A systematic review and expert Delphi Consensus recommendation on the use of vaccines in patients receiving dupilumab: A position paper of the American College of Allergy, Asthma and Immunology.

BACKGROUND: Dupilumab is a monoclonal antibody that targets the interleukin (IL)-4 receptor alpha subunit, thus blocking the effects of IL-4 and IL-13, and has shown efficacy in treating various conditions including asthma, atopic dermatitis, eosinophilic esophagitis, and others. Because of its immune modulatory effects, clinical trials that studied dupilumab did not allow patients to receive live vaccines during the clinical trials because of an abundance of caution, and thus package inserts recommend that patients who are being treated with dupilumab should avoid live vaccines. Because dupilumab is now approved for use in patients from 6 months of age for the treatment of atopic dermatitis, this reported contraindication is now posing a clinical dilemma for patients and clinicians. OBJECTIVE: To perform a systematic review of literature on the safety and efficacy of vaccinations in patients who are receiving dupilumab and to provide expert guidance on the use of vaccines in patients who are receiving dupilumab. METHODS: A systematic review of the literature was performed, and an expert Delphi Panel was assembled. RESULTS: The available literature on patients who received vaccinations while using dupilumab overall suggests that live vaccines are safe and that the vaccine efficacy, in general, is not affected by dupilumab. The expert Delphi panel agreed that the use of vaccines in patients receiving dupilumab was likely safe and effective. CONCLUSION: Vaccines (including live vaccines) can be administered to patients receiving dupilumab in a shared decision-making capacity.

Impaired Response to Polysaccharide Vaccine in Selective IgE Deficiency.

PURPOSE: Immunoglobulin E deficiency (IgED) (defined as IgE < 2 IU/mL) is enriched in patients with primary antibody deficiency (PAD). We hypothesized that selective IgED (sIgED) is a more sensitive predictor of the development of PAD than declining IgG, as IgE production typically requires two class switch recombination (CSR) events in contrast to IgG. Thus, the inability of patients with sIgED to mount an appropriate antibody response to a T-cell independent antigen or evidence of aberrant induction of ɛ germ line (ɛGL) or IgE heavy chain (IgEHC) transcripts in vitro would support the concept that sIgED is a biomarker for emerging PAD. METHODS: We compared pre- and post-polysaccharide vaccination titers in healthy patients with sIgED without a history of recurrent infections or autoimmunity (n = 20) and in healthy controls (HCs) (n = 17). Subsequently, we assessed in vitro induction of εGL and IgEHC transcripts in patients with sIgED and HC (n = 6) in response to IL-4 + CD40L stimulation. RESULTS: Thirty percent of patients with sIgED did not have a robust vaccine response compared to 0% of HCs (p = 0.017). Individuals with sIgED with an abnormal vaccine response demonstrated persistent germline mRNA expression in their B-cells at day 5, with lower levels of IgEHC, compared to both HCs and sIgED participants with a normal vaccine response. CONCLUSION: Patients with sIgED are more likely to have abnormal antibody responses to a T cell-independent antigen and may have dysregulated CSR machinery. Following individuals with sIgED longitudinally may be beneficial in the early identification of PAD.

Further evidence of a type 2 inflammatory signature in chronic obstructive pulmonary disease or emphysema.

BACKGROUND: There is increasing recognition of a type 2 (T2) inflammatory pattern in a subset of patients with chronic obstructive pulmonary disease (COPD) or emphysema, characterized by blood and airway eosinophilia. The mechanism underlying this is not well established. The recognition that CD125 (interleukin [IL]-5 receptor alpha) is expressed on some lung neutrophils and eosinophils in patients with asthma led us to speculate that CD125 may also be expressed on lung neutrophils in patients with COPD or emphysema. OBJECTIVE: To interrogate the expression of CD125 on lung neutrophils (and, when present, eosinophils) in patients with COPD/emphysema and identify a meaningful biomarker to predict neutrophil CD125 expression, including other markers of T2 inflammation. METHODS: We obtained blood and bronchoalveolar lavage (BAL) samples from patients with physician-diagnosed COPD/emphysema undergoing a clinically indicated bronchoscopy. RESULTS: We found that a highly variable percentage of BAL neutrophils indeed expressed surface CD125 (0%-78.7%), with obvious clustering of CD125high and CD125low patterns. No correlation was found with clinical characteristics, blood or BAL eosinophil or neutrophil counts, BAL cytokines, or BAL eosinophil CD125 expression. CONCLUSION: We conclude that, similar to asthma, lung neutrophils from patients with COPD display interleukin-5 receptor alpha (CD125) on their surface. This along with the frequent presence of IL-4 and IL-5 in airway fluid further suggests a possible role of the T2 pathway in contributing to COPD severity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03984799.

