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This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history.
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Anafilaxia , COVID-19 , Hipersensibilidade Imediata , Humanos , Vacinas contra COVID-19/efeitos adversos , Abordagem GRADE , Consenso , Excipientes de Vacinas , COVID-19/prevenção & controle , ExcipientesRESUMO
BACKGROUND: Allergic and nonallergic adverse reactions have been reported with global coronavirus disease 2019 (COVID-19) vaccination. It was previously hypothesized that polyethylene glycol (PEG) may be responsible for anaphylactic reactions to messenger RNA (mRNA) COVID-19 vaccines. OBJECTIVE: To report the workflow established at our institution, types, and frequency of adverse reactions to mRNA COVID-19 vaccines in patients presenting for allergy evaluation. METHODS: A COVID-19 vaccine adverse reaction registry was established. We used PEG prick skin testing, followed by PEG challenges in selected cases, to ensure PEG tolerance and encourage completion of COVID-19 vaccination series. RESULTS: A total of 113 patients were included. Most vaccine reactions (86.7%) occurred in women. Anaphylaxis occurred only in women, all of which had a history of allergic disease and two-thirds had asthma. Anaphylaxis rate was 40.6 cases per million. None of the anaphylactic cases developed hypotension, required intubation, or required hospital admission. Systemic allergic symptoms, not fulfilling anaphylaxis criteria, were significantly more common in Pfizer-BioNTech than Moderna-vaccinated patients (P = .02). We observed a higher incidence of dermatologic nonurticarial reactions in men (P = .004). Among first-dose reactors, 86.7% received and tolerated the second dose. We observed a high rate of false-positive intradermal skin test results and frequent subjective symptoms with oral PEG challenge. CONCLUSION: Intradermal PEG testing has limited utility in evaluating anaphylaxis to mRNA vaccines. Most severe postvaccination allergic symptoms are not caused by hypersensitivity to PEG. Most people with reaction to the initial mRNA vaccine can be safely revaccinated. Patients with anaphylaxis to COVID-19 vaccines benefit from physician-observed vaccination.
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Anafilaxia , Vacinas contra COVID-19/efeitos adversos , COVID-19 , Hesitação Vacinal , Anafilaxia/etiologia , COVID-19/prevenção & controle , Feminino , Humanos , Masculino , Polietilenoglicóis/efeitos adversos , Testes Cutâneos , Vacinas Sintéticas/efeitos adversos , Vacinas de mRNA/efeitos adversosRESUMO
INTRODUCTION: Bacillus clausii as a probiotic supplement is increasingly used in both adult and paediatric patient populations. There is limited awareness about potential adverse effects. CASE PRESENTATION: We report a case of prolonged (111 days) B. clausii bacteraemia after brief probiotic use in a 17-month-old immunocompetent child, without a definite focus of infection and in the absence of predisposing risk factors or underlying co-morbidities. We identified seven probiotic use-associated cases of prolonged B. clausii bacteraemia (mean duration [range] 64 days [14-93 days] where data were available) in the literature, all with underlying co-morbidities. CONCLUSION: B. clausii probiotic preparations may cause prolonged bacteraemia, rendering patients with underlying co-morbidities as well as those with unrecognized risk factors vulnerable for significant infectious complications.
