Knowledge, Attitudes, and Practices of Allergists/Immunologists Regarding Transition of Care for Primary Immunodeficiency Patients.

PURPOSE: Only some allergists/immunologists provide care throughout the lifespan despite their training. Although transition of care (TOC) guidelines exist, research on provider perspectives on TOC for pediatric primary immunodeficiency (PID) patients is lacking. We aimed to characterize knowledge, attitudes, and practices and establish clinician needs using a needs assessment survey. METHODS: The 15-min online survey was adapted from an existing rheumatology TOC survey and was emailed to the American Academy of Allergy Asthma and Immunology (AAAAI) and Clinical Immunology Society (CIS) members. Our primary hypothesis was that both AAAAI and CIS providers report being underprepared for TOC and would express interest in TOC resources and consensus. RESULTS: Forty-nine of 1250 eligible AAAAI and 67 of 698 eligible CIS participants completed the survey (4.8% vs 11.3% participation rate). Many (53.1% vs 59.7%) respondents transition their own patients but also retain adult patients (59.2% vs 52.2%). Many accepted transition patients (85.7% vs 92.5%). In total, 24.1% of respondents did not have a TOC policy while 18.9% have an informal policy. Only 25.0% were satisfied with their current practices while 43.9% agreed that a consensus statement would be useful. CONCLUSION: Despite a small sample size and high rate of unanswered questions, our findings show that TOC remains overlooked in our specialty and that providers want and need additional training and resources. There is a clear need to develop and evaluate the effectiveness of evidence-based TOC guidelines, resources, and best practices for PID patients.

Anaphylaxis among elderly emergency department patients in a large health system in New York.

BACKGROUND: Anaphylaxis in the elderly is poorly understood. OBJECTIVE: To elucidate demographic, clinical, and management characteristics of older adults presenting to emergency departments (EDs) with National Institute of Allergy and Infectious Diseases (NIAID) criteria-confirmed anaphylaxis vs milder, non-anaphylactic acute allergic reactions (AARs). METHODS: A retrospective analysis of ED patients more than or equal to 65 years was conducted, using anaphylaxis International Classification of Diseases, Ninth Revision (ICD-9) codes or ICD-9-based algorithms incorporating the NIAID diagnostic criteria. Descriptive statistics were generated, and the abovementioned characteristics were compared between cohorts. RESULTS: Of 164 eligible visits, 71 (43.3%), 90 (54.9%), and 3 (1.8%) cases were identified by ICD-9 codes, the algorithms, or both, respectively. Only half fulfilled NIAID diagnostic criteria. Compared with the non-anaphylactic AAR group, criteria-confirmed anaphylaxis group had lower drug allergy rates (43.9% vs 61.0%, P = .03) but higher food allergy rates (26.8% vs 12.2%, P = .02). For the criteria-confirmed anaphylaxis group, presenting signs and symptoms in descending frequency were mucocutaneous, respiratory, cardiovascular, and gastrointestinal. Criteria-confirmed anaphylaxis group had higher rates of prior anaphylaxis (13.4% vs 2.4%, P = .009), pre-ED (12.2% vs 0.0%, P = .001) or ED (72.0% vs 4.9%, P < .001) epinephrine administration, and allergy referral (17.1% vs 2.4%, P = .002). Tryptase levels were rarely ordered, occurring once in the criteria-confirmed anaphylaxis group and never in the non-anaphylactic AAR group. Despite low mortality (n = 1), 64.6% of the criteria-confirmed anaphylaxis cohort required hospitalization, with 23.2% admitted to intensive care unit. CONCLUSION: Diagnosis of elderly ED patients with anaphylaxis remains suboptimal. Identifying NIAID criteria-confirmed cases remain challenging, using the existing methods. Management of these patients poorly adheres to current guidelines.

Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees.

Secondary hypogammaglobulinemia (SHG) is characterized by reduced immunoglobulin levels due to acquired causes of decreased antibody production or increased antibody loss. Clarification regarding whether the hypogammaglobulinemia is secondary or primary is important because this has implications for evaluation and management. Prior receipt of immunosuppressive medications and/or presence of conditions associated with SHG development, including protein loss syndromes, are histories that raise suspicion for SHG. In patients with these histories, a thorough investigation of potential etiologies of SHG reviewed in this report is needed to devise an effective treatment plan focused on removal of iatrogenic causes (eg, discontinuation of an offending drug) or treatment of the underlying condition (eg, management of nephrotic syndrome). When iatrogenic causes cannot be removed or underlying conditions cannot be reversed, therapeutic options are not clearly delineated but include heightened monitoring for clinical infections, supportive antimicrobials, and in some cases, immunoglobulin replacement therapy. This report serves to summarize the existing literature regarding immunosuppressive medications and populations (autoimmune, neurologic, hematologic/oncologic, pulmonary, posttransplant, protein-losing) associated with SHG and highlights key areas for future investigation.

