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.

Are Obstetrics and Gynecology Residents Equipped to Care for Transgender and Gender Nonconforming Patients? A National Survey Study.

Purpose: Our study aims to assess three self-reported outcomes: (1) comfort of, (2) competency in, and (3) curricular satisfaction of OB-GYN residents in caring for transgender and gender nonconforming (TGNC) patients. Methods: This was a cross-sectional survey of a convenience sample of OB-GYN residents consisting of 28 questions on a 4-point Likert scale. The survey was distributed to OB-GYN residents via residency program directors and coordinators. Descriptive statistics and multivariate linear regression modeling were performed to identify demographic and training characteristics associated with differences in comfort, competency, and curricular satisfaction. Results: One-hundred twenty-six surveys were completed by OB-GYN residents (response rate=12.6%). Composite mean scores were calculated in the three self-reported outcome domains: comfort (2.8±0.67), competency (2.7±0.61), and satisfaction (2.2±0.82) which correlate to being "somewhat not" and "somewhat" comfortable, competent, and satisfied. Trainees who identified as lesbian, gay, bisexual, or queer were found to have higher comfort scores. Older age and male gender identity were associated with higher competency scores. No significant differences in comfort, competency, and satisfaction scores between residency training level were observed. The majority (78.1%, N=89) of trainees "strongly agreed" that it was important for them to obtain training in TGNC care topics. Conclusion: OB-GYN residents strongly agreed that learning about care for TGNC patients was important. Residents reported being more competent and comfortable than satisfied, which suggests that further curricular and clinical exposure is necessary to address the unique health care needs of this underserved patient population and to meet the educational needs of OB-GYN residents.

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.

T(H)2-like chemokine patterns correlate with disease severity in patients with recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP), characterized by the recurrent growth of benign tumors of the respiratory tract, is caused by infection with human papillomavirus (HPV), predominantly types 6 and 11. Surgical removal of these lesions can be required as frequently as every 3 to 4 wks to maintain a patent airway. There is no approved medical treatment for this disease. In this study, we have characterized the T(H)2-like chemokine profile (CCL17, CCL18, CCL20, CCL22) in patients with RRP and asked whether it was modulated in patients who had achieved significant clinical improvement. CCL17, CCL18 and CCL22 messenger RNAs (mRNAs) were increased in papillomas compared with clinically normal laryngeal epithelium of the RRP patients. Overall, CCL20 mRNA expression was not increased, but there was intense, selective CCL20 protein expression in the basal layer of the papillomas. Patients with RRP expressed more CCL17 (p = 0.003), CCL18 (p = 0.0003), and CCL22 (p = 0.007) in their plasma than controls. Plasma CCL18 decreased over time in three patients enrolled in a pilot clinical trial of celecoxib, and the decrease occurred in conjunction with clinical improvement. There was a significant correlation between sustained clinical remission in additional patients with RRP and reduced levels of CCL17 (p = 0.01), CCL22 (p = 0.002) and CCL18 (p = 0.05). Thus, the change in expression of these three plasma T(H)2-like chemokines may, with future studies, prove to serve as a useful biomarker for predicting disease prognosis.

Immune suppression in premalignant respiratory papillomas: enriched functional CD4+Foxp3+ regulatory T cells and PD-1/PD-L1/L2 expression.