Natural history of infants with non-SCID T cell lymphopenia identified on newborn screen.

Newborn screening (NBS) for severe combined immunodeficiency (SCID) can identify infants with non-SCID T cell lymphopenia (TCL). The purpose of this study was to characterize the natural history and genetic findings of infants with non-SCID TCL identified on NBS. We analyzed data from 80 infants with non-SCID TCL in the mid-Atlantic region between 2012 and 2019. 66 patients underwent genetic testing and 41 (51%) had identified genetic variant(s). The most common genetic variants were thymic defects (33%), defects with unknown mechanisms (12%) and bone marrow production defects (5%). The genetic cohort had significantly lower median initial CD3+, CD4+, CD8+ and CD4/CD45RA+ T cell counts compared to the non-genetic cohort. Thirty-six (45%) had either viral, bacterial, or fungal infection; only one patient had an opportunistic infection (vaccine strain VZV infection). Twenty-six (31%) of patients had resolution of TCL during the study period.

Navigating diagnostic options for inborn errors of immunity in children: a case-based illustration.

PURPOSE OF REVIEW: In recent years, there has been a dramatic increase in the number of recognized inborn errors of immunity (IEI), many of which present in childhood. This review discusses diagnostic approaches for some of the more common presentations of IEI in childhood. RECENT FINDINGS: Implementation of newborn screening (NBS) using the T cell receptor excision circle (TREC) assay has led to the timely identification of patients with severe combined immunodeficiency (SCID) as well as both syndromic and nonsyndromic forms of T cell lymphopenia, including DiGeorge syndrome. Improvements in the availability of immunophenotyping assays, genetic testing and advanced diagnostic techniques such as the artificial thymic organoid system can improve diagnostic clarity and impact management plans. Diagnostic improvements in humoral immunodeficiency include development of novel assays to quantify and functionally evaluate polysaccharide vaccine response. SUMMARY: IEI represent a rapidly growing field, particularly in paediatrics. Use of state-of-the-art diagnostic testing can facilitate rapid identification of IEI, hopefully allowing for initiation of prompt treatment and improved patient outcomes.

Specific antibody deficiency: pearls and pitfalls for diagnosis.

OBJECTIVE: To summarize the pitfalls associated with defining exactly what constitutes an "impaired" antibody response to polysaccharide antigens and the importance of documenting actual pyogenic infections before making a diagnosis of an immune deficiency. Specific antibody deficiency is an immune deficiency defined by the presence of normal quantitative levels of immunoglobulins, but impaired antibody responses to polysaccharide antigens, in patients presenting with frequent otosinopulmonary infections with pyogenic bacteria. DATA SOURCES: PubMed review using the following keywords: specific antibody deficiency, pneumococcal vaccination, Salmonella vaccination, infectious sinusitis. STUDY SELECTION: This review focused on key studies that have been utilized to define what constitutes a "normal" humoral immune response to pneumococcal and Salmonella vaccination in healthy subjects and on published studies defining current expert opinion. RESULTS: Published studies demonstrate wide variability in response to pneumococcal vaccination in healthy individuals, making it daunting to define what constitutes an abnormal response. These challenges are exacerbated by striking laboratory variability in reporting results. CONCLUSION: Clinical examinations in individuals with self-reported recurrent acute sinusitis or lower respiratory infections need to document an infectious etiology with pyogenic bacteria and must rule out an underlying primary airway inflammatory disorder before consideration is made regarding the presence of an immune deficiency. In addition, decision making regarding diagnosis and treatment of patients who are examined for humoral immunodeficiency should not hinge solely on the strict application of defined cutoffs for "normal" response to a single polysaccharide vaccine, but rather a global assessment of humoral immune function in the context of the clinical presentation.

Lower viral loads in subjects with rhinovirus-challenged allergy despite reduced innate immunity.