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BACKGROUND: Cytokine storm is a marker of coronavirus disease 2019 (COVID-19) illness severity and increased mortality. Immunomodulatory treatments have been repurposed to improve mortality outcomes. RESEARCH QUESTION: Do immunomodulatory therapies improve survival in patients with COVID-19 cytokine storm (CCS)? STUDY DESIGN AND METHODS: We conducted a retrospective analysis of electronic health records across the Northwell Health system. COVID-19 patients hospitalized between March 1, 2020, and April 24, 2020, were included. CCS was defined by inflammatory markers: ferritin, > 700 ng/mL; C-reactive protein (CRP), > 30 mg/dL; or lactate dehydrogenase (LDH), > 300 U/L. Patients were subdivided into six groups: no immunomodulatory treatment (standard of care) and five groups that received either corticosteroids, anti-IL-6 antibody (tocilizumab), or anti-IL-1 therapy (anakinra) alone or in combination with corticosteroids. The primary outcome was hospital mortality. RESULTS: Five thousand seven hundred seventy-six patients met the inclusion criteria. The most common comorbidities were hypertension (44%-59%), diabetes (32%-46%), and cardiovascular disease (5%-14%). Patients most frequently met criteria with high LDH (76.2%) alone or in combination, followed by ferritin (63.2%) and CRP (8.4%). More than 80% of patients showed an elevated D-dimer. Patients treated with corticosteroids and tocilizumab combination showed lower mortality compared with patients receiving standard-of-care (SoC) treatment (hazard ratio [HR], 0.44; 95% CI, 0.35-0.55; P < .0001) and with patients treated with corticosteroids alone (HR, 0.66; 95% CI, 0.53-0.83; P = .004) or in combination with anakinra (HR, 0.64; 95% CI, 0.50-0.81; P = .003). Corticosteroids when administered alone (HR, 0.66; 95% CI, 0.57-0.76; P < .0001) or in combination with tocilizumab (HR, 0.43; 95% CI, 0.35-0.55; P < .0001) or anakinra (HR, 0.68; 95% CI, 0.57-0.81; P < .0001) improved hospital survival compared with SoC treatment. INTERPRETATION: The combination of corticosteroids with tocilizumab showed superior survival outcome when compared with SoC treatment as well as treatment with corticosteroids alone or in combination with anakinra. Furthermore, corticosteroid use either alone or in combination with tocilizumab or anakinra was associated with reduced hospital mortality for patients with CCS compared with patients receiving SoC treatment.
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Corticosteroides/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , COVID-19 , Síndrome da Liberação de Citocina , Imunomodulação , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/terapia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Síndrome da Liberação de Citocina/virologia , Reposicionamento de Medicamentos , Quimioterapia Combinada/métodos , Registros Eletrônicos de Saúde/estatística & dados numéricos , Humanos , Imunossupressores/administração & dosagem , Conduta do Tratamento Medicamentoso/estatística & dados numéricos , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Estudos Retrospectivos , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Análise de Sobrevida , Estados Unidos/epidemiologiaRESUMO
The clinical progression of the severe acute respiratory syndrome coronavirus 2 infection, coronavirus 2019 (COVID-19), to critical illness is associated with an exaggerated immune response, leading to magnified inflammation termed the "cytokine storm." This response is thought to contribute to the pathogenicity of severe COVID-19. There is an initial weak interferon response and macrophage activation that results in delayed neutrophil recruitment leading to impeded viral clearance. This causes prolonged immune stimulation and the release of proinflammatory cytokines. Elevated inflammatory markers in COVID-19 (e.g., d-dimer, C-reactive protein, lactate dehydrogenase, ferritin, and interleukin-6) are reminiscent of the cytokine storm seen in severe hyperinflammatory macrophage disorders. The dysfunctional immune response in COVID-19 also includes lymphopenia, reduced T cells, reduced natural killer cell maturation, and unmitigated plasmablast proliferation causing aberrant IgG levels. The progression to severe disease is accompanied by endotheliopathy, immunothrombosis, and hypercoagulability. Thus, both parts of the immune system-innate and adaptive-play a significant role in the cytokine storm, multiorgan dysfunction, and coagulopathy. This review highlights the importance of understanding the immunologic mechanisms of COVID-19 as they inform the clinical presentation and advise potential therapeutic targets.