Allergic reactions to coronavirus disease 2019 vaccines and addressing vaccine hesitancy: Northwell Health experience.

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.

Characterization of Infants with Idiopathic Transient and Persistent T Cell Lymphopenia Identified by Newborn Screening-a Single-Center Experience in New York State.

PURPOSE: Newborn screening (NBS) quantifies T cell receptor excision circles (TREC) and identifies infants with T cell lymphopenia (TCL). This study elucidates the demographics, laboratory characteristics, genetics, and clinical outcomes following live viral vaccine administration of term infants with transient or persistent idiopathic TCL. METHODS: A single-center retrospective analysis was performed from September 2010 through June 2018. Laboratory variables were compared with Mann-Whitney tests. Correlations between initial TREC levels and T cell counts were determined by Spearman tests. RESULTS: Twenty-two transient and 21 persistent TCL infants were identified. Males comprised 68% of the transient and 52% of the persistent TCL cohorts. Whites comprised 23% of the transient and 29% of the persistent cohorts. Median initial TREC levels did not differ (66 vs. 60 TRECs/µL of blood, P = 0.58). The transient cohort had higher median initial CD3+ (2135 vs. 1169 cells/µL, P < 0.001), CD4+ (1460 vs. 866 cells/µL, P < 0.001), and CD8+ (538 vs. 277 cells/µL, P < 0.001) counts. The median age of resolution for the transient cohort was 38 days. Genetic testing revealed 2 genes of interest which warrant further study and several variants of uncertain significance in immunology-related genes in the persistent cohort. 19 transient and 14 persistent subjects received the initial rotavirus and/or MMRV immunization. No adverse reactions to live viral vaccines were reported in either cohort. CONCLUSION: Transient and persistent TCL infants differ by demographic, laboratory, and clinical characteristics. Select transient and persistent TCL patients may safely receive live attenuated viral vaccines, but larger confirmatory studies are needed.

PROMIS-29 survey confirms major impact of fatigue on health-related quality of life in common variable immunodeficiency.

Health-related quality of life (HRQOL) is an emerging topic of interest in patients with immunodeficiency. Information about HRQOL in common variable immunodeficiency (CVID) is limited. The primary objective was to compare primary immunodeficiency disease (PIDD) patients with and without common variable immunodeficiency (CVID) on HRQOL domains using Patient-Reported Outcomes Measurement Information System (PROMIS-29) survey data from the United States Immunodeficiency Network (USIDNET) registry. The primary endpoint variables were scores on 7 HRQOL domains. The USIDNET registry was used to select patients with baseline PROMIS-29 data collected between 2015 and 2018. Descriptive statistics, Fisher's exact test, and Student's two-sample t test were used to compare patients with CVID versus patients with non-CVID on demographic and clinical characteristics. The single-sample t test was used to compare sample means to the normed population mean of 50. A general linear model approach to multiple regression with backward selection was used to remove factors that did not contribute significant information to the multivariable models, while controlling for multiple testing. Potential explanatory variables included group (CVID/non-CVID), sex, age, and BMI. Among 184 PIDD patients, 146 (79%) were diagnosed with CVID. Patients had a mean (SD) age of 53 (13.8), were predominantly female (83%), and were Caucasian (98%). PROMIS-29 results revealed a significant effect of group (CVID/non-CVID) on the anxiety, fatigue, and social participation domains, with fatigue being the most statistically significant. Fatigue, anxiety, and social participation may be key factors influencing HRQOL among patients with CVID. Future prospective longitudinal studies using PROMIS-29 will be needed to confirm these findings and to determine the mechanisms through which these factors develop in CVID, and how they can be improved.

New York State cases of anaphylaxis in elderly patients from 2000 to 2010.