BACKGROUND: Viral infections, especially those caused by rhinovirus, are the most common cause of asthma exacerbations. Previous studies have argued that impaired innate antiviral immunity and, as a consequence, more severe infections contribute to these exacerbations. OBJECTIVE: These studies explored the innate immune response in the upper airway of volunteers with allergic rhinitis and asthma in comparison to healthy controls and interrogated how these differences corresponded to severity of infection. METHODS: Volunteers with allergic rhinitis, those with asthma, and those who are healthy were inoculated with rhinovirus A16 and monitored for clinical symptoms. Tissue and nasal wash samples were evaluated for antiviral signature and viral load. RESULTS: Both subjects with allergic rhinitis and asthma were found to have more severe cold symptoms. Subjects with asthma had worsened asthma control and increased bronchial hyperreactivity in the setting of higher fractional exhaled breath nitric oxide and blood eosinophils. These studies confirmed reduced expression of interferons and virus-specific pattern recognition receptors in both cohorts with atopy. Nevertheless, despite this defect in innate immunity, volunteers with allergic rhinitis/asthma had reduced rhinovirus concentrations in comparison to the controls. CONCLUSION: These results confirm that the presence of an allergic inflammatory disorder of the airway is associated with reduced innate immune responsive to rhinovirus infection. Despite this, these volunteers with allergy have reduced viral loads, arguing for the presence of a compensatory mechanism to clear the infection. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02910401.

Interleukin-5 receptor alpha (CD125) expression on human blood and lung neutrophils.

BACKGROUND: Our previous studies revealed the presence of interleukin-5 (IL-5) receptor alpha chain (IL-5Rα, CD125) on neutrophils in a murine model of influenza and in the lung fluid of children with severe asthma. OBJECTIVE: To further evaluate the functional characteristics and effects of clinical factors and inflammatory variables on neutrophil surface IL-5Rα abundance in lung fluid and blood. METHODS: IL-5Rα expression was quantified by flow cytometry performed on purified neutrophils from blood and bronchoalveolar lavage fluid samples obtained from healthy controls and individuals with asthma. Expression was further confirmed by immunohistochemistry. Functional signaling through the IL-5Rα was evaluated by measurement of IL-5-inducible modulation of neutrophil surface CD62L and IL-5Rα expression. RESULTS: IL-5Rα was consistently present but at a variable magnitude on blood and lung neutrophils. Expression on lung neutrophils was significantly higher than that on blood cells (p"?>P < .001) where their expression was higher in the presence of airway pathogens, especially with respiratory viruses. Increased receptor expression occurred in response to the translocation of preformed receptors from intracellular stores. Receptors were functional as revealed by IL-5-mediated down-regulation of CD62L and the feed-forward up-regulation of reception expression. CONCLUSION: In addition to the expression on eosinophils and basophils, the IL-5Rα is consistently and abundantly expressed on the surface of blood and especially air space neutrophils. These observations support the concept that some of the efficacy of IL-5/IL-5R-targeting biologics observed in asthma may reflect their ability to target neutrophilic air space inflammation.

Bronchoalveolar lavage cytokine patterns in children with severe neutrophilic and paucigranulocytic asthma.

BACKGROUND: Asthma is a complex heterogeneous disease occurring in adults and children that is characterized by distinct inflammatory patterns. While numerous studies have been performed in adults, little is known regarding the heterogeneity of severe asthma in children, particularly inflammatory signatures involving the air spaces. OBJECTIVE: We sought to determine the relationship of bronchoalveolar lavage (BAL) cytokine/chemokine expression patterns in children with severe therapy-resistant asthma stratified according to neutrophilic versus nonneutrophilic BAL inflammatory cell patterns. METHODS: Children with severe asthma with inadequate symptom control despite therapy underwent diagnostic bronchoscopy and BAL. Inflammatory cytokine/chemokine concentrations were determined using a multiplex protein bead assay. RESULTS: Analysis of BAL constituents with an unbiased clustering approach revealed distinct cytokine/chemokine patterns, and these aligned with pathways associated with type 2 innate lymphoid cells, monocytes, neutrophil trafficking, and T effector cells. All cytokines examined (n = 27) with 1 exception (vascular endothelial growth factor) were overexpressed with BAL neutrophilia compared with nonneutrophilic asthma, and this was confirmed in a cross-validation analysis. Cytokines specifically responsible for Th17 (IL-17, IL-6, G-CSF) and Th1 differentiation and expression (IL-12, TNF-α, IFN-γ) were enhanced in the neutrophilic cohorts. Neutrophilic groups were also characterized by higher prevalence of bacterial and viral pathogens; however, cytokine expression patterns manifested independently of pathogen expression. CONCLUSIONS: The results demonstrate that children with refractory asthma and neutrophilic inflammation had a BAL cytokine pattern consistent with a mixed Th17/Th1/Th2 response. In contrast, nonneutrophilic asthma presented independently of cytokine overexpression.

Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology.

Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.

Birds of a feather: Common variable immune deficiencies.