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Imunidade Adaptativa/imunologia , COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Imunidade Inata/imunologia , Síndrome do Desconforto Respiratório/imunologia , Formação de Anticorpos , Antivirais/uso terapêutico , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , COVID-19/sangue , COVID-19/fisiopatologia , Inativadores do Complemento/uso terapêutico , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Endotélio Vascular/imunologia , Endotélio Vascular/fisiopatologia , Humanos , Imunidade Humoral/imunologia , Imunoglobulina G/imunologia , Fatores Imunológicos/uso terapêutico , Memória Imunológica , Imunossupressores/uso terapêutico , Interferons/imunologia , Células Matadoras Naturais/imunologia , Linfopenia/imunologia , Ativação de Macrófagos/imunologia , Infiltração de Neutrófilos/imunologia , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Trombofilia/sangue , Trombofilia/imunologia , Trombose/sangue , Trombose/imunologia , Tratamento Farmacológico da COVID-19RESUMO
Secondary hypogammaglobulinemia is a common development in patients treated with immunomodulatory agents for autoimmune, connective tissue, and malignant diseases. It has been observed in the medical management of patients undergoing hematopoietic stem cell and solid organ transplantation. Some patients have preexisting immunodeficiency associated with these illnesses; immunosuppressive treatment magnifies their immune defect. This article reviews immunosuppressive medications, including biological treatments that cause secondary hypogammaglobulinemia. It summarizes risk factors for rituximab-induced hypogammaglobulinemia, such as preexisting low immunoglobulin G levels, CD19 levels, host factors, and additive effect of all immunomodulatory drugs used. The evaluation and management of secondary hypogammaglobulinemia are discussed.
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Agamaglobulinemia/complicações , Agamaglobulinemia/terapia , Fatores Imunológicos/efeitos adversos , Transplante de Órgãos/efeitos adversos , Agamaglobulinemia/etiologia , Terapia Biológica/efeitos adversos , Terapia Biológica/métodos , Gerenciamento Clínico , Humanos , Imunidade Humoral , Fatores Imunológicos/uso terapêutico , Imunossupressores/efeitos adversos , Neoplasias/complicações , Neoplasias/terapia , Fatores de RiscoRESUMO
[This corrects the article on p. 798 in vol. 8, PMID: 28769923.].
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Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag-/- natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity. We aimed to analyze NK cell phenotype and function in patients with mutations in RAG and in non-homologous end joining (NHEJ) genes. Here, we provide evidence that NK cells from these patients have an immature phenotype, with significant expansion of CD56bright CD16-/int CD57- cells, yet increased degranulation and high perforin content. Correlation was observed between in vitro recombinase activity of the mutant proteins, NK cell abnormalities, and in vivo clinical phenotype. Addition of serotherapy in the conditioning regimen, with the aim of depleting the autologous NK cell compartment, may be important to facilitate engraftment and immune reconstitution in patients with RAG and NHEJ defects treated by HSCT.
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Physicians underrecognize and undertreat anaphylaxis. Effective interventions are needed to improve physician knowledge and competency regarding evidence-based anaphylaxis diagnosis and management (ADAM). We designed and evaluated an educational program to improve ADAM in pediatrics, internal medicine, and emergency medicine residents from two academic medical centers. Anonymous questionnaires queried participants' demographics, prior ADAM clinical experience, competency, and comfort. A pretest assessing baseline knowledge preceded a 45-minute allergist-led evidence-based presentation, including practice with epinephrine autoinjectors, immediately followed by a posttest. A follow-up test assessed long-term knowledge retention twelve weeks later. 159 residents participated in the pretest, 152 participated in the posttest, and 86 participated in the follow-up test. There were no significant differences by specialty or site. With a possible score of 10, the mean pretest score (7.31 ± 1.50) was lower than the posttest score (8.79 ± 1.29) and follow-up score (8.17 ± 1.72) (P < 0.001 for both). Although participants' perceived confidence in diagnosing or managing anaphylaxis improved from baseline to follow-up (P < 0.001 for both), participants' self-reported clinical experience with ADAM or autoinjector use was unchanged. Allergist-led face-to-face educational intervention improves residents' short-term knowledge and perceived confidence in ADAM. Limited clinical experience or reinforcement contributes to the observed decreased knowledge.