PURPOSE: Respiratory papillomas, caused by human papillomaviruses types 6 and 11 (HPV6/11), are premalignant lesions with potential for malignant conversion. The cytokine and chemokine micromilieu of papillomas is T(H)2-like with a marked absence of IFN-γ expression. To illuminate why patients with recurrent respiratory papillomatosis (RRP) fail to effectively control their disease, we further investigated the suppressive cellular microenvironment in papillomas. EXPERIMENTAL DESIGN: CD4(+)CD25(+)CD127(low/-)Foxp3(+) regulatory T cells (Treg) and CD4(+)CD25(-)CD127(low/-)Foxp3(-) T cells within papillomas were characterized and isolated. Their suppressor function was measured by inhibition of peripheral blood mononuclear cell (PBMC) proliferation. Expression of PD-1, CD69, and Helios was identified on these T cells. PD-L1, PD-L2, CCL17, and CCL22 mRNA was also identified in papillomas by quantitative PCR. RESULTS: Functional Tregs were markedly enriched in papillomas and strongly inhibited anti-CD3 and anti-CD28 antibody activated PBMC proliferation. The natural Treg marker Helios was reduced on Tregs from papillomas, indicating that the majority of Tregs in papillomas are adaptive. The majority of the papilloma-derived CD4(+) T cells expressed the CD4(+)CD25(-)CD127(low/-)Foxp3(-)PD1(+)CD69(+) phenotype and failed to suppress PBMC proliferation, suggesting that they are chronically activated and exhausted. The Treg-attracting chemokine CCL22 was equally expressed by all laryngeal tissues examined. However, CCL17 was robustly expressed by papillomas compared with unaffected laryngeal tissues from RRP patients and individuals without RRP. PD-L1 was elevated in papillomas compared with control laryngeal tissues. CONCLUSIONS: Papilloma CD4(+) T cells are enriched with functional Tregs, and the adaptive Helios(-) Treg fraction was increased within the T(H)2-like papilloma micromilieu. CD4(+)CD25(-)CD127(low/-)Foxp3(-) T-cells failed to suppress PBMC proliferation and may be exhausted. The PD-1/PDL-1 pathway may represent an additional immunosuppressive mechanism that contributes to defective HPV6/11 clearance in RRP.

Papillomavirus-specific CD4+ T cells exhibit reduced STAT-5 signaling and altered cytokine profiles in patients with recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is caused by human papillomavirus type 6 (HPV-6) or HPV-11. Specific HLA-DR haplotypes DRB1*01:02 and DRB1*03:01 are associated with the development of RRP, disease severity, and Th2-like responses to HPV early proteins. Th1-like responses to HPV proteins have been shown to be protective in animal models. Therefore, we investigated the hypothesis that RRP patients have dysfunctional Th1-like, HPV-specific T cell responses. Using MHC class II tetramers, we identified immunogenic peptides within HPV-11 early proteins. Two distinct peptides (E6(113-132) and E2(1-20)) contained DRB1*01:02- or DRB1*03:01-restricted epitopes, respectively. An additional peptide (E2(281-300)) contained an epitope presented by both alleles. Peptide binding, tetramer, and proliferation assays identified minimal epitopes within these peptides. These epitopes elicited E2/E6-specific CD4(+) T cell responses in RRP patients and healthy control subjects, allowing the isolation of HPV-specific T cell lines using tetramers. The cytokine profiles and STAT signaling of these tetramer-positive T cells were measured to compare the polarization and responsiveness of HPV-specific T cells from patients with RRP and healthy subjects. HPV-specific IFN-γ secretion was substantially lower in T cells from RRP patients. HPV-specific IL-13 secretion was seen at modest levels in T cells from RRP patients and was absent in T cells from healthy control subjects. HPV-specific T cells from RRP patients exhibited reduced STAT-5 phosphorylation and reduced IL-2 secretion, suggesting anergy. Levels of STAT-5 phosphorylation and IFN-γ secretion could be improved through addition of IL-2 to HPV-specific T cell lines from RRP patients. Therapeutic vaccination or interventions aimed at restoring Th1-like cytokine responses to HPV proteins and reversing anergy could improve clinical outcomes for RRP patients.

Recurrent respiratory papillomatosis: a complex defect in immune responsiveness to human papillomavirus-6 and -11.

Recurrent respiratory papillomatosis (RRP) is a rare disease of the larynx caused by infection with human papillomaviruses (HPV) -6 or -11, associated with significant morbidity and on occasion mortality. Here we summarize our current understanding of the permissive adaptive and innate responses made by patients with RRP that support chronic HPV infection and prevent immune clearance of these viruses. Furthermore, we provide new evidence of T(H)2-like polarization in papillomas and blood of patients with RRP, restricted CD4 and CD8 Vbeta repertoires, the effect of HPV-11 early protein E6 on T-cell alloreactivity, enriched Langerhans cell presence in papillomas, and evidence that natural killer cells are dysfunctional in RRP. We review the immunogenetic mechanisms that regulate the dysfunctional responses made by patients with RRP in response to HPV infection of the upper airway. In addition, we are identifying T-cell epitopes on HPV-11 early proteins, in the context of human leukocyte antigen (HLA) class II alleles enriched in RRP that should help generate a therapeutic vaccine. Taken together, RRP is a complex, multigene disease manifesting as a tissue and HPV-specific, immune deficiency that prevents effective clearance and/or control of HPV-6 and -11 infection.

