within a 6‐month period. The incidence of HAT was significantly higher in the UFH group (1.36%, 95% confidence interval [CI] 0.79–2.17) than in the LMWH group (0.54%, 95% CI 0.44–0.64). As compared with LMWH, UFH significantly increased the risk of HAT in female patients (adjusted hazard ratio [HR] 4.90%, 95% CI 2.58–9.31, P = 0.001) but not in male patients (adjusted HR 1.60%, 95% CI 0.64–3.97, P = 0.31); P = 0.027 for comparison. In each gender, the UFH‐associated excess risk was confined to patients with VTE unrelated to cancer. The poor prognosis of patients with thrombocytopenia was not influenced by the type of heparin therapy. Conclusions: In routine clinical practice, treatment of VTE with UFH seems to confer a higher risk of thrombocytopenia than does treatment with LMWH, especially in women and non‐cancerous patients.     

Recent advances in search of oral heparin therapeutics

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are first choices of clinicians among available anticoagulants. Currently, these agents are administered either parenterally or subcutaneously, which reduces patient compliance and acceptability. Oral heparin may serve as an alternative to both parenteral heparin as well as presently available oral anticoagulants such as warfarin. This review focuses mainly upon recent perspectives in the development of heparin as an oral anticoagulant. The possibility of its success with special emphasis to nanotechnological approaches has been elaborated. Important strategies such as the use of penetration enhancers, the development of lipid conjugates of heparin, and the incorporation of heparin in polymeric matrix systems have been discussed. Additionally, introductory information on biological activities, physiochemical aspects, and pharmacokinetic and pharmacodynamic parameters of heparin is summarized. A brief comparison of UFH and LMWH is also included for reader's benefit. Informative discussion on clinical trials with the successes and limitations of oral heparin formulations is also presented. Overall, the present review provides complete insight to the research that has been carried out for the development of heparin as oral anticoagulant.     

Hypocalcemia and massive pulmonary embolism in SLE patient with COVID‐19 infection: A case report

A 16‐year‐old female patient presented to our ED with fever and coughing of blood for 3 days. She is known to have SLE for 5 months and takes oral prednisone. She was tested positive for COVID‐19. She developed hypocalcemia with clinically diagnosed massive pulmonary embolism. She was treated with heparin and recovered.     

N‐glycan profiling alterations of serum and immunoglobulin G in immune thrombocytopenia

BackgroundThe glycosylation alterations of serum and IgG are involved in a variety of autoimmune and inflammatory diseases and have shown great potential in biomarker field. The diagnosis of immune thrombocytopenia (ITP) is exclusive. Our study aimed to discover the potential glyco‐biomarkers for auxiliary diagnosis of ITP.MethodsThe serum samples were obtained from 61 ITP patients and 35 healthy controls, and IgG samples were purified from 34 out of 61 ITP patients and 35 healthy controls. DNA sequencer‐assisted fluorophore‐assisted carbohydrate electrophoresis (DSA‐FACE) was used to analyze serum and IgG N‐glycan profiling.Results6 of 12 serum N‐glycan peaks, 6 of 7 IgG N‐glycan peaks, serum fucosylation, and IgG galactosylation were significantly different between ITP patients and healthy controls (p < 0.05). IgG peak 7 showed good diagnostic efficacy for discriminating ITP patients from healthy individuals (AUC 0.967). ITP patients with severe thrombocytopenia had a significantly lower serum fucosylation than ITP patients with mild and moderate thrombocytopenia (p < 0.05). Serum fucosylation and serum peak 5 were correlated with platelet counts in ITP patients with severe thrombocytopenia, and the absolute values of correlation coefficient were both over 0.5.ConclusionsThe specific N‐glycan patterns of serum and IgG were observed in ITP patients. IgG peak 7 was a potential biomarker for auxiliary diagnosis of ITP.     