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BACKGROUND: As the indications and use of rituximab continue to expand, the reports of long-term effects of anti-CD20--mediated B-cell depletion on the immune system accumulate. OBJECTIVE: We report a group of patients with immunodeficiency who were treated with rituximab and present their immunologic data. METHODS: A retrospective chart review identified patients with immunodeficiency who received rituximab for treatment of their primary disease and required immunoglobulin replacement therapy (IGRT). Pre-IGRT immunoglobulins, specific antibodies, B-cells, and B-cell phenotype were recorded and analyzed. RESULTS: We identified 11 patients with immunodeficiency who received rituximab and required IGRT. Two of these patients were diagnosed with common variable immunodeficiency before rituximab treatment. Nine other patients had hypogammaglobulinemia and did not achieve an adequate response to polysaccharide vaccine. There was a significant delay in B-cell recovery. B-cell phenotypes identified predominantly naive B cells in the blood of these patients with significant decrease in switched and memory B cells. CONCLUSION: There are patients with persistent B-cell dysfunction long after rituximab treatment was discontinued. Some of these patients required IGRT. These patients should be distinguished from patients with primary immunodeficiency diseases. Routine baseline B-cell numbers and serum immunoglobulin levels before starting immunomodulatory therapy are required to help distinguish primary immunodeficiency diseases from secondary rituximab-induced, transient, and, at times, prolonged immune suppression. Periodic monitoring is prudent to identify immune recovery. Post-rituximab B-cell phenotyping may help identify the patients who will develop persistent immune dysfunction caused by an unidentified underlying disease or the prolonged effect of rituximab treatment.
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Anticorpos Monoclonais Murinos/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Adolescente , Adulto , Idoso , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Pré-Escolar , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/imunologia , Contagem de Linfócitos , Pessoa de Meia-Idade , Rituximab , Adulto JovemRESUMO
BACKGROUND: Severe combined immunodeficiency (SCID) is a rare primary immunodeficiency characterized by abnormal lymphocyte development and lymphopenia. It often presents during the first year of life with recurrent, opportunistic infections, failure to thrive, and malabsorption. OBJECTIVE: To advocate newborn screening for SCID. METHODS: We reviewed the case histories of dizygotic twins with Pneumocystis carinii pneumonia (PCP) at the age of 6 months. RESULTS: Full-term fraternal twin girls were born to nonconsanguineous parents. Twin A developed recurrent oral candidiasis at 2 months, followed by pneumococcal bacteremia and PCP. At 5 months she had failure to thrive, but her absolute lymphocyte count was normal (5,887 cells/mm3). Subsequently, twin B presented with acute respiratory distress and was also diagnosed as having PCP; her absolute lymphocyte count was 5,852 cells/mm3. Flow cytometric analysis of peripheral blood lymphocytes from both girls demonstrated a T-B+NK+ phenotype consistent with interleukin 7 receptor alpha-chain-mutation SCID. Both girls received a haploidentical T-cell-depleted bone marrow transplant from their mother. In the interim, a homozygous point mutation in the interleukin 7 receptor alpha-chain gene was identified in twin B. Both parents were found to be carriers. Twin A died of chronic lung disease 8 months after transplantation; twin B is currently thriving. CONCLUSIONS: Early diagnosis and treatment of SCID are associated with an increased rate of survival and improved long-term outcome. Some patients with SCID can present without lymphopenia. Thus, we advocate that more sensitive screening tests be considered for inclusion in the newborn screening program currently used in most states.
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Transplante de Medula Óssea , Receptores de Interleucina-7/genética , Imunodeficiência Combinada Severa/cirurgia , Feminino , Humanos , Lactente , Recém-Nascido , Linfopenia , Programas de Rastreamento , Mutação , Pneumonia por Pneumocystis/complicações , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/genética , Linfócitos TRESUMO
Over the last several years, virologic assays for the detection and measurement of HIV-1 RNA have become important in the diagnosis and management of perinatal HIV infection. Since AIDS Clinical Trials Group 076, a number of prospective and retrospective analyses have investigated the role of viral load in perinatal transmission. Although no universal virologic threshold for perinatal HIV transmission has been established, much has been learned about the timing of perinatal transmission and the relationship between maternal viral load and disease progression in HIV-infected neonates. Virologic assays have become accepted as standards of care in monitoring viral load during pregnancy, diagnosing neonatal infection, and establishing prognosis and response to therapy in infected infants.