Activating killer cell immunoglobulin-like receptors 3DS1 and 2DS1 protect against developing the severe form of recurrent respiratory papillomatosis.

The polymorphic killer cell immunoglobulin-like receptors (KIR) control natural killer (NK) cell response against viral infection and tumor transformation. Here we investigated if select KIR genes are associated with recurrent respiratory papillomatosis (RRP), a rare disease of the larynx and upper airway caused by human papillomaviruses (HPV)-6/11. DNA from 66 RRP patients and 195 healthy controls were characterized for KIR and HLA gene polymorphism. Patients lacking activating KIR genes 3DS1 and 2DS1 were more common in severe RRP compared with mild-moderate RRP (78.8% vs 48.5%, p = 0.019). Further, patients carrying any of the known susceptible HLA-DRB1/DQB1 alleles were more frequently negative for KIR3DS1 (p = 0.006), KIR2DS1 (p = 0.003) or KIR2DS5 (p = 0.004) compared with controls carrying any of these HLA allotypes. Nearly 80% of the patients with severe disease were missing the protective HLA-DQB1*0602 allele as well as both KIR3DS1 and KIR2DS1 genes. Phenotyping of papilloma-infiltrating mononuclear-cells revealed an elevated numbers of NK cells and CD57(+)CD4(+) T cells in KIR3DS1(-)KIR2DS1(-) patients compared with patients carrying either one or both of these KIRs. Our data suggest that NK cells expressing activating receptors KIR3DS1 and KIR2DS1 may be necessary to trigger an effective early immune response against HPV-infected targets to establish resistance to RRP development.

Induction of heme oxygenase-1 and ferritin in the kidney in warm antibody hemolytic anemia.

Warm antibody autoimmune hemolytic anemia usually is associated with extravascular hemolysis. We report a case of a 42-year-old man with sustained and moderately severe warm antibody autoimmune hemolytic anemia, hemoglobinuria, hemosiderinuria, and acute kidney injury. We show marked induction of heme oxygenase-1 and increased ferritin expression in renal tubules, along with increased iron deposition in renal proximal tubules. These findings in this clinical case thus recapitulate those observed in experimental models of heme protein-induced kidney injury in which a coupled induction of heme oxygenase-1 and ferritin occurs in the kidney. We discuss the pathobiological significance of these findings and suggest that this linked response confers cytoprotection to the kidney exposed to hemoglobin and mitigates the severity of acute kidney injury that may otherwise occur. Finally, this case report documents that nephrotic-range proteinuria can occur in patients with autoimmune hemolytic anemia complicated by hemoglobinuria.

Immune dysregulation and tumor-associated gene changes in recurrent respiratory papillomatosis: a paired microarray analysis.

Recurrent respiratory papillomas (RRP) are benign airway tumors, caused primarily by human papillomaviruses (HPV) types 6 and 11. The disease is characterized by multiple recurrences after surgical removal, with limited effective therapy. To identify novel targets for future therapy, we established transcriptional profiles for actively growing papillomas compared with autologous, clinically normal, laryngeal epithelia (adjacent tissue). Total ribonucleic acid (RNA) from 12 papillomas and 12 adjacent tissues were analyzed by microarray, and the matched sets of tissues compared by paired t test, to identify differentially expressed genes in papilloma tissues while minimizing variations intrinsic to individual patients. Quantitative polymerase chain reaction (PCR) was used to confirm the relative expression levels for a subset of genes. Within the 109 differentially expressed transcripts whose expression varied at least three-fold were two large groups of genes with related functions. The first group consisted of 18 genes related to host defense, including both innate and adaptive immunity. The second group contained 37 genes that likely contribute to growth of papillomas as benign tumors, since the altered pattern of expression also had been reported previously in many cancers. Our results support our previous studies that document a systemic T(H)2-like adaptive immune response in RRP, and suggest that there is a role for altered innate immunity in RRP as well. We propose that HPV 6 and 11 infection establishes a tumorigenic microenvironment characterized by alteration of both innate inflammatory signals and adaptive immune responses that prevent effective T(H)1-like response, in conjunction with altered expression of numerous genes that regulate cellular growth and differentiation.