BACKGROUND: Limited information is available on the effect of anaphylaxis, a severe, potentially life-threatening allergic reaction, in the elderly population. OBJECTIVE: To elucidate the frequency of anaphylaxis and the demographic characteristics of elderly patients admitted to New York hospitals from 2000 to 2010. METHODS: A retrospective analysis of hospitalized patients aged 65 years and older in New York from 2000 to 2010 was conducted using the Statewide Planning and Research Cooperative System, a statewide administrative database. Cases were identified using anaphylaxis International Classification of Diseases, Ninth Revision (ICD-9) codes or an ICD-9-based diagnostic algorithm incorporating the National Institutes of Allergy and Infectious Disease diagnostic criteria. The χ2 test was used to measure the association between demographic characteristics and group membership. Regression was used to model group and age as a function of hospital rates. RESULTS: A total of 3673 hospitalizations were analyzed. Anaphylaxis ICD-9 codes identified 1790 cases (48.7%), the algorithms identified 1701 cases (46.3.%), and 182 cases (5.0%) were identified by both. Hospitalization rates increased significantly during this period (P < .001). Women comprised 61.5% and people of white race comprised 69.8% of the sample. Distribution by age differed by ascertainment method (ICD-9 vs algorithm) among the early-old group (65-74 years of age; 53.8% vs 41.8%) and among the late-old group (≥85 years of age; 11.2% vs 19.3%). CONCLUSION: Hospitalization rates and anaphylaxis cases increased during the study period among the hospitalized elderly population of New York. Relying on anaphylaxis ICD-9 codes alone missed approximately half of possible cases. The identification and possibly the effect of anaphylaxis among the elderly population may differ, depending on age, race, payer, New York County, and disposition.

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.

Utilization of high-fidelity simulation to address challenges with the basic science immunology education of preclinical medical students.

BACKGROUND: Immune function and dysfunction are highly complex basic science concepts introduced in the preclinical medical school curriculum. A challenge for early learners is connecting the intricate details and concepts in immunology with clinical manifestations. This impedes relevance and applicability. The impetus in medical education reform is promoting consolidation of basic science and clinical medicine during the first two years of medical school. Simulation is an innovation now widely employed in medical schools to enhance clinical learning. Its use in basic science curriculums is largely deficient. The authors piloted simulation as a novel curricular approach to enhance fundamental immunology knowledge and clinical integration. METHODS: The authors introduced a Primary Immunodeficiency Disease (PIDD) simulation during a basic science immunology course for second-year medical students at the Zucker School of Medicine at Hofstra/Northwell. The simulation tasked small groups of students with evaluating, diagnosing and managing an infant with previously undiagnosed immunodeficiency. Joint facilitation by clinical and science faculty during terminal debriefings engaged students in Socratic discussion. Debriefing aimed to immerse basic science content in the context of the clinical case. Students completed a post-simulation Likert survey, assessing utility in reinforcing clinical reasoning, integration of basic science and clinical immunology, enhanced knowledge and understanding of immunodeficiency, and enhanced learning. A summative Immunodeficiency Objective Structured Clinical Examination (OSCE) question was created by faculty to assess students' recognition of a PIDD and clinical reasoning. RESULTS: The simulation was well received by students with > 90% endorsing each of the objectives on the post-simulation survey. The authors also determined a statistically significant score variance on the summative OSCE question. Higher scores were achieved by the cohort of students completing the OSCE post-simulation versus the cohort completing the OSCE pre-simulation. CONCLUSIONS: The innovative use of simulation in a highly complex basic science immunology course provides relevance and consolidation for preclinical learners. Additional data will be collected to continuously assess application of concepts and proficiency stemming from this novel curricular intervention. The authors advocate the initiation and/or expansion of simulation in non-clinical basic science courses such as immunology to bridge the gap between theory and practice.

Considerations in the Diagnosis of Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency that is caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease presents in most patients initially with infection, especially of the lymph nodes, lung, liver, bone, and skin. Patients with CGD are susceptible to a narrow spectrum of pathogens, and Staphylococcus aureus, Burkholderia cepacia complex, Serratia marcescens, Nocardia species, and Aspergillus species are the most common organisms implicated in North America. Granuloma formation, most frequently in the gastrointestinal and genitourinary systems, is a common complication of CGD and can be seen even before diagnosis. An increased incidence of autoimmune disease has also been described in patients with CGD and X-linked female carriers. In patients who present with signs and symptoms consistent with CGD, a flow cytometric dihydrorhodamine neutrophil respiratory burst assay is a quick and cost-effective way to evaluate NADPH oxidase function. The purpose of this review is to highlight considerations for and challenges in the diagnosis of CGD.

Noninfectious Manifestations and Complications of Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD), a primary immunodeficiency characterized by a deficient neutrophil oxidative burst and the inadequate killing of microbes, is well known to cause a significantly increased risk of invasive infection. However, infectious complications are not the sole manifestations of CGD; substantial additional morbidity is driven by noninfectious complications also. These complications can include, for example, a wide range of inflammatory diseases that affect the gastrointestinal tract, lung, skin, and genitourinary tract and overt autoimmune disease. These diseases can occur at any age and are especially problematic in adolescents and adults with CGD. Many of these noninfectious complications present a highly challenging therapeutic conundrum, wherein immunosuppression must be balanced against an already markedly increased risk of invasive fungal and bacterial infections. In this review, the myriad noninfectious complications of CGD are discussed, as are important gaps in our understanding of these processes, which warrant further investigation.