Clinical course involving thrombocytosis and thrombocytopenia in a patient with bladder cancer treated with gemcitabine and cisplatin

Gemcitabine induce thrombocytopenia and thrombocytosis as toxicity. In this report, we show detailed time‐course for platelet fluctuation. Our case emphasis attention to monitor see‐saw‐like toxicity on platelet count.     

Allergy to polyethylene glycol and polysorbates in a patient cohort: Diagnostic work‐up and decision points for vaccination during the COVID‐19 pandemic

BackgroundDuring the COVID‐19 pandemic focus has been on polyethylene glycol (PEG) and polysorbate as these excipients are constituents in the first vaccines and possible elicitors of allergic reactions to the vaccines. We aimed to evaluate the possibility of vaccinating patients with PEG and/or polysorbate allergy against COVID‐19.MethodsTwenty‐five patients with a history of an allergic reaction to drugs, vaccines and mouth hygiene products containing PEG or polysorbate and sensitization (skin test or in vitro test) or a positive challenge were included. We re‐evaluated 19 of 21 patients diagnosed before 2021 and four new patients by skin prick tests (SPT) and Basophil Histamine Release (BaHR) for PEGs, polysorbates and approved COVID‐19 vaccines as well as measurement of specific IgE (PEG 2000, 10,000). Patients were offered vaccination based on decision points from the primary diagnosis and re‐evaluation.ResultsMost common primary elicitors were depot‐steroids and laxatives. Most patients had experienced more than one reaction. SPT was superior to BaHR test although many SPTs became negative over time. After careful re‐evaluation three patients were successfully vaccinated with the Pfizer/BioNTech vaccine. Three were vaccinated before referral. Eleven were offered the Johnson‐Johnson vaccine; four were vaccinated successfully, seven abstained. Six patients could not be vaccinated with PEG or polysorbate containing vaccines.ConclusionHypersensitivity to excipients in COVID‐19 vaccines constitutes a risk to patients with allergy to PEG or polysorbates. After diagnostic evaluation, a safe COVID‐19 vaccine could be offered to most patients, the remainders will await new vaccines containing different excipients.     

The new anticoagulants

Currently, the anticoagulants available are limited to warfarin, heparin compounds, and direct thrombin inhibitors. Warfarin, the most commonly used outpatient anticoagulant, has significant shortcomings. There are numerous drug/drug and drug/food interactions, and there is difficulty in dosing for one-third of patients. Numerous new anticoagulants are undergoing testing. The meta-pentasaccharides use the core molecule of heparin and replace one or more of the sulphated groups. They are administered by subcutaneous injection, but they require only once per week dosing. Numerous studies have shown equivalents or superiority to warfarin in treatment for thromboembolic events. Direct thrombin inhibitors block thrombin (IIa) and are used mostly for heparin-induced thrombosis or during coronary interventions. However, there is an orally administered direct thrombin inhibitor, Dabigatran, which is undergoing phase III testing. It can be given without regard to weight, age, or gender with minimal drug interactions. This drug has been proven to be equivalent to low molecular weight heparin (LMWH) in deep venous thrombosis (DVT) prophylaxis and showed no excess bleeding. Another promising group of anticoagulants with numerous investigations underway are the direct X inhibitors. Most are excreted renally as opposed to hepatic clearance with intravenous or oral dosing. Numerous phase II studies have shown them to have equivalent or superior prophylaxis for DVT when compared with LMWH. Oral IXa inhibitors and an oral thrombin cofactor inhibitor are also under development. It is clear that in the near future, anticoagulants will be available that offer significant advantages when compared to those currently in use.     