Comparison between gadolinium and iodine contrast for percutaneous intervention in atherosclerotic renal artery stenosis: clinical outcomes.

BACKGROUND: Percutaneous angiography with iodinated contrast in patients with chronic kidney disease carries a risk of contrast nephropathy, which is independently associated with renal disease progression and increased mortality. Gadolinium contrast is a potential alternative to iodinated contrast for percutaneous transluminal renal angioplasty (PTRA), and appears to be safe and well tolerated. The aim of this study was to assess the results of gadolinium use to facilitate PTRA in patients with chronic kidney disease. METHODS: Clinical outcomes were compared between patients with serum creatinine (Cr) >/= 176 micromol/L (2 mg/dL), who had either gadolinium (n = 57; gadoteridol or gadodiamide), iodinated (n = 68; iohexol or iodixanol) or a combination of gadolinium and iodinated-contrast-enhanced (n = 38) PTRA. RESULTS: Despite similar degrees of pre-procedural renal insufficiency, the incidence of immediate contrast nephropathy [defined as an increase in serum Cr of 44 micromol/L (0.5 mg/dL) within 7 days without other identifiable causes] was lowest in the gadolinium group (3/57, 5.3%) compared to those receiving a combination of modest iodinated contrast in addition to gadolinium (4/38, 10.5%) or solely iodinated contrast (14/68, 20.6%). This was associated with a reduction in the 30-day progression to need for renal replacement therapy (RRT) (P < 0.005). Yet, over a mean follow-up of 40 +/- 22 months, renal function outcomes or all-cause mortality were not different between the contrast groups. The type of contrast used had no effect on technical success and both short- and long-term blood pressure outcomes were comparable between the groups. Two patients developed pathology-proven nephrogenic fibrosing dermopathy, a serious skin condition that has been seen in patients with kidney disease following administration of gadolinium. CONCLUSIONS: Gadolinium contrast appears to be an effective agent for interventional renal angiograms. Compared to iodinated contrast, gadolinium contrast is associated with a significantly lower incidence of contrast nephropathy and early progression to end-stage renal disease (ESRD) in patients with pre-existing chronic kidney disease. The risk of fibrosing dermopathy however and remains to be established.

Urinary podocyte excretion as a marker for preeclampsia.

OBJECTIVE: The objective of this study was to examine whether podocyturia, which is the urinary excretion of viable podocytes (glomerular epithelial cells), is present in urinary sediments of patients with preeclampsia. We also aimed to compare the test characteristics of podocyturia to those angiogenic factors that have been shown to play an important role in the pathogenesis of preeclampsia (s-Flt-1, PlGF, and endoglin). STUDY DESIGN: Serum angiogenic factors were measured in 44 patients with preeclampsia and 23 normotensive control patients. In a patient subset (15 cases and 16 control patients), urinary proteinuria were identified and quantified on the basis of their expressions of podocyte-specific proteins. RESULTS: Urinary podocyte excretion occurred in all patients with preeclampsia. The positive predictive value for the diagnosis of preeclampsia was greater for podocyturia than for any of the measured angiogenic factors. CONCLUSION: Podocyturia is a highly sensitive and specific marker for preeclampsia. It may contribute to the development of proteinuria in preeclampsia.

Immunodeficiency in children with acute lymphoblastic leukemia after completion of modern aggressive chemotherapeutic regimens.