Immunodeficiencies Associated with Abnormal Newborn Screening for T Cell and B Cell Lymphopenia.

Newborn screening for SCID has revealed the association of low T cells with a number of unexpected syndromes associated with low T cells, some of which were not appreciated to have this feature. This review will discuss diagnostic approaches and the features of some of the syndromes likely to be encountered following newborn screening for immune deficiencies.

A Simple Allergist-Led Intervention Improves Resident Training in Anaphylaxis.

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.

Small reservoirs: jail screening for gonorrhea and Chlamydia in low prevalence areas.

Public health agencies can use jail as an opportunity to reach populations disproportionately affected by sexually transmitted infections (STI). The emphasis that STI control programs place on screening jail entrants varies considerably. Nine million individuals passed through U.S. jails in 2005, many in counties where STIs are rare. A pilot program of screening for Neisseria gonorrhoeae and Chlamydia trachomatis was implemented at the intake sites for the combined jail and prison system of Rhode Island, a state with a low prevalence of STIs. Prevalence of either gonorrhea or chlamydia among detainees was 4.6%, but in women aged 25 and younger, the rate was 24 times that of similar-aged women statewide. Screening led to treatment for 22 (81%) of the infected inmates and 10 of their partners. The heterogeneity of both jail demographics and STI epidemiology suggests a need to tailor the choice of screening strategy to local conditions.

Radioimmunotherapy of experimental human metastatic melanoma with melanin-binding antibodies and in combination with dacarbazine.

PURPOSE: Melanin has emerged as an attractive target for radioimmunotherapy (RIT) of melanoma, and a radiolabeled monoclonal antibody (mAb) 6D2 to melanin is currently in clinical evaluation. We investigated two approaches to improve the targeting of radiation to tumors using melanin-binding mAbs: (a) the use of an additional mAb to melanin could provide information on whether using antibodies to melanin can serve as a general approach to development of therapeutics for melanoma, and (b) as melanin targeting involves the antibody binding to extracellular melanin released from necrotic melanoma cells, we hypothesized that the administration of a chemotherapeutic agent followed by RIT would facilitate the delivery of radiation to the tumors due to the increased presence of free melanin. EXPERIMENTAL DESIGN: We evaluated the therapeutic efficacy of two melanin-binding IgM mAbs labeled with (188)Re (6D2 and 11B11). We compared the efficacy of RIT with (188)Re-6D2 to chemotherapy with dacarbazine (DTIC) and to combined chemotherapy and RIT in human metastatic melanoma-bearing nude mice. RESULTS: Therapeutic efficacy of (188)Re-labeled 6D2 and 11B11 was comparable despite differences in their affinity and binding site numbers. Comparison of chemotherapy with DTIC and RIT revealed that RIT was more effective in slowing tumor growth in mice. Administration of DTIC followed by RIT was more effective than either modality alone. CONCLUSIONS: These results provide encouragement for the development of RIT for melanoma with melanin-binding mAbs and suggest that combining chemotherapy and RIT may be a promising approach for the treatment of metastatic melanoma.

Improved transfection and new selectable markers for the rodent malaria parasite Plasmodium yoelii.

The rodent malaria Plasmodium yoelii is a useful model to study protective immunity to pre-erythrocytic stages of infection, pathogenesis of erythrocytic stages, and vaccine development. However, the utility of the P. yoelii model system has not been fully realized because transfection and genetic manipulation methodologies for this rodent species are less developed than that of another rodent species Plasmodium berghei. Here we report improved transfection efficiency using the AMAXA nucleofector system compared to conventional transfection methodologies. We also show that heterologous promoters from P. berghei can be used to drive expression of a green fluorescent protein (GFP) reporter protein in P. yoelii. In an effort to develop additional selectable markers for this parasite, we also tested positive selectable markers that have been used successfully in P. falciparum and P. berghei. Human dihydrofolate reductase (hdhfr) and Toxoplasma gondii dihydrofolate reductase-thymidylate synthase (Tgdhfr-ts) conferred drug resistance to WR99210 and pyrimethamine, respectively, when introduced as episomes. These improvements should make genetic manipulation of P. yoelii more amenable and facilitate further studies of host-parasite interactions using this attractive rodent model.