Protocol of safe vaccination against COVID‐19 in patients with high risk of allergic reactions

BackgroundSars‐CoV‐2 infections are hazardous, especially to the elderly and patients with comorbidities. With no efficient treatment available, newly developed vaccines are the only way to change the course of the pandemic. However, reports of allergic reactions resulted in some patients and practicing physicians being concerned about the safety of vaccine administration, particularly in people with severe anaphylactic reactions to multiple or unknown factors in their medical history.This study aimed to develop an allergic work‐up protocol based on skin prick tests (SPT), intradermal testing (IDT) and intramuscular provocations, and desensitisation which may contribute to diagnosis and management of anti‐COVID‐19 vaccine allergy.MethodsTwo hundred and eighty‐five patients were enrolled. Two hundred and five of them entered the study based on severe anaphylactic reaction to unknown or multiple factors in their medical history which disqualified them for standard treatment. Another 80 patients were enrolled after developing an allergic reaction to the first dose of one such vaccine. In all subjects, SPT and IDT were performed. Serum tryptase was assessed in 79 patients randomly chosen from the study group.ResultsTwo hundred and seventy‐seven patients with negative tests were given a vaccine without complications. Seven patients had positive skin tests. In two cases, tests confirmed Comirnaty allergy, while the other five confirmed solely skin sensitisation with no exposure prior to the study. Six patients with positive tests received titrated challenge using desensitisation protocol with a reasonable tolerance. One patient did not consent to desensitisation and one patient resigned despite negative tests. Overall, 283 (99%) patients were vaccinated using this newly developed protocol. Patients with adverse reactions to the first dose of the vaccine before the study had a significantly lower basal serum tryptase concentration (p = 0.001).ConclusionSkin tests with anti‐COVID‐19 vaccines are a useful tool in the vaccination protocol. This protocol enables safe immunisation of high‐allergy‐risk patients even in cases of positive skin tests.     

Erythema Multiforme Major following SARS‐CoV‐2 vaccine

Erythema multiforme major, an immune‐mediated skin reaction to infections or medications with oral involvement, should be taken into account as a potential side effect of several vaccines, including SARS‐CoV‐2. Correct patient history collection allows prompt recognition and subsequent successful medical management with oral corticosteroids.     

Topical inflammasome inhibition with disulfiram prevents irritant contact dermatitis

BackgroundThe pathogenesis of contact dermatitis, a common inflammatory skin disease with limited treatment options, is held to be driven by inflammasome activation induced by allergens and irritants. We here aim to identify inflammasome‐targeting treatment strategies for irritant contact dermatitis.MethodsA high content screen with 41,184 small molecules was performed using fluorescent Apoptosis associated speck‐like protein containing a CARD (ASC) speck formation as a readout for inflammasome activation. Hit compounds were validated for inhibition of interleukin (IL)‐1β secretion. Of these, the approved thiuramdisulfide derivative disulfiram was selected and tested in a patch test model of irritant contact dermatitis in 25 healthy volunteers. Topical application of disulfiram, mometasone or vehicle was followed by application of sodiumdodecylsulfate (SDS) for 24 h each. Eczema induction was quantified by mexameter and laser speckle imaging. Corneocyte sampling of lesional skin was performed to assess inflammasome‐mediated cytokines IL‐1β and IL‐18.ResultsDisulfiram induced a dose‐dependent inhibition of ASC speck formation and IL‐1β release in cellular assays in vitro. In vivo, treatment with disulfiram, but not with vehicle and less mometasone, inhibited SDS‐induced eczema. This was demonstrated by significantly lower erythema and total perfusion values assessed by mexameter and laser speckle imaging for disulfiram compared to vehicle (p < 0.001) and/or mometasone (p < 0.001). Also, corneocyte IL‐18 levels were significantly reduced after application of disulfiram compared to vehicle (p < 0.001).ConclusionWe show that disulfiram is a dose‐dependent inhibitor of inflammasome pathway activation in vitro and inhibitor of SDS‐induced eczema in vivo. Topical application of disulfiram represents a potential treatment option for irritant contact dermatitis.     

Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents

Summary.  Heparin, low molecular weight heparin (LMWH) and coumarins are familiar to most clinicians, inexpensive, highly effective when correctly used and widely available. However, coumarin has a delayed onset of action, interacts with many medications, has a narrow therapeutic window, and can cause thrombosis in some settings (e.g. hereditary protein C deficiency, heparin induced thrombocytopenia, warfarin loading). Additionally, warfarin and heparin require monitoring of their therapeutic effect. These real and perceived limitations have led to the development of 'novel' anticoagulants. However, these new agents have one general limitation – a lack of a widely available antidote. We focus on the management of bleeding in anticoagulated patients, with particular regard to novel anticoagulants.     

A likely unavoidable clinical scenario during treatment for venous thromboembolism complicated with severe immune thrombocytopenia: A case report

Patients with immune thrombocytopenia have increased risks of bleeding and thrombosis. The acute‐phase treatment for venous thromboembolism complicated with severe immune thrombocytopenia involves a “platelet dilemma” in therapeutic decision‐making.     

Salivary Epithelial Cells as Model to Study Immune Response Against Cutaneous Pathogens

The human skin not only provides passive protection as a physical barrier against external injury, but also mediates active surveillance via epidermal cell surface receptors that recognize and respond to potential invaders. Primary keratinocytes and immortalized cell lines, the commonly used sources to investigate immune responses of cutaneous epithelium are often difficult to obtain and/or potentially exhibit changes in cellular genetic make‐up. Here we investigated the possibility of using salivary epithelial cells (SEC) to evaluate the host response to cutaneous microbes. Elevated secretion of IFN‐γ and IL‐12 was observed in the SEC stimulated with Staphylococcus aureus, a transient pathogen of the skin, as mono species biofilm as compared to SEC stimulated with a commensal microbe, the Staphylococcus epidermidis. Co‐culture of the SEC with both microbes as dual species biofilm elicited maximum cytokine response. Stimulation with S. aureus alone but not with S. epidermidis alone induced maximum toll‐like receptor‐2 (TLR‐2) expression in the SEC. Exposure to dual species biofilm induced a sustained upregulation of TLR‐2 in the SEC for up to an hour. The data support novel application of the SEC as efficient biospecimen that may be used to investigate personalized response to cutaneous microflora.     

Triggering Receptor Expressed on Myeloid Cells in Cutaneous Melanoma

The tumor microenvironment plays an important role in the progression of melanoma, the prototypical immunologic cutaneous malignancy. The triggering receptor expressed on myeloid cells (TREM) family of innate immune receptors modulates inflammatory and innate immune signaling. It has been investigated in various neoplastic diseases, but not in melanoma. This study examines the expression of TREM‐1 (a proinflammatory amplifier) and TREM‐2 (an anti‐inflammatory modulator and phagocytic promoter) in human cutaneous melanoma and surrounding tissue. Indirect immunofluorescence staining was performed on skin biopsies from 10 melanoma patients and staining intensity was semiquantitatively scored. Expression of TREM‐1 and TREM‐2 was higher in keratinocytes than melanoma tissue (TREM‐1: p < 0.01; TREM‐2: p < 0.01). Whereas TREM‐2 was the dominant isoform expressed in normal keratinocytes, TREM‐1 expression predominated in melanoma tissue (TREM‐1 to TREM‐2 ratio: keratinocytes = 0.78; melanoma = 2.08; p < 0.01). The increased TREM ratio in melanoma tissue could give rise to a proinflammatory and protumor state of the microenvironment. This evidence may be suggestive of a TREM‐1/TREM‐2 paradigm in which relative levels dictate inflammatory and immune states, rather than absolute expression of one or the other. Further investigation regarding this paradigm is warranted and could carry prognostic or therapeutic value in treatment for melanoma.     