OBJECTIVE: To determine the prevalence, duration, and a potential cause of humoral defect(s) in children with acute lymphoblastic leukemia (ALL) at least 1 year after completion of chemotherapy. STUDY DESIGN: Antibody titers for mumps, rubeola, rubella, tetanus and diphtheria toxoid, poliovirus serotypes 1, 2,and 3, Haemophilus influenzae type b, varicella, and hepatitis B were obtained from 100 children with ALL. Children with non-protective titers to these microbial antigens were re-vaccinated and re-studied after anamnestic vaccine challenge. RESULTS: The percent of children with ALL who had protective titers was markedly less than that anticipated for immunized control subjects. Longitudinally, many titers fluctuate between protective and non-protective antibody responses after re-immunization. The chemotherapy protocol used did not affect the ability of these children to express protective antibody responses. T-, B-, and NK-cell numbers and proliferative responses to mitogens were all normal. Age correlated with titer results for certain vaccines. CONCLUSIONS: Children in remission from ALL have a high prevalence of humoral immune defects that are not related to any specific chemotherapy regimen. This antibody deficiency may place children with ALL at risk for the development of these bacterial and viral diseases, even after completion of chemotherapy. Pediatricians, oncologists, or both should periodically monitor humoral immunity after chemotherapy and re-vaccinate these children, as needed, to ensure prolonged immunoprotection.

Dye coupling among satellite glial cells in mammalian dorsal root ganglia.

Dorsal root ganglia (DRG) are key elements in sensory signaling under physiological and pathological conditions. Little is known about electrical coupling among cells in these ganglia. In this study, we injected the fluorescent dye Lucifer yellow (LY) into single cells to examine dye coupling in DRG. We found no dye coupling between neurons or between neurons and their attendant satellite glial cells (SGCs). In mouse DRG, we observed that in 26.2% of the cases SGCs that surround a given neuron were dye coupled. In only 3.2% of the cases SGCs that make envelopes around different neurons were coupled. The data from mouse ganglia were very similar to those from rat and guinea pig DRG. The results obtained by injection of the tracer biocytin were very similar to those observed with LY. The coupling incidence within the envelopes increased 3.1-fold by high extracellular pH (8.0), but coupling between envelopes was not affected. Acidic pH (6.8) reduced the coupling. High extracellular K+ (9.4 mM) increased the coupling 2.4-fold and 4.7-fold within and between envelopes, respectively. Low extracellular Ca2+ (0.5, 1.0 mM) partly reversed the effect of high K+ on coupling. The results showed that SGCs in mammalian sensory ganglia are connected by gap junctions. This coupling is very sensitive to changes in pH, and can therefore be modulated under various physiological and pathological conditions. The dependence of the coupling on extracellular K+ and Ca2+ suggests that the permeability of gap junctions can be altered by physiological and pharmacological stimuli.

HLA alleles, IFN-gamma responses to HPV-11 E6, and disease severity in patients with recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) remains an immunologic enigma. Human papillomavirus (HPV) types 6 and 11 are the predominant HPV viruses that cause papilloma development. However, it is unclear why only a very small fraction of HPV-exposed individuals develop RRP. We performed high-resolution HLA class I and II genotyping on 70 randomly selected patients (56 Caucasians and 14 African-Americans) with RRP. We report, for the first time, an increased frequency of HLA-DRB1*0102 in Caucasian patients with RRP, suggesting that this allele predisposes individuals to RRP. Additionally, HLA-DRB1*0301, DQB1*0201, and DQB1*0202 alleles were selectively enriched in Caucasians with severe disease, suggesting that these alleles may regulate disease severity. In contrast, HLA-DQB1*0602 was more frequent in controls than in Caucasians with severe disease, suggesting a severity-sparing effect of this allele. Furthermore, both DQB1*0201 and DQB1*0202 were enriched, whereas DQB1*0602 was absent, in African-Americans. Interestingly, HLA-DRB1*0301 and DQB1*0201 correlated with reduced interferon-gamma expression in patients with RRP. Larger studies are needed to identify other class II major histocompatibility complex alleles that may influence disease predisposition, disease severity, or both, especially in African-American patients, to ultimately illuminate the regulatory effects of these alleles in the predisposition and severity of RRP.