OBJECTIVE: To update the reader on recently proposed common variable immune deficiency (CVID) diagnostic criteria, newly uncovered CVID pathobiology, freshly identified CVID-related genes, and novel CVID therapies. DATA SOURCES: PubMed Central. STUDY SELECTIONS: We selected 60 clinical and translational research articles that have shaped CVID diagnostic criteria, introduced personalized therapies, and advanced our understanding of CVID biology and genetics. We have incorporated recent articles and older published work that are foundational to the modern understanding of this protean disease. RESULTS: CVID has proven to be a heterogenous group of antibody deficiency diseases driven by defects in diverse biologic processes, including B-cell development, activation, tolerance, class-switch recombination, somatic hypermutation, and lymphoproliferation. Recent genetic advances have enabled identification of several CVID-related gene defects that may contribute to patients' infectious and noninfectious symptoms. CONCLUSION: Improved understanding of the aberrant biologic processes that drive CVID and the disease's genetic basis may be useful in directing therapeutic decisions, especially in cases complicated by autoimmune, lymphoproliferative, and inflammatory features.

TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status.

BACKGROUND: The pathogenesis of severe asthma in childhood remains poorly understood. OBJECTIVE: We sought to construct the immunologic landscape in the airways of children with severe asthma. METHODS: Comprehensive analysis of multiple cell types and mediators was performed by using flow cytometry and a multiplex assay with bronchoalveolar lavage (BAL) specimens (n = 68) from 52 highly characterized allergic and nonallergic children (0.5-17 years) with severe treatment-refractory asthma. Multiple relationships were tested by using linear mixed-effects modeling. RESULTS: Memory CCR5+ TH1 cells were enriched in BAL fluid versus blood, and pathogenic respiratory viruses and bacteria were readily detected. IFN-γ+IL-17+ and IFN-γ-IL-17+ subsets constituted secondary TH types, and BAL fluid CD8+ T cells were almost exclusively IFN-γ+. The TH17-associated mediators IL-23 and macrophage inflammatory protein 3α/CCL20 were highly expressed. Despite low TH2 numbers, TH2 cytokines were detected, and TH2 skewing correlated with total IgE levels. Type 2 innate lymphoid cells and basophils were scarce in BAL fluid. Levels of IL-5, IL-33, and IL-28A/IFN-λ2 were increased in multisensitized children and correlated with IgE levels to dust mite, ryegrass, and fungi but not cat, ragweed, or food sources. Additionally, levels of IL-5, but no other cytokine, increased with age and correlated with eosinophil numbers in BAL fluid and blood. Both plasmacytoid and IgE+FcεRI+ myeloid dendritic cells were present in BAL fluid. CONCLUSIONS: The lower airways of children with severe asthma display a dominant TH1 signature and atypical cytokine profiles that link to allergic status. Our findings deviate from established paradigms and warrant further assessment of the pathogenicity of TH1 cells in patients with severe asthma.

Low Serum IgE Is a Sensitive and Specific Marker for Common Variable Immunodeficiency (CVID).

Although small prior studies have suggested that IgE can be low in common variable immunodeficiency (CVID), the workup for patients with recurrent infections and suspected hypogammaglobulinemia does not include the routine measurement of serum IgE. We sought to test the hypothesis that low/undetectable serum IgE is characteristic of CVID by comparing the frequency of low/undetectable serum IgE in healthy controls and patients with CVID. We measured total serum IgE in a large multi-center cohort of patients with CVID (n = 354) and compared this to large population-based cohorts of children and adults. We further compared IgE levels in patients with CVID to those with other forms of humoral immunodeficiency, and in a subset, measured levels of allergen-specific serum IgE and IgG subclasses. Lastly, we evaluated for the presence of IgE in commercially available immunoglobulin replacement therapy (IgRT) products. An undetectable serum IgE (< 2 IU/ml) occurs in only 3.3% (95% CI, 1.9-5.7%) of the general population. In contrast, an undetectable IgE occurs in 75.6% (95% CI, 65.6-85.7%) of patients with CVID. Conversely, a high IgE (> 180 IU/ml) is very uncommon in CVID (0.3% of patients). IgE is > 2 IU/ml in 91.2% of patients with secondary hypogammaglobulinemia, and thus, an IgE < LLOD is suggestive of a primary humoral immunodeficiency. Allergen-specific IgE is not detectable in 96.5% of patients with CVID. Sufficient quantities of IgE to change the total serum IgE are not contained in IgRT. The IgG1/IgG4 ratio is increased in subjects with low IgE, regardless of whether they are controls or have CVID. These findings support the routine measurement of serum IgE in the workup of patients with hypogammaglobulinemia.

Correction to: Use of Genetic Testing for Primary Immunodeficiency Patients.

The original version of this article unfortunately contained mistakes in some of the author names and affiliations. The correct list of author names and affiliations is below, with the corrections in bold.

Use of Genetic Testing for Primary Immunodeficiency Patients.

Genetic testing plays a critical role in diagnosis for many primary immunodeficiency diseases. The goals of this report are to outline some of the challenges that clinical immunologists face routinely in the use of genetic testing for patient care. In addition, we provide a review of the types of genetic testing used in the diagnosis of PID, including their strengths and limitations. We describe the strengths and limitations of different genetic testing approaches for specific clinical contexts that raise concern for specific PID disorders in light of the challenges reported by the clinical immunologist members of the CIS in a recent membership survey. Finally, we delineate the CIS's recommendations for the use of genetic testing in light of these issues.

Cytokine-targeting biologics for allergic diseases.

OBJECTIVE: Asthma and allergic diseases continue to increase in prevalence, creating a financial burden on the health care system and affecting the quality of life for those who have these diseases. Many intrinsic and extrinsic factors are involved in the initiation and maintenance of the allergic response. Cytokines are proteins with growth, differentiation, and activation functions that regulate and direct the nature of immune responses. DATA SOURCES: clinicaltrials.gov and PubMed. STUDY SELECTIONS: Relevant clinical trials and recent basic science studies were chosen for discussion. RESULTS: Many cytokines have been implicated in the development and perpetuation of the allergic response. Biologics have been and are continuing to be developed that target these molecules for use in patients with asthma and atopic dermatitis where standard treatment options fail. The current state of cytokine-targeting therapies is discussed. CONCLUSION: This review focused on cytokines involved in the allergic response with an emphasis on those for which therapies are being or have been developed.

Pathogenic CD4+ T cells in patients with asthma.

Asthma encompasses a variety of clinical phenotypes that involve distinct T cell-driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4+ T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, TH2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of TH2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell "hubs" are discussed. We also describe advances in understanding the origins of atypical TH2 cells in asthmatic patients, the role of TH1 cells and other non-TH2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell-based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments.

Half-life of IgE in serum and skin: Consequences for anti-IgE therapy in patients with allergic disease.

We present results from clinical studies on plasma infusion done in the late 1970s in patients with hypogammaglobulinemia in which we documented the short half-life of both total and allergen-specific IgE in serum. The development of specific allergic sensitization in the skin of those patients followed by the gradual decrease in sensitization over 50 days was also documented. The data are included here along with a discussion of the existing literature about the half-life of IgE in both the circulation and skin. This rostrum reinterprets the earlier clinical studies in light of new insights and mechanisms that could explain the rapid removal of IgE from the circulation. These mechanisms have clinical implications that relate to the increasing use of anti-IgE mAbs for the treatment of allergic disease.

Gastrointestinal Manifestations of STAT3-Deficient Hyper-IgE Syndrome.

OBJECTIVE: STAT 3 deficiency (autosomal dominant hyper immunoglobulin E syndrome (AD-HIES)) is a primary immunodeficiency disorder with multi-organ involvement caused by dominant negative signal transducer and activator of transcription gene 3 (STAT3) mutations. We sought to describe the gastrointestinal (GI) manifestations of this disease. METHODS: Seventy subjects aged five to 60 years with a molecular diagnosis of AD-HIES were evaluated at the National Institutes of Health (NIH). Data collection involved a GI symptom questionnaire and retrospective chart review. RESULTS: In our cohort of 70 subjects, we found that 60% had GI symptoms (42/70). The most common manifestations were gastroesophageal reflux disease (GERD) observed in 41%, dysphagia in 31%, and abdominal pain in 24%. The most serious complications were food impaction in 13% and colonic perforation in 6%. Diffuse esophageal wall thickening in 74%, solid stool in the right colon in 50% (12/24), and hiatal hernia in 26% were the most prevalent radiologic findings. Esophagogastroduodenoscopy (EGD) demonstrated esophageal tortuosity in 35% (8/23), esophageal ulceration in 17% (4/23), esophageal strictures requiring dilation in 9% (2/23), and gastric ulceration in 17% (4/23). Esophageal eosinophilic infiltration was an unexpected histologic finding seen in 65% (11/17). CONCLUSION: The majority of AD-HIES subjects develop GI manifestations as part of their disease. Most notable are the symptoms and radiologic findings of GI dysmotility, as well as significant eosinophilic infiltration, concerning for a secondary eosinophilic esophagitis. These findings suggest that the STAT3 pathway may be implicated in a new mechanism for the pathogenesis of several GI disorders.