Prevention of venous thromboembolism in the hospitalized medical patient

Hospitalized acutely ill medical patients are at high risk for venous thromboembolism (VTE), and clinical trials clearly demonstrate that pharmacologic prophylaxis of VTE for up to 14 days significantly reduces the incidence of VTE in this population. Guidelines recommend use of low-molecular-weight heparin (LMWH) or unfractionated heparin (5,000 U three times daily) for VTE prophylaxis in hospitalized medical patients with risk factors for VTE; in patients with contraindications to anticoagulants, mechanical prophylaxis is recommended. All hospitalized medical patients should be assessed for their risk of VTE at admission and daily thereafter, and those with reduced mobility and one or more other VTE risk factors are candidates for aggressive VTE prophylaxis. Based on results from the recently reported EXCLAIM trial, extended postdischarge prophylaxis with LMWH for 28 days should be considered for hospitalized medical patients with reduced mobility who are older than age 75 or have a cancer diagnosis or a history of VTE.     

COVID‐19 vaccine‐related new‐onset lichen planus

Coronavirus disease 2019 (COVID‐19) vaccines significantly impacted world health and well‐being. However, various adverse events have been observed following severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccination. Cutaneous reactions have been prevalent following many vaccines, including COVID‐19 vaccines. Here, we present a case of new‐onset lichen planus in a patient who received the COVID‐19 vaccine at the same time as being infected with SARS‐CoV‐2. A 52‐year‐old woman presented to the clinic with extensive pruritic skin lesions. The eruptions had appeared a week after her second dose of the Sinopharm COVID‐19 vaccine. She mentioned a history of SARS‐CoV‐2 infection approximately 10 days following the first dose of her vaccine, causing a 1‐month delay in getting the second dose. Her past medical history was not significant. On examination, erythematous and squamous papules were demonstrated predominantly on the extremities, including inguinal and axillary folds. Moreover, desquamation of the lips was visible, and buccal lesions were also found. After consultation with a dermatologist, a skin biopsy was indicated for the patient, but she refused to undergo the procedure. Therefore, considering the typical appearance of the eruptions, lichen planus was suspected, for which she was treated with oral antihistamines and topical corticosteroids.     

Atypical localization of demodicosis after COVID‐19 infection

Since its outbreak in December 2019, a consistent number of case reports have been published describing a complex spectrum of skin manifestations associated with COVID‐19. We report a first observation of demodicosis of the scalp after a severe acute respiratory syndrome coronavirus 2 (SARS‐COV‐2) infection.     

Patients with suspected allergic reactions to COVID‐19 vaccines can be safely revaccinated after diagnostic work‐up

BackgroundWhen initiating the Danish vaccination program against COVID‐19, the incidence of anaphylaxis was estimated to be 10 times higher compared to other virus‐based vaccines. In this study, we present data on patients referred with suspected allergic reactions to COVID‐19 vaccines. The main purpose of the study is to investigate the incidence and severity of the allergic reactions, and to evaluate the safety of revaccination.MethodsAll patients in the region of Southern Denmark with case histories of allergic reactions to COVID‐19 vaccines in a defined period are included in this study. Diagnostic work up consisted of a detailed case history, evaluation of Brighton level of diagnostic certainty and World Allergy Organization grade of anaphylaxis and skin prick testing‐ and basophil histamine release testing with COVID‐19 vaccines and relevant drug excipients. Patients were revaccinated at the Allergy Center when possible.ResultsSixty‐one patients are included in this study. In 199,377 doses administered, nine patients fulfilled the criteria of anaphylaxis when using the Brighton Criteria (incidence being 45 per million). Of 55 patients with reactions to the first dose, 52 patients were revaccinated without adverse reactions. We found no proven cases of immediate anaphylaxis due to COVID‐19 vaccines. By skin prick test, we diagnosed three patients with drug excipient allergy and further a patient with mastocytosis was found.ConclusionsAnaphylactic reactions to COVID‐19 vaccines are rare and the incidence is similar to what is seen with other virus‐based vaccines. Revaccination is safe in the majority of patients; however, allergological evaluation is important since some prove to have drug excipient